WO2021058027A1 - Dérivé de pyrrolo hétéroaryle ou conjugué de celui-ci, son procédé de préparation et son application - Google Patents

Dérivé de pyrrolo hétéroaryle ou conjugué de celui-ci, son procédé de préparation et son application Download PDF

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WO2021058027A1
WO2021058027A1 PCT/CN2020/118837 CN2020118837W WO2021058027A1 WO 2021058027 A1 WO2021058027 A1 WO 2021058027A1 CN 2020118837 W CN2020118837 W CN 2020118837W WO 2021058027 A1 WO2021058027 A1 WO 2021058027A1
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alkyl
cycloalkyl
amino
halogen
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许建烟
章瑛
蔡晓锋
张喆
梁金栋
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This disclosure relates to a new type of pyrroloheteroaryl derivatives or conjugates thereof. Specifically, the present disclosure relates to a pyrroloheteroaryl derivative and an antibody-drug conjugate containing the structure, and a preparation method thereof, and a pharmaceutical composition containing the conjugate and the conjugate Or the use of the pharmaceutical composition.
  • Antibody drug conjugate connects monoclonal antibodies or antibody fragments with biologically active drugs through stable chemical linkers, making full use of the specificity and binding of antibodies to normal cells and tumor cell surface antigens.
  • the high efficiency of the drug avoids the shortcomings of the former's low curative effect and the latter's excessive side effects. This means that compared with traditional chemotherapy drugs in the past, antibody-drug conjugates can accurately bind to tumor cells and reduce the impact on normal cells (Mullard A, (2013) Nature Reviews Drug Discovery, 12: 329- 332; DiJoseph JF, Armellino DC, (2004) Blood, 103: 1807-1814).
  • TLR Toll-like receptors
  • PRR pattern recognition receptors
  • TLR is mainly expressed on immune cells, but also on epithelial, endothelial and tumor cells. After the TLR on the immune cell is activated, it transmits information through some adaptor protein molecules in the cytoplasm (such as MyD88, TIRAP, TRIF, etc.). These adaptor molecules will cause a series of signal molecule cascade reactions to activate transcription factors NF-kB and IRFs , Leading to the release of inflammatory factors (such as IL-2, IL-12, TNF-a, etc.), which further activates a variety of downstream immune cells, including NK cells, T cells and DC cells, thereby killing tumor cells or It is a pathogen.
  • adaptor protein molecules in the cytoplasm such as MyD88, TIRAP, TRIF, etc.
  • TLR 7 agonist Imiquimod
  • BCG Bacillus Calmette-Guerin
  • MPLA monophosphoryl lipid A
  • TLR2/4 agonist monophosphoryl lipid A
  • TLR7 agonist a compound represented by general formula (D), and its ligand-drug conjugate or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3 is selected from an amino group, a heterocyclic group, -NH (R a), - R b -NH 2, -R b -C (O) R 6a -OH, -R b -NHC (O) R 6a -OH- , R b -R W -, aminoheterocyclyl, heterocyclylamino and cycloalkylamino, wherein said amino, cycloalkyl and heterocyclyl are each independently optionally selected from alkyl, alkoxy , Halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, R w , one of -C(O)R 6 and -NHC(O)R 6 or Replaced by multiple substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R 6 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, and the alkyl group is optionally selected from a hydroxyl group, a halogen, an amino group, a heterocyclic group and a cycloalkane Substituted by one or more substituents in the group;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • R w The structure of R w is as follows:
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the present disclosure provides a compound represented by general formula (D) or a conjugate or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3 is selected from amino, -NH(R a ), -R b -NH 2 , -R b -C(O)-R 6a -OH, -R b -NH-C(O)-R 6a -OH, -R b -R W and the formula The shown N-containing heterocyclic ring B; G 3 is a carbon atom or a nitrogen atom;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • R w The structure of R w is as follows:
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the present disclosure provides a TLR7 agonist having a compound represented by general formula (D) or a conjugate or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3 is selected from amino, -NH(R a ), -R b -NH 2 , -R b -C(O)-R 6a -OH, -R b -NH-C(O)-R 6a -OH, -R b -R W and the formula The shown N-containing heterocyclic ring B; G 3 is a carbon atom or a nitrogen atom;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • R w The structure of R w is as follows:
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • R 3 is a heterocyclic group, preferably a N-containing heterocyclic group, more preferably a monocyclic ring containing 2 N atoms Heterocyclic group, bispiro heterocyclic group, bicyclic fused heterocycl
  • R a is selected from alkyl, cycloalkyl and heterocyclyl, said alkyl optionally substituted selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • the R b is selected from bond, alkylene, heterocyclylene and cycloalkylene, and the alkylene, heterocyclylene and cycloalkylene are each independently optionally selected from alkyl, Alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group are substituted by one or more substituents;
  • the heterocyclylene and sub Cycloalkyl is preferably monocyclic heterocyclylene or monocyclic cycloalkylene;
  • G 3 is a carbon atom or a nitrogen atom
  • the ring B is an N-containing heterocyclic group, and the heterocyclic group is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group and a bicyclic bridged heterocyclic group.
  • R a , R b , and R 6a are as defined in the general formula D;
  • G 3 is a carbon atom or a nitrogen atom, preferably a nitrogen atom.
  • R a is selected from alkyl, cycloalkyl and heterocyclyl, said alkyl optionally substituted selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • the R b is selected from bond, alkylene, heterocyclylene and cycloalkylene, and the alkylene, heterocyclylene and cycloalkylene are each independently optionally selected from alkyl, Alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group are substituted by one or more substituents;
  • the heterocyclylene and sub Cycloalkyl is preferably monocyclic heterocyclylene or monocyclic cycloalkylene;
  • G 3 is a carbon atom or a nitrogen atom
  • the ring B is selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group and a bicyclic bridged heterocyclic group.
  • Another aspect of the present disclosure provides a ligand-drug conjugate having a structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein the structure represented by the general formula (D-) as follows:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )-C( O)-, -C(O)-N(R 5 )-, -N(R 5 )-S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-, wherein the heterocyclylene is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy , Hydroxyalkyl, cyano, amino and nitro substituted by one or more substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • Dotted line in general formula (-D) It means that the oxygen atom or nitrogen atom on the R 3a group is covalently connected to the linker unit or to the antibody that binds to the antigen expressed by the target cell;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • Another aspect of the present disclosure provides a ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate has a structure represented by the general formula (D-):
  • the general formula (D-) is the drug part of the general formula compound (D) in the ligand-drug conjugate;
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene, -R b -NH- , -R b -C(O)R 6a -O-, -R b -NHC(O)R 6a -O -And -R b -R W -;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • R w The structure of R w is as follows:
  • Dotted line in general formula (-D) Represents a hydrogen atom; or through the oxygen atom or nitrogen atom on the R 3a group, it is covalently linked to the linker unit or to the antibody that binds to the antigen expressed by the target cell;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • Another aspect of the present disclosure provides a ligand-drug conjugate having a structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein the structure represented by the general formula (D-) as follows:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is a N atom or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )-C( O)-, -C(O)-N(R 5 )-, -N(R 5 )-S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • Dotted line in general formula (-D) It means that the oxygen atom or nitrogen atom on the R 3a group is covalently connected to the linker unit or to the antibody that binds to the antigen expressed by the target cell;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof is a ligand-drug conjugate represented by the general formula (Pc-LD) or a pharmaceutically acceptable salt thereof Accepted salt:
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-; wherein the heterocyclylene is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxyl , Hydroxyalkyl, cyano, amino and nitro substituted by one or more substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • Ring A, G 1 , G 2 , R, R 1 , R 2 , L 1 , L 2 , n are as defined in the general formula (D-);
  • y is an integer or decimal from 1 to 10;
  • Pc is a ligand
  • L is the joint unit.
