[go: up one dir, main page]

WO2025162492A1 - Lieur, conjugué ligand-médicament et utilisation médicale associée - Google Patents

Lieur, conjugué ligand-médicament et utilisation médicale associée

Info

Publication number
WO2025162492A1
WO2025162492A1 PCT/CN2025/075857 CN2025075857W WO2025162492A1 WO 2025162492 A1 WO2025162492 A1 WO 2025162492A1 CN 2025075857 W CN2025075857 W CN 2025075857W WO 2025162492 A1 WO2025162492 A1 WO 2025162492A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
membered
alkyl
alkylene
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/075857
Other languages
English (en)
Chinese (zh)
Inventor
孙英杰
焦娇
崔梦函
王佳星
车黎明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gan and Lee Pharmaceuticals Co Ltd
Original Assignee
Gan and Lee Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gan and Lee Pharmaceuticals Co Ltd filed Critical Gan and Lee Pharmaceuticals Co Ltd
Publication of WO2025162492A1 publication Critical patent/WO2025162492A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells

Definitions

  • the present invention relates to the field of medical technology, and in particular to a novel linker, a ligand-drug conjugate, a pharmaceutical composition comprising the conjugate, and uses of the conjugate or the pharmaceutical composition.
  • Antibody-drug conjugates consist of three components: an antibody (mAb), a cytotoxic payload, and a linker (connecting unit or structure).
  • the linker connects the antibody to the cytotoxic drug, conferring cell-targeting and cell-killing potency to the ADC, enabling precise and efficient elimination of cancer cells.
  • Nectin-4 also known as poliovirus receptor-related protein 4 (PVRL4), is a type I transmembrane protein belonging to the Nextins family of immunoglobulin-like molecules. Studies have found that nectin-4 has limited expression in healthy adult tissues but is overexpressed in various malignancies, including bladder cancer, breast cancer, and lung cancer. As a tumor-associated inducer, it is associated with various aspects of tumor progression, including proliferation, metastasis, and epithelial-mesenchymal transition, making it an ideal anti-tumor drug target (Chatterjee, S., S. Sinha, and C.N. Kundu, Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. Eur J Pharmacol, 2021.911: p.174516).
  • Eribulin is a mitotic microtubule dynamics inhibitor that has demonstrated therapeutic activity against a variety of tumors (such as breast cancer, soft tissue sarcoma, and urothelial carcinoma) in clinical trials, with a favorable bystander effect. Eribulin has been extensively studied in the treatment of advanced breast cancer and is typically used in patients who have received at least two prior chemotherapy regimens. Eribulin primarily inhibits microtubule dynamics by binding to specific sites on tubulin, leading to irreversible mitotic arrest and subsequent cell apoptosis, potentially overcoming resistance to other anti-tumor drugs.
  • tumors such as breast cancer, soft tissue sarcoma, and urothelial carcinoma
  • eribulin can reverse epithelial-mesenchymal transition (EMT), overcome immune escape and lead to vascular remodeling, thereby inhibiting the migration and spread of tumor cells (Menis, J. and C. Twelves, Eribulin (Halaven): a new, effective treatment for women with heavily pretreated metastatic breast cancer. Breast Cancer (Dove Med Press), 2011.3: p.101-11; Seshadri, P., B. Deb, and P. Kumar, Multifarious targets beyond microtubules-role of eribulin in cancer therapy. Front Biosci (Schol Ed), 2021.13(2): p.157-172).
  • EMT epithelial-mesenchymal transition
  • ADC drugs have been used in clinical practice or clinical research, but further development of ADC drugs with better efficacy is still needed.
  • the first aspect of the present invention provides a compound as shown in Formula 1-1 or a pharmaceutically acceptable salt thereof, TML 1 ——L 23 -L 4 -L 5 -G Formula 1-1
  • T is a linker unit; preferably T is selected from R at each occurrence is independently selected from halogen and -S-Ar; preferably, R at each occurrence is independently selected from F, Cl, Br, I and -S-Ar;
  • Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 0, 1, 2, 3 or 4 Ra ;
  • Ar is selected from phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 1, 2 or 3 Ra ;
  • W is selected from amino, -NR
  • M is selected from a single bond, a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, and a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene being unsubstituted or optionally substituted with one or more Ra ;
  • L is selected from a single bond, alkynylene, alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, alkylene, and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more Ra ;
  • L 5 is a spacer unit having a side chain comprising a hydrophilic unit; wherein the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof, preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; provided that, when L 23 is a single bond, L 5 does not contain a triazole ring; or,
  • L 23 is selected from -(CH 2 ) n7 -(OCH 2 CH 2 ) n8 -(CH 2 ) n10 -C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group, or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more Ra ; provided that when T is When L 1 contains an alkynylene group, L 5 is a spacer unit having a side chain containing a hydrophilic unit;
  • n7, and n10 are each independently selected from 0, 1, 2, 3, 4, 5 and 6;
  • n8 and n17 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • M, L 1 , and L 23 are not single bonds at the same time;
  • L 4 is a peptide residue consisting of amino acids or -NR a -alkylene-NR a -, wherein the alkylene, and amino acids are unsubstituted or optionally substituted with one or more Ra ;
  • G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO 2 ; and
  • Each occurrence of Ra is independently selected from H, a deuterium atom, a halogen, a C1-10 alkyl group, a C1-10 deuterated alkyl group, a C2-10 heteroalkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C1-10 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a 3-15 membered cycloalkyl group, a 3-15 membered heterocycloalkyl group, a carboxyl group, a -NH- C1-6 alkyl group, a C1 - C6 alkyl-C(O)-, a C1 - C6 alkyl-OC(O)-, a C1 - C6 alkyl-NHC ( O)-, a -C1-6 alkylene- NH2 , a -C1-6 alkylene-NH2 , a -
  • alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl.
  • L5 is selected from a single bond, -N( Rb )-( CH2 ) g -O-( CH2 ) g -OC(O)-, -N( Rb )-( CH2 ) g -O-( CH2 - CH2 -O) g -C(O)-,
  • L 23 is selected from -(CH 2 ) n7 -(OCH 2 CH 2 ) n8 -(CH 2 ) n10 -C(O)-, and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group or the heterocycloalkylene group is unsubstituted or
  • L 5 is a spacer unit having a side chain comprising a hydrophilic unit; the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, a saccharide, a phosphate, a sulfonate and a combination thereof; preferably, the hydrophilic unit
  • Cy 1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted with one or more Ra ; preferably, Cy 1 is independently 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, or 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ; preferably, Cy 1 is selected from Preferably, Cy 1 is selected from
  • n1, n2 and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28;
  • n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;
  • n8 and n17 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 at each occurrence; and n12 and n15 are not both 0;
  • n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • j is independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;
  • Cy 3 is independently selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a ; preferably, Cy 3 is selected from Preferably, Cy 3 is
  • g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6;
  • R a and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C (O) -, C 1 -C 6 alkyl-OC (O) -, C 1 -C 6 alkyl-NHC (O) -, -C 1 -6 alkylene-C (O) -NH 2 , C 1 -6 alkylOC (O) NH-, -C 1 -6 alkylene-C (O) -NH
  • the second aspect of the present invention provides a compound as shown in Formula 1 or a pharmaceutically acceptable salt thereof, TML 1 -L 2 -L 3 -L 4 -L 5 -G Formula 1
  • T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar;
  • Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 0, 1, 2, 3 or 4 Ra ;
  • Ar is selected from phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 1, 2 or 3 Ra ;
  • W is selected from amino, -NR
  • M is selected from a single bond, a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, and a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene being unsubstituted or optionally substituted with one or more Ra ;
  • L is selected from a single bond, C 2-10 alkynylene, C 2-10 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 2-10 alkylene, and a combination of 1, 2, 3 or more C 1-10 heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more Ra ;
  • L2 is a single bond, -( CH2 ) n3- ( OCH2CH2 ) n1 -O-( CH2 ) n2- , or -( CH2 ) n3- ( OCH2CH2 ) n1- ;
  • L 3 is selected from a single bond, -C(O)-, -Cy 1 -C 1-10 alkylene-C(O)-, -Cy 1 -C(O)-, and -Cy 1 -(CH 2 ) n3 -(OCH 2 CH 2 ) n1 -O-(CH 2 ) n2 -C(O)-;
  • Cy 1 is independently selected at each occurrence from a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, or a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, or heterocycloalkylene being unsubstituted or optionally substituted with one or more Ra ; preferably, said arylene, heteroarylene, cycloalkylene, or heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5, or 6 Ras ;
  • L 4 is a peptide residue composed of amino acids or -NR a -C 1-6 alkylene-NR a -; wherein the amino acid and alkylene are unsubstituted or optionally substituted with one or more R a ;
  • L 5 is a spacer unit having a side chain comprising a hydrophilic unit; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamate glucosamine, glycosyl, phosphate, sulfonate and combinations thereof;
  • G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO 2 ;
  • n1, n2, and n3 are each independently selected from an integer from 0 to 30; preferably, n1, n2, and n3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28; and
  • R a is independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C (O) -, C 1 -C 6 alkyl-OC (O) -, C 1 -C 6 alkyl-NHC (O) -, -C 1 -6 alkylene-C (O) -NH 2 , C 1 -6 alkylOC (O) NH-, -C 1 -6 alkylene-NHC (O) -NH
  • L 5 is
  • L a is selected from the combination of 1, 2, 3 or more of a single bond, C 2-10 alkynylene, C 2-10 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 1-10 alkylene and C 2-10 heteroalkylene; wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with one or more Ra ; preferably, L a is selected from the combination of 1, 2, 3 or more of a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene and C 1-6 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or
  • Cy is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene and heterocycloalkylene are unsubstituted or optionally further substituted with one or more Ra ; preferably, Cy is selected from 6-10 membered arylene, 5-10 membered heteroarylene, 3-12 membered cycloalkylene and 3-12 membered heterocycloalkylene, wherein the arylene, heteroarylene, cycloalkylene and heterocycloalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ;
  • L is selected from a single bond, alkynylene, alkenylene, -NR a -, O, -C(O)-, -NR a -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with one or more Ra ; preferably, L is selected from a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene and C 1-6 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ;
