Ligand-drug complex and its use

Abstract

There is provided a ligand-drug complex and its use. Specifically, there is provided a ligand-drug complex represented by Formula I or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. JPEG2025518554000199.jpg3664I

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, particularly ligand-drug conjugates and their uses.

Background Art

[0002] Antibody-drug conjugates (ADCs) are macromolecules of a novel therapy that combine the strong lethality of small molecule drugs and the high specific targeting of antibodies. Due to the specificity of the antibody, the drug can act precisely on the tumor part or / and tumor cells in vivo so as not to kill normal cells, thereby reducing side effects during the treatment process. An ADC consists of three parts, namely an antibody, a drug, and a linker. When the antibody part of the ADC specifically binds to a specific antigen on the surface of tumor cells, the cell membrane of the tumor cells sinks inward to form an endosome and takes in the ADC, which is also called internalization. The antibody part or linker of the ADC is decomposed by some enzymes inside the cell, thereby releasing the drug, and the released drug starts to kill the tumor cells. In the development process of ADC drugs, linker + drug (payload) is an important intermediate, which consists of a linker and a cytotoxic molecule (drug). At the current stage, the cytotoxic molecules of the payload mainly include tubulin inhibitors and topoisomerase inhibitors.

Summary of the Invention

[0003] Content of the Invention To improve the therapeutic efficacy of a ligand-drug conjugate (e.g., an antibody-drug conjugate ADC) and expand the therapeutic range, the present invention provides a ligand-drug conjugate represented by Formula I, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The ligand-drug conjugate is conjugated to two different drugs, namely, a repair inhibitor with low toxicity and low killing activity and a damaging agent with high killing activity, and the ligand (e.g., an antibody) is conjugated to the low-toxicity repair inhibitor and the high-toxicity damaging agent simultaneously. The resulting dual-drug ADC drug has higher killing activity than an ADC conjugated with the ligand (e.g., an antibody) as a single agent. The ligand-drug conjugate (e.g., a dual-drug ADC) has a significantly higher tumor inhibitory effect at the cellular level.

[0004] For this purpose, in a first aspect, the present invention provides a compound of Formula I: [Chemical formula] Formula I Wherein, Ab is a targeting moiety selected from the group consisting of an antibody, an antibody fragment, a targeting protein, and an Fc fusion protein; D1 is a first drug linked to L1; D2 is a second drug selected from DNA damage repair inhibitors, and is linked to L2; L1 is a first linking unit that links the first drug and the targeting moiety; L2 is a second linking unit that links the second drug and the targeting moiety; m is an integer selected from 0 to 20 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20); n is an integer selected from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and provides a ligand-drug conjugate, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0005] In certain embodiments, the second drug is selected from the group consisting of an ATR inhibitor, an ATM inhibitor, a PARP inhibitor, a WEE1 inhibitor, a CHK1 inhibitor, and a DNA-PK inhibitor. In certain embodiments, the ATR inhibitor is

Chem.

Chem.

Chem.

[0006] In certain embodiments, X1 is selected from the group consisting of O and S. In certain embodiments, X1 is O. In certain embodiments, X2 is N and X3 is CH. In certain embodiments, X4 and X6 are N and X5 is CH. In certain embodiments, X7 is C(R0). In certain embodiments, R0 is R b R a is N-. In certain embodiments, R a , R b are each H. In certain embodiments, R1, R2, R3, R4, R5 are each independently H and

Chemical formula

[0007] In certain embodiments, any one of R1, R2, R3, R4, R5 is

Chemical formula

Chemical formula

Chemical formula

[0008] In certain embodiments, the PARP inhibitor is

Chemical formula

[0009] In certain embodiments, the ATM inhibitor is

Chemical formula

Chemical formula

[0010] In certain embodiments, the CHK1 inhibitor is

Chemical formula

[0011] In certain embodiments, the DNA-PK inhibitor is

Chemical formula

[0012] In certain embodiments, the second linking unit is a cleavable or non-cleavable linking unit. In certain embodiments, L2 is L 21 -L 22 -L 23 -L24 and L 24 is linked to D2, and L 21 is linked to Ab (preferably, L 21 is bound to Ab via a thiol group), L 21 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] In certain embodiments, L 23 is a peptide residue consisting of 2 to 4 (preferably, 2) amino acid residues, and its carbonyl terminus is linked to L 24 ; preferably, the amino acids are selected from the group consisting of valine, alanine, phenylalanine, glycine, lysine, citrulline, serine, glutamic acid, and aspartic acid, and more preferably, the amino acids are selected from the group consisting of valine, alanine, and citrulline. In certain embodiments, L 23is selected from the group consisting of valine-alanine (Val-Ala) and valine-citrulline (Val-Cit), and its carbonyl terminus is L 24 is linked to. In certain embodiments, L 23 is

Chemical formula

[0014] In certain embodiments, L2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0015] In certain embodiments, D2-L2- is

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

[0016] In certain embodiments, the first drug is selected without limitation from the group consisting of tubulin binders, DNA damaging agents, enzyme inhibitors, immunomodulators, peptides, and nucleotides. In certain embodiments, the first drug is a) alkylating agents, PBD and its derivatives, chlorphenamate, chlorpromazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, dimethoxamine hydrochloride, mechlorethamine oxide, amlodipine hydrochloride, mycophenolic acid, dulcitol, pipobroman, novobiocin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil; CC-1065; docamycin; benzodiazepine dimer; nitrosourea; alkyl sulfonate; triazene; platinum-containing compounds; aziridine such as chromanone, quinolone, meturedepa, and madopa; hexamethylmelamine, triethylenetriamine, triethylphosphoramide, triethylenethiophosphoramide, and trimethylolmethylamine and its derivatives and deuterides including ethyleneimine and methylmelamine; b) Plant alkaloids, vinca alkaloids, taxol and its analogs, maytansinoids and their analogs, cryptophycins, epothilones, erythrobins, discodermolides, bryostatins, aplisiatoxins, auristatins, tubulysins, cephalostatins, pancratistatins, sarcodictyins, spongistatins, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansinoids (e.g., maytansine DM1, maytansine DM4), amatoxins and their derivatives and deuterides; c) DNA topoisomerase inhibitors, etoposide, teniposide, 9 - aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acid, teniposide, topotecan, 9 - nitrocamptothecin, SN38, mitomycin and its derivatives and deuterides; d) Antimetabolites, folic acid antagonists, DHFR inhibitors; MP dehydrogenase inhibitors; ribonucleotide reductase inhibitors; pyrimidine analogs, uracil analogs; cytosine analogs; purine analogs; folic acid supplements; e) Hormone therapy agents, receptor antagonists, anti - estrogen agents, LHRH agonists; anti - androgen agents; retinoids, vitamin D3 analogs; photodynamic therapy agents; cytokines, TNF - containing human proteins and their derivatives and deuterides; f) Kinase inhibitors, BIBW2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080, mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, visomodegib, iniparib, luxolitinib, CYT387, axitinib, tibosutinib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib and their derivatives and deuterides; g) Antibiotics, Engineered antibiotics, Aclacinomycin, Anthramycin, Amrinomycin, Azaserine, Bleomycin, Cethoxydim, Caracemide, Carminomycin, Carthinophorin, Doxorubicin, Morpholinodoxorubicin, 2-Pyrrolidodoxorubicin and Daunorubicin, Epirubicin, Aclarubicin, Idarubicin, Marcomycin, Mycin, Mycophenolic acid, Lopimycin, Pelomycin, Puromycin, Triferric doxorubicin, Streptozotocin, Streptozotocin, Tubercidin, Ubenimex, Zinostatin, Zorubicin, PNU-159682 and its derivatives and deuterides; h) Polyketides, in particular, platensimycin and platencin; gemcitabine, epoxomicin, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, dibencozide, PLX4032, STA-9090, Stimuvax, alovectin-7, Xgeva, probenecid, Yarovoy, prenylation inhibitors, dopaminergic neurotoxins, actinomycin, bleomycin, anthracycline antibiotics, doxorubicin, idarubicin, epirubicin, larrubicin, zorubicin, mitoxantrone, MDR inhibitors, Ca2+ adenosine triphosphate degrading enzyme inhibitors, histone deacetylase inhibitors, celecoxib, glitazone, epigallocatechin gallate, disulfiram, salinosporamide A; aminoglutethimide, mitotane, trilostane, aceglatone, aldophosphamide, aminolevulinic acid, amsacrine, arabinoside, bestrabucil, bisantrene, edatrexate, defofamine, meikexin, diacron, eflornithine, elfornithine, elitism, ethyl glucuronate, gallium nitrate, cytosine, hydroxyurea, ibandronic acid, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazine, procarbazine; PSK (registered trademark); razoxane; lysomycin; sizzo; spirogermanium; tenuazonic acid, triaziquone; trichlorotriethylamine; trichothecene, polyurethane, siRNA and antisense drugs, and derivatives and deuterides thereof selected from the group consisting of

[0017] In certain embodiments, the first drug D1 is a camptothecin-based compound or a deuteride thereof. In certain embodiments, the camptothecin-based compound has the formula B:

Chemical formula

[0018] In certain embodiments, R' is selected from the group consisting of H and C1-C6 alkyl. In certain embodiments, R' is H. In certain embodiments, R 1’ is selected from the group consisting of H and C1-C6 alkyl. In certain embodiments, R 1’ is selected from C1-C6 alkyl. In certain embodiments, R 1’ is methyl. In certain embodiments, R 2’ is selected from halogen. In certain embodiments, R 2’ is F. In certain embodiments, X' is selected from -C(O)-(CR 3’ R 4’ )t-CR a’ R b’ -O-, preferably with its carbonyl terminus attached to the N atom. In certain embodiments, X' is -C(O)-CR a’ R b’Selected from -O-, preferably, its carbonyl terminus is linked to an N atom. In certain embodiments, R a’ is selected from the group consisting of H and C1-C6 alkyl. In certain embodiments, R a’ is H. In certain embodiments, R b’ is selected from the group consisting of H, D, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl. In certain embodiments, R b’ is selected from the group consisting of H, D, methyl, cyclopropyl, and trifluoromethyl. In certain embodiments, t is 0.

[0019] In certain embodiments, X’ is the following structure:

Chemical formula

[0020] In certain embodiments, the compound represented by formula B is

Chemical formula

[0021] In certain embodiments, the first drug is

Chemical formula

[0022] In certain embodiments, the first linking unit is a cleavable or non-cleavable linking unit. In certain embodiments, L1 is L11 -L 12 -L 13 -L 14 and L 14 is linked to D1, and L 11 is linked to Ab (preferably, L 11 is bound to Ab via a thiol group); L 11 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0023] In certain embodiments, L 13 is selected from a direct bond, an amino acid residue, or a peptide residue consisting of 2 to 4 amino acid residues, and when L 13 is selected from an amino acid residue or a peptide residue consisting of 2 to 4 amino acid residues, its carbonyl terminus is linked to L14 is linked to, preferably, the amino acid is selected from the group consisting of valine, alanine, phenylalanine, glycine, lysine, citrulline, serine, glutamic acid, and aspartic acid, more preferably, the amino acid is selected from the group consisting of valine, alanine, phenylalanine, glycine, citrulline, and lysine.