  • the ligand-drug conjugate having a structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (Pc-LD) Body-drug conjugate or its pharmaceutically acceptable salt:
  • Ring A, G 1 , G 2 , R, R 1 , R 2 , L 1 , L 2 , n are defined in the general formula (D-);
  • y is an average value, ranging from 1 to 10, which can be an integer or a decimal;
  • Pc is a ligand
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy It is substituted by one or more substituents among the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, and heterocyclic group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the ligand-drug conjugate or a pharmaceutically acceptable salt thereof ,
  • y is an average value, in the range of 0 to 12, 0 to 10, preferably 1 to 8, more preferably 2 to 8, most preferably 3 to 8, 3 to 7, 3-6, 4-8, 4-7 , 5-8 or 5-7.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein Pc is an antibody, preferably a monoclonal antibody.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein R 3a is a heterocyclylene, and
  • the heterocyclylene is an N-containing heterocyclic group, preferably a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group containing 2 N atoms; wherein the N atom and the linker unit Or covalently linked to an antibody that binds to the antigen expressed by the target cell.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein R 3a is selected from:
  • the R a is selected from alkyl, heterocyclic and cycloalkyl, and the alkyl is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 3 is a carbon atom or a nitrogen atom
  • the R c is a heterocyclylene, and the heterocyclylene is preferably a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein R 3a is selected from:
  • R a is selected from alkyl, cycloalkyl and heterocyclyl, said alkyl optionally substituted selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 3 is a carbon atom or a nitrogen atom
  • the ring C is a heterocyclylene
  • the heterocyclylene is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable salt thereof, wherein R 3a is selected from:
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of, wherein said ring A is aryl or heteroaryl, preferably phenyl, pyridyl or thienyl.
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of, wherein the G 1 is a N atom.
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of which G 2 is -O-.
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of, wherein said L 1 is an alkylene group.
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of, wherein said L 2 is an alkylene group.
  • the compound represented by the general formula (D), or the ligand-drug conjugate having the structure represented by the general formula (D-) or a pharmaceutically acceptable compound thereof The salt of, wherein R is selected from hydrogen atom, alkyl group and cyano group, preferably cyano group.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein the linker unit -L- is -XL a -L b -L c -L d -,
  • X is -CH 2 (CH 2 ) r CH 2 -S- or a chemical bond; r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3, most preferably 1;
  • L a is selected from -(succinimidyl-3-yl-N)-WC(O)-, -(succinimidyl-3-yl-N)-W- or -C(O)-WC(O )- ⁇
  • W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkyl group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group contains 1 to 3 Heteroatoms selected from N, O and S, wherein the C 1-8 alkylene, cycloalkyl and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, cyano, amino , Alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl substituted by one or more substituents;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is an aryl group or a heteroaryl group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the linker unit -L- is -L a -L b -L c -L d -,
  • L a is selected from -(succinimidyl-3-yl-N)-WC(O)-, -(succinimidyl-3-yl-N)-W- or -C(O)-WC(O )-
  • W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkyl group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group contains 1 to 3 Selected from N, O and S heteroatoms, wherein the C 1-8 alkylene, cycloalkyl and linear heteroalkylene are each independently optionally further selected from halogen, hydroxy, cyano, amino, Substituted by one or more substituents of alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is an aryl group or a heteroaryl group.
  • L a is preferably selected from - (succinimidyl-3-yl -N) - (CH 2) 5 -C (O) - and - (succinimidyl-3-yl -N) -CH 2 - cyclohexyl - C(O)-.
  • L a is preferably selected from - (succinimidyl-3-yl -N) - (CH 2) 5 -C (O) -, - ( succinimidyl-3-yl -N) - (CH 2) 2 - C(O)- and -(succinimidyl-3-yl-N)-CH 2 -cyclohexyl-C(O)-.
  • W is selected from C 1-8 alkylene and -C 1-8 alkylene-cycloalkyl-.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein L b is a chemical bond or the following structural formula:
  • the structural formula and the N-terminal L a is connected to two C-terminal two linking arms, and connected to L c.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein W is selected from C 1-8 alkylene and -C 1-8 alkyl -C 3-6 cycloalkyl-, preferably C 5 alkylene or -CH 2 -cyclohexyl-.
  • the ligand-drug conjugate having a structure represented by the general formula (D-), wherein the peptide residue of L c is composed of one or more benzene residues selected from benzene Peptide residues formed by amino acids in alanine, glycine, valine, lysine, citrulline, serine, glutamic acid, and aspartic acid; preferably tetrapeptide residues, dipeptide residues or chemical bonds ; More preferably, it is a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline.
  • D- general formula (D-)
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the linker unit L d is selected from -NH-C(R 8 R 9 )-OC (R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 )t-OC(O)- and chemical bond;
  • L d is selected from the following structural formulas:
  • R 8 -R 12 , t is as defined in the linker unit -L-, and t is selected from any integer from 1 to 6.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the linker unit -L- is -L a -, selected from -(succinimide Amine-3-yl-N)-WC(O)- or -(succinimidyl-3-yl-N)-W-, wherein W is selected from C 1-8 alkylene and -C 1-8 alkylene Alkyl-cycloalkyl-.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein the linker unit -L- is -XL a -L b -L c -L d -,
  • X is -CH 2 (CH 2 ) r CH 2 -S- or a chemical bond; r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3; most preferably 1;
  • L a is W is selected from C 1-8 alkylene or -C 1-8 alkylene-cycloalkyl-;
  • L b is a chemical bond
  • L c is a tetrapeptide residue, a dipeptide residue or a chemical bond; preferably a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline;
  • L d is selected from the following structural formulas:
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the linker unit -L-, the X end of which is connected to the ligand, L The d terminal is connected to the compound represented by the general formula (D).
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein the linker unit -L- is -L a -L b -L c -L d -,
  • L a is s 1 is an integer from 2 to 8, and W is selected from C 1-8 alkylene and -C 1-8 alkylene-cycloalkylene-;
  • L b is a chemical bond
  • L c is a tetrapeptide residue, a dipeptide residue or a chemical bond; preferably a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline;
  • L d is selected from the following structural formulas:
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.