  • L c is selected from CR a R s
  • R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate and a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate, or a combination of two or more thereof; preferably, R s is selected from More preferably, Rs is selected from
  • j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;
  • n is independently selected from any integer between 1 and 30; preferably, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • Ld is selected from a single bond, C2-10 alkynylene, C2-10 alkenylene, -NRa- , O, -C(O)-, -NRa -C(O)-, C1-10 alkylene and C1-10 heteroalkylene, 1, 2, 3 or more combinations thereof; wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more Ra ; preferably, Ld is selected from a single bond, C2-6 alkynylene, C2-6 alkenylene, -NRa- , O, -C(O)-, -NRa -C(O)-, C1-6 alkylene and C1-6 heteroalkylene, 1, 2, 3 or more combinations thereof, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 Ra ;
  • R a is independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C (O) -, C 1 -C 6 alkyl-OC (O) -, C 1 -C 6 alkyl-NHC (O) -, -C 1 -6 alkylene-C (O) -NH 2 , C 1 -6 alkylOC (O) NH-, -C 1 -6 alkylene-NHC (O) -NH
  • L5 is selected from n is independently selected from any integer between 1 and 30 at each occurrence; preferably, n is independently selected from 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence; R is independently selected from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl , C 1 -C 6 deuterated alkyl , C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C(O)-, C 1 -C 6 alkyl-OC(O)-, C 1 -C
  • the compound is as shown in Formula 4: TML 1 ——M a -L 6 -L 7 -G Formula 4
  • T is a linker unit; preferably T is selected from R is selected from halogen and -S-Ar; preferably, R is selected from F, Cl, Br, I and -S-Ar;
  • Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 0, 1, 2, 3 or 4 Ra ;
  • Ar is selected from phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl,
  • the phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 1, 2 or 3 Ra ;
  • W is selected from amino, -NR
  • M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group, and the heterocycloalkylene group are unsubstituted or optionally substituted with one or more R b ;
  • L 1 is selected from a single bond, alkynylene, alkenylene, -NR b -, -O-, -C(O)-, -NR b -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with one or more R b ;
  • Ma is selected from and one, two, three or more combinations of chemically linked structures comprising 1 to 30 hydrophilic units and simultaneously comprising a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group or a 3-15 membered heterocycloalkylene group; the arylene group, the heteroarylene group, the cycloalkylene group or the heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b ; the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, a glycosyl group, a phosphate group, a sulfonate group and a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine,
  • L 6 is a peptide residue consisting of amino acids or -NR b -alkylene-NR b -; wherein the alkylene, and amino acids are unsubstituted or optionally further substituted with one or more R b ;
  • L 7 is a spacer unit; provided that, when T is When L 1 contains an alkynylene group, L 7 is a spacer unit having a side chain containing a hydrophilic unit;
  • G is a leaving group; preferably, G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO 2 ;
  • R a and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C (O) -, C 1 -C 6 alkyl-OC (O) -, C 1 -C 6 alkyl-NHC (O) -, -C 1 -6 alkylene-C (O) -NH 2 , C 1 -6 alkylOC (O) NH-, -C 1 -6 alkylene-C (O) -NH
  • n17 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28.
  • M a is selected from -(CH 2 ) n7 -(OCH 2 CH 2 ) n8 -O-(CH 2 ) n9 -Cy 3 -(CH 2 ) n10 -C(O)-,
  • n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;
  • n8 and n17 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time;
  • j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;
  • Cy 3 is independently selected at each occurrence from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a ; preferably, Cy 3 is independently selected at each occurrence from Preferably, Cy 3 is and/or
  • L7 is selected from a single bond, -N( Rb )-( CH2 ) g -O-( CH2 ) g -OC(O)-, -N( Rb )-( CH2 ) g -O-( CH2 - CH2 -O) g -C(O)-,
  • g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6;
  • n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • Ra and Rb are selected from H, a deuterium atom, F, Cl, Br, I, a C1 - C6 alkyl group, a C1 - C6 deuterated alkyl group, a C2 - C6 heteroalkyl group, a C2 - C6 alkenyl group, a C2 - C6 alkynyl group, a C1 - C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a C3 - C6 cycloalkyl group, a 3-6 membered heterocyclic group, a C1 - C6 alkylamino group, a C1 - C6 alkyl-C(O)NH-, a C1 - C6 alkyl-OC(O)-NH-, a C1 - C6 alkyl-NHC(O)-NH-, a C6 - C15 ary
  • T is selected from R is independently selected from halogen and -S-Ar at each occurrence; preferably, R is independently selected from F, Cl, Br, I and -S-Ar at each occurrence; Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl and 1-methylimidazol-2-yl are optionally substituted by 0, 1, 2, 3 or 4 Ra ; preferably, Ar is selected from phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, The phenyl, C 1-3 alkylphenyl, C 1-3 alkoxyphenyl, 2-
  • T is selected from
  • M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, and a 3-15 membered heterocycloalkylene group, wherein the arylene group, the heteroarylene group, the cycloalkylene group, and the heterocycloalkylene group are unsubstituted or optionally substituted with 1, 2, 3, 4, 5, or 6 Ras ; preferably, M is selected from a single bond, a phenylene group, a 5-7 membered heteroarylene group, a 3-7 membered cycloalkylene group, and a 3-7 ...
  • L is selected from a single bond, C2-6 alkynylene, C2-6 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 1-6 alkylene and C 1-6 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a ; preferably, L is selected from a single bond, C2-3 alkynylene, C2-3 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-3 alkylene and C 1-3 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a a substitution; preferably, L 1 is selected from a
  • L23 and Ma are each independently selected from wherein each occurrence of n17 is independently selected from 6, 8, 12, and 24;
  • L 4 and L 6 are each independently a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NR b -C 1-6 alkylene-NR b -, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene and amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 Ra ; preferably, L 4 and L 6 are each independently selected from -NH-CH 2 CH 2 -NH-,
  • L5 and L7 are each independently selected from: a single bond
  • G is selected from hydrogen, halogen, hydroxyl, -Ots, -O-(4-nitrophenyl) and -ONO 2 ; preferably, G is selected from hydrogen, F, Cl, Br, I, hydroxyl, -Ots, -O-(4-nitrophenyl) and -ONO 2 ;
  • Ra and Rb are selected from H, a deuterium atom, F, Cl, Br, I, a C1 - C6 alkyl group, a C1 - C6 deuterated alkyl group, a C2 - C6 heteroalkyl group, a C2 - C6 alkenyl group, a C2 - C6 alkynyl group, a C1 - C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a C3 - C6 cycloalkyl group, a 3-6 membered heterocyclic group, a C1 - C6 alkylamino group, a C1- C6 alkyl-C(O)-, a C1 - C6 alkyloxyacyl group, a C1 - C6 alkylaminoacyl group, a -C1-6 alkylene-C(O) -NH2 ,
  • T is the linker unit
  • M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a ;
  • L is selected from a single bond, alkynylene, alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R a ;
  • L 23 is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate, or a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate, or a combination thereof;
  • L4 is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group and the amino acid group are unsubstituted or optionally further substituted with one or more Ra;
  • L 5 is any spacer unit, or L 5 is a spacer unit having a side chain comprising a hydrophilic unit;
  • the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid glucosamine, glycosyl, phosphate, sulfonate or a combination thereof;
  • G is a leaving group
  • n1, n2, and n3 are independently selected from a natural number between 0 and 30;
  • Ra is selected from H, a deuterium atom, a halogen, a C1-10 alkyl group, a C1-10 deuterated alkyl group, a C2-10 heteroalkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C2-10 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a 3-15 membered cycloalkyl group, a 3-15 membered heterocyclic group, -NH-C1-6 alkyl group , C1-6 alkylNH2, -C1-6 alkylNHCOC1-6 alkyl group , -C1-6 alkylCONH2, C1-6 alkylO-CONH, -C1-6 alkylNHCONH2 , 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycl
  • the conditions are:
  • L23 is or L 23 is a chemically linked structure comprising 1-30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a ;
  • n17 is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28;
  • T is the linker unit
  • M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R a ;
  • L is selected from a single bond, C 2-10 alkynylene, C 2-10 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 2-10 alkylene, and a combination of 1, 2, 3 or more C 1-10 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally further substituted with 1 or more R a ;
  • L2 is a single bond or -( CH2 ) n3- ( OCH2CH2 ) n1 -O-( CH2 ) n2- , -( CH2 ) n3- ( OCH2CH2 ) n1- ;
  • L 3 is selected from a single bond, -C(O)-, -Cy 1 -C 1-10 alkylene-C(O)-, -Cy 1 -C(O)-, and -Cy 1 -(CH 2 ) n3 -(OCH 2 CH 2 ) n1 -O-(CH 2 ) n2 -C(O)-;
  • Cy 1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more Ras ; preferably, the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one
  • L4 is a peptide residue consisting of amino acids; wherein the amino acid is unsubstituted or optionally further substituted with one or more R a ;
  • L5 is a spacer unit having a side chain comprising a hydrophilic unit
  • G is a leaving group
  • n1, n2, and n3 are independently selected from a natural number between 0 and 30;
  • Ra is selected from H, a deuterium atom, a halogen, a C1-10 alkyl group, a C1-10 deuterated alkyl group, a C2-10 heteroalkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C2-10 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a 3-15 membered cycloalkyl group, a 3-15 membered heterocyclic group, -NH-C1-6 alkyl group , C1-6 alkylNH2, -C1-6 alkylNHCOC1-6 alkyl group , -C1-6 alkylCONH2, C1-6 alkylO-CONH, -C1-6 alkylNHCONH2 , 6-10 membered aryl and 5-13 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycl
  • L a is selected from the combination of 1, 2, 3 or more of a single bond, C 2-10 alkynylene, C 2-10 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 1-10 alkylene, and C 2-10 heteroalkylene; wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with 1 or more R a ; preferably, L a is selected from the combination of 1, 2, 3 or more of a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene, and C 1-6 heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with 1, 2, 3, 4,
  • Cy2 is selected from 6-13 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene, unsubstituted or optionally further substituted with one or more Ra ; preferably Cy2 is selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene, 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene, unsubstituted or optionally further substituted with one, two, three, four, five or six Ra;