[0024] In certain embodiments, L 13 is selected from the group consisting of a direct bond, lysine, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), valine-alanine (Val-Ala), and valine-citrulline (Val-Cit), and L 13 is selected from the group consisting of lysine, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), valine-alanine (Val-Ala), and valine-citrulline (Val-Cit), and its carbonyl terminus is linked to L 14 . In certain embodiments, L 13 is a direct bond,

Chemical formula

Chemical formula

[0025] In certain embodiments, L1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0026] In certain embodiments, D1-L1- is

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

[0027] In certain embodiments, m is an integer selected from 1 to 10. In certain embodiments, m is an integer selected from 2 to 8. In certain embodiments, m is selected from the group consisting of 2, 4, and 8. In certain embodiments, n is an integer selected from 1 to 10. In certain embodiments, n is an integer selected from 2 to 8. In certain embodiments, n is selected from the group consisting of 2, 4, and 8. In certain embodiments, Ab is selected from the group consisting of a murine antibody, a chimeric antibody, a humanized antibody, a fully humanized antibody, an antibody fragment, a bispecific antibody, and a multispecific antibody. In certain embodiments, Ab forms a linking bond with a linking unit via its cysteine thiol group (-SH). In certain embodiments, Ab is a monoclonal antibody selected from the group consisting of an anti-EGFRvIII antibody, an anti-DLL-3 antibody, an anti-PSMA antibody, an anti-CD70 antibody, an anti-MUC16 antibody, an anti-ENPP3 antibody, an anti-TDGF1 antibody, an anti-ETBR antibody, an anti-MSLN antibody, an anti-TIM-1 antibody, an anti-LRRC15 antibody, an anti-LIV-1 antibody, an anti-CanAg / AFP antibody, an anti-claudin 18.2 antibody, an anti-mesothelin antibody, an anti-HER2 (ErbB2) antibody, an anti-EGFR antibody, an anti-c-MET antibody, an anti-SLITRK6 antibody, an anti-KIT / CD117 antibody, an anti-STEAP1 antibody, an anti-SLAMF7 / CS1 antibody, an anti-NaPi2B / SLC34A2 antibody, an anti-GPNMB antibody, an anti-HER3 (ErbB3) antibody, an anti-MUC1 / CD227 antibody, an anti-AXL antibody, an anti-CD166 antibody, an anti-B7-H3 (CD276) antibody, an anti-PTK7 / CCK4 antibody, an anti-PRLR antibody, an anti-EFNA4 antibody, an anti-5T4 antibody, an anti-NOTCH3 antibody, an anti-nectin 4 antibody, an anti-TROP-2 antibody, an anti-CD142 antibody, an anti-CA6 antibody, an anti-GPR20 antibody, an anti-CD174 antibody, an anti-CD71 antibody, an anti-EphA2 antibody, an anti-LYPD3 antibody, an anti-FGFR2 antibody, an anti-FGFR3 antibody, an anti-FRα antibody, an anti-CEACAMs antibody, an anti-GCC antibody, an anti-integrin Av antibody, an anti-CAIX antibody, an anti-P-cadherin antibody, an anti-GD3 antibody, an anti-cadherin 6 antibody, an anti-LAMP1 antibody, an anti-FLT3 antibody, an anti-BCMA antibody, an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD33 antibody, an anti-CD56 antibody, an anti-CD74 antibody, an anti-CD22 antibody, an anti-CD30 antibody, an anti-CD37 antibody, an anti-CD47 antibody, an anti-CD138 antibody, an anti-CD352 antibody, an anti-CD25 antibody, and an anti-CD123 antibody.

[0028] In certain embodiments, Ab is an antibody selected from the group consisting of anti-CD33, an anti-CD33 antibody; anti-Trop2-1, an anti-Trop2 antibody; anti-Trop2-2, an anti-Trop2 antibody; Trastuzumab (Tras), an anti-HER2 antibody; and Tras-016, an anti-HER2 antibody, and the related sequences are as follows. Sequence of anti-CD33, an anti-CD33 antibody >Light chain - LC DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC (SEQ ID NO: 1) >Heavy chain - HC EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 2) Sequence of anti-Trop2-1, an anti-Trop2 antibody >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDINKYLAWYQQKPGKVPKLLIYSTSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYDDLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 3) >Heavy chain - HC QVQLVQSGAEVKKPGASVKLSCKASGYTFTSFDINWVRQAPEQRLEWMGWIFPGDGNTKYSQKFQGRATITRDTSASTAYMELSSLRSEDTAVYYCVRGEALYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 4) Sequence of anti - Trop2 - 2, an anti - Trop2 antibody >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDINKYLAWYQQKPGKVPKLLIYSTSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYDDLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC (SEQ ID NO: 5) >Heavy chain - HC QVQLVQSGAEVKKPGASVKLSCKASGYTFTSFDINWVRQAPEQRLEWMGWIFPGDGNTKYSQKFQGRATITRDTSASTAYMELSSLRSEDTAVYYCVRGEALYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 6) Sequence of trastuzumab (Tras), an anti - HER2 antibody >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 7) >Heavy chain - HC EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 8) Sequence of Tras-016, an anti-HER2 antibody > Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC (SEQ ID NO: 9) > Heavy chain - HC EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:10)

[0029] In certain embodiments, both D1-L1- and D2-L2- are attached to the Ab via a thiol group. In certain embodiments, the source of the thiol group is selected from the group consisting of a thiol group on a cysteine residue formed after reduction of an intramolecular disulfide bond present in the targeting moiety, a thiol group on a cysteine residue formed by site-directed mutagenesis of a specific original amino acid of the targeting moiety, a thiol group on a cysteine residue formed by site-directed insertion of cysteine into the targeting moiety, and a thiol group on a cysteine residue formed by site-directed insertion of a cysteine-containing peptide into the targeting moiety. In certain embodiments, D1-L1- and D2-L2- are each attached to the Ab via a different thiol group of the source. In certain embodiments, one of D1-L1- and D2-L2- is attached to the Ab via a thiol group on a cysteine residue formed after reduction of an intramolecular disulfide bond present in the targeting moiety, and the other is attached to the Ab via a thiol group on a cysteine residue formed by site-directed mutagenesis of a specific original amino acid of the targeting moiety, a thiol group on a cysteine residue formed by site-directed insertion of cysteine into the targeting moiety, or a thiol group on a cysteine residue formed by site-directed insertion of a cysteine-containing peptide into the targeting moiety.

[0030] In certain embodiments, the ligand-drug conjugate is Ab-R01(2)-Ex01(8), Ab-R01(8)-Ex01(2), Ab-R01(4)-Ex01(4), Ab-R01(4)-Ex01(8), Ab-R01(8)-Ex01(4), Ab-R01(2)-Ex02(8), Ab-R01(8)-Ex02(2), Ab-R01(4)-Ex02(4), Ab-R01(2)-Ex03(8), Ab-R01(8)-Ex03(2), Ab-R01(4)-Ex03(4), Ab-R01(2)-Ex04(8), Ab-R01(8)-Ex04(2), Ab-R01(4)-Ex04(4), Ab-R01(2)-Ex05(8), Ab-R01(8)-Ex05(2), Ab-R01(4)-Ex05(4), Ab-R01(2)-Ex06(8), Ab-R01(8)-Ex06(2), Ab-R01(4)-Ex06(4), Ab-R01-1(2)-Ex01(8), Ab-R01-1(8)-Ex01(2), Ab-R01-1(4)-Ex01(4), Ab-R01-1(8)-Ex01(4), Ab-R01-1(4)-Ex01(8), Ab-R01-1(2)-Ex02(8), Ab-R01-1(8)-Ex02(2), Ab-R01-1(4)-Ex02(4), Ab-R01-1(2)-Ex03(8), Ab-R01-1(8)-Ex03(2), Ab-R01-1(4)-Ex03(4), Ab-R01-1(2)-Ex04(8), Ab-R01-1(8)-Ex04(2), Ab-R01-1(4)-Ex04(4), Ab-R01-1(2)-Ex05(8), Ab-R01-1(8)-Ex05(2), Ab-R01-1(4)-Ex05(4), Ab-R01-1(2)-Ex06(8), Ab-R01-1(8)-Ex06(2), Ab-R01-1(4)-Ex06(4), Ab-R01-1(2)-PB01(8), Ab-R01-1(2)-PB02(8), Ab-R01-1(8)-PNU01(2), Ab-R01-1(8)-PNU02(2), Ab-R01-1(2)-CBI01(8), Ab-R01-1(2)-CBI02(8), Ab-R01-1(2)-CBI03(8), Ab-R01-1(2)-PBD01(8), Ab-R01-1(2)-PBD02(8), Ab-R01-1(2)-PBD-CBI01(8), Ab-R01-1(2)-PBD-CBI02(8), Ab-R01-1(8)-M01(2), Ab-R01-1(8)-M02(2), Ab-R01-1(8)-M03(2), Ab-AT01(2)-Ex01(8), Ab-AT02(2)-Ex01(8), Ab-AT03(2)-Ex01(8), Ab-AT04(2)-Ex01(8), Ab-TA01(2)-Ex01(8), Ab-VE01(2)-Ex01(8), Ab-E01(2)-Ex01(8), Ab-RU01(2)-Ex01(8), Ab-PA01(2)-Ex01(8), Ab-CEP01(2)-Ex01(8), Ab-TM01(2)-Ex01(8), Ab-TM02(2)-Ex01(8), Ab-WE01(2)-Ex01(8), Ab-CH01(2)-Ex01(8), Ab-CH02(2)-Ex01(8), Ab-CH03(2)-Ex01(8), Ab-CH04(2)-Ex01(8), Ab-DP01(2)-Ex01(8), Ab-DP02(2)-Ex01(8), and Ab-DP03(2)-Ex01(8) is selected from the group consisting of.

[0031] Regarding the meaning of the structural formula of the above ligand-drug conjugate such as Ab-R01(2)-Ex01(8), this is Formula I:

Chemical formula

Chemical formula

[0032] In a second aspect, the present invention provides a drug-linking unit complex selected from the group consisting of drug-linking unit complexes, or stereoisomers thereof, prodrugs thereof, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

Table 3-12

Table 3-13

Table 3-14

Table 3-15

[0033] In a third aspect, the present invention provides a pharmaceutical composition comprising a ligand-drug conjugate as described above, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a drug-linking unit conjugate as described above or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and optionally one or more adjuvants.

[0034] In a fourth aspect, the present invention provides the use of a ligand-drug conjugate as described above, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a drug-linking unit conjugate as described above or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition as described above, in the preparation of a medicament for the treatment and / or prevention of a disease, wherein the disease is cancer. In certain embodiments, the cancer is selected from the group consisting of skin cancer, lymphoma, esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, solid tumor, non-Hodgkin lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, neuroblastoma, gliosarcoma or sarcoma), melanoma, prostate cancer, thyroid cancer, bone cancer, urinary tract cancer, salivary gland cancer, leukemia (e.g., acute myeloid leukemia), and other solid tumors and hematological tumors. In certain embodiments, the cancer is selected from the group consisting of lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, and kidney cancer.

[0035] In a fifth aspect, the present invention provides a ligand-drug conjugate as described above, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a drug-linking unit conjugate as described above or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition as described above for use in the treatment and / or prevention of a disease, wherein the disease is cancer. In certain embodiments, the cancer is selected from the group consisting of skin cancer, lymphoma, esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, solid tumor, non-Hodgkin lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, neuroblastoma, gliosarcoma or sarcoma), melanoma, prostate cancer, thyroid cancer, bone cancer, urinary tract cancer, salivary gland cancer, leukemia (e.g., acute myeloid leukemia), and other solid tumors and hematological tumors. In certain embodiments, the cancer is selected from the group consisting of lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, and kidney cancer.

[0036] In a sixth aspect, the present invention provides a method for the treatment and / or prevention of a disease, wherein the disease is cancer and the method comprises administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a ligand-drug conjugate as described above, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a drug-linking unit conjugate as described above or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition as described above. In certain embodiments, the cancer is selected from the group consisting of skin cancer, lymphoma, esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, solid tumor, non-Hodgkin lymphoma, central nervous system tumor (e.g., glioma, glioblastoma multiforme, neuroblastoma, gliosarcoma or sarcoma), melanoma, prostate cancer, thyroid cancer, bone cancer, urinary tract cancer, salivary gland cancer, leukemia (e.g., acute myeloid leukemia), and other solid tumors and hematological tumors. In certain embodiments, the cancer is selected from the group consisting of lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, and kidney cancer.