  • the ligand-drug conjugate having the structure represented by the general formula (D-), wherein the linker unit -L- is -L a -L b -L c -L d -,
  • L a is s 1 is an integer from 2 to 8;
  • L b is a chemical bond
  • L c is a tetrapeptide residue, a dipeptide residue or a chemical bond; preferably a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline;
  • L d is selected from the following structural formulas:
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof is a ligand-drug conjugate represented by the general formula (Pc-Lu1-D) or Its pharmaceutically acceptable salt:
  • X, W, L b , L c , L d are as defined in the joint unit L;
  • Ring A, G 1 , G 2 , R 1 , R 2 , R 3a , L 1 , L 2 , n are as defined in the general formula (D-);
  • Pc and y are as defined in the general formula (Pc-L-D).
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof is a ligand-drug conjugate represented by the general formula (Pc-Lu'-D) Or its pharmaceutically acceptable salt:
  • L a is selected from Wherein W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkylene group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group comprises 1 to 3 A heteroatom selected from N, O and S, wherein the C 1-8 alkylene, cycloalkylene and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, cyano , Amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl substituted by one or more substituents;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is aryl or heteroaryl
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is N or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-, wherein the heterocyclylene is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy , Hydroxyalkyl, cyano, amino and nitro substituted by one or more substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • Pc is a ligand
  • y is an integer from 1 to 10 or a decimal.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) is a ligand-drug conjugate represented by the general formula (Pc-Lu-D) Conjugate or its pharmaceutically acceptable salt:
  • W, L b , L c , L d are as defined in the joint unit -L a -L b -L c -L d -;
  • Ring A, G 1 , G 2 , R 1 , R 2 , R 3a , L 1 , L 2 , n are as defined in the general formula (D-);
  • Pc and y are as defined in the general formula (Pc-L-D).
  • the ligand-drug conjugate having the structure represented by the general formula (D-) is a ligand-drug conjugate represented by the general formula (Pc-Lu-D) Conjugate or its pharmaceutically acceptable salt:
  • W, L b , L c , L d are as defined in the joint unit -L a -L b -L c -L d -;
  • Ring A, G 1 , G 2 , R 1 , R 2 , R 3a , L 1 , L 2 , n are as defined in the general formula (D-);
  • Pc and y are as defined in the general formula (Pc-L-D);
  • W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkylene group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group includes 1 to 3 Heteroatoms selected from N, O and S, wherein the C 1-8 alkylene, cycloalkylene and linear heteroalkylene are each independently optionally further selected from halogen, hydroxy, cyano, One or more substituents of amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is aryl or heteroaryl
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is N or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • Pc is a ligand
  • y is an integer from 1 to 10 or a decimal.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof is of the general formula (Pc-Lu-D) or (Pc-Lu-DA) or (Pc -Lu-DB) Ligand-drug conjugate or pharmaceutically acceptable salt thereof:
  • W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkylene group- or a linear heteroalkylene group of 1 to 8 atoms
  • the heteroalkylene group comprises 1 to 3 A heteroatom selected from N, O and S, wherein the C 1-8 alkylene, cycloalkylene and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, cyano , Amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl substituted by one or more substituents;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is aryl or heteroaryl
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is N or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-; wherein the heterocyclylene is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxyl , Hydroxyalkyl, cyano, amino and nitro substituted by one or more substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • Pc is a ligand
  • y is an integer from 1 to 10 or a decimal.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) is a ligand-drug conjugate represented by the general formula (Pc-Lu-D) The conjugate or a pharmaceutically acceptable salt thereof, wherein
  • Ring A is heteroaryl or heteroaryl, preferably phenyl, pyridine or thiophene;
  • G 2 is -O-
  • R 1 is an alkyl group
  • R 2 is selected from alkyl, alkoxy and halogen
  • L 1 is an alkylene group
  • L 2 is an alkylene group
  • R 3 is selected from -NH(R a ), N-containing heterocyclic group and -R b -NH 2 ;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from hydrogen atom, alkylene, cycloalkylene and heterocyclylene, wherein the alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkane Substituted by one or more substituents among oxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano and amino;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • n 0, 1 or 2;
  • W is selected from C 1-8 alkylene or -C 1-8 alkyl-C 3-6 cycloalkyl-
  • L b is a chemical bond
  • L c is a tetrapeptide residue or a dipeptide residue; preferably a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline;
  • L d is selected from the following structural formulas:
  • Pc is an antibody
  • y is an integer or decimal of 1-10.
  • the ligand-drug conjugate having the structure represented by the general formula (D-) includes a linking unit -L-, and the linking unit -L- includes, but does not Limited to:
  • end a is connected to the ligand Pc
  • the end b is connected to the drug end R 3a
  • r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • the ligand-drug conjugates include, but are not limited to:
  • Pc is a ligand
  • y is an integer from 1 to 10 or a decimal
  • r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • a mixture of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof is provided, which is selected from the following combinations:
  • Pc is a ligand
  • y is an integer from 1 to 10 or a decimal
  • r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the Pc is an antibody In other embodiments of the present disclosure, the ligand-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the Pc is an antibody.
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein the antibody is selected from the group consisting of anti-TLR7 antibody, anti-HER2 (ErbB2) antibody, and anti-EGFR antibody , Anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) 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
  • the ligand-drug conjugate or a pharmaceutically acceptable salt thereof wherein the antibody is selected from Trastuzumab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96 and Glematumamab.
  • the ligand-drug conjugate represented by the general formula (Pc-L-D) of the present disclosure includes, but is not limited to, the following structural formulas:
  • y is selected from an integer or decimal between 1-10; more preferably from 1 to 8, and from 2 to 8, which can be an integer or a decimal; most preferably, it is from 3 to 8, which can be an integer , Can also be a decimal.
  • r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3, most preferably 1.
  • a mixture of a ligand-drug conjugate or a pharmaceutically acceptable salt thereof which is selected from the following combinations:
  • y is an integer from 1 to 10 or a decimal
  • r is 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • Another aspect of the present disclosure provides a compound represented by the general formula (D) or a conjugate or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (D 1 ) or a conjugate thereof ⁇ or its pharmaceutically acceptable salt:
  • Ring A is heteroaryl or heteroaryl, preferably phenyl, pyridyl or thienyl;
  • G 2 is -O-
  • R 1 is an alkyl group
  • R 2 is selected from alkyl, alkoxy or halogen
  • L 1 is an alkylene group
  • L 2 is an alkylene group
  • R 3 is selected from -NH(R a ), N-containing heterocyclic group, -R b -NH 2 and -R b -C(O)R 6a -OH, -R b -NHC(O)R 6a -OH;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, wherein the alkyl group, a cycloalkyl group and a heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from a hydrogen atom, an alkylene group, a cycloalkylene group, and a heterocyclylene group, wherein the alkylene group, the cycloalkylene group and the heterocyclylene group are each independently optionally selected from an alkyl group, an alkane group Substituted by one or more substituents among oxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • n 0, 1, or 2.