  • L is selected from a single bond, alkynylene, alkenylene, -NR a -, O, -C(O)-, -NR a -C(O)-, alkylene, and a combination of 1, 2, 3 or more thereof; wherein alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted with 1 or more R a ; preferably, L is selected from a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene, and a combination of 1, 2, 3 or more thereof, wherein alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a ;
  • L c is selected from CR a R s
  • R s is a side chain comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, R s is selected from
  • Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • L d is selected from a single bond, C 2-10 alkynylene, C 2-10 alkenylene, -NR a -, O, -C(O)-, -NR a -C(O)-, C 1-10 alkylene, and a combination of 1, 2 , 3 or more thereof; wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted by 1 or more R a ; preferably, L d is selected from a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene, and a combination of 1, 2, 3 or more thereof, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted by 1, 2, 3, 4, 5 or 6 R a .
  • T is the linker unit
  • M is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more R b ;
  • L 1 is selected from a single bond, alkynylene, alkenylene, -NR b -, -O-, -C(O)-, -NR b -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, heteroalkylene is unsubstituted or optionally further substituted with one or more R b ;
  • Ma is or Ma is a chemically linked structure comprising 1-30 hydrophilic units and simultaneously comprises a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with one or more Ra groups;
  • L 6 is a peptide residue composed of amino acids or -NR b -alkylene-NR b -; wherein the alkylene group or amino acid is unsubstituted or optionally further substituted with one or more R b ;
  • G is a leaving group
  • R is selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a hetero
  • M a is selected from -(CH 2 ) n7 -(OCH 2 CH 2 ) n8 -O-(CH 2 ) n9 -Cy 3 -(CH 2 ) n10 -CO-,
  • n7, n9, n10, n10, n11, n13, and n14 is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • n8 and n17 are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28;
  • n12 and n15 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15;
  • n12 and n15 are not 0 at the same time
  • Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • Cy 3 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with 1, 2, 3, 4, 5, or 6 R a groups; preferably, Cy 3 is selected from Preferably, Cy 3 is selected from and/or
  • Each occurrence of g is independently selected from 1, 2, 3, 4, 5, and 6;
  • R b is selected from H, a deuterium atom, F, Cl, Br, I, a C 1 -C 6 alkyl group, a C 1 -C 6 deuterated alkyl group, a C 1 -C 6 heteroalkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 1 -C 6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, a C 3 -C 6 cycloalkyl group, a 3-6 membered heterocyclic group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylCONH 2 , a C 1 -C 6 alkylOCONH 2 , a C 1 -C 6 alkylNHCONH 2 , a C 6 -C 15 aryl group and a 5-15 membered hetero
  • T is selected from R is selected from halogen, -S-Ar;
  • Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl,
  • the phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl may be optionally substituted by 0, 1, 2, 3, or 4 Ra ; and/or
  • M is selected from a single bond, a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ; and/or
  • L is selected from a single bond, C2-6 alkynylene, C2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene, and C 1-6 heteroalkylene, and a combination of 1, 2, 3 or more thereof, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a ; and/or
  • L 4 is -NR b -C 1-6 alkylene-NR b -, or a peptide residue consisting of 2-7 amino acids, wherein the amino acids are selected from D/L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ; preferably, L 4 is selected from -NH-C 2 H 4 -NH-,
  • n1, n2, n3 each occurrence are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; and/or
  • R a is selected from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic group, C 1 -C 6 alkylamino, C 1 -C 6 alkylacyl, C 1 -C 6 alkyloxyacyl, C 1 -C 6 alkylaminoacyl, C 6 -C 15 aryl and 5-13 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C
  • T is selected from R is selected from halogen, -S-Ar;
  • Ar is selected from phenyl, C 1-6 alkylphenyl, C 1-6 alkoxyphenyl, 2-pyridyl, 2-pyrimidinyl, 1-methylimidazol-2-yl, wherein W is selected from amino, -NR a -C 1-6 alkyl, and/or
  • M is selected from a single bond, a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, heterocycloalkylene being unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ; and/or
  • L is selected from a single bond, C2-6 alkynylene, C2-6 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-6 alkylene, and C 1-6 heteroalkylene, and a combination of 1, 2, 3 or more thereof, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 R a ; and/or
  • Cy 1 is a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, or a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, or heterocycloalkylene group is unsubstituted or optionally further substituted with 1, 2, 3, 4, 5, or 6 R a groups; preferably, Cy 1 is selected from Preferably, Cy 1 is selected from and/or
  • L4 is a peptide residue consisting of 2-7 amino acids, wherein the amino acids are selected from D/L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine, asparagine, which are unsubstituted or optionally further substituted with 1, 2, 3, 4, 5 or 6 Ra ; preferably, L4 is selected from and/or
  • G is selected from halogen, hydroxy, -Ots, -O-(4-nitrophenyl) and -ONO 2 ; and/or
  • n1, n2, n3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 , 13 , 14 , 15 ; and/or Ra is selected from H, a deuterium atom, F, Cl, Br, I, C1 - C6 alkyl, C1 - C6 deuterated alkyl, C1 - C6 heteroalkyl, C2-C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxy, hydroxy, nitro, cyano, amino, C3 - C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C6 alkylamino, C1 - C6 alkylacyl, C1 - C6 alkyloxyacyl, C1 -C6 alkylaminoacyl, C6- C15 aryl and 5-13 membered heteroaryl, wherein said C1 - C6 alkyl, C1- C6 C 6 hetero
  • Each occurrence of j is independently selected from 0, 1, 2, 3, 4, 5, and 6;
  • each occurrence of n is independently selected from any integer between 1 and 30.
  • each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
  • the compound is selected from:
  • the third aspect of the present invention provides a compound as shown in Formula 2-1, 2-2 or 2-3 or a pharmaceutically acceptable salt thereof,
  • T, M, L 1 , L 2 , L 3 , L 4 , L 5 , Ma , L 6 , L 7 and L 23 are as defined above;
  • D is selected from the group consisting of cytotoxic drug moieties, drug moieties for treating autoimmune diseases, and anti-inflammatory drug moieties; preferably, D is selected from the group consisting of cytotoxic drug moieties; preferably, D is selected from the group consisting of topoisomerase I (TOP1) inhibitor moieties, tubulin polymerization inhibitor moieties, topoisomerase II (TOP2) inhibitor moieties, dihydrofolate reductase inhibitor moieties, DNA alkylating agent moieties, thymidine synthetase inhibitor moieties, purine nucleoside synthetase inhibitor moieties, ribonucleotide reductase inhibitor moieties, DNA polymerase inhibitor moieties, RNA polymerase II inhibitor moieties, and other compound moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the connection point between D and L.
  • the compound is selected from:
  • n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence.
  • the fourth aspect of the present invention provides a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate is as shown in Formula 3-1,
  • Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof;
  • n is any integer or decimal from 1 to 12;
  • D is selected from the group consisting of a cytotoxic drug moiety, a drug moiety for treating autoimmune diseases, and an anti-inflammatory drug moiety; preferably, D is a cytotoxic drug moiety; preferably, D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor moiety, a tubulin polymerization inhibitor moiety, a topoisomerase II (TOP2) inhibitor moiety, a dihydrofolate reductase inhibitor moiety, a DNA alkylating agent moiety, a thymidine synthetase inhibitor moiety, a purine nucleoside synthetase inhibitor moiety, a ribonucleotide reductase inhibitor moiety, a DNA polymerase inhibitor moiety, an RNA polymerase II inhibitor moiety, and other moieties capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the connection point between D and
  • L is Among them , the represents the connection point with the antibody or antigen-binding fragment thereof, L 5c Indicates the connection point with D;
  • T a is selected from Wherein the left side of the T a structure Indicates the connection point with the antibody or its antigen-binding fragment, the right side of the T a structure Indicates the connection point with Mc ;
  • Mc is selected from a single bond, a 6-10 membered arylene, a 5-13 membered heteroarylene, a 3-15 membered cycloalkylene, and a 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene being unsubstituted or optionally substituted with one or more Ra ;
  • L 1c is selected from a combination of 1, 2, 3 or more of a single bond, alkynylene, alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, alkylene and heteroalkylene, wherein the alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally substituted with one or more Ra ;
  • L 2c is selected from single bonds, -(CH 2 ) n7 -(OCH 2 CH 2 ) n8 -O-(CH 2 ) n9 -Cy 3 -(CH 2 ) n10 -C(O)-, -(CH 2 ) n7 -(CH 2 CH 2 O) n8 -(CH 2 ) n9 -Cy 3 -(CH 2 ) n10 -C(O)-, -(CH 2 ) n7 -Cy 3 -(CH 2 CH 2 O) n8 -(CH 2 ) n9 -C(O)-, -(CH 2 ) n11 -(OCH 2 CH 2 ) n12 -O-(CH 2 ) n13 -Cy 3 -(CH 2 ) n14 -(OCH 2 CH 2 ) n15 -C(O)-, -(CH 2 ) n7 -(OCH 2
  • n7, n9, n10, n11, n13 and n14 are each independently selected from 0, 1, 2, 3, 4, 5 and 6 at each occurrence;
  • n8 and n17 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • n12 and n15 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, and n12 and n15 are not 0 at the same time;
  • j is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, and 6;
  • Cy 3 is selected from 6-10 membered arylene, 5-13 membered heteroarylene, 3-15 membered cycloalkylene and 3-15 membered heterocycloalkylene, said arylene, heteroarylene, cycloalkylene and heterocycloalkylene being unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a ;
  • Mc , L1c , and L2c are not single bonds at the same time;
  • L 4c is a peptide residue consisting of amino acids or -NRa-alkylene-NRa-, wherein the alkylene, and amino acids are unsubstituted or optionally further substituted with one or more Ra;
  • L 5c is selected from a single bond, -N(R b )-(CH 2 ) g -O-(CH 2 ) g -OC(O)-, -N(R b )-(CH 2 ) g -O-(CH 2 -CH 2 -O) g -C(O)-, When L 2c is selected from a single bond, L 5c is not When Ta is When L 1c contains an alkynylene group, L 5c is
  • n is independently selected from any integer between 1 and 30; preferably, each occurrence of n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • g is independently selected at each occurrence from 1, 2, 3, 4, 5, and 6;
  • R a and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, hydroxy, nitro, cyano, amino, carboxyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkylamino, C 1 -C 6 alkyl-C (O) -, C 1 -C 6 alkyl-OC (O) -, C 1 -C 6 alkyl-NHC (O) -, -C 1 -6 alkylene-C (O) -NH 2 , C 1 -6 alkylOC (O) NH-, -C 1 -6 alkylene-C (O) -NH 2
  • n is any integer or decimal from 1 to 10; preferably, m is any integer or decimal from 2 to 8; preferably, m is any integer or decimal from 2 to 6; and/or