[0037] Definition of Terms In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. Also, research methods in cell culture, molecular genetics, nucleic acid chemistry, and immunology, when used herein, are all conventional methods widely used in the relevant fields. However, for a better understanding of the present invention, definitions and explanations of related terms are provided below. In the present invention, examples of the term "pharmaceutically acceptable salt" are organic acid addition salts formed from organic acids that produce pharmaceutically acceptable anions, including but not limited to formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, α-ketoglutarate, α-glycerophosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methyl sulfonate or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate. Suitable inorganic salts can also be formed, including but not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, etc. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

[0038] In the present invention, the term "prodrug" refers to a derivative that can provide the compounds of the present invention through hydrolysis, oxidation, or other reactions under biological conditions (in vitro or in vivo). A prodrug becomes an active compound only by this reaction under biological conditions, or is non-reactive or has only low activity. Prodrugs can generally be prepared using well-known methods such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th Edition).

[0039] Stereoisomers of the compounds described herein should be understood to have a predominant configuration as the (R) isomer or (S) isomer, respectively, when specified by chemical name as the (R) isomer or (S) isomer. Any asymmetric carbon atoms may be present in the (R) configuration, (S) configuration, or (R,S) configuration, preferably the (R) configuration or (S) configuration. In the present invention, the terms "solvated compound" or "solvate" can be used interchangeably and refer to a compound that exists in combination with specific solvent molecules. This combination may include a stoichiometric amount of a specific solvent such as a monohydrate or dihydrate, or may include any amount of water. As another example, "alcoholates" may be formed using methanol or ethanol, which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to the solid form, that is, a compound in solution with a solvent may be solvated, but it is not the solvate referred to by the term used herein. In the present invention, the term "deuteride" refers to a substance obtained by replacing one or more hydrogen atoms in a compound with deuterium atoms.

[0040] In the present invention, an adjuvant refers to an excipient and an additive used in the manufacture and formulation of a drug, and refers to a substance that is reasonably evaluated for safety and formulated into a pharmaceutical preparation in addition to the active ingredient. Adjuvants have important functions such as solubilization, solubilization assistance, sustained release, controlled release, etc. in addition to shaping, acting as a vehicle, and improving stability, and are important components that can affect the quality, safety, and efficacy of drugs. They can be classified into natural substances, semi-synthetic substances, and fully synthetic substances according to their sources. They can be classified into solvents, propellants, solubilizing agents, co-solvents, emulsifiers, coloring agents, binders, disintegrants, bulking agents, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow promoters, flavoring agents, preservatives, anti-precipitants, coating agents, fragrances, anti-caking agents, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickening agents, encapsulating agents, moisturizing agents, absorbents, diluents, aggregating agents and peptizing agents, filter aids, release retardants, etc. according to their roles and uses. They can be classified into oral administration, injection, mucosal administration, transdermal administration or topical administration, nasal or oral inhalation administration, intraocular administration, etc. according to the administration route. The same adjuvant can be used for different administration routes of pharmaceutical preparations and has different roles and uses.

[0041] In the present invention, the pharmaceutical composition can be prepared into various appropriate dosage forms according to the administration route. For example, tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants, aerosols, powder aerosols, sprays, etc. Here, the pharmaceutical composition or the appropriate dosage form may contain a compound as described herein or a pharmaceutically acceptable salt or complex thereof in an amount of 0.01 mg to 1000 mg, appropriately 0.1 mg to 800 mg, preferably 0.5 to 500 mg, preferably 0.5 to 350 mg, and particularly preferably 1 to 250 mg. The pharmaceutical composition can be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. Here, examples of usable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils such as monoglyceride or diglyceride can also be used as a solvent or a suspension medium.

[0042] In the present invention, the term "treatment" generally refers to the attainment of the required pharmacological and / or physiological effects. The effects can be preventive in that they completely or partially prevent a disease or its symptoms, and / or therapeutic in that they partially or completely stabilize or cure a disease and / or side effects caused by the disease. As used herein, the term "treatment" encompasses any treatment of a disease in a patient, including (a) preventing a disease or its symptoms in a patient who is susceptible to but has not yet been diagnosed as having the disease or its symptoms, (b) suppressing the symptoms of a disease, i.e., preventing its onset, or (c) alleviating the symptoms of a disease, i.e., causing regression of the disease or its symptoms. In the present invention, the term "subject" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal human individuals. As used herein, the term "non-human animal" includes all vertebrates, including non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and / or breeding animals (e.g., sheep, dogs, cats, cows, pigs, etc.). In the present invention, the term "effective amount" refers to the amount of a compound that, when administered, alleviates to some extent one or more symptoms of the condition being treated.

[0043] In the present invention, the term "targeting moiety" refers to a part of a complex that can specifically bind to a target (or a part of a target) on the cell surface. The complex can be delivered to a specific cell population by the interaction between the targeting moiety and the target. Preferably, the targeting moiety is an antibody. In the present invention, the term "antibody" as most broadly construed includes intact monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, as long as they have the necessary biological activity. In the present invention, the terms "antibody" and "immunoglobulin" may be used interchangeably. In the present invention, the term "monoclonal antibody" refers to an antibody of a substantially homogeneous population of antibodies, i.e., the antibodies comprising the population are all the same except for the possible presence of minor natural mutations. Monoclonal antibodies have high specificity for one antigenic determinant (epitope), whereas polyclonal antibodies contain different antibodies against different determinants (epitopes). In addition to specificity, monoclonal antibodies have the advantage that they can be synthesized without contamination by other antibodies. The modifier "monoclonal" as used herein is not to be construed as meaning that the antibody must be prepared by a particular method, but rather as being characterized by the antibody being derived from a substantially homogeneous population of antibodies. In certain embodiments of the present invention, monoclonal antibodies also include, in particular, chimeric antibodies, i.e., antibodies in which a portion of the heavy and / or light chain is identical or homologous to an antibody of a particular type, class or subclass, and the remaining portion is identical or homologous to an antibody of another type, class or subclass as long as they have the necessary biological activity (see, e.g., US 4,816,567 and Morrison et al, 1984, PNAS, 81: 6851-6855). Chimeric antibodies that can be used include primatized antibodies comprising variable region antigen-binding sequences derived from non-human primates (e.g., Old World monkeys, orangutans, etc.) and human constant region sequences.

[0044] In the present invention, the term "antibody fragment" refers to a portion of an antibody, preferably the antigen-binding region or variable region. Examples of antibody fragments include Fab, Fab’, F(ab’)2, Fd, Fv, dAb, and complementarity determining region fragments, diabodies, linear antibodies, and single-chain antibody molecules. In the present invention, the term "bispecific antibody" is also referred to as a "bifunctional antibody complex" and refers to a complex formed by a first antibody (fragment) and a second antibody (fragment) via a linker arm, and is bifunctional and bispecific since it retains the activities of the individual antibodies. In the present invention, the term "multispecific antibody" includes, for example, a trispecific antibody which is an antibody having three different antigen-binding specificities, and a tetravalent antibody which is an antibody having four different antigen-binding specificities. In the present invention, the term "intact antibody" refers to an antibody comprising an antigen-binding variable region and a light chain constant region (CL), and a heavy chain constant region (CH1, CH2, and CH3). The constant region can be a native sequence (e.g., a human native constant region sequence) or an amino acid sequence variant thereof. The intact antibody is preferably an intact antibody having one or more effector functions.

[0045] In the present invention, the "humanized" form of a non-human (e.g., mouse) antibody refers to a chimeric antibody that contains minimal non-human immunoglobulin sequences. Most humanized antibodies are obtained by replacing the hypervariable region residues of a human recipient immunoglobulin with non-human (e.g., mouse, rat, rabbit, or non-human primate) hypervariable region residues (donor antibody) that have the required specificity, affinity, and function. In certain embodiments, the framework region (FR) residues of the human immunoglobulin are also replaced with non-human residues. Additionally, the humanized antibody may also contain residues that are not present in the recipient antibody or the donor antibody. These modifications are made to further optimize the performance of the antibody. Humanized antibodies generally contain at least one, and typically two, variable regions in which all or substantially all of the hypervariable loops correspond to non-human immunoglobulins and the FRs are fully or substantially fully of human immunoglobulin sequence. A humanized antibody may also contain at least a portion of the immunoglobulin constant region (Fc, generally a human immunoglobulin Fc). For details, see, for example, Jones et al, 1986, Nature, 321: 522-525; Riechmann et al, 1988, Nature, 332: 323-329; and Presta, 1992, Curr Op Struct Bwl 2: 593-596. The monoclonal antibodies used herein can be made by several methods. For example, the monoclonal antibodies used herein may be obtained by the hybridoma method (see, e.g., Kohler et al, 1975, Nature, 256: 495) using various species (including mouse, hamster, rat, and human cells), or may be made by recombinant DNA technology (see, e.g., US4,816,567), or may be isolated from a phage antibody library (see, e.g., Clackson et al, 1991, Nature, 352: 624-628; and Marks et al, 1991, Journal of Molecular Biology, 222: 581-597).

[0046] In the present invention, unless otherwise specified, the expressions "each... is independently selected from" and "... are each independently selected from" are interchangeable and should be understood in a broad sense, which means that specific options represented by the same or different symbols in different groups do not affect each other, or specific options represented by the same or different symbols in the same group do not affect each other. In the present invention, formula A:

Chemical formula

Chemical formula

[0047] In the present invention, the term "direct bond" means that the groups on both sides are directly connected. For example, when L1 is L 11 -L 12 -L 13 -L 14 and L 13 is a direct bond, L1 is L 11 -L 12 -L 14 That is, L 12 is directly connected to L 14 . Other similar definitions can be understood with reference to the following. In each part of the present invention, the substituents of the compounds of the present invention are disclosed according to the type or range of the groups. The present invention particularly shows that it includes each independent secondary combination of various members of these types and ranges of groups. For example, the term "C1-C6 alkyl" particularly refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. In the present invention, the term "alkyl" means including branched-chain and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl containing 1 to 6 carbon atoms, and includes, for example, "C1-C3 alkyl" or "C1-C4 alkyl", methyl, ethyl, etc. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.

[0048] In the present invention, the term "C1-C4 alkyl" refers to a straight-chain or branched-chain alkyl containing 1 to 4 carbon atoms, and includes, for example, "C1-C3 alkyl", methyl, ethyl, etc. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. In the present invention, the term "deuterated alkyl" refers to a group obtained by substituting one or more hydrogen atoms of an alkyl with deuterium atoms. Here, the alkyl can be C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl. Alkyl, C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl are as defined above. In the present invention, the term "haloalkyl" refers to a group obtained by substituting one or more hydrogen atoms of an alkyl with a halogen. For example, it can be a "C1-C6 haloalkyl" which refers to a group obtained by substituting one or more hydrogen atoms of a C1-C6 alkyl (such as C1-C4 alkyl, C1-C3 alkyl, etc.) with a halogen (preferably fluorine, chlorine), and includes, for example, monofluoromethyl, difluoroethyl, trifluoromethyl, etc. Alkyl, C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl are as defined above.