  • Another aspect of the present disclosure provides a compound represented by general formula (D) or a conjugate or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (D1) or a conjugate or Pharmaceutically acceptable salt:
  • Ring A is heteroaryl or heteroaryl, preferably phenyl, pyridyl or thienyl;
  • G 2 is -O-
  • R 1 is an alkyl group
  • R 2 is selected from alkyl, alkoxy and halogen
  • L 1 is an alkylene group
  • L 2 is an alkylene group
  • R 3 is selected from -NH(R a ), -R b -NH 2 , -R b -C(O)-R 6a -OH, -R b -NH-C(O)-R 6a -OH and the formula The shown N-containing heterocyclic ring B; G 3 is a carbon atom or a nitrogen atom;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from hydrogen atom, alkylene, cycloalkylene and heterocyclylene, wherein the alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkane Substituted by one or more substituents among oxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic groups;
  • R 6a is an alkylene group, and the alkylene group is optionally substituted by one or more substituents selected from the group consisting of hydroxy, halogen, amino, heterocyclyl and cycloalkyl;
  • n 0, 1, or 2.
  • the compounds represented by the general formula (D) described in this disclosure include, but are not limited to:
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is N or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-, wherein the heterocyclylene is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy , Hydroxyalkyl, cyano, amino and nitro substituted by one or more substituents;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • L a is selected from Wherein W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkyl group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group contains 1 to 3 Heteroatoms selected from N, O and S, wherein the C 1-8 alkylene, cycloalkyl and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, cyano, amino , Alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl substituted by one or more substituents;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is an aryl group or a heteroaryl group.
  • Ring A, G 1 , G 2 , R, R 1 , R 2 , R 3a , L 1 , L 2 , n are as defined in the general formula (D-);
  • W, L b , L c , and L d are as defined in the general formula (Pc-Lu-D);
  • Ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl;
  • G 1 is N or CR 4 ;
  • G 2 is selected from -O-, -S-, -C(O)-, -NR 5 -, -C(O)-OR 5 , -S(O) m -, -N(R 5 )C(O )-, -C(O)N(R 5 )-, -N(R 5 )S(O) m -, -S(O) m N(R 5 )- and covalent bonds;
  • R 1 is selected from alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from deuterium atom, alkyl group, alkoxy group, halogen, halogenated alkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, ring Substituted by one or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxy Substituted by one or more substituents in alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • L 1 is an alkylene group, wherein the alkylene group is optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and hetero One or more substituents in the cyclic group are substituted;
  • L 2 is an alkylene group, wherein the alkylene group is optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Substituted by one or more substituents in the cyclic group, aryl group and heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 3a is selected from -N(R a )-, heterocyclylene and -R b -NH-;
  • R a is selected from a hydrogen atom, an alkyl group, a cycloalkyl group and a heterocyclic group, wherein the alkyl group, the cycloalkyl group and the heterocyclic group are each independently optionally selected from an alkyl group, an alkoxy group, a halogen, and a halogenated alkyl group. Substituted by one or more substituents in the group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • R b is selected from bond, alkylene, cycloalkylene and heterocyclylene, wherein said alkylene, cycloalkylene and heterocyclylene are each independently optionally selected from alkyl, alkoxy Substituted by one or more substituents in the group, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl;
  • W is selected from a C 1-8 alkylene group, a -C 1-8 alkylene group-cycloalkyl group- or a linear heteroalkylene group of 1 to 8 atoms, and the heteroalkylene group contains 1 to 3 Heteroatoms selected from N, O and S, wherein the C 1-8 alkylene, cycloalkyl and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, cyano, amino , Alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl substituted by one or more substituents;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; L b is preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is an aryl group or a heteroaryl group.
  • R 3a is a heterocyclylene
  • the heterocyclylene is an N-containing heterocyclic group, preferably A monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group containing 2 N atoms; wherein the N atom is covalently connected to the linker unit or to the antibody that binds to the antigen expressed by the target cell.
  • R a is selected from alkyl, cycloalkyl and heterocyclyl, said alkyl optionally substituted selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 3 is a carbon atom or a nitrogen atom
  • the R c is a heterocyclylene, and the heterocyclylene is preferably a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group.
  • R a is selected from alkyl, cycloalkyl and heterocyclyl, said alkyl optionally substituted selected from alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino , Nitro, cycloalkyl and heterocyclic group substituted by one or more substituents; the heterocyclic group or cycloalkyl group is preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 3 is a carbon atom or a nitrogen atom
  • the ring C is a heterocyclylene
  • the heterocyclylene is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group.
  • the compound represented by the general formula (L u -D), wherein R is selected from a hydrogen atom, an alkyl group and a cyano group, and a cyano group is preferred.
  • R 2 is the same or different, and each independently is a hydrogen atom, an alkyl group, an alkoxy group, or a halogen.
  • L a is selected from -(succinimidyl-3-yl-N)-WC(O)-, -(succinimidyl-3-yl-N)-W- or -C(O)-WC(O )-, wherein W is selected from C 1-8 alkyl, -C 1-8 alkylene-cycloalkylene- or linear heteroalkylene of 1 to 8 atoms, said heteroalkylene comprises 1 To 3 heteroatoms selected from N, O and S, wherein the C 1-8 alkylene, cycloalkylene and linear heteroalkylene are each independently optionally further selected from halogen, hydroxyl, Substituted by one or more substituents of cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl;
  • L b is selected from -NR 7 (CH 2 CH 2 O)p 1 CH 2 CH 2 C(O)-, -NR 7 (CH 2 CH 2 O)p 1 CH 2 C(O)-, -S(CH 2 ) p 1 C(O)- and a chemical bond, where p 1 is an integer from 1 to 20; preferably a chemical bond;
  • L c is a peptide residue or chemical bond composed of 2 to 7 amino acids, wherein the amino acid is optionally selected from halogen, hydroxyl, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and Substituted by one or more substituents in the cycloalkyl group;
  • L d is selected from -NR 7 (CR 8 R 9 )t-, -NH-C(R 8 R 9 )-OC(R 10 R 11 )-C(O)-, -NH-R 12 -(CH 2 ) t-OC(O)-, -C(O)NR 7 , -C(O)NR 7 (CH 2 )t- and chemical bonds, where t is an integer from 1 to 6;
  • R 7 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group and a hydroxyalkyl group;
  • R 8 or R 9 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, and a hydroxyalkyl group;
  • R 10 is selected from alkyl, cycloalkylalkyl and cycloalkyl;
  • R 11 is selected from a hydrogen atom, an alkyl group and a halogenated alkyl group
  • R 10 and R 11 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 12 is an aryl group or a heteroaryl group.
  • L a is selected from - (succinimidyl-3-yl -N) -WC (O) -, or -(Succinimidyl-3-yl-N)-W-, wherein W is selected from C 1-8 alkylene or -C 1-8 alkylene-cycloalkylene-, wherein said C 1 -8 alkylene and cycloalkylene are each independently optionally further selected from one of halogen, hydroxy, cyano, amino, alkyl, chloroalkyl, deuterated alkyl, alkoxy and cycloalkyl Or substituted by multiple substituents;
  • L a is preferably selected from - (succinimidyl-3-yl -N) - (CH 2) 5 -C (O) - ( succinimidyl-3-yl -N) - (CH 2) 2 -C (O)-or-(succinimidyl-3-yl-N)-CH 2 -cyclohexyl-C(O)-.