  • D is selected from the group consisting of a topoisomerase I (TOP1) inhibitor portion, a tubulin polymerization inhibitor portion, a topoisomerase II (TOP2) inhibitor portion, a dihydrofolate reductase inhibitor portion, a DNA alkylating agent portion, a thymidine synthetase inhibitor portion, a purine nucleoside synthetase inhibitor portion, a ribonucleotide reductase inhibitor portion, a DNA polymerase inhibitor portion, an RNA polymerase II inhibitor portion, and other compound portions capable of inhibiting cell proliferation; preferably, D is selected from the group consisting of (Eribulin portion) and The wavy line indicates the point where D and L connect; and/or
  • L 1c is selected from a single bond, C 2-6 alkynylene, C 2-6 alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, C 1-6 alkylene and C 1-6 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a ; preferably, L 1c is selected from a single bond, C 2-3 alkynylene, C 2-3 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-3 alkylene and C 1-3 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 R a a replaced; and/or
  • Cy 3 is selected from Preferably, Cy 3 is selected from and/or
  • L 4c is a peptide residue consisting of 2, 3, 4, 5, 6 or 7 amino acids or -NRa-C 1-6 alkylene-NRa-, wherein the amino acid is selected from D-alanine, L-alanine, phenylalanine, glycine, valine, lysine, leucine, citrulline, serine, glutamic acid, aspartic acid, arginine and asparagine, and the alkylene and amino acid are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 Ra ; preferably, L 4c is selected from -NH-CH 2 CH 2 -NH-, and/or
  • L 5c is selected from: a single bond, and/or
  • Ra and Rb are each independently selected at each occurrence from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1 - C3 alkylamino, C1 - C3 alkyl and C1 - C3 alkoxy.
  • D is selected from (Eribulin portion) and The wavy line indicates the point where D and L connect; and/or
  • Mc is selected from a single bond, and/or
  • L 1c is selected from a single bond, C 2-3 alkynylene, C 2-3 alkenylene, -NR a -, -C(O)-, -NR a -C(O)-, C 1-3 alkylene and C 1-3 heteroalkylene, wherein the alkynylene, alkenylene, alkylene and heteroalkylene are unsubstituted or optionally substituted with 1, 2, 3, 4, 5 or 6 Ra ; and/or
  • L 2c is selected from a single bond, wherein n17 is independently selected from 6, 8, 12 and 24 at each occurrence;
  • L 4c is selected from -NH-CH 2 CH 2 -NH-, and/or
  • L 5c is selected from: a single bond, and or
  • Ra and Rb are each independently selected at each occurrence from H, cyano, a deuterium atom, F, Cl, Br, I, carboxyl, hydroxyl, amino, C1 - C3 alkylamino, C1 - C3 alkyl and C1 - C3 alkoxy.
  • L is wherein Ta is as defined above, and M, L1 , L2 , L3 , L4 , L5 , Ma , L6 , L7 and L23 are as defined above.
  • L is selected from the following structures:
  • n and n1 are each independently selected from any integer between 1 and 30; preferably, n and n1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28;
  • n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28 at each occurrence.
  • Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment capable of binding to nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and/or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and/or the antibody heavy chain sequence is as shown in SEQ ID NO: 3; m is any integer or decimal from 1 to 10;
  • L is a chemical linking structure
  • T a is selected from
  • Mc is selected from a single bond, a 6-10 membered arylene group, a 5-13 membered heteroarylene group, a 3-15 membered cycloalkylene group, a 3-15 membered heterocycloalkylene group, wherein the arylene group, heteroarylene group, cycloalkylene group, heterocycloalkylene group is unsubstituted or optionally further substituted with one or more Ra groups ;
  • L 1c is selected from a single bond, alkynylene, alkenylene, -NR a -, -O-, -C(O)-, -NR a -C(O)-, alkylene, and heteroalkylene, wherein alkynylene, alkenylene, alkylene, and heteroalkylene are unsubstituted or optionally further substituted with one or more R a ;
  • L 2c is a single bond or a chemically linked structure comprising 1-30 hydrophilic units, wherein the hydrophilic unit is selected from -CH 2 -CH 2 -O-, any hydrophilic amino acid, glucosamine, glycosyl, phosphate, sulfonate, or a combination thereof; preferably, the hydrophilic unit is selected from -CH 2 -CH 2 -O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamic acid, glucosamine, glycosyl, phosphate, sulfonate, or a combination thereof;
  • L 4c is a peptide residue composed of amino acids or -NRa-alkylene-NRa-; wherein the alkylene group or amino acid is unsubstituted or optionally further substituted with one or more Ra;
  • L 5c is any spacer unit
  • Ra is selected from H, a deuterium atom, a halogen, a C1-10 alkyl group, a C1-10 deuterated alkyl group, a C2-10 heteroalkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C2-10 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a 3-15 membered cycloalkyl group, a 3-15 membered heterocyclic group, -NH-C1-6 alkyl group , C1-6 alkylNH2, -C1-6 alkylNHCOC1-6 alkyl group , -C1-6 alkylCONH2, C1-6 alkylO-CONH, -C1-6 alkylNHCONH2 , 6-10 membered aryl and 5-13 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycl
  • L is wherein -M-, -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -M a -, L 6 and L 7 are as defined in claim 8.
  • Ab is a ligand; preferably, the ligand is an antibody or antigen-binding fragment against nectin-4; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 1; and/or the antibody heavy chain sequence is as shown in SEQ ID NO: 2; preferably, the antibody light chain sequence is as shown in SEQ ID NO: 4; and/or the antibody heavy chain sequence is as shown in SEQ ID NO: 3;
  • n is any integer or decimal from 1 to 10;
  • Ta is a linker portion that connects to a ligand, preferably, Ta is selected from
  • the ligand-drug conjugate is selected from the following structures:
  • Ab is a ligand, and the ligand is an antibody or an antigen-binding fragment thereof;
  • m and m1 are each independently selected from integers or decimals from 1 to 12 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 1 to 10 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 8 at each occurrence; preferably, m and m1 are each independently selected from integers or decimals from 2 to 6 at each occurrence; preferably, m and m1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 at each occurrence; and
  • n1, n8 and n5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8 at each occurrence.
  • the antibody is selected from the group consisting of a chimeric antibody, a humanized antibody and a fully human antibody;
  • the antibody or antigen-binding fragment thereof is selected from anti-nectin-4 antibody, anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-
  • the ligand is an anti-nectin-4 antibody or an antigen-binding fragment thereof;
  • the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and/or a light chain, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises three heavy chain complementarity determining regions (HCDRs), wherein the amino acid sequence of heavy chain complementarity determining region 1 (HCDR1) is shown in SEQ ID NO: 7, the amino acid sequence of heavy chain complementarity determining region 2 (HCDR2) is shown in SEQ ID NO: 8, and the amino acid sequence of heavy chain complementarity determining region 3 (HCDR3) is shown in SEQ ID NO: 9; and/or the light chain comprises a light chain variable region, wherein the light chain variable region comprises three light chain complementarity determining regions (LCDRs), wherein the amino acid sequence of light chain complementarity determining region 1 (LCDR1) is shown in SEQ ID NO: 10, the amino acid sequence of light chain complementarity determining region 2 (LCDR2) is shown in SEQ ID NO: 11, and the amino acid sequence of light chain complementarity
  • the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and/or a light chain variable region, wherein the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 14; and/or the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 13;
  • the anti-nectin-4 antibody or antigen-binding fragment thereof comprises a heavy chain and/or a light chain, wherein the amino acid sequence of the heavy chain is shown in SEQ ID NO: 1, and/or the amino acid sequence of the light chain is shown in SEQ ID NO: 2; or, the amino acid sequence of the light chain is shown in SEQ ID NO: 4, and/or the amino acid sequence of the heavy chain is shown in SEQ ID NO: 3; or, the antibody light chain sequence is shown in SEQ ID NO: 6, and/or the antibody heavy chain sequence is shown in SEQ ID NO: 5;
  • the anti-nectin-4 antibody or its antigen-binding fragment comprises a heavy chain and/or a light chain, wherein the amino acid sequence of the light chain is as shown in SEQ ID NO: 4, and/or the amino acid sequence of the heavy chain is as shown in SEQ ID NO: 3.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or any of the aforementioned ligand-drug conjugates or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing tumors;
  • the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.
  • the present invention also provides a method for preventing or treating tumors, comprising administering to a subject in need thereof an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above;
  • the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, or the ligand-drug conjugate or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above, for use in preventing or treating tumors;
  • the tumor is a cancer associated with Nectin-4 expression, preferably, the cancer is breast cancer, bladder cancer or lung cancer.
  • the antibody-drug conjugate of the present invention achieves an average DAR value of 3.5-4.5 by adopting a novel bridged maleimide linker and a cleavable linker, significantly improving the homogeneity of the antibody-drug conjugate and specifically releasing the cytotoxic payload under the action of tumor cell lysosomes, thereby improving the safety of the drug while ensuring efficacy;
  • the Nectin4-targeted antibody-drug conjugate of the present invention with Eribulin as the payload has a significant inhibitory effect on triple-negative breast cancer, breast cancer, and bladder cancer tumors.
  • the antibody-drug conjugate of the present invention has better efficacy than the positive control drug Enfortumab vedotin and the positive control drug 9MW2821.
  • the antibody-drug conjugate of the present invention has a TGI of 100% and 99.73% in the triple-negative breast cancer MDA-MB-468 CDX model and the breast cancer MDA-MB-453 CDX model, respectively, showing significant efficacy.
  • the antibody-drug conjugate of the present invention has better efficacy than Enfortumab vedotin.
  • the tumor inhibition rate of the antibody-drug conjugate of the present invention is comparable to that of Enfortumab vedotin at a dose of 5 mg/kg.
  • the antibody-drug conjugate of the present invention has better safety.
  • obvious adverse reactions and mouse deaths were observed in the Enfortumab vedotin control group, while no mouse deaths were observed in the antibody-drug conjugate group obtained by the present invention, and the survival rate was high, that is, it has better safety and can reduce the serious side effects of Nectin4 target skin toxicity to a certain extent.
  • Figure 1 shows the changes in tumor volume in the MDA-MB-468 model.
  • Figure 2 shows the changes in tumor volume in the MDA-MB-453 model.
  • Figure 3 shows the changes in tumor volume in the HT1376 model at a dose of 4 mg/kg.