[0049] In the present invention, the term "hydroxyalkyl" refers to a group obtained by substituting one or more hydrogen atoms of an alkyl with hydroxy. For example, it can be a "C1-C6 hydroxyalkyl" which refers to a group obtained by substituting one or more hydrogen atoms of a C1-C6 alkyl (for example, C1-C4 alkyl, C1-C3 alkyl, etc.) with hydroxy, and can be, for example, hydroxymethyl, 2-hydroxyethyl, etc. Alkyl, C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl are as defined above. In the present invention, the term "alkoxy" refers to any of the above-defined alkyls (for example, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) bonded to the remainder of the molecule via an oxygen atom (-O-). In the present invention, the term "cycloalkyl" refers to a hydrocarbon group having a saturated carbon ring monocyclic ring system, and can be, for example, C3-C6 cycloalkyl, and specifically can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Halogen refers to fluorine, chlorine, bromine or iodine.

[0050] In the present invention, "aryl" refers to substituted and unsubstituted aromatic 6-membered monocyclic groups, 10-membered bicyclic groups, and tricyclic groups having 10 or more members, all of which have no ring heteroatoms and contain ring carbon atoms. Specifically, aryl can be phenyl or naphthyl. In the present invention, the term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 8-, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups having at least one heteroatom (N, O or S) in at least one ring, and the heteroatom-containing ring optionally further having 1, 2 or 3 heteroatoms selected from N, O or S. In particular, substituted and unsubstituted aromatic 8-, 9- or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups having at least one heteroatom (N, O or S) in at least one ring are "condensed heteroaryl groups". For bicyclic or tricyclic heteroaryl, the entire bicyclic or tricyclic structure is required to form an aromatic system. Heteroaryl may be bonded to any available nitrogen or carbon atom of any ring. And those skilled in the art will understand that two adjacent atoms (preferably carbon atoms) are shared between each two rings of the fused rings. Exemplary monocyclic heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and the like. Exemplary bicyclic heteroaryls include, but are not limited to, indolyl, 5-azaindolyl, pyrrolo[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridyl, pyrrolo[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furanopyridyl, isoindolyl, and the like.

[0051] In the present invention, the terms "heterocyclic ring", "heterocyclic" or "heterocyclyl" are used interchangeably and may contain one or more double bonds but do not form an aromatic ring, and at least one ring is a substituted and unsubstituted 3- to 7-membered (preferably 4- to 7-membered, more preferably 5- to 6-membered) monocyclic group, 7- to 11-membered bicyclic group, and 10- to 15-membered tricyclic group having at least one heteroatom (N, O or S). The fused rings that complete the bicyclic and tricyclic groups may contain only carbon atoms, are saturated or partially saturated, and do not form an aromatic ring. The heterocyclic group may be bonded at any available nitrogen or carbon atom. Exemplary monocyclic heterocyclyls include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, 1-pyridonyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolanyl, and the like. Here, "saturated heterocyclic ring" means that the heterocyclic ring defined above does not contain an unsaturated bond, for example, it does not contain a double bond. For example, "nitrogen-containing saturated heterocyclyl" is

Chemical formula

[0052] In the present invention, "substituted", "substituted" or "substitution" are used interchangeably and refer to the selective substitution of any one or more hydrogen atoms on a specific atom or group with a specific group, as long as the normal valence state of the specific atom is not exceeded. When one or more substituents are present, each substituent is independently selected from the group consisting of deuterium, halogen, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclyl, and halogen, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclyl are as defined above. From all of the above descriptions, it should be clear to those skilled in the art that a radical whose name is a composite name, for example "cycloalkylalkyl", should be construed as being derived, conventionally from left to right from that part, for example in the case of "cycloalkylalkyl", from "alkyl" in which "cycloalkyl" has been substituted, where cycloalkyl and alkyl are as defined above.

Brief Description of the Drawings

[0053]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Modes for Carrying Out the Invention

[0054] Advantageous Effects 1. In the ADC drug of the present invention, according to the concept of synthetic lethality that damages cancer cells with drugs and inhibits their damage repair to kill cancer cells, the dosage of the cell damage repair inhibitor can be reduced compared to combination therapy, and the potential damage to normal cells is further reduced. 2. The ADC using the damage repair inhibitor of the present invention can enhance the sensitivity to moderately toxic drugs (or increase the availability or administration mode of moderately toxic drugs). 3. In the ADC using the damage repair inhibitor of the present invention, when the toxin drug is a highly toxic compound, the window can be expanded.

[0055] Specific modes for carrying out the present invention Although not intended to be limiting, the present invention will be further described by the following description of specific embodiments. Those skilled in the art can make various modifications or improvements in light of the teachings of the present invention without departing from the basic spirit and scope of the present invention. All reagents or instruments not indicated by the manufacturer are all commercially available conventional products. This application discloses an antibody-drug conjugate in which a targeting protein is simultaneously conjugated with a DNA damage repair inhibitor and an additional drug. In particular, in certain embodiments, one of the DNA damage inhibitor and the additional drug is conjugated to the original chain-intra disulfide cysteine (Cys) residue of the targeting protein, and the other is linked to the cysteine (Cys) residue of the targeting protein in a site-specific binding mode, and this site-specific binding mechanism is such that some of the original amino acids on the targeting protein undergo site-specific mutagenesis to become cysteine, or a cysteine or a polypeptide containing cysteine undergoes site-specific insertion.

[0056] In the present invention, the correspondence between the abbreviations of some drugs and their structural formulas is shown as follows.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Examples

[0057] The present invention will be further described by the following combinations of examples. Unless otherwise specified, all starting materials are commercially available. Example 1 Synthesis of Compound A-4:

Chemical formula

[0058] Step 3: Synthesis of Compound A-3 Add A-2 (77.0 g) to a 2 L Erlenmeyer flask, dissolve it in 150 mL of DMF, then add 38 mL of diethylamine, and react at room temperature for 2 hours while monitoring the end point of the reaction by TLC. After the reaction was completed, 800 mL of methyl tert-butyl ether was added to the reaction solution to precipitate a white solid, which was then filtered and dried to obtain compound A-3 (33.7 g), yield 96.6%, LCMS: [M-H] - = 183.1. Step 4: Synthesis of compound A-4 Add compound A-3 (10.02 g, 54.4 mmol) and compound SM2 (14.48 g, 36.3 mmol) [synthesized according to the method of CN108452321] to a 100 mL Erlenmeyer flask, dissolve them in 100 mL of DMF, then add EEDQ (13.5 g, 54.8 mmol), and react at room temperature for 2 hours while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by preparative liquid chromatography to obtain a product preparation solution, which was then lyophilized to obtain compound A-4 (9.94 g), yield 48%, LCMS: [M-H] - = 563.2.

[0059] Example 2 Synthesis of compound A-6:

Chemical formula

[0060] Example 3 Synthesis of Compound A-8: [Chemical formula] Project 1: Synthesis of Compound A-7 Into a 50 mL single-necked flask, Compound A-4 (2.5 g, 4.4 mmol) and Compound VCPAB-OH (2.0 g, 5.28 mmol) were added, dissolved in 25 mL of DMF, then EDCI (1.01 g, 5.28 mmol), HOBt (0.72 g, 5.28 mmol) and DIEA (1.1 mL, 6.6 mmol) were added, and the reaction was carried out at room temperature for 2 hours while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by preparative liquid chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain a white solid Compound A-7 (1.96 g), yield 48%, LCMS: [M+H] + = 926.4. Project 2: Synthesis of Compound A-8 Into a 50 mL single-necked flask, Compound A-7 (1.85 g, 2.0 mmol) and bis(p-nitrophenyl) carbonate (NPC, 3.65 g, 12.0 mmol) were added, dissolved in 15 mL of DMF, then DIEA (1.05 mL, 6.0 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours while monitoring the end point of the reaction by TLC. After the reaction was completed, the reaction solution was purified by column chromatography to obtain Compound A-8 (1.77 g), yield 81%, LCMS: [M+H] + = 1091.5.

[0061] Example 4 Synthesis of Compound B-1:

Chem.

[0062] Example 5 Synthesis of Compound B-2:

Chem.

[0063] Example 6 Synthesis of Compound B-3:

Chem.

[0064] Example 7 Synthesis of compound R01': [Chemical formula] Step 1: Synthesis of compound 1 To a 25 mL one-necked flask, compound VE-822 (840.5 mg, 1.81 mmol), A-6 (1.9231 g, 1.90 mmol), and HOBt (369.0 mg, 2.72 mmol) were added, dissolved in 10 mL of DMF, then DIEA (300 μL, 1.81 mmol) was added, and the reaction was carried out at room temperature for 1 hour while monitoring by TLC. After the reaction was completed, the reaction solution was purified by high-performance liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was freeze-dried to obtain yellow solid compound 1 (1.9270 g), with a yield of 80%, LCMS: [M+H] + = 1329.6. Step 2: Synthesis of compound 2 Into a 100 mL single-neck flask, compound 1 (604.2 mg, 0.45 mmol) and zinc bromide (2017.6 mg, 9.09 mmol) were added and dissolved in 18 mL of CH3NO2 to obtain a uniform yellow turbid solution. While monitoring the end point of the reaction by HPLC, the reaction was carried out at 40 °C for 0.5 h, and the solvent was removed by concentrating under reduced pressure at 45 °C using a water pump. The concentrated solution was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was freeze-dried to obtain compound 2 (225.6 mg), with a yield of 42%, LCMS: [M+H] + = 1173.4. Step 3: Synthesis of compound R01’ Into a 10 mL PE pipe, compound 2 (27.73 mg, 0.02 mmol) and azido-β-cyclodextrin (purchased product, 33.0 mg, 0.026 mmol) were added and dissolved in 2 mL of DMF and 0.2 mL of water. Then, CuSO4·5H2O (38.07 mg, 0.075 mmol) and sodium ascorbate (21.99 mg, 0.075 mmol) were added, and the reaction was carried out at room temperature for 1 h while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was freeze-dried to obtain compound R01’ (46.11 mg), with a yield of 83.6%, LC-MS: [M+2H] 2+ = 1167.4.

[0065] Example 8 Synthesis of compound R01-1’:

Chemical formula

[0066] Example 9 Synthesis of compound R02’:

Chemical formula

[0067] Example 10 Synthesis of compound R01-4’:

Chemical formula

[0068] Example 11 Synthesis of Compound Ex01’:

Chem.

[0069] Example 12 Synthesis of Compound 10:

Chem.

[0070] Step 4: Synthesis of Compound 9 Into a 50 mL single-necked flask, compound 8 (500 mg, 0.51 mmol) was added and dissolved in 10 mL of DMF to obtain a clear solution. PyBOP (396 mg, 0.76 mmol), HOBt (103 mg, 0.76 mmol), and exatecan methanesulfonate (270 mg, 0.51 mmol) were sequentially added in an ice-water bath, and then DIEA (252 μL, 1.52 mmol) was added. The reaction was carried out at room temperature for 2 hours while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain 500 mg of white solid compound 9 with a yield of 70%, LC-MS m / z (M+H) + : 1402.2. Step 5: Synthesis of compound 10 Into a 100 mL round-bottom flask, compound 9 (450.1 mg, 0.32 mmol) and zinc bromide (1448.2 mg, 6.42 mmol) were added and dissolved in 30 mL of CH3NO2. The reaction was carried out at 45 °C for 0.5 hour while monitoring the end point of the reaction by HPLC, and the solvent was removed by concentrating at 45 °C under reduced pressure using a water pump. The concentrated solution was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound 10 (203.9 mg) with a yield of 51%, LCMS: [M+H] + = 1245.6.

[0071] Example 13 Synthesis of compound Ex02’:

Chemical Structure

[0072] Example 14 Synthesis of compound Ex03’

Chemical formula

[0073] Example 15 Synthesis of compound Ex04’

Chemical formula

[0074] Example 16 Synthesis of compound PB01’:

Chemical formula

[0075] Example 17 Synthesis of compound PB02’: [Chemical formula] Referring to the synthetic route of Example 8, compound PB02’ (43.6 mg) was synthesized using compound 13 and compound B-1, with a yield of 77.5%, LC-MS: [M+2H] 2+ m / z = 1173.1.