  • L d is selected from the following structural formulas:
  • R 8 -R 12 are as defined above.
  • L a is s 1 is an integer from 2 to 8;
  • L b is a chemical bond
  • L c is a tetrapeptide residue, a dipeptide residue or a chemical bond; preferably a tetrapeptide residue of glycine-glycine-phenylalanine-glycine or a dipeptide residue of valine-citrulline;
  • L d is selected from the following structural formulas:
  • the compounds represented by the general formula (Lu-D) described in this disclosure include, but are not limited to:
  • Another aspect of the present disclosure provides a compound represented by general formula (D) or a conjugate or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (DI) or (D-II) Or its conjugate or its pharmaceutically acceptable salt:
  • Ra is a heterocyclic group or a cycloalkyl group, preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • the ring B is an N-containing heterocyclic group, and the heterocyclic group is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group;
  • G 1, G 2, L 1 , L 2, R 1, R 2, R a and n are as formula (D) as defined above.
  • Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (D), which includes the following steps:
  • R 3 is -NH(R a ); said Ra is a heterocyclic group or a cycloalkyl group, preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 1 , G 2 , L 1 , L 2 , R 1 , R 2 and n are as defined in the general formula (D).
  • a method for preparing a compound represented by general formula (D) which includes the following steps:
  • R 3 is as The N-containing heterocyclic group ring B is shown; the ring B is an N-containing heterocyclic group, and the heterocyclic group is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, and a bicyclic fused heterocyclic group Or a bicyclic bridged heterocyclic group;
  • G 1 , G 2 , L 1 , L 2 , R 1 , R 2 and n are as defined in the general formula (D).
  • Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (D-I), which includes the following steps:
  • Said Ra is a heterocyclic group or a cycloalkyl group, preferably a monocyclic heterocyclic group or a monocyclic cycloalkyl group;
  • G 1 , G 2 , L 1 , L 2 , R 1 , R 2 and n are as defined in the general formula (D).
  • Another aspect of the present disclosure provides a method for preparing a compound represented by general formula (D-II), which includes the following steps:
  • Ring B is an N-containing heterocyclic group, and the heterocyclic group is preferably selected from a monocyclic heterocyclic group, a bispiro heterocyclic group, a bicyclic fused heterocyclic group and a bicyclic bridged heterocyclic group;
  • G 1 , G 2 , L 1 , L 2 , R 1 , R 2 and n are as defined in the general formula (D).
  • Another aspect of the present disclosure provides a method for preparing a compound represented by the general formula (LuA1-D), the method comprising:
  • Ring A, R 1 , R 2 , R 3 , G 1 , G 2 , L 1 , L 2 and n are as defined in the general formula (LuA1-D).
  • Another aspect of the present disclosure provides a method for preparing a ligand-drug conjugate represented by the general formula (Pc-L-D), which includes the following steps:
  • the reducing agent is preferably TCEP;
  • Pc is a ligand
  • Ring A, W, R 1 , R 2 , R 3a , G 1 , G 2 , L 1 , L 2 , L b , L C , L d , y and n are as defined in the general formula (Pc-Lu-D) definition.
  • Another aspect of the present disclosure provides a method for preparing a ligand-drug conjugate represented by the general formula (Pc-Lu'-D), which includes the following steps:
  • L a is selected from
  • Pc is a ligand; G 1 , G 2 , L 1 , L b , L c , L d , R 3a , ring A, W, L 2 , R 1 , R 2 , n and y are as in the general formula (Pc-Lu As defined in'-D).
  • Another aspect of the present disclosure provides a method for preparing a ligand-drug conjugate represented by the general formula (Pc-L-D), which includes the following steps:
  • Pc' is obtained by reducing Pc, and performing coupling reaction with a compound of general formula (Lu-D) to obtain a ligand-drug conjugate of general formula (Pc-Lu-D);
  • the reducing agent is preferably TCEP;
  • Pc is a ligand
  • Ring A, W, L 1 , L 2 , R 1 , R 2 , R 3a , G 1 , G 2 , L b , L C , L d , y and n are as defined in the general formula (Pc-Lu-D) definition.
  • Another aspect of the present disclosure further relates to a pharmaceutical composition, which contains a therapeutically effective amount of the compound or its ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, as described in the present disclosure, and a Or multiple pharmaceutically acceptable carriers, diluents or excipients.
  • Another aspect of the present disclosure further relates to a pharmaceutical composition, which contains a therapeutically effective amount of the compound or conjugate or pharmaceutically acceptable salt thereof as described in the present disclosure, and a pharmaceutically acceptable carrier, Diluent or excipient; or it contains a therapeutically effective amount of the ligand-drug conjugate or pharmaceutically acceptable salt or combination thereof as described in the present disclosure, and one or more pharmaceutically acceptable The carrier, diluent or excipient.
  • Another aspect of the present disclosure further relates to a ligand-drug conjugate comprising a ligand and a drug connected to the ligand, wherein the drug is selected from the compounds described in the present disclosure, and preferably the drug is connected to the ligand via a linker.
  • the ligand is a monoclonal antibody.
  • Another aspect of the present disclosure further relates to a method for preparing a ligand-drug conjugate, comprising the step of connecting the compound described in the present disclosure with the ligand, preferably via a linker, preferably the ligand is a monoclonal antibody.
  • the linker unit -L- is -L a -L b -L c -L d -
  • the L a end is connected to the ligand
  • the L d end is connected to the drug.
  • Another aspect of the present disclosure further relates to the compound described in the present disclosure or its ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, or a composition thereof, or a pharmaceutical composition thereof, for use as a medicine.
  • Another aspect of the present disclosure further relates to the compound described in the present disclosure or its ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, or a composition thereof, or a pharmaceutical composition thereof in preparation for treatment or Use in drugs for preventing tumors; preferably, the tumors are cancers related to the expression of TLR7, HER2, HER3 or EGFR.
  • Another aspect of the present disclosure further relates to the use of the compound described in the present disclosure or its ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of cancer
  • the cancer is preferably selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, Glioma, neuroblastoma, sarcoma, lung cancer (for example, small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (for example, acute lymphocytic leukemia, acute myeloid leukemia, Acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer,
  • Another aspect of the present disclosure further relates to the compound described in the present disclosure or its ligand-drug conjugate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preparing a drug for the treatment of infection caused by a virus.
  • the virus is selected from the group consisting of dengue fever virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses.
  • Another aspect of the present disclosure further relates to a method for treating and/or preventing tumors, the method comprising administering a therapeutically effective dose of the compound of the present disclosure or its ligand-drug conjugate to a patient in need thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same; preferably, the tumor is a cancer related to the expression of TLR7, HER2, HER3 or EGFR.