  • Figure 4 shows the changes in tumor volume in the HT1376 model at a dose of 8 mg/kg.
  • Figure 5 shows the changes in tumor volume in the HT1376 model.
  • Figure 6 shows the changes in tumor volume in the RT4/Nectin 4 model.
  • Figure 7 shows the acute toxicity survival curve of BALB/C mice.
  • Figure 8 is the body weight change curve of BALB/C mice in acute toxicity.
  • Figure 9 shows the long-term toxicity survival curve of BALB/C mice.
  • Figure 10 is the body weight change curve of BALB/C mice after long-term toxicity.
  • Figure 11 shows the HIC analysis results of the ADC drug Enfortumab vedotin.
  • Figure 12 shows the results of NECTIN 4-ADC-11 HIC analysis.
  • FIG. 13 shows the results of NECTIN 4-ADC-18 HIC analysis.
  • Figure 14 shows the results of NECTIN 4-ADC-26 HIC analysis.
  • FIG15 shows the tumor volume inhibition rate of the MDA-MB-453 model.
  • FIG16 shows the MDA-MB-468 tumor volume inhibition rate.
  • Figure 17 shows the survival curve of the humanized mouse toxicology MTD experiment.
  • Figure 18 shows the body weight change rate in the toxicology MTD experiment of humanized mice.
  • Figure 19 shows the survival curve of repeated-dose toxicology experiments in humanized mice.
  • Figure 20 shows the body weight change rate in repeated-dose toxicology experiments in humanized mice.
  • FIG21 shows the pharmacokinetic results of MMAE and Eribulin free payload in BALB/c mice.
  • compositions of the present invention may exist in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereomers and enantiomers), tautomers, solvates, polymorphs and isotopic compounds, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite thereof. Therefore, when referring to a "compound of the present invention” herein, it is also intended to encompass the various derivative forms of the compound described above.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without any adverse biological effects.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, including salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as malic acid, fumaric acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid, etc.; or (2) base addition salts, including salts formed with alkali metals such as lithium, sodium, potassium, etc.; and salts formed with alka
  • Prodrugs of the compounds of the present invention are included in the scope of protection of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into the desired compound in vivo. Therefore, the term "administration" in the treatment methods provided by the present invention includes the administration of the compounds disclosed in the present invention, or although not explicitly disclosed, it can be converted into the compounds disclosed in the present invention in vivo after administration to the subject to treat the various diseases mentioned. Conventional methods for selecting and preparing suitable prodrug derivatives have been recorded in books such as "Design of Prodrugs" (H. Bundgaard, Elsevier, 1985).
  • the compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention do not have a precise stereostructure at any particular position within the compounds.
  • the present invention encompasses all stereoisomers of the compounds and pharmaceutically acceptable salts thereof.
  • mixtures of stereoisomers and isolated specific stereoisomers are also encompassed by the present invention.
  • the resulting products may be mixtures of stereoisomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent used to form the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and the like can be used.
  • the present invention also includes all pharmaceutically acceptable isotopic compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); isotopes of chlorine (e.g., 37Cl ); isotopes of iodine (e.g., 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 17O and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 34S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H )
  • isotopes of carbon e.g., 13C and 14C
  • isotopes of chlorine e.g.
  • ligand refers to a macromolecular compound that recognizes and binds to an antigen or receptor associated with a target cell.
  • the function of a ligand is to present a drug to the target cell population bound to the ligand.
  • the ligand is represented by an Ab.
  • the ligand can form a bond with a linker through a heteroatom on the ligand.
  • the ligand is preferably an antibody, an antigen-binding fragment thereof, or a polypeptide.
  • the antibody is selected from a chimeric antibody, a humanized antibody, a fully human antibody, or a murine antibody; preferably, a monoclonal antibody.
  • drug refers to a chemical substance that can alter or identify physiological functions and pathological states of the body and can be used to prevent, diagnose, and treat disease.
  • Drugs include cytotoxic drugs. There is no strict distinction between drugs and poisons. Poisons are chemical substances that can have toxic effects on the body at relatively low doses, potentially damaging human health. Excessive doses of any drug can produce toxic reactions.
  • Cytotoxic drugs are substances that inhibit or prevent cellular function and/or cause cell death or destruction. Cytotoxic drugs can, in principle, kill tumor cells at sufficiently high concentrations. However, due to their lack of specificity, they can also induce apoptosis of normal cells while killing tumor cells, leading to serious side effects. Cytotoxic drugs include toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, radioactive isotopes, chemotherapeutic agents, antibiotics, and nucleolytic enzymes.
  • linker unit or “linking fragment” or “linking unit” refers to a fragment or bond in a chemical structure that is connected to a ligand at one end and to a drug at the other end, and can also be connected to other linkers before being connected to the drug.
  • ligand-drug conjugate refers to a ligand linked to a biologically active drug via a stable linker.
  • the "ligand-drug conjugate” is preferably an antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker.
  • ADC antibody-drug conjugate
  • Drug loading also known as the drug-to-antibody ratio (DAR) is the average number of drugs conjugated to each antibody in the ADC. It can be, for example, in the range of about 1 to about 12 drugs conjugated to each antibody, and in certain embodiments, in the range of about 1 to about 8 drugs conjugated to each antibody, preferably in the range of 2-8, 2-7, 2-6, 2-5, 2-4, 3-4, 3-5, 5-6, 5-7, 5-8, and 6-8. Exemplarily, the drug loading can be an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments of the present invention, the drug loading can be expressed as m or m1, which is a decimal or integer. Drug loading can be determined by conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA assay, and HPLC.
  • hydrophilic unit refers to -CH2 - CH2 -O-, hydrophilic amino acids, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof; preferably, the hydrophilic unit is selected from -CH2 - CH2- O-, sarcosine, alanine, serine, asparagine, glutamine, tyrosine, lysine, arginine, histidine, aspartic acid, glutamate, glucosamine, glycosyl, phosphate, sulfonate or a combination thereof.
  • antibody refers to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and order of the constant region of immunoglobulins' heavy chains vary, resulting in different antigenicity. Consequently, immunoglobulins can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • Igs are further divided into subclasses based on the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified as either kappa or lambda chains based on differences in their constant regions.
  • Each of the five Ig classes can have either kappa or lambda chains.
  • the antibodies disclosed herein are preferably specific antibodies against cell surface antigens on target cells, and non-limiting examples include the following antibodies: anti-TROP-2 antibody, anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-LIV-1 antibody, anti-ROR1 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA 2 antibody, anti-G250 antibody, anti-MUCl antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC
  • the antibodies of the present invention include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, with humanized antibodies and fully human antibodies being preferred.
  • murine antibody refers to antibodies produced in mice according to the knowledge and skills in the art. During production, a test subject is injected with a specific antigen and then a hybridoma expressing an antibody with the desired sequence or functional properties is isolated.
  • chimeric antibody refers to an antibody created by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can mitigate the immune response induced by the mouse antibody.
  • To create a chimeric antibody one must first establish a hybridoma that secretes mouse-specific monoclonal antibodies. The variable region genes are then cloned from the mouse hybridoma cells. Furthermore, the constant region genes of the human antibody are cloned as needed. The mouse variable region genes and human constant region genes are then linked to form a chimeric gene, which is then inserted into an expression vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic system.
  • humanized antibody also known as a CDR-grafted antibody, refers to an antibody produced by grafting murine CDR sequences onto a human variable region framework, i.e., a different type of human germline antibody framework sequence. This overcomes the xenobiotic response induced by chimeric antibodies due to their large presence of murine protein components.
  • antigen-binding fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used to perform the antigen-binding function of an antibody.
  • binding fragments included in "antigen-binding fragments” include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab') 2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge on the hinge region, (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of the VH and VL domains of a single arm of an antibody; (v) single domain or dAb fragments (Ward et al., (1989) Nature 341: 544-546), which consist of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii)
  • the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be connected by synthetic linkers using recombinant methods, so that they can be produced as a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85: 5879-5883).
  • single-chain Fv single-chain Fv
  • Such single-chain antibodies are also intended to be included in the term "antigen-binding fragment" of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA technology or by enzymatic or chemical fragmentation of intact immunoglobulins.
  • Fab is an antibody fragment having a molecular weight of approximately 50,000 and antigen-binding activity, among fragments obtained by treating IgG antibody molecules with the protease papain (cleaving the amino acid residue at position 224 of the H chain), in which approximately half of the N-terminal side of the H chain and the entire L chain are bound together by a disulfide bond.
  • F(ab') 2 is an antibody fragment having a molecular weight of about 100,000 and comprising two Fab regions linked at the hinge position, obtained by digesting the portion below the two disulfide bonds in the hinge region of IgG with the enzyme pepsin, and having antigen-binding activity.
  • Fab' is an antibody fragment having a molecular weight of about 50,000 and antigen-binding activity, obtained by cleaving the disulfide bond of the hinge region of the above-mentioned F(ab')2.