[0076] Example 18 Synthesis of compound CBI01’: [Chemical formula] Step 1: Synthesis of compound 15 In a 25 mL single-neck flask, compound A-6 (231.6 mg, 0.23 mmol) and compound 14 (purchased product, 50.0 mg, 0.22 mmol) were added, dissolved in 10 mL of DMF, then DIEA (42 μL, 0.25 mmol) was added, and the reaction was carried out at room temperature for 1 hour while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high-performance liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound 15 (190.9 mg), with a yield of 78%, LCMS: [M+H] + = 1113.5. Step 2: Synthesis of compound 16 In a 50 mL single-neck flask, compound 15 (180.5 mg, 0.163 mmol) and zinc bromide (740.8 mg, 3.28 mmol) were added, dissolved in 10 mL of CH3NO2, reacted at room temperature for 0.5 hour, and the solvent was removed by concentrating under reduced pressure at 45 °C using a water pump to obtain a residue. This residue was purified by high-performance liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound 16 (73.8 mg), with a yield of 48%, LCMS: [M+H] + = 957.2. Step 3: Synthesis of compound CBI01’ In a 25 mL vial, compound 16 (30.5 mg, 0.032 mmol) and compound B-3 (18.0 mg, 0.035 mmol) were added, dissolved in 2 mL of DMF and 0.5 mL of water, then CuSO4·5H2O (8.0 mg, 0.032 mmol) and sodium ascorbate (6.4 mg, 0.032 mmol) were added, and the reaction was carried out at room temperature for 1 hour while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high performance liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound CBI01’ (29.5 mg), yield 62.5%, LC-MS: [M+H] + m / z = 1515.6.

[0077] Example 19 Synthesis of compound CBI02’

Chemical Structure

[0078] Example 20 Synthesis of compound CBI03’

Chemical Structure

[0079] Example 21 Synthesis of compound 25:

Chemical Structure

[0080] Step 3: Synthesis of Compound 20 In a 100 mL single-neck flask, compound 19 (2.2 g, 4.16 mmol) was added, dissolved in 30 mL of 5% formic acid / methanol solution. This solution was cooled to 5 °C or below in an ice-water bath, and zinc powder (5.44 g, 83.2 mmol) was slowly added thereto with stirring. Then, this solution was reacted at room temperature for 1 hour while monitoring the end point of the reaction by TLC. After the reaction was completed, the reaction solution was filtered while it was hot, the filter cake was washed with a small amount of methanol, the filtrate was adjusted to pH = 7 with saturated sodium bicarbonate solution, and then concentrated under reduced pressure at 45 °C to remove the solvent, obtaining a brownish-yellow oily substance. 60 mL of DCM was added thereto. The organic layer was separated, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure at 45 °C to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 1:1 to 1:3) to obtain compound 20 (1.87 g, pale yellow solid), with a yield of 90.1%, LC-MS: [M+H] + = 500.2. Step 4: Synthesis of compound 21 In a 50 mL single-neck flask, compound 20 (1.8 g, 3.6 mmol) and Fmoc-VA-PABO-PNP (purchased product, 2.45 g, 3.6 mmol) were added, dissolved in 15 mL of DMF to obtain a clear solution. Then, DIEA (893 μL, 5.4 mmol) was added, and the reaction was carried out at room temperature for 2 hours while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound 21 (2.94 g, pale yellow solid), with a yield of 78.3%, LC-MS: [M+H] + = 1040.5.

[0081] Step 5: Synthesis of compound 22 In a 50 mL single-neck flask, compound 21 (2.9 g, 2.78 mmol) was added, dissolved in 8 mL of THF and 8 mL of water. Then, 20 mL of glacial acetic acid was added, and the reaction was carried out at room temperature while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was slowly dropped into 400 mL of saturated sodium bicarbonate solution, ethyl acetate (100 mL *It was extracted in (3), the organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1 to 5:1) to obtain Compound 22 (1.94 g, pale yellow solid) in a yield of 75%, LC-MS: [M+H] + = 926.3. Step 6: Synthesis of Compound 23 To a 100 mL three-necked flask was added Compound 22 (1.9 g, 2.0 mmol). Under nitrogen protection, it was dissolved in 40 mL of anhydrous DCM, and Dess-Martin periodinane reagent (0.93 g, 2.2 mmol) was added. The reaction was carried out at room temperature for 4 hours while monitoring the end point of the reaction by TLC. After the reaction was completed, the reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate solution, water and saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain Compound 23 (1.61 g, off-white solid) in a yield of 85%, LC-MS: [M+H] + = 924.4.

[0082] Step 7: Synthesis of Compound 24 To a 50 mL single-necked flask was added Compound 23 (1.5 g, 1.62 mmol), which was dissolved in 15 mL of DMF to obtain a clear solution. Then 3 mL of diethylamine was added, and the reaction was carried out at room temperature for 1 hour while monitoring the end point of the reaction by TLC. After the reaction was completed, the reaction solution was poured into 100 mL of methyl tert-butyl ether to precipitate a solid, which was filtered to obtain a deprotected product. The deprotected product was dissolved in 15 mL of DMF, and then Compound A-4 (0.92 g, 1.62 mmol) and EEDQ (0.48 g, 1.94 mmol) were added. The reaction was carried out at room temperature for 2 hours while monitoring the end point of the reaction by HPLC. After the reaction was completed, the reaction solution was purified by high performance liquid fractionation chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain Compound 24 (1.30 g, off-white solid) in a yield of 64.2%, LC-MS: [M+H] + = 1248.5. Step 8: Synthesis of Compound 25 To a 50 mL single-necked flask, compound 24 (500 mg, 0.4 mmol) was added and dissolved in 5 mL of DCM. Then trifluoroacetic acid (5 mL) was added, and the reaction was carried out at room temperature for 1 hour while monitoring the end point of the reaction by HPLC. After the reaction was completed, the solvent was removed by concentration at 45 °C under reduced pressure to obtain a residue. The residue was purified by high-speed liquid preparative chromatography to obtain a product preparation solution, and then the preparation solution was lyophilized to obtain compound 25 (294 mg), yield 67.4%, LC-MS: [M+H] + = 1092.4.

[0083] Example 22 Synthesis of Compound PBD01’

Chemical Structure

[0084] Example 23 Synthesis of Compound PBD02’

Chemical Structure

[0085] Example 24 Synthesis of Compound 27:

Chemical Structure

[0086] Example 25 Synthesis of compound M01':

Chemical formula

[0087] Example 26 Synthesis of compound M02':

Chemical formula

[0088] Example 27 Synthesis of Compound M03’:

Chemical Structure

[0089] Example 28 Sequence of the antibody used: Sequence of anti-CD33 antibody anti-CD33 > Light chain - LC DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC > Heavy chain - HC EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Sequence of anti-Trop2 antibody anti-Trop2-1 >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDINKYLAWYQQKPGKVPKLLIYSTSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYDDLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >Heavy chain - HC QVQLVQSGAEVKKPGASVKLSCKASGYTFTSFDINWVRQAPEQRLEWMGWIFPGDGNTKYSQKFQGRATITRDTSASTAYMELSSLRSEDTAVYYCVRGEALYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Sequence of anti-Trop2 antibody anti-Trop2-2 >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDINKYLAWYQQKPGKVPKLLIYSTSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLQYDDLFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC >Heavy chain - HC QVQLVQSGAEVKKPGASVKLSCKASGYTFTSFDINWVRQAPEQRLEWMGWIFPGDGNTKYSQKFQGRATITRDTSASTAYMELSSLRSEDTAVYYCVRGEALYYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Sequence of anti-HER2 antibody trastuzumab (Tras) >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >Heavy chain - HC EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Sequence of anti-HER2 antibody Tras-016 >Light chain - LC DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVCTKSFNRGEC >Heavy chain - HC EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[0090] Example 29 Preparation of Monoclonal ADC (DAR = 8) (General Method) The antibody-drug conjugate sample was prepared by conjugating antibody A with L1-D1 or L2-D2: After expression in cells and purification by protein A affinity chromatography and molecular sieve chromatography, antibody A was buffer-exchanged with 20 mM NaAc-HAc, pH 6.0 solution, and concentrated or diluted to a protein concentration of 5 mg / mL. L1-D1 or L2-D2 was dissolved in N,N-dimethylacetamide (DMA) to a concentration of 10 mg / mL for later use. To break the intra-chain disulfide bonds of antibody A, first, tris(2-carboxyethyl)phosphine (TCEP) was added at a molar ratio of 15 - 25 times and reacted at room temperature for 2 hours. Next, the L1-D1 or L2-D2 solution was added at a molar ratio of 15 - 25 times and reacted at room temperature for 2 hours. After the reaction was completed, buffer exchange was performed using a 30KDa ultrafiltration spin column to remove unbound L1-D1 or L2-D2, and an antibody A-D1 (DAR = 8) or antibody A-D2(8) sample was obtained.

[0091] Example 30 Preparation of single-agent ADC (DAR = 10) and dual-agent ADC (DAR = 2 + 8) (general method) Antibody-drug conjugate samples B-D2(2)-D1(8), antibody B-D1(2)-D2(8), antibody B-D1(10) or antibody B-D2(10) were prepared by conjugating antibody B with L1-D1 and L2-D2: After expression in cells and purification by protein A affinity chromatography and molecular sieve chromatography, antibody B was buffer-exchanged with a 20 mM NaAc-HAc, pH 6.0 solution, and concentrated or diluted to a protein concentration of 5 mg / mL. L1-D1 or L2-D2 was dissolved in DMA to a concentration of 10 mg / mL for later use. First, TCEP was added at a molar ratio of 15 - 25 times and reacted at room temperature for 2 - 4 hours to reduce the intra-chain disulfide bonds of antibody B or to reduce the cysteine side chains introduced into the antibody to thiol groups. After the reaction was completed, buffer exchange was performed using a 30KDa ultrafiltration spin column to remove impurities in the reaction solution, and an antibody B reduction sample was obtained. The dehydroascorbic acid (dHA) solution was added to the antibody B-reduced sample solution at a molar ratio of 15 to 25 times, and reacted at room temperature for 2 to 4 hours to oxidize the reduced thiol groups on the antibody to form intramolecular disulfide bonds. Next, the L2-D2 or L1-D1 solution was added at a molar ratio of 5 to 15 times and reacted with the disulfide bonds introduced into the antibody at room temperature for 2 hours. After the reaction was completed, a 30KDa ultrafiltration spin column was used for buffer exchange to remove unbound L2-D2 or L1-D1, and an antibody B-D2(2) or antibody B-D1(2) complex sample was obtained. First, TCEP was added to antibody B-D2(2) or antibody B-D1(2) at a molar ratio of 15 to 25 times and reacted at room temperature for 2 hours to break the intramolecular disulfide bonds of the antibody on antibody B-D2(2) or antibody B-D1(2). Next, the L1-D1 or L2-D2 solution was added at a molar ratio of 15 to 25 times and reacted with the intramolecular disulfide bonds of the antibody at room temperature for 2 hours. After the reaction was completed, a 30KDa ultrafiltration spin column was used for buffer exchange to remove unreacted L1-D1 or L2-D2, and an antibody B-D2(2)-D1(8), antibody B-D1(2)-D2(8), antibody B-D1(10) or antibody B-D2(10) complex sample was obtained. Referring to the above method, the following ADCs were synthesized using anti-CD33, anti-Trop2-1, anti-Trop2-2, Tras, and Tras-016 antibodies, respectively.