  • Another aspect of the present disclosure further relates to a method for treating or preventing cancer, the method comprising administering to a patient in need thereof a therapeutically effective dose of the compound of the present disclosure or its ligand-drug conjugate, or The pharmaceutically acceptable salt or the pharmaceutical composition containing the same;
  • the cancer is preferably selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, Endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (such as small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (E.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer
  • Another aspect of the present disclosure further relates to a method for treating infections caused by viruses, the method comprising administering a therapeutically effective dose of the compound of the present disclosure or its ligand-drug conjugate to a patient in need thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same;
  • the virus is selected from: dengue fever virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza viruses.
  • the active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose.
  • the expression of the unit dose of the compound or composition of the present invention can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.
  • the dosage of the compound or composition used in the treatment method of the present invention will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose may be 0.1-1000 mg.
  • the pharmaceutical composition of the present invention may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain binders, fillers, lubricants, disintegrants or pharmaceutically acceptable wetting agents, etc.
  • the similar composition may also contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing.
  • the aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oils.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.
  • the pharmaceutical composition can also be dispersible powders and granules used to prepare aqueous suspensions to provide active ingredients by adding one or more of a water-mixed dispersant, wetting agent, suspending agent or preservative. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is added to the mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspending medium.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (I) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • Figure 1A Full mass spectrum of ADC-7 molecule
  • Figure 1B Amplified light chain region of the mass spectrum of ADC-7 molecule
  • Figure 1C Mass spectrum of ADC-7 molecule, enlarged region of the heavy chain region
  • Figure 1D The enlarged region of the heavy chain region of the mass spectrum of the ADC-7 molecule
  • Figure 2B Amplified light chain region of the mass spectrum of ADC-9 molecule
  • Figure 2C The enlarged region of the heavy chain region of the mass spectrum of the ADC-9 molecule
  • Figure 2D The enlarged region of the heavy chain region of the mass spectrum of the ADC-9 molecule
  • FIG. 3 Pharmacodynamics of ADC of the present disclosure in CT26 tumor model
  • the applicant intends to include the formulation of the trade name product, the generic drug and the active drug portion of the trade name product.
  • ligand is a macromolecular compound that can recognize and bind to an antigen or receptor associated with a target cell.
  • the role of the ligand is to present the drug to the target cell population that binds to the ligand.
  • ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells.
  • the ligand is represented by Pc, and the ligand can form a link with the linking unit through a heteroatom on the ligand, preferably an antibody or an antigen-binding fragment thereof, and the antibody is selected from a chimeric antibody, a human Antibodies, fully human antibodies or murine antibodies; preferably monoclonal antibodies.
  • drug refers to cytotoxic drugs or immunomodulators.
  • Cytotoxic drugs can have strong chemical molecules in tumor cells that destroy their normal growth. In principle, cytotoxic drugs can kill tumor cells at a sufficiently high concentration, but due to lack of specificity, while killing tumor cells, it will also cause normal cell apoptosis, leading to serious side effects.
  • the term includes toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, radioisotopes (e.g.
  • Immunomodulators are inhibitors of immune checkpoint molecules.
  • the drug is denoted as D, which is an immunomodulator, especially a TLR7 agonist.
  • linker unit refers to a chemical structural fragment or bond with one end connected to a ligand and the other end to a drug, and it can also be connected to other linkers before being connected to the drug.
  • Linkers including extensions, spacers and amino acid units, can be synthesized by methods known in the art, such as those described in US2005-0238649A1.
  • the linker may be a "cleavable linker" that facilitates the release of the drug in the cell.
  • acid-labile linkers such as hydrazone
  • protease-sensitive such as peptidase-sensitive
  • light-labile linkers dimethyl linkers, or disulfide-containing linkers
  • Part of the joint of the present invention can form an open-loop structure under certain conditions, as described in Example 4 in CN108430515A.
  • ligand-drug conjugate means that the ligand is connected to the biologically active drug through a stable linking unit.
  • the "ligand-drug conjugate” is preferably an antibody-drug conjugate (ADC), which refers to connecting a monoclonal antibody or antibody fragment to a toxic drug with biological activity through a stable connecting unit .
  • ADC antibody-drug conjugate
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • full-length antibody refers to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five categories, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE.
  • the corresponding heavy chains are ⁇ chain, ⁇ chain, and ⁇ chain. , ⁇ chain, and ⁇ chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • the light chain is divided into a kappa chain or a lambda chain by the difference of the constant region.
  • Each of the five types of Ig can have a kappa chain or a lambda chain.
  • the antibodies described in the present disclosure are preferably specific antibodies against cell surface antigens on target cells.
  • Non-limiting examples are the following antibodies: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met Antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) 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- One or more of C antibody, anti-SLC44A4 antibody or anti-Mesothelin antibody; preferably Trastuzumab (Trastuzumab, trade name
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly and is the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable and are the constant region.
  • the variable region includes 3 hypervariable regions (HVR) and 4 framework regions (FR) with relatively conserved sequences. Three hypervariable regions determine the specificity of the antibody, also known as complementarity determining regions (CDR).
  • Each light chain variable region (LCVR) and heavy chain variable region (HCVR) is composed of 3 CDR regions and 4 FR regions.
  • the sequence from the amino terminus to the carboxy terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the antibodies of the present disclosure include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, preferably humanized antibodies and fully human antibodies.
  • murine-derived antibody in this disclosure refers to the preparation of antibodies with mice based on knowledge and skills in the art. During preparation, a test subject is injected with a specific antigen, and then hybridomas expressing antibodies with desired sequences or functional properties are isolated.
  • chimeric antibody is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can alleviate the immune response induced by the murine antibody.
  • To establish a chimeric antibody it is necessary to first establish a hybridoma secreting murine-derived specific monoclonal antibodies, then clone the variable region genes from the murine hybridoma cells, and then clone the constant region genes of the human antibody as needed, and replace the murine variable region genes. It is connected with the human constant region gene to form a chimeric gene and inserted into an expression vector, and finally the chimeric antibody molecule is expressed in a eukaryotic system or a prokaryotic system.
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into the framework of human antibody variable regions, that is, different types of human germline antibodies Antibodies produced in the framework sequence. It can overcome the heterogeneous reaction induced by the chimeric antibody because it carries a large amount of murine protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk/vbase ), as well as in Kabat, EA, etc.
  • human antibody variable region framework sequence can be subjected to minimal reverse mutations or back mutations to maintain activity.
  • the humanized antibodies of the present disclosure also include humanized antibodies that are further subjected to affinity maturation for CDR by phage display. Documents that further describe methods that can be used for mouse antibodies involved in humanization include, for example, Queen et al., Proc., Natl. Acad. Sci.
  • Fully human antibody means “fully human antibody”, “fully human antibody” or “fully human antibody”, also known as “fully human monoclonal antibody”, the variable and constant regions of the antibody are of human origin, removing the immunogen Sex and side effects.
  • monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
  • This disclosure is a fully human monoclonal antibody.
  • the related technologies of fully human antibody preparation mainly include: human hybridoma technology, EBV transformed B lymphocyte technology, phage display technology (phage display), transgenic mouse antibody preparation technology (transgenic mouse) and single B cell antibody preparation technology.