  • the Fab' fragment of the antibody can be produced by inserting a DNA encoding the Fab' fragment into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryotic or eukaryotic organism to express the Fab'.
  • single-chain antibody refers to a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker.
  • Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH.
  • Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, for example, variants using 1-4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448).
  • linkers that can be used in the present disclosure are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56 and Roovers et al. (2001), Cancer Immunol.
  • CDR refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contributes to antigen binding.
  • CDR refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contributes to antigen binding.
  • One of the most commonly used definitions of the six CDRs is provided by Kabat E.A. et al. (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242).
  • the Kabat definition of CDR applies only to CDR1, CDR2, and CDR3 (LCDR1, LCDR2, LCDR3 or L1, L2, L3) of the light chain variable domain, and CDR1, CDR2, and CDR3 (HCDR1, HCDR2, HCDR3 or H1, H2, H3) of the heavy chain variable domain.
  • a vector refers to a nucleic acid molecule capable of transporting another nucleic acid connected thereto.
  • a vector is a "plasmid", which refers to a circular double-stranded DNA loop into which another DNA segment can be connected.
  • a vector is a viral vector, in which another DNA segment can be connected to a viral genome.
  • Vectors disclosed herein can autonomously replicate in the host cell into which they have been introduced (e.g., bacterial vectors and additional mammalian vectors with a bacterial origin of replication) or can be integrated into the genome of the host cell after introducing the host cell, thereby replicating (e.g., non-additional mammalian vectors) with the host genome.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms).
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, etc.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms.
  • monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyls include spirocyclic, fused, and bridged heterocyclyls.
  • aryl refers to a 6- to 15-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, with phenyl being preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 15 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.
  • haloalkyl refers to an alkyl group substituted with one or more halogens.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • substituted and “substituted” mean that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valency in the present context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted, or (2) substituted. If an atom or group is described as optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced with independently selected, optional substituents. If a substituent is described as "independently selected from” or “each independently is,” each substituent is selected independently of the others. Thus, each substituent may be the same as or different from another substituent.
  • R groups such as, but not limited to, R2, R3, Rh, Ri, Rx, and/or Ry
  • each R is selected independently of the others, i.e., may be the same or different.
  • the same is true for the selection of numerical values such as d, g, m, and n.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • a “pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered and which is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • active ingredient refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.
  • the term "effective amount” refers to an amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the appearance of the condition or its symptoms.
  • cell strains or cell lines used in the examples of the present invention can be obtained through commercial channels.
  • Example 21 was synthesized by referring to the synthetic route of Example 20.
  • the structural formula and LC-MS results are shown in the table below.
  • Example 24 was synthesized by referring to Example 23 and the synthetic route.
  • the structural formula and LC-MS are shown in the table below.
  • Example 27 was synthesized by referring to the synthetic route of Example 26. Its structure and LC-MS information are shown in the table below.
  • Example 28 was synthesized by referring to the synthetic route of Example 7. Its structure and LC-MS results are shown in the table below.
  • Example 36 Except for replacing the corresponding reaction raw materials (for example, the payload used in Example 36 was monomethyl auristatin E (MMAE), purchased from MCE (MedChemExpress)), the compounds of Examples 31-36 were synthesized according to the synthetic route of Example 11, and their structural formulas are shown in the table below.
  • MMAE monomethyl auristatin E
  • MCE MedChemExpress
  • the antibody 1 disclosed herein was prepared from AGSM6 with reference to Example 2 of WO2012047724, and its heavy chain and light chain amino acid sequences are shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • Antibody 2 of the present invention is hH2L1, which was prepared with reference to the sequence of Example 1 of CN117942409A, and its heavy chain and light chain amino acid sequences are shown in SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • hH2L1 heavy chain (SEQ ID NO: 5)
  • the anti-nectin-4 antibody A heavy chain selected in the present invention is SEQ ID NO: 3
  • the light chain of Nectin-4 antibody A selected in the present invention is SEQ ID NO: 4
  • the CDRs of the antibody A are shown in SEQ ID NO: 7-12.
  • HCDR1 SEQ ID NO: 7
  • HCDR2 SEQ ID NO: 8
  • HCDR3 SEQ ID NO: 9
  • the antibody-drug conjugates shown in Table 7 were prepared, among which NECTIN 4-ADC-1 to NECTIN 4-ADC-4, NECTIN 4-ADC-7-1, NECTIN 4-ADC-8, NECTIN 4-ADC-9-1, and NECTIN 4-ADC-10 conjugated antibodies were positive control antibody 1, and NECTIN 4-ADC-7-2, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-22 to NECTIN 4-ADC-24 conjugated antibodies were antibody A.
  • m or m1 is the drug-to-antibody ratio (DAR).
  • the antibody-drug conjugates shown in Table 8 were prepared, among which 9MW2821 and NECTIN 4-ADC-29 conjugated antibodies were the positive control antibody 2hH2L1, NECTIN 4-ADC-5-1, NECTIN 4-ADC-6, and NECTIN 4-ADC-28 conjugated antibodies were the positive control antibody 1AGSM6, and NECTIN 4-ADC-5-2, NECTIN 4-ADC-11 to NECTIN 4-ADC-21, NECTIN 4-ADC-25, NECTIN 4-ADC-26, and NECTIN 4-ADC-27 conjugated antibodies were antibody A.
  • m is the drug-antibody ratio
  • the maleimide ring of the double conjugated bridge part ADC has two forms: open ring and closed ring.
  • the maleimide of the linker part in ADC is hydrolyzed to form (Closed loop) becomes (Open loop).
  • the ADCs listed in Table 8-1 of the present invention exist in both open-ring and closed-ring forms.
  • the maleimide hydrolysis rate in nectin 4-ADC-14, nectin 4-ADC-15, nectin 4-ADC-14, and nectin 4-ADC-20 ADCs exceeded 80%, with nectin 4-ADC-11 completely hydrolyzed. This indicates that the introduction of aromatic groups can effectively control the hydrolysis of the maleimide moiety and improve ADC stability.
  • HPLC-HIC analysis was used to determine whether the coupling was successful and to detect the DAR value; SEC-HPLC was used to detect the purity of ADC.
  • MDA-MB-468 (breast cancer cells, Kebai, CBP60387) was used. This cell line has a high expression of Nectin 4.
  • Cell suspensions were prepared in fresh cell culture medium containing 10% FBS at a density of 5 ⁇ 104 cells/mL. 100 ⁇ L was added to each well of a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium to a 4 ⁇ M concentration. Using this as the starting concentration, the samples were serially diluted tenfold in PBS for a total of nine concentrations. 50 ⁇ L of culture medium was aspirated from each well and 50 ⁇ L of the ADC solution was added, resulting in a 2 ⁇ M ADC concentration in the first well. The final volume was 100 ⁇ L per well.
  • the cells were incubated at 37°C in 5% CO2 for 5 days. The supernatant was discarded, and 100 ⁇ L of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark) and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.
  • MDA-MB-453 (breast cancer cells, Kebai, CBP60386) was used. This cell line has a high expression of Nectin 4.
  • Cell suspensions were prepared in fresh cell culture medium containing 10% FBS at a density of 5 ⁇ 104 cells/mL. 100 ⁇ L was added to each well of a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium to a 0.8 ⁇ M concentration. Using this as the starting concentration, the samples were serially diluted fivefold with PBS for a total of nine concentrations. 50 ⁇ L of culture medium was aspirated from each well and supplemented with 50 ⁇ L of the ADC solution, resulting in a starting ADC concentration of 0.4 ⁇ M in the first well. The final volume was 100 ⁇ L per well.
  • the cells were incubated at 37°C in 5% CO2 for 5 days. The supernatant was discarded, and 100 ⁇ L of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark) and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.
  • HT1376 (bladder cancer cells, Kebai, CBP60310) was used, which is a cell line with medium to high expression of Nectin 4.
  • Cell suspensions were prepared in fresh cell culture medium containing 10% FBS at a density of 3 ⁇ 104 cells/mL. 100 ⁇ L was added to each well of a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium at 0.4 ⁇ M, 2 ⁇ M, and 7 ⁇ M concentrations. These concentrations were used as the initial concentrations and then serially diluted fivefold in PBS for a total of nine concentrations. 50 ⁇ L of culture medium was aspirated from each well and 50 ⁇ L of the ADC solution was added, resulting in a 5 ⁇ M ADC concentration in the initial well. The final volume was 100 ⁇ L per well.
  • the cells were incubated at 37°C in 5% CO2 for 3 days. The supernatant was discarded, and 100 ⁇ L of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark) and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.
  • T47D ductal breast carcinoma cell line, Kebai, CBP60397
  • Kebai ductal breast carcinoma cell line
  • CBP60397 ductal breast carcinoma cell line
  • Cell suspensions were prepared in fresh cell culture medium containing 10% FBS at a density of 1 ⁇ 105 cells/mL. 100 ⁇ L was added to each well of a 96-well cell culture plate (Fisherries Scientific, 310109027) and incubated at 37°C in 5% CO2 for 24 hours. ADC samples were prepared in fresh culture medium at 0.4 ⁇ M, 2 ⁇ M, and 7 ⁇ M concentrations, respectively. These concentrations were used as the initial concentrations and then serially diluted fivefold in PBS for a total of nine concentrations. 50 ⁇ L of culture medium was aspirated from each well and 50 ⁇ L of the ADC solution was added, resulting in a 5 ⁇ M ADC concentration in the initial well.
  • the final volume was 100 ⁇ L per well.
  • the cells were incubated at 37°C in 5% CO2 for 3 days. The supernatant was discarded, and 100 ⁇ L of CCK8 (Biyuntian, C0042) was added to each well. The cells were incubated at 37°C for 4 hours. Chemiluminescence was measured on a microplate reader (TECAN, Spark) and data were analyzed using Graphpad Prism 5 software. The results are shown in Table 10 below.