Table 4

[0092] Test Example 1: Two-drug ADC cell killing test using CD33, Trop2, and HER2 as targets 1. Instruments, consumables, and reagents

Table 5

[0093] 2. Sample information

Table 6

[0094] 3. Principle and Method 3.1 Principle of Cell Killing Test by MTS Method Pharmacodynamic test at the cell level: Cell seeding was performed at a specific density in a 96-well plate. After the cells adhered to the wall surface (usually taking at least 4 hours), a series of drugs were added to each well plate at several-fold dilutions and allowed to act for a specific period to kill the cells. At the end of the drug action, a specific amount of MTS was added and reacted at 37°C under 5% CO2 for 1 - 4 hours. After color development using the MTS reagent, the OD490nm absorbance value was detected using a microplate reader, and then the IC 50 of cell killing was analyzed and calculated. Here, MTS [3-(4,5-diethyl-thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] is a new generation of blue tetrazolium compound, and the formazan product formed by its reduction has higher solubility and stability in water and faster color development. MTS is based on the same application principle as MTT, that is, it is reduced by several dehydrogenases in the mitochondria of living cells to form formazan products of various colors, and the color intensity has a high correlation with the number of living cells of several sensitive cell lines within a specific range.

[0095] 3.2. Method 3.2.1. Sample Preparation Before addition, according to the concentration of each test sample, the drug (5× stock solution concentration) was prepared using preheated 1% FBS culture medium at an initial concentration of 5.0 μM, then diluted at a 10-fold gradient concentration to a total of 8 detection points, and then left standing for subsequent use. During the preparation, each concentration was mixed uniformly by vibrating with an oscillator, specifically, vibrating 2 - 3 seconds each time, vibrating again at an interval of 1 second, and repeating this 2 - 3 times. The final concentrations of the antibody and antibody-conjugated drug were 0 (vehicle), 0.6 pM, 4.25 pM, 29.75 pM, 0.21 nM, 1.46 nM, 10.20 nM, 71.43 nM, 500 nM. 3.2.2. Test 1) Cell recovery: Preheat in a 37°C water bath, collect 9 mL of culture medium, and place it in a centrifuge tube for later use. Take out the cells from liquid nitrogen, immediately thaw them completely by rapid shaking at 37°C, then transfer them to the centrifuge tube, centrifuge at 1000 rpm for 3 minutes at room temperature. Discard the supernatant, resuspend the precipitate in 1 mL of complete culture medium (this step must be carried out gently so that no bubbles are blown out to reduce damage to the cells). Transfer the cells to a culture flask and culture them in a cell incubator at 37°C, 5% CO2, and 95% relative humidity. After 24 hours of recovery, observe the cell state and replace the culture medium with a new one during subculture and cell counting. 2) Cell seeding: After recovering all cell lines used in in vitro pharmacodynamic tests, they each needed to undergo 3 passages of subculture. According to the confirmed cell seeding density, dilute the cell suspension with cell culture medium containing 1% FBS, gently add 80 μL / well to a 96-well plate, and finally add 200 μL of sterile PBS or sterile ddH2O to the 96-well plate so that the edge does not contain the cell suspension for edge sealing. Then place the plate in a CO2 incubator and culture overnight. 3) Add the drug to the well plates (e.g., B2 - B10, C2 - C10, D2 - D10, E2 - E10, F2 - F10, or G2 - G10) at 5 times the expected concentration, and add 20 μL / well sequentially according to the principle of triplicates for each concentration of each test molecule. The drug concentration in the first well is 1000 nM, and two types of test drugs can be added to each 96-well plate. Generally, wells B11, C11, D11 containing cells supplemented with only 20 μL of 1% FBS culture medium were used as negative controls. Wells E11, F11, G11 supplemented with only 100 μL of 1% FBS culture medium without cells were used as blank controls. 4) Generally, the treatment period with the ADC drug is 5 days. During this period, observe the effect of the drug after addition under an inverted microscope at 24 hours, 48 hours, and 72 hours. 5) The CellTiter 96 (registered trademark) One Solution Reagen MTS reagent was taken out from the -20°C environment, thawed at room temperature in the dark, vortexed thoroughly, and mixed. Next, in a biosafety cabinet, 20 μL of the CellTiter 96 (registered trademark) One Solution Reagen MTS reagent was added along the side wall of the well for every 100 μL of cell culture volume. The MTS reagent was added at an equal ratio for different cell culture volumes. The MTS solution was uniformly mixed by gently tapping the plate surface, and then placed in a cell incubator and incubated in the dark for 2 - 4 hours. 6) After the reaction was completed, the 96-well plate was taken out, and the OD490nm absorbance value was detected using a microplate reader, and the data was recorded, sorted, and saved. 7) The data was processed and analyzed according to the following formula, and the cell viability was calculated at different drug concentrations.

Number

[0096] 4. Results and Analysis 4.1 CD33 cell killing assay: Using the CD33-high-expressing acute myeloid leukemia cell line HEL92.1.7, the CD33-moderate-expressing acute myeloid leukemia cell lines CMK, U937 and HL-60, and the skin squamous cell carcinoma cell line A431 that does not express CD33 as target cells respectively, first, the CD33 expression level of the target cells was determined by flow cytometry, and then, the cell killing activity of the CD33 dual-agent ADC was evaluated by the MTS method. The results are shown in Figures 1-10 and Tables 1 and 2.

Table 7

Table 8

[0097] 4.2 Trop2 cell killing test: Using the Trop2-high-expressing cell line N87 and the heterotumor cancer cells A431+SW620 as target cells respectively, first, the Trop2 expression level of the target cells was determined by flow cytometry, and then, the cell killing activity of the Trop2 dual-agent ADC was evaluated by the MTS method. The results are shown in Figures 11-14 and Tables 3 and 4.

Table 9

Table 10

[0098] Conclusion: Under these test conditions, in the killing tests of two cell models, 1. The naked antibodies of Trop2 anti-Trop2-1-mAb and anti-Trop2-2-mAb had no significant killing activity against these two cell lines; 2. In the Trop2 high-expression cell line and the negative cell line, the dual-agent ADCs obtained by binding a high killing activity agent and simultaneously binding a low-toxicity and low-activity repair inhibitor to the anti-Trop2 antibody, namely, anti-Trop2-2-R01-1(2)-Ex01(8) and anti-Trop2-2-R02(2)-Ex01(8), showed significantly better in vitro sensitivity against tumor cells than the single-agent ADC obtained by binding only the high killing activity agent, namely, anti-Trop2-1-Ex01(8), and also showed significantly better in vitro sensitivity than the single-agent ADC anti-Trop2-2-Ex01(10).

[0099] 4.3 HER2 cell killing test: Using cell lines SK-BR-3, H1975, MDA-MB-453, and MDA-MB-468 showing various degrees of HER2 expression as target cells respectively, first, the HER2 expression levels of the target cells were determined by flow analysis, and then the cell killing activity of the HER2 dual-agent ADCs was evaluated by the MTS method. The results are shown in Figures 15 to 18 and Tables 5 and 6.

Table 11

Table 12

[0100] Conclusion: Under these test conditions, in the killing tests of four cell models, 1. The single-agent ADCs obtained by conjugating a highly cytotoxic agent to an anti-HER2 antibody, namely Tras-Ex01 (DAR8) and Tras-016-Ex01 (DAR10), showed significant differences in cytotoxic activity against tumor cells. When the DAR was 10, the activity was significantly higher than when it was 8. 2. In cell lines showing various HER2 expressions, the dual-agent ADCs obtained by conjugating a highly cytotoxic agent and simultaneously conjugating a low-toxicity and low-activity repair inhibitor to an anti-HER2 antibody, namely Tras-016-R01-1(2)-Ex01(8) and Tras-016-R02(2)-Ex01(8), showed significantly better in vitro sensitivity against tumor cells than the single-agent ADC obtained by conjugating only the highly cytotoxic agent, namely Tras-Ex01 (DAR8), and showed significantly better activity than the single-agent ADC Tras-016-Ex01 (DAR10).

[0101] Test Example 2: Test of the binding of an anti-CD33 antibody-drug conjugate to recombinant human CD33 protein by ELISA The binding ability of an antibody to an antigen can be judged in advance by ELISA. Here, recombinant human CD33 protein was immobilized on an enzyme strip, and a series of concentration gradients of CD33 antibody were added for testing. 1. Coating: CD33 diluted to 0.5 μg / mL with 1×PBS, 100 μL per well, and coated overnight at 4°C. 2. Plate washing: The plate was washed with plate washing buffer (1×PBS + 0.05% Tween20), 200 μL per well, and left standing for 1 minute each time, 3 times. 3. Sealing: After blotting dry the third washing buffer, seal with sealing buffer (1×PBS + 0.05% Tween20 + 1% BSA), 200 μL per well, and seal at 37°C for 1 hour. 4. Plate washing: The plate was washed with plate washing buffer, 200 μL per well, and left standing for 1 minute each time, 3 times. 5. Addition of primary antibody: The antibody-drug conjugate (the same as in Test Example 1) was diluted from 2 μg / mL in a three-fold gradient using a sample diluent (1×PBS + 0.05% Tween 20 + 1% BSA); the plate was allowed to stand and washed three times for 1 minute each with 200 μL per well of the plate wash buffer. 6. Addition of secondary antibody: Diluted at a ratio of 1:10000 with an assay buffer (1×PBS + 0.05% Tween 20 + 1% BSA) to 100 μL per well and allowed to stand at 37°C for 1 hour. 7. Plate washing: The plate was allowed to stand and washed three times for 1 minute each with 200 μL per well of the plate wash buffer. 8. Reading: After adding the TMB chromogenic solution (50 μL / well) and allowing it to develop color for 7 minutes, 2M H2SO4 (50 μL / well) was added to terminate the color development. The plate was read at 450 nm using a microplate reader. The results of the test are shown in Figures 19 and 20.

[0102] Conclusion: The binding ability of the anti-CD33 antibody-drug conjugate, single-agent ADC: anti-CD33-Ex01(10), dual-agent ADC: anti-CD33-R01-1(2)-Ex01(8), and anti-CD33-Ex01(2)-R01-1(8) to the recombinant human CD33 protein was basically the same as that of the naked anti-CD33 antibody to the recombinant human CD33 protein, and there was no significant difference.

[0103] Test Example 3: Plasma stability test of anti-CD33 antibody and antibody-drug conjugate Mixtures of the naked anti-CD33 antibody and ADC (anti-CD33-R01-1(2)-Ex01(8)) with human plasma from which IgG had been removed were respectively formulated, with the final concentrations of the naked antibody and ADC being 0.6 mg / ml, incubated in a water bath in an incubator at 37°C for 0, 3, and 7 days, and non-incubated, non-extracted controls and non-incubated, extracted controls were set. After incubation, the samples were tested by SEC-HPLC method. The results are shown in Table 7.

Table 13

[0104] Although specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and variations can be made to the details in light of the overall teachings of the present invention, and all such changes are within the scope of the present invention. The full scope of the present invention is indicated by the appended claims and their equivalents.

Claims

1. Formula I: 【Chemistry 1】 Equation I During the ceremony, Ab is a targeting portion selected from the group consisting of antibodies, antibody fragments, targeted proteins, and Fc fusion proteins; D 1 is, L 1 The first drug linked to; D 2 It is a second drug selected from DNA damage repair inhibitors, and L 2 It is linked to; L 1 This is a first linking unit that connects the first drug and the targeted portion; L 2 This is a second linking unit that connects the second drug and the targeting portion; m is an integer selected from 0 to 20; n is an integer selected from 1 to 20. A ligand-drug conjugate represented by , or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate.