  • 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 antibodies.
  • binding fragments contained in "antigen-binding fragments" include (i) Fab fragments, which are monovalent fragments composed of VL, VH, CL and CH1 domains; (ii) F(ab') 2 fragments, which include A bivalent fragment of two Fab fragments connected by a disulfide bridge, (iii) Fd fragment composed of VH and CH1 domains; (iv) Fv fragment composed of VH and VL domains of one arm of an antibody; (v ) A single domain or dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) can optionally be passed A combination of two
  • the two domains VL and VH of the Fv fragment are encoded by separate genes, recombination methods can be used to connect them through a synthetic linker so that it can be produced as a single protein in which the VL and VH regions are paired to form a monovalent molecule.
  • Chain referred to as 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).
  • Such single chain antibodies are also intended to be included in the term "antigen-binding fragments" of antibodies.
  • the antigen-binding portion can be produced by recombinant DNA technology or by enzymatic or chemical fragmentation of the intact immunoglobulin.
  • the antibodies may be antibodies of different isotypes, for example, IgG (e.g., IgG1, IgG2, IgG3 or IgG4 subtype), IgA1, IgA2, IgD, IgE or IgM antibodies.
  • Fab is an antibody fragment that has a molecular weight of about 50,000 and has 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), wherein the H chain is N-terminal About half of the side and the entire L chain are joined together by disulfide bonds.
  • F(ab')2 is obtained by digesting the lower part of the two disulfide bonds in the hinge region of IgG with the enzyme pepsin. It has a molecular weight of about 100,000 and has antigen binding activity and contains two Fab regions connected at the hinge position. Antibody fragments.
  • Fab' is an antibody fragment obtained by cleaving the disulfide bond in the hinge region of F(ab')2 and having a molecular weight of about 50,000 and having antigen-binding activity.
  • the Fab' can be produced by inserting DNA encoding the Fab' fragment of the antibody into a prokaryotic expression vector or eukaryotic expression vector and introducing the vector into a prokaryotic organism or eukaryotic organism to express Fab'.
  • single-chain antibody means to comprise an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker Of molecules.
  • Such scFv molecules may have the general structure: NH 2 -VL-linker-VH-COOH or NH 2 -VH-linker-VL-COOH.
  • a suitable prior art linker consists of a repeated GGGGS amino acid sequence or variants thereof, for example using 1-4 repeated variants (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 in the variable domain of an antibody that mainly contribute to antigen binding.
  • 6 CDRs One of the most commonly used definitions of the 6 CDRs is provided by Kabat E.A. et al. (1991) Sequences of Proteins of Immunological Interest. NIH Publication 91-3242).
  • antibody framework refers to a part of the variable domain VL or VH, which serves as a scaffold for the antigen binding loop (CDR) of the variable domain. Essentially, it is a variable domain without CDRs.
  • epitopes refers to the site on an antigen where an immunoglobulin or antibody specifically binds.
  • Epitopes usually include at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive or non-contiguous amino acids in a unique spatial conformation. See, for example, Epitope Mapping Protocols in Methods in Molecular B iology, Volume 66, G.E. Morris, Ed. (1996).
  • antibodies bind with an affinity (KD) of approximately less than 10 -7 M, such as approximately less than 10 -8 M, 10 -9 M, or 10 -10 M or less.
  • nucleic acid molecule refers to DNA molecules and RNA molecules.
  • the nucleic acid molecule may be single-stranded or double-stranded, but is preferably double-stranded DNA.
  • the nucleic acid is "operably linked.” For example, if a promoter or enhancer affects the transcription of a coding sequence, the promoter or enhancer is effectively linked to the coding sequence.
  • vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • the vector is a "plasmid”, which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated.
  • the vector is a viral vector in which additional DNA segments can be ligated into the viral genome.
  • the vectors disclosed herein can replicate autonomously in the host cell into which they have been introduced (for example, bacterial vectors with a bacterial origin of replication and episomal mammalian vectors) or can be integrated into the genome of the host cell after being introduced into the host cell, so as to follow The host genome replicates together (e.g., a non-episomal mammalian vector).
  • Antigen-binding fragments can also be prepared by conventional methods.
  • the antibody or antigen-binding fragment of the invention is genetically engineered to add one or more human FR regions to the non-human CDR region.
  • Human FR germline sequence can be obtained from ImmunoGeneTics (IMGT) website http://imgt.cines.fr by comparing the IMGT human antibody variable region germline gene database and MOE software, or from the Journal of Immunoglobulin, 2001ISBN012441351 obtain.
  • host cell refers to a cell into which an expression vector has been introduced.
  • Host cells may include bacteria, microorganisms, plant or animal cells.
  • Bacteria that are easily transformed include members of the enterobacteriaceae, such as Escherichia coli or Salmonella strains; Bacillaceae such as Bacillus subtilis; Pneumococcus; Streptococcus and Haemophilus influenzae.
  • Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris.
  • Suitable animal host cell lines include CHO (Chinese Hamster Ovary cell line) and NS0 cells.
  • the engineered antibodies or antigen-binding fragments of the present disclosure can be prepared and purified by conventional methods.
  • the cDNA sequences encoding the heavy and light chains can be cloned and recombined into a GS expression vector.
  • the recombinant immunoglobulin expression vector can be stably transfected into CHO cells.
  • mammalian expression systems can lead to glycosylation of antibodies, especially in the highly conserved N-terminal sites of the Fc region.
  • Positive clones are expanded in the serum-free medium of the bioreactor to produce antibodies.
  • the culture medium from which the antibody is secreted can be purified by conventional techniques. For example, use A or G Sepharose FF column with adjusted buffer for purification.
  • the bound antibody was eluted by the PH gradient method, and the antibody fragments were detected by SDS-PAGE and collected.
  • the antibody can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange. The resulting product needs to be immediately, such as -70°C, or lyophilized.
  • peptide refers to a fragment of a compound between amino acids and proteins. It is composed of two or more amino acid molecules connected to each other by peptide bonds. They are structural and functional fragments of proteins, such as hormones, enzymes, etc. in essence. All are peptides.
  • sucrose refers to a biological macromolecule composed of three elements: C, H, and O, which can be divided into monosaccharides, disaccharides and polysaccharides.
  • fluorescent probe refers to the characteristic fluorescence in the ultraviolet-visible-near-infrared region, and its fluorescent properties (excitation and emission wavelength, intensity, lifetime, polarization, etc.) can vary with the properties of the environment, such as polarity, refractive index A type of fluorescent molecules that change sensitively due to changes in, viscosity, etc., which non-covalently interact with nucleic acids (DNA or RNA), proteins or other macromolecular structures to change one or several fluorescent properties, which can be used for research The nature and behavior of macromolecular substances.
  • toxic drug refers to a substance that inhibits or prevents the function of cells and/or causes cell death or destruction. Including toxins and other compounds that can be used in tumor treatment.