  • the antibody-drug conjugate prepared in this disclosure exhibits excellent inhibitory activity in various Nectin 4-expressing cell lines (e.g., breast cancer and bladder cancer cells), and its inhibitory activity is significantly superior to that of the control drug, enfortumab vedotin.
  • the ADC with eribulin as the payload exhibits superior tumor inhibitory activity compared to the ADC with MMAE as the payload (Nectin 4-ADC-27).
  • the experimental data were statistically analyzed using Excel 2016 software: the mean was calculated as average; the SD was calculated as STDEV; and the SEM was calculated as STDEV/SQRT.
  • the calculation formulas for each indicator are as follows:
  • V 1/2L long diameter ⁇ (L short diameter) 2
  • RTV Relative tumor volume
  • Relative tumor proliferation rate T/C (%) TRTV/CRTV ⁇ 100%
  • Tumor inhibition rate (%) (CRTV-TRTV)/CRTV (%)
  • Tumor weight inhibition rate (%) (1-average tumor weight of the treatment group/average tumor weight of the control group) * 100%
  • V0 and VT are the tumor volumes at the beginning and end of the experiment, respectively.
  • CRTV and TRTV are the relative tumor volumes of the blank control group (PBS) and the experimental group, respectively, at the end of the experiment.
  • mice BALB/c-Nude nude mice were subcutaneously inoculated with human triple-negative breast cancer MDA-MB-468 cells (Kebai) (1 x 10 ⁇ 7/200 ⁇ L/mouse, in a 50% growth factor-reduced artificial basement membrane) in the right flank. After 7 days of inoculation, tumors grew to approximately 135 mm3 . The animals were then randomly divided into groups (D0), with 6 mice per group.
  • mice were administered via tail vein injection at multiple doses of 2 mg/kg, 1 mg/kg, and 0.5 mg/kg, with single injections administered, and observed for 21 days.
  • Tumor volume and body weight were measured twice weekly, and the data were recorded and used to calculate the tumor volume inhibition rate.
  • Data were analyzed using Excel 2016 statistical software: mean was calculated as average; SD was calculated as STDEV; and SEM was calculated as STDEV/SQRT.
  • the exemplary compound NECTIN 4-ADC-11 of the present disclosure has a significant tumor growth inhibitory effect at a dose of 0.5-2 mg/kg. Its tumor growth inhibitory effect is significantly better than that of enfortumab vedotin. Even the tumor inhibitory effect of 0.5 mg/kg NECTIN 4-ADC-11 is better than that of 2 mg/kg enfortumab vedotin.
  • the TGI of 2 mg/kg NECTIN 4-ADC-11 is as high as 100%.
  • mice BALB/c-Nude nude mice were subcutaneously inoculated with human breast cancer MDA-MB-453 cells (Kebai) (1 x 10 ⁇ 7/200 ⁇ L/mouse, in a 50% growth factor-reduced artificial basement membrane) in the right flank. After inoculation, tumors were allowed to grow for 7 days. Once the tumor volume reached approximately 120 mm3 , the animals were randomly divided into groups (D0), with 5 mice per group.
  • the drug was administered via tail vein injection, with a single dose of 1 mg/kg administered in parallel, and observation was continued for 20 days. Tumor volume and body weight were measured twice a week and the data were recorded.
  • the exemplary antibody-drug conjugates NECTIN 4-ADC-11 and NECTIN 4-ADC-22 disclosed herein have significant tumor growth inhibitory effects and have better tumor inhibitory effects than Enfortumab vedotin.
  • mice BALB/c-Nude nude mice were subcutaneously inoculated with human breast cancer HT1376 cells (Kebai) (1 x 10 ⁇ 7/200 ⁇ L/mouse, in a 50% growth factor-reduced artificial basement membrane) in the right flank. After inoculation, tumors were allowed to grow for 8 days. Once the tumor volume reached approximately 120 mm3 , the animals were randomly divided into groups (D0), with 5 mice per group.
  • the drug was administered by tail vein injection, with multiple doses of 8 mg/kg and 4 mg/kg administered in parallel, and single injection administered, for 21 days. Tumor volume and body weight were measured twice weekly and the data were recorded.
  • the exemplary antibody-drug conjugates NECTIN 4-ADC-7-2, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11 disclosed herein have significant tumor growth inhibitory effects, and their tumor inhibitory effects are better than or equivalent to those of Enfortumab vedotin.
  • mice BALB/c-Nude nude mice were subcutaneously inoculated with human breast cancer HT1375 cells (Kebai) (1 x 10 ⁇ 7/200 ⁇ L/mouse, in a 50% growth factor-reduced artificial basement membrane) in the right flank. After inoculation, tumors were allowed to grow for 8 days. Once the tumor volume reached approximately 120 mm3 , the animals were randomly divided into groups (D0), with 6 mice per group.
  • the drug was administered by tail vein injection, with multiple doses of 5 mg/kg, 2.5 mg/kg, and 1 mg/kg administered in parallel, and observed for 21 days. Tumor volume and body weight were measured twice weekly, and the data were recorded to calculate the tumor volume inhibition rate.
  • mice were subcutaneously inoculated with human bladder transitional cell papilloma cells (RT4/Nectin 4) (9 x 10 ⁇ 6/200 ⁇ L/mouse, supplemented with a 50% growth factor-reduced artificial basement membrane) in the right flank. After 7 days of inoculation, tumors grew to approximately 110-120 mm3 in volume. The animals were then randomly divided into groups (D0), with 5 mice per group.
  • RT4/Nectin 4 human bladder transitional cell papilloma cells
  • the animals were injected via tail vein at a single dose of 5 mg/kg and observed for 21 days. Tumor volume and body weight were measured twice weekly and the data were recorded.
  • the exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed in the present invention has a significant tumor growth inhibitory effect in the RT4/Nectin 4 CDX model, and its tumor inhibitory effect is significantly better than that of Enfortumab vedotin.
  • mice were subcutaneously inoculated with human breast cancer MDA-MB-453 cells (Kebai) (1 ⁇ 10 7 /200 ⁇ L/mouse, with 50% reduced growth factor artificial basement membrane) in the right flank. After inoculation, tumors grew for 6 days. When the tumor volume reached approximately 135 mm 3 , the animals were randomly divided into groups (D0), with 6 mice per group.
  • the exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed in the present invention can effectively inhibit the growth of MDA-MB-453 transplanted tumors in tumor-bearing nude mice at doses of 0.5-2 mg/kg in a dose-dependent manner, and its efficacy is significantly better than that of positive drugs.
  • mice were subcutaneously inoculated with human triple-negative breast cancer cells (MDA-MB-468) (1 ⁇ 10 7 /200 ⁇ L/mouse, with 50% reduced growth factor artificial basement membrane) in the right flank. After cell inoculation, tumors grew for 10-11 days. When the tumor volume reached approximately 115-135 mm 3 , the animals were randomly divided into groups (D0), with 5 mice per group.
  • MDA-MB-468 human triple-negative breast cancer cells
  • the exemplary antibody-drug conjugate NECTIN 4-ADC-11 disclosed herein can effectively inhibit the growth of MDA-MB-468 transplanted tumors in tumor-bearing nude mice at doses of 1 mg/kg and 2 mg/kg in a dose-dependent manner, and its efficacy is significantly better than that of the positive drug 9MW2821.
  • Acute toxicity studies were conducted in 6-8 week-old BALB/c mice treated with Vital River. Enfortumab vedotin, NECTIN 4-ADC-9-2, NECTIN 4-ADC-11, and NECTIN 4-ADC-22 were administered once via tail vein injection at a dose of 100 mg/kg in a volume of 200 ⁇ L per group. Four experimental groups (6 mice each, 3 males and 3 females) were administered, respectively.
  • Body weight recorded once before administration and twice a week after administration; the recording time is Day 0, Day 4, Day 7, Day 12 and Day 14.
  • Acute toxicity experiments were conducted in 6-8 week old BALB/c mice.
  • Enfortumab vedotin, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11 were administered by tail vein injection at a dose of 60 mg/kg in a volume of 200 ⁇ L/group.
  • the mice were administered twice (day 0 and day 7) and observed for 14 days.
  • the solvent control group (PBS group) consisted of 4 mice (2 males and 2 females); the experimental group consisted of 6 mice (3 males and 3 females) in each group. There were 3 groups in total, which were administered with Enfortumab vedotin, NECTIN 4-ADC-9-2, and NECTIN 4-ADC-11, respectively.
  • Body weight once before administration, once a week after administration, and once before autopsy (twice a week in this experiment)
  • NECTIN 4-ADC-9-2, NECTIN 4-ADC-11, and NECTIN 4-ADC-22 disclosed herein had survival rates comparable to those of the vehicle group during the observation period, had good safety, and were significantly superior to Enfortumab vedotin in terms of mouse survival rate.
  • Administration route and frequency Tail vein injection, once a week, with the day of administration being Day 0. The results are shown in Figures 17 and 18.
  • TK toxicokinetics
  • ADA anti-drug antibody
  • Administration route Tail vein injection, once a week, the day of administration is Day 1, and the drug is administered on Days 1, 8, 15, and 22, for a total of 4 doses.
  • Frequency of administration Multiple doses, once a week;
  • the exemplary antibody-drug conjugate NECTIN 4-ADC-11 of this application is well tolerated and has a higher tolerance dose than the positive drug Enfortumab vedotin.
  • the degree of weight loss at the same dose is lower than that of the positive drug, and it can reduce the serious side effects of Nectin 4 target skin toxicity to a certain extent.
  • mice After a single injection of NECTIN 4-ADC-11 and control via the tail vein of mice, their basic pharmacokinetic characteristics in mice were observed.
  • Dosage frequency and method Single administration via tail vein.
  • the first blood draw from each animal was done via the orbital venous plexus; the blood volume was 0.15 mL/time point.
  • the second blood draw was done by enucleation of the eyeball; the blood volume was 0.5 mL/time point.
  • three mice were used as a cohort, with each cohort consisting of 24 mice.
  • mice were subcutaneously inoculated with human breast cancer HT1376 cells (Kebai) (1 ⁇ 10 7 /200 ⁇ L/mouse, with a 50% growth factor-reduced artificial basement membrane). After 17 days of inoculation, tumors grew to approximately 250-300 mm 3 in volume. The animals were then randomly divided into 24 groups (D0), with 3 animals per group. (PBS, Enfortumab vedotin, and NECTIN 4-ADC-11 were administered.)
  • the drug was administered by tail vein injection, with a single dose of 6 mg/kg.
  • the antibody-drug conjugate NECTIN 4-ADC-11 of the present invention specifically accumulates in tumors, has lower payload exposure in serum than the positive control drug Enfortumab vedotin, and has higher safety in vivo.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Plant Pathology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un nouveau lieur de médicament, et un système lieur-médicament préparé en outre sur la base du lieur, un conjugué ligand-médicament, un médicament conjugué d'anticorps, une composition pharmaceutique comprenant le conjugué, et l'utilisation médicale du conjugué et de la composition pharmaceutique. Le nouveau système de lieur de médicament a une valeur de rapport médicament-anticorps (DAR) relativement élevée, et le conjugué médicament-ligand préparé sur cette base a un effet inhibiteur de tumeur relativement bon et a une perspective d'application clinique relativement bonne.
PCT/CN2025/075857 2024-01-29 2025-02-05 Lieur, conjugué ligand-médicament et utilisation médicale associée Pending WO2025162492A1 (fr)