2. The second drug is selected from the group consisting of ATR inhibitors, ATM inhibitors, PARP inhibitors, WEE1 inhibitors, CHK1 inhibitors, and DNA-PK inhibitors; Preferably, the ATR inhibitor is 【Chemistry 2】 , and formula A: 【Transformation 3】 Formula A During the ceremony, X 1 These are O, S, NH, and CH 2 Selected from the group consisting of; Preferably, X 1 is selected from the group consisting of O and S; Comfortably, X 1 is O; X 2 , X 3 Each is independently selected from the group consisting of N and CH; Preferably, X 2 is N, X 3 is CH; X 4 , X 5 , X 6 Each is independently selected from the group consisting of N and CH; Preferably, X 4 and X 6 is N, X 5 is CH; X 7 N and C(R 0 Selected from the group consisting of; Preferably, X 7 is C(R 0 ) and; R 0 H, C1-C6 alkyl, and R b R a Selected from the group consisting of N-; Preferably, R 0 is R b R a It is N-; R a , R b Each is independently selected from the group consisting of H and C1-C6 alkyl groups; Preferably, R a , R b is H; R 1 , R 2 , R 3 , R 4 , R 5 Each of these is independently H, C1-C6 alkyl, and 【Chemistry 4】 Selected from the group consisting of; Preferably, R 1 , R 2 , R 3 , R 4 , R 5 These are H and, respectively, independently. 【Transformation 5】 Selected from; More specifically, R 1 , R 2 , R 3 , R 4 , R 5 One of the following is 【Transformation 6】 And the remaining thing is H; Most preferably, R 3 teeth, 【Transformation 7】 And R 1 , R 2 , R 4 , and R 5 is H; R c is selected from the group consisting of H and C1-C6 alkyl groups; Preferably, R c It is selected from C1-C6 alkyl groups; More specifically, R c It is isopropyl; R 6 , R 7 , R 8 , R 9 Each is independently selected from the group consisting of H and C1-C6 alkyl groups; Preferably, R 6 , R 7 , R 8 , and R 9 is H; R d is selected from the group consisting of H and C1-C6 alkyl groups; Preferably, R d It is selected from C1-C6 alkyl groups; More specifically, R d It is methyl; p is selected from the group consisting of 1, 2, 3, 4, 5, and 6; Preferably, p is selected from the group consisting of 1, 2, and 3; More preferably, p is 1. Selected from the group consisting of compounds represented by or their deuterated derivatives; More preferably, the compound represented by formula A is 【Transformation 8】 And; Preferably, the PARP inhibitor is 【Chemistry 9】 Selected from the group consisting of; Preferably, the ATM inhibitor is 【Chemistry 10】 Selected from the group consisting of; Preferably, the WEE1 inhibitor is 【Chemistry 11】 And; Preferably, the CHK1 inhibitor is 【Chemistry 12】 Selected from the group consisting of; Preferably, the DNA-PK inhibitor is 【Chemistry 13】 Selected from the group consisting of, A ligand-drug conjugate according to claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

3. The second linking unit is a collapsible or non-collapsible linking unit; Preferably, L 2 is, L 21 -L 22 -L 23 -L 24 And L 24 is D 2 It is connected to L 21 It is connected to Ab (preferably L 21 (It is bonded to Ab via a thiol group.) L 21 teeth, 【Chemistry 14】 Selected from the group consisting of, its N-terminus is L 22 It is connected to, L 22 teeth, 【Chemistry 15】 Selected from the group consisting of, its carbonyl terminus is L 23 It is linked to; L 23 It is selected from an amino acid residue or a peptide residue consisting of 2 to 10 amino acid residues, and its carbonyl terminus is L 24 It is linked to; Preferably, L 23 It is a peptide residue consisting of 2 to 4 (preferably 2) amino acid residues, and its carbonyl terminus is L 24 The amino acid is linked to, preferably, selected from the group consisting of valine, alanine, phenylalanine, glycine, lysine, citrulline, serine, glutamic acid, and aspartic acid, and more preferably, selected from the group consisting of valine, alanine, and citrulline; more, L 23 It is selected from the group consisting of valine-alanine (Val-Ala) and valine-citrulline (Val-Cit), and its carbonyl terminus is L 24 It is linked to; Most preferably, L 23 teeth, 【Chemistry 16】 Selected from, its carbonyl terminus is L 24 It is linked to; L 24 is 【Chemistry 17】 or direct bond, L 24 but [Chemistry 18] If so, the carbonyl terminus is D 2 It is linked to; Preferably, L 2 teeth, 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 Selected from the group consisting of, its carbonyl terminus is D 2 It is connected to, A ligand-drug conjugate according to claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

4. D 2 -L 2 -but Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 A ligand-drug conjugate according to claim 1, selected from the group consisting of the following, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

5. The first drug is selected without limitation from the group consisting of tubulin binders, DNA damaging agents, enzyme inhibitors, immunomodulators, peptides, and nucleotides; Preferably, the first drug is a) Alkylating agents, PBD and its derivatives, chlorpheniramate, chlorpromazine, cyclophosphamide, dacarbazine, estramustine, ifosphamide, mechloretamine, dimethoxyamine hydrochloride, mechloretamine oxide, amlodipine hydrochloride, mycophenolic acid, dalucitol, pipobromane, novoenicin, phenesterine, prednimustine, thiotepa, trophosphamide, uracil; CC-1065; docamycin; benzodiazepine dimers; nitrosourea; alkyl sulfonates; triazenes; platinum-containing compounds; aziridines such as chromanone, quinolone, metsuredepa, and madopar; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenetriamine, triethylphosphoramide, triethylenethiophosphoramide, and trimethylolmethylamine and their derivatives and deuterated compounds; b) Plant alkaloids, vinca alkaloids, taxol and their analogues, maytansinoids and their analogues, cryptophycin, epothyron, eryuterobin, discodermold, bryostatin, apriciatoxin, auristatin, tubulisin, cephalostatin, pancrotistatin, sarcodicuciin, spongistatin, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansinoids (e.g., maytansin DM1, maytansin DM4), amatoxin and Its derivatives and deuterides; c) DNA topoisomerase inhibitors, etoposide, teniposide, 9-aminocamptothecin, camptothecin, crisnator, daunomycin, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acid, teniposide, topotecan, 9-nitrocamptothecin, SN38, mitomycin and its derivatives and deuterated compounds; d) Antimetabolites, folate antagonists, DHFR inhibitors; MP dehydrogenase inhibitors; ribonucleotide reductase inhibitors; pyrimidine analogs, uracil analogs; cytosine analogs; purine analogs; folate supplements; e) Hormone therapy agents, receptor antagonists, anti-estrogen agents, LHRH agonists; anti-androgens; retinoids, vitamin D3 analogues; photodynamic therapy agents; cytokines, TNF-containing human proteins and their derivatives and deuterated compounds; f) Kinase inhibitors, BIBW2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080, mbritinib, ponatinib, bafetinib, bosutinib, cabozantinib, bismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib and their derivatives and deuterated products; g) Antibiotics, engine antibiotics, acrasinomycin, anthramycin, amrinomycin, azaserin, bleomycin, cetocycline, calamycin, carminomycin, cartinophylline, doxorubicin, morpholinodoxorubicin, 2-pyrrolidoxorubicin and deoxydaunorubicin, epirubicin, akurarubicin, idarubicin, marcomycin, mycin, mycophenolic acid, lopimycin, peromycin, puromycin, tripheric doxorubicin, streptozotocin, streptozotocin, tubercidine, ubenimex, dinostatin, zolbicin, PNU-159682 and its derivatives and deuterated compounds; h) Polyketides, especially bratacin and bratacinone; gemcitabine, epoxomicin, bortezomib, thalidomide, lenalidomide, pomaluidomide, tosedostat, gibberestat, PLX4032, STA-9090, Stimbax, allobectin-7, Xegeva, Provenge, Yervoy, prenylation inhibitors, dopaminergic neurotoxins, actinomycin, bleomycin Anthracycline antibiotics, doxorubicin, idarubicin, epirubicin, larbicin, zorubicin, mitoxantrone, MDR inhibitors, Ca2+ adenosine triphosphate inhibitors, histone deacetylase inhibitors, celecoxib, glitazone, epigallocatechin gallate, disulfiram, salinosporamide A; aminoglutethimide, mitotane, trilostane, acegraton, al Dophosphoramide, aminolevulinic acid, amsacrine, arabinoside, bestAbuci, bisanthren, edatrexate, defofamine, meikexin, diazicone, eflornithine, elfornithine, ceruptium, ethylgluconate, gallium nitrate, cytosine, hydroxyurea, ibandronate, lentinan, ronidamin, mitogwazone, mitoxantrone, mopidamol, nitracrine, pentostatin, fenamet, pirarubicin, podophyllic acid, 2-ethylhydrazine, procarbazine; PSK (registered trademark); razoxane; lyzomycin; schizzo; spirogermanium; tenuazonic acid, triadiquan; trichlorotriethylamine; trichothecene, polyurethane, siRNA and antisense drugs, as well as their derivatives and deuterated derivatives. Selected from the group consisting of; More preferably, the first drug D1 is a camptothecin compound or a deuterated thereof; Preferably, the camptothecin compound is of formula B 【Chemistry 20】 Formula B During the ceremony, The first chiral carbon atom linked to the N atom has an absolute chiral structure in either the R configuration or the S configuration; R' is selected from the group consisting of H, D, halogens, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, aryl, and heteroaryl; Preferably, R' is selected from the group consisting of H and C1-C6 alkyl groups; More preferably, R' is H; R 1 ' is selected from the group consisting of H, D, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, carboxyl, heterocyclyl, aryl, substituted aryl and heteroaryl; Preferably, R 1’ is selected from the group consisting of H and C1-C6 alkyl groups; More specifically, R 1’ It is selected from C1-C6 alkyl groups; Most preferably, R 1’ It is methyl; R 2’ This is selected from the group consisting of H, D, halogen, alkyl, substituted alkyl, deuterated alkyl, cycloalkylalkyl, alkoxyalkyl, carboxyl, heterocyclyl, aryl, substituted aryl, and heteroaryl. Preferably, R 2’ It is selected from halogens; More specifically, R 2’ is F; X' is -C(O)-(CR 3’ R 4’ ) t-CR a’ R b’ -O-, -C(O)-(CR 3’ R 4’ ) t-CR a’ R b’ -NH- and -C(O)-(CR 3’ R 4’ ) t-CR a’ R b’ Selected from the group consisting of -S-, preferably with its carbonyl end linked to an N atom; Preferably, X' is -C(O)-(CR 3’ R 4’ ) t-CR a’ R b’ Selected from -O-, preferably with its carbonyl end linked to an N atom; More preferably, X' is -C(O)-CR a’ R b’ Selected from -O-, preferably with its carbonyl end linked to an N atom; R a’ This is selected from the group consisting of H, D, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, and heteroaryl; Preferably, R a’ is selected from the group consisting of H and C1-C6 alkyl groups; More specifically, R a’ is H; R b’ This is selected from the group consisting of H, D, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl, and heteroaryl; Preferably, R b’ This is selected from the group consisting of H, D, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 haloalkyl; More specifically, R b’ is selected from the group consisting of H, D, methyl, cyclopropyl, and trifluoromethyl; or R a’ , R b’ The carbon atoms linked to them form a C3-C6 cycloalkyl, cycloalkylalkyl, or heterocyclyl; R 3’ , R 4’ They are either the same or different, and each is independently selected from the group consisting of H, D, halogen, alkyl, haloalkyl, deuterated alkyl, alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl and heterocyclyl; or R 3’ , R 4’ The carbon atoms linked to them form a C3-C6 cycloalkyl, cycloalkylalkyl, or heterocyclyl; The wavy line to the right connected to X' is L 1 It is linked to; t is an integer selected from 0 to 4; Preferably, t is 0; Preferably, X' has the following structure: 【Chemistry 21】 Selected without restriction from the group consisting of; During the ceremony, The second chiral carbon atom has an absolute chiral structure in either the R configuration or the S configuration; The wavy line on the left is connected to N in the compound represented by formula B, and the wavy line on the right is connected to L. 1 It is connected to, It has a structure represented by; Preferably, the compound represented by formula B is 【Chemistry 22】 Selected from the group consisting of; Preferably, the first drug is 【Chemistry 23】 A ligand-drug conjugate according to claim 1, selected from the group consisting of the following, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