  • chemotherapeutic drug is a chemical compound that can be used to treat tumors. This definition also includes antihormonal agents that act to modulate, reduce, block, or inhibit the effects of hormones that promote cancer growth, and are often in the form of systemic or systemic therapy. They can be hormones themselves.
  • 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 containing 1 to 10 carbon atoms An alkyl group having 1 to 8 carbon atoms, most preferably an alkyl group having 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
  • heteroalkyl refers to an alkyl group containing one or more heteroatoms selected from N, O or S, wherein the alkyl group is as defined above.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) Wait.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , Cycloalkylthio, heterocycloalkylthio and oxo groups are substituted by one or more substituents.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl or cycloalkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 Carbon atoms, most preferably 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • cycloalkylene refers to a cycloalkyl group having two residues derived from the removal of two hydrogen atoms from the ring atoms of the parent cycloalkyl group.
  • the cycloalkyl group is as defined above.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spirocyclic, condensed, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) Heteroatoms of m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo.
  • heterocyclylene refers to a heterocyclic group having two residues derived from the same or different ring atoms of the parent heterocyclic group by removing two hydrogen atoms.
  • the heterocyclic group is as defined above.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl, preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrakis Azole and so on.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include 9-fluorenylmethyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably 9-fluorenylmethyloxycarbonyl.
  • aminoheterocyclyl refers to a heterocyclic group substituted by one or more amino groups, preferably by one amino group, wherein the heterocyclic group is as defined above, and "amino” refers to -NH 2 .
  • aminoheterocyclyl refers to a heterocyclic group substituted by one or more amino groups, preferably by one amino group, wherein the heterocyclic group is as defined above, and "amino” refers to -NH 2 .
  • heterocyclylamino refers to an amino group substituted with one or more heterocyclic groups, preferably one heterocyclic group, wherein amino is as defined above and heterocyclyl is as defined above. Representative examples of this disclosure are as follows:
  • cycloalkylamino refers to an amino group substituted with one or more cycloalkyl groups, preferably with a cycloalkyl group, where amino is as defined above and where cycloalkyl is as defined above.
  • Representative examples of this disclosure are as follows:
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, preferably one cycloalkyl group, where alkyl is as defined above and where cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • nitro refers to -NO 2 .
  • amido refers to -C(O)N(alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • carboxylate group refers to -C(O)O(alkyl) or (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize the deuterated form of the compound of formula (I).
  • Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents.
  • Deuterated reagents include, but are not limited to, deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • pharmaceutical composition means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • pharmaceutically acceptable salt refers to the salt of the ligand-drug conjugate of the present disclosure, or the salt of the compound described in the present disclosure, when such salts are used in mammals. It is safe and effective, and has due biological activity.
  • the antibody-antibody drug conjugate compound of the present disclosure contains at least one amino group, so it can form a salt with an acid.
  • Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride , Hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pearate, hydrogen phosphate, diphosphate Hydrogen salt, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, P-toluenesulfonate.
  • drug loading refers to the average number of cytotoxic drugs loaded on each ligand in the molecule of formula (I). It can also be expressed as the ratio of the amount of drug to the amount of antibody.
  • the range of drug loading can be for each ligand.
  • Pc Connect 0-12, preferably 1-10 cytotoxic drugs (D).
  • the drug loading amount is expressed as y, which can be an exemplary average value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and the range is 0-12, preferably 1. -10, more preferably 1-8, or 2-8, or 2-7, or 3-8, or 3-7, or 3-6, or 4-7, or 4-6, or the average value of 4-5 .
  • Conventional methods such as UV/visible light spectroscopy, mass spectrometry, ELISA test, CE-SDS method and HPLC characteristics can be used to identify the average number of drugs per ADC molecule after the coupling reaction.
  • the cytotoxic drug is coupled to the N-terminal amino group of the ligand and/or the ⁇ -amino group of the lysine residue through the linking unit.
  • the cytotoxic drug can be coupled to the antibody in the coupling reaction.
  • the number of drug molecules will be less than the theoretical maximum.
  • ligand cytotoxic drug conjugates including:
  • carrier is used for the drug in the present disclosure, and refers to a system that can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the targeted organ.
  • the drug carrier release and targeting system can reduce drug degradation and loss, reduce side effects, and improve bioavailability.
  • polymer surfactants that can be used as carriers can self-assemble to form various forms of aggregates due to their unique amphiphilic structure. Preferred examples are micelles, microemulsions, gels, liquid crystals, vesicles, etc. . These aggregates have the ability to contain drug molecules, and at the same time have good permeability to the membrane, and can be used as excellent drug carriers.
  • excipient is an addition to the main drug in a pharmaceutical preparation, and can also be referred to as an adjuvant.
  • adjuvant such as binders, fillers, disintegrants, lubricants in tablets; base parts in semi-solid preparations ointments and creams; preservatives, antioxidants, flavors, fragrances, and auxiliary agents in liquid preparations
  • Solvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. can all be called excipients.
  • diluent is also called a filler, and its main purpose is to increase the weight and volume of the tablet.
  • the addition of diluent not only guarantees a certain volume, but also reduces the deviation of the dosage of the main components, and improves the compression molding of the drug.
  • an absorbent should be added to absorb the oily substance to keep it in a “dry” state, so as to facilitate the manufacture of tablets.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • the acceptable solvents and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is added to the mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be used to prepare injections.
  • the present disclosure relates to a type of cleavable linker with a specific structure and an active substance with a specific structure, and an antibody drug conjugate (ADC) composed of a linker, an active substance and an antibody.
  • ADC antibody drug conjugate
  • This type of ADC is a complex formed by linking a toxic substance to an antibody via a spacer.
  • the antibody-conjugated drug (ADC) is degraded in the body to release active molecules, thereby playing an anti-tumor effect.
  • the experimental methods that do not indicate specific conditions in the embodiments of this disclosure usually follow conventional conditions or conditions suggested by raw material or commodity manufacturers.
  • the reagents without specific sources are the conventional reagents purchased on the market.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • MS uses Agilent 1200/1290DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the following antibodies are prepared according to conventional antibody methods: for example, vector construction can be carried out, transfected into eukaryotic cells such as HEK293 cells (Life Technologies Cat. No. 11625019), and purified and expressed.
  • eukaryotic cells such as HEK293 cells (Life Technologies Cat. No. 11625019)
  • reaction solution was poured into 10mL water, extracted with ethyl acetate (10mL ⁇ 3), the organic phases were combined, the organic phases were washed with water (20mL), washed with saturated sodium chloride solution (20mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (342 mg, yield: 68.5%).
  • reaction solution was poured into 10mL water, extracted with ethyl acetate (10mL ⁇ 3), the organic phases were combined, the organic phases were washed with water (20mL), washed with saturated sodium chloride solution (20mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 4b (340 mg, yield: 68.0%).
  • reaction solution was concentrated under reduced pressure, the residue was added to 30mL of water, extracted with ethyl acetate (15mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5b (319 mg, yield: 81.1%).

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Abstract

L'invention concerne un dérivé de pyrrolo hétéroaryle