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
CN202410116532 2024-01-29
CN202410116532.5 2024-01-29
CN202410564053 2024-05-08
CN202410564053.X 2024-05-08
CN202411388187.7 2024-10-08
CN202411388187 2024-10-08
CN202411429096.3 2024-10-14
CN202411429922 2024-10-14
CN202411429096 2024-10-14
CN202411429922.4 2024-10-14
CN202411783791 2024-12-06
CN202411783791.X 2024-12-06
CN202411795873 2024-12-09
CN202411795873.6 2024-12-09
CN202411947010 2024-12-27
CN202411947010.6 2024-12-27

Publications (1)

Publication Number Publication Date
WO2025162492A1 true WO2025162492A1 (fr) 2025-08-07

Family

ID=96589562

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2025/075857 Pending WO2025162492A1 (fr) 2024-01-29 2025-02-05 Lieur, conjugué ligand-médicament et utilisation médicale associée
PCT/CN2025/075858 Pending WO2025162493A1 (fr) 2024-01-29 2025-02-05 Conjugué anticorps anti-nectine-4/ligand-médicament et son utilisation

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/075858 Pending WO2025162493A1 (fr) 2024-01-29 2025-02-05 Conjugué anticorps anti-nectine-4/ligand-médicament et son utilisation

Country Status (1)

Country Link
WO (2) WO2025162492A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883198A (zh) * 2016-03-02 2018-11-23 卫材研究发展管理有限公司 基于艾日布林的抗体-药物偶联物和使用方法
CN111433188A (zh) * 2018-12-17 2020-07-17 荣昌生物制药(烟台)股份有限公司 一种用于抗体药物偶联物的连接子及其应用
WO2021148003A1 (fr) * 2020-01-22 2021-07-29 上海森辉医药有限公司 Conjugué de médicament à base de dérivé d'éribuline, son procédé de préparation et son application en médecine
CN115252813A (zh) * 2021-04-30 2022-11-01 江苏迈威康新药研发有限公司 靶向Nectin-4的抗体药物偶联物及其制备方法和用途
WO2022228406A1 (fr) * 2021-04-26 2022-11-03 江苏恒瑞医药股份有限公司 Anticorps anti-nectine-4 et conjugué anticorps anti-nectine-4-médicament et utilisateur médicinal de ceux-ci
CN115698079A (zh) * 2020-07-27 2023-02-03 上海拓界生物医药科技有限公司 抗cd79b抗体药物偶联物、其制备方法及其医药用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8637642B2 (en) * 2010-09-29 2014-01-28 Seattle Genetics, Inc. Antibody drug conjugates (ADC) that bind to 191P4D12 proteins
CN113527486B (zh) * 2020-04-21 2025-12-02 迈威(上海)生物科技股份有限公司 一种抗Nectin-4的抗体及其应用
CR20230128A (es) * 2020-09-16 2023-06-23 Sichuan Kelun Biotech Biopharmaceutical Co Ltd Anticuerpo anti-nectina-4, conjugado que lo incluye y aplicación de los mismos
EP4538291A1 (fr) * 2022-07-14 2025-04-16 Bio-Thera Solutions, Ltd. Anticorps anti-nectine-4, conjugué anticorps-médicament et utilisation associée
KR20250097908A (ko) * 2022-10-28 2025-06-30 장쑤 맵웰 헬스 파마수티컬 알앤디 컴퍼니, 리미티드 항-넥틴-4(anti-nectin-4)항체-약물 접합체(Antibody-Drug Conjugate)를 포함하는 제형 및 이의 용도

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883198A (zh) * 2016-03-02 2018-11-23 卫材研究发展管理有限公司 基于艾日布林的抗体-药物偶联物和使用方法
CN111433188A (zh) * 2018-12-17 2020-07-17 荣昌生物制药(烟台)股份有限公司 一种用于抗体药物偶联物的连接子及其应用
WO2021148003A1 (fr) * 2020-01-22 2021-07-29 上海森辉医药有限公司 Conjugué de médicament à base de dérivé d'éribuline, son procédé de préparation et son application en médecine
CN115698079A (zh) * 2020-07-27 2023-02-03 上海拓界生物医药科技有限公司 抗cd79b抗体药物偶联物、其制备方法及其医药用途
WO2022228406A1 (fr) * 2021-04-26 2022-11-03 江苏恒瑞医药股份有限公司 Anticorps anti-nectine-4 et conjugué anticorps anti-nectine-4-médicament et utilisateur médicinal de ceux-ci
CN115252813A (zh) * 2021-04-30 2022-11-01 江苏迈威康新药研发有限公司 靶向Nectin-4的抗体药物偶联物及其制备方法和用途

Also Published As

Publication number Publication date
WO2025162493A1 (fr) 2025-08-07

Similar Documents

Publication Publication Date Title
WO2023138635A1 (fr) Conjugué dérivé d'exatecan-anticorps et son utilisation médicale
TWI801396B (zh) 包含可裂解連接子之化合物及其用途
WO2020063676A1 (fr) Conjugué ligand-médicament d'un analogue de l'exatécan, son procédé de préparation et application associée
CN114206392A (zh) 免疫调节剂抗体药物偶联物及其用途
CN114269749A (zh) 5H-吡咯并[3,2-d]嘧啶-2,4-二氨基化合物及其抗体偶联物
CN115942978A (zh) 包含抗b7-h3抗体的抗体-药物缀合物
US12144869B2 (en) Anti-ROR1 antibody conjugates, compositions comprising anti ROR1 antibody conjugates, and methods of making and using anti-ROR1 antibody conjugates
CN110575548A (zh) 靶向于cd73的抗体-药物偶联物及其制法和用途
CN118647408A (zh) 抗体-艾日布林或其衍生物的偶联物、其中间体、制备方法、药物组合物和用途
WO2025051124A1 (fr) Analogue de l'auristatine f, conjugué anticorps-médicament et son utilisation
TW202506105A (zh) 連接子－藥物分子及抗體藥物偶聯物、其製備方法和應用
CN113423431A (zh) 包含可裂解接头的化合物及其用途
CN118613286A (zh) Gpc3抗体药物偶联物及其用途
CN119053607A (zh) 喜树碱类化合物及其偶联物、其制备方法和用途
WO2024230678A1 (fr) Composé de camptothécine et conjugué de celui-ci, son procédé de préparation et son utilisation
WO2025162492A1 (fr) Lieur, conjugué ligand-médicament et utilisation médicale associée
CN120239617A (zh) 稠环类化合物及其偶联物和用途
WO2024230752A1 (fr) Dérivé de camptothécine, lieur, conjugué ligand-médicament et leur utilisation médicale
WO2024193692A1 (fr) Lieur et son utilisation dans un conjugué ligand-médicament
CN120393042A (zh) 含季铵盐的抗体偶联药物及其医药用途
TW202508638A (zh) 連結子化合物及配體－藥物接合物、其製備方法及用途
WO2023222019A9 (fr) Conjugué ligand-médicament et son utilisation
WO2025168066A1 (fr) Composé de camptothécine et son conjugué, son procédé de préparation et son utilisation
WO2025252101A1 (fr) Composé de camptothécine et son utilisation
CN119421724A (zh) 治疗实体瘤的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25748052

Country of ref document: EP

Kind code of ref document: A1