6. The first linking unit is a collapsible or non-collapsible linking unit; Preferably, L 1 is, L 11 -L 12 -L 13 -L 14 And L 14 is D 1 It is connected to L 11 It is connected to Ab (preferably L 11 (It is bonded to Ab via a thiol group.) L 11 teeth, 【Chemistry 24】 Selected from the group consisting of, its N-terminus is L 12 It is connected to, L 12 teeth, 【Chemistry 25-1】 【Chemistry 25-2】 Selected from the group consisting of, its carbonyl terminus is L 13 or L 14 It is linked to; L 13 It is selected from direct bonds, amino acid residues, or peptide residues consisting of 2 to 10 amino acid residues, L 13 If is selected from an amino acid residue or a peptide residue consisting of 2 to 10 amino acid residues, its carbonyl terminus is L 14 It is linked to; Preferably, L 13 It is selected from direct bonds, amino acid residues, and peptide residues consisting of 2 to 4 amino acid residues, L 13 If is selected from an amino acid residue or a peptide residue consisting of 2 to 4 amino acid residues, its carbonyl terminus is L 14 Linked to, preferably, the amino acid is selected from the group consisting of valine, alanine, phenylalanine, glycine, lysine, citrulline, serine, glutamic acid, and aspartic acid, and more preferably, the amino acid is selected from the group consisting of valine, alanine, phenylalanine, glycine, citrulline, and lysine; more, L 13 L is selected from the group consisting of direct linkage, lysine, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), valine-alanine (Val-Ala), and valine-citrulline (Val-Cit). 13 If is selected from the group consisting of lysine, glycine-glycine-phenylalanine-glycine (Gly-Gly-Phe-Gly), valine-alanine (Val-Ala), and valine-citrulline (Val-Cit), then its carbonyl terminus is L 14 It is linked to; Most preferably, L 13 Direct coupling, 【Chemistry 26】 Selected from the group consisting of L 13 but 【Chemistry 27】 When selected from the group consisting of L, the carbonyl terminus is L 14 It is linked to; L 14 teeth, 【Chemistry 28】 Selected from the group consisting of, and its amino terminus is L 13 or L 12 It is linked to and its carbonyl or carbon terminus is D 1 It is linked to; Preferably, L 1 teeth, 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 Selected from the group consisting of, its carbonyl end or 【Transformation 30】 The terminal carbon terminus containing D 1 It is connected to, A ligand-drug conjugate according to claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

7. D 1 -L 1 -but Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 A ligand-drug conjugate according to claim 1, selected from the group consisting of the following, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

8. m is an integer selected from 1 to 10; Preferably, m is an integer selected from 2 to 8; More preferably, m is selected from the group consisting of 2, 4, and 8; Alternatively, n is an integer selected from 1 to 10; Alternatively, n is preferably an integer selected from 2 to 8; Or more preferably, n is selected from the group consisting of 2, 4, and 8. A ligand-drug conjugate according to claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

9. Ab is selected from the group consisting of mouse antibodies, chimeric antibodies, humanized antibodies, fully humanized antibodies, antibody fragments, bispecific antibodies, and multispecific antibodies, and preferably Ab forms linkage bonds with linking units via its cysteinethiol group (-SH); Preferably, the Ab is anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDG antibody. F1 antibody, anti-ETBR antibody, anti-MSLN antibody, anti-TIM-1 antibody, anti-LRRC15 antibody, anti-LIV-1 antibody, anti-CanAg / AFP antibody, anti-cladin 18.2 antibody, anti-mesothelin antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-c-MET antibody, anti-SLITRK6 antibody, anti-KIT / CD117 antibody, anti-STEAP 1 antibody, anti-SLAMF7 / CS1 antibody, anti-NaPi2B / SLC34A2 antibody, anti-GPNMB antibody, anti-HER3 (ErbB3) antibody, anti-MUC1 / CD227 antibody, anti-AXL anti- body, anti-CD166 antibody, anti-B7-H3 (CD276) antibody, anti-PTK7 / CCK4 antibody, anti-PRLR antibody, anti-EFNA4 antibody, anti-5T4 antibody, anti-NOTCH3 antibody, anti-Nectin 4 antibodies, anti-TROP-2 antibody, anti-CD142 antibody, anti-CA6 antibody, anti-GPR20 antibody, anti-CD174 antibody, anti-CD71 antibody, anti-EphA2 antibody, anti-LYPD3 antibody, anti-FGFR A ligand-drug conjugate according to claim 1, wherein the antibody is a monoclonal antibody selected from the group consisting of 2 antibodies, anti-FGFR3 antibody, anti-FRα antibody, anti-CEACAM antibody, anti-GCC antibody, anti-integrin Av antibody, anti-CAIX antibody, anti-P-cadherin antibody, anti-GD3 antibody, anti-cadherin 6 antibody, anti-LAMP1 antibody, anti-FLT3 antibody, anti-BCMA antibody, anti-CD79b antibody, anti-CD19 antibody, anti-CD33 antibody, anti-CD56 antibody, anti-CD74 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD37 antibody, anti-CD47 antibody, anti-CD138 antibody, anti-CD352 antibody, anti-CD25 antibody, and anti-CD123 antibody, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

10. D 1 -L 1 - and D 2 -L 2 - is bonded to Ab via a thiol group; Preferably, the source of the thiol group is selected from the group consisting of thiol groups on cysteine ​​residues formed after reduction of intrachain disulfide bonds present in the targeted region, thiol groups on cysteine ​​residues formed by site-directed mutagenesis of a specific original amino acid in the targeted region, thiol groups on cysteine ​​residues formed by site-directed insertion of cysteine ​​into the targeted region, and thiol groups on cysteine ​​residues formed by site-directed insertion of a cysteine-containing peptide into the targeted region; Preferably, D 1 -L 1 - and D 2 -L 2 Each of these is bonded to Ab via thiol groups from different sources; Preferably, D 1 -L 1 - and D 2 -L 2 Either one of the following is bound to Ab via a thiol group on a cysteine ​​residue formed after reduction of an intrachain disulfide bond present in the targeting region, and the other is bound to Ab via a thiol group on a cysteine ​​residue formed by site-directed mutagenesis of a specific original amino acid in the targeting region, a thiol group on a cysteine ​​residue formed by site-directed insertion of cysteine ​​into the targeting region, or a thiol group on a cysteine ​​residue formed by site-directed insertion of a cysteine-containing peptide into the targeting region, as described in claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

11. The ligand-drug conjugate Ab-R01(2)-Ex01(8), Ab-R01(8)-Ex01(2), Ab-R01(4)-Ex01(4), Ab-R01(4)-Ex01(8), Ab-R01(8)-Ex01(4), Ab-R01(2)-Ex02(8), Ab-R01(8)-Ex02(2), Ab-R01(4)-Ex02(4), Ab-R01(2)-Ex03(8), Ab-R01(8)-Ex03(2), Ab-R01(4)-Ex03(4), Ab-R01(2)-Ex04(8), Ab-R01(8)-Ex04(2), Ab-R01(4)-Ex04(4), Ab-R01(2)-Ex05(8), Ab-R01(8)-Ex05(2), Ab-R01(4)-Ex05(4), Ab-R01(2)-Ex06(8), Ab-R01(8)-Ex06(2), Ab-R01(4)-Ex06(4), Ab-R01-1(2)-Ex01(8), Ab-R01-1(8)-Ex01(2), Ab-R01-1(4)-Ex01(4), Ab-R01-1(8)-Ex01(4), Ab-R01-1(4)-Ex01(8), Ab-R01-1(2)-Ex02(8), Ab-R01-1(8)-Ex02(2), Ab-R01-1(4)-Ex02(4), Ab-R01-1(2)-Ex03(8), Ab-R01-1(8)-Ex03(2), Ab-R01-1(4)-Ex03(4), Ab-R01-1(2)-Ex04(8), Ab-R01-1(8)-Ex04(2), Ab-R01-1(4)-Ex04(4), Ab-R01-1(2)-Ex05(8), Ab-R01-1(8)-Ex05(2), Ab-R01-1(4)-Ex05(4), Ab-R01-1(2)-Ex06(8), Ab-R01-1(8)-Ex06(2), Ab-R01-1(4)-Ex06(4), Ab-R01-1(2)-PB01(8), Ab-R01-1(2)-PB02(8), Ab-R01-1(8)-PNU01(2), Ab-R01-1(8)-PNU02(2), Ab-R01-1(2)-CBI01(8), Ab-R01-1(2)-CBI02(8), Ab-R01-1(2)-CBI03(8), Ab-R01-1(2)-PBD01(8), Ab-R01-1(2)-PBD02(8), Ab-R01-1(2)-PBD-CBI01(8), Ab-R01-1(2)-PBD-CBI02(8), Ab-R01-1(8)-M01(2), Ab-R01-1(8)-M02(2), Ab-R01-1(8)-M03(2), Ab-AT01(2)-Ex01(8), Ab-AT02(2)-Ex01(8), Ab-AT03(2)-Ex01(8), Ab-AT04(2)-Ex01(8), Ab-TA01(2)-Ex01(8), Ab-VE01(2)-Ex01(8), Ab-E01(2)-Ex01(8), Ab-RU01(2)-Ex01(8), Ab-PA01(2)-Ex01(8), Ab-CEP01(2)-Ex01(8), Ab-TM01(2)-Ex01(8), Ab-TM02(2)-Ex01(8), Ab-WE01(2)-Ex01(8), Ab-CH01(2)-Ex01(8), Ab-CH02(2)-Ex01(8), Ab-CH03(2)-Ex01(8), Ab-CH04(2)-Ex01(8), Ab-DP01(2)-Ex01(8), Ab-DP02(2)-Ex01(8), and Ab-DP03(2)-Ex01(8) A ligand-drug conjugate according to claim 1, selected from the group consisting of the following, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

12. Drug-binding unit complex Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 A drug linking unit complex, or its stereoisomer, prodrug, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof, selected from the group consisting of the above.

13. A pharmaceutical composition comprising the ligand-drug conjugate described in claim 1, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally comprising one or more pharmaceutically acceptable agents.

14. A pharmaceutical composition comprising the drug linking unit complex described in Claim 12, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally comprising one or more pharmaceutically acceptable agents.

15. The use of a ligand-drug complex according to any one of claims 1 to 11, or its stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or a drug-linking unit complex according to claim 12, or its stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or a pharmaceutical composition according to claim 13 or 14, wherein the disease is cancer; Preferably, the cancer is selected from the group consisting of skin cancer, lymphoma, esophageal cancer (e.g., esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, kidney cancer, solid tumors, non-Hodgkin lymphoma, central nervous system tumors (e.g., glioma, glioblastoma multiforme, neuroblastoma, glioma or sarcoma), melanoma, prostate cancer, thyroid cancer, bone cancer, urinary tract cancer, salivary gland cancer, leukemia (e.g., acute myeloid leukemia), and other solid tumors and hematological malignancies; More preferably, the cancer is selected from the group consisting of lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, and kidney cancer. use.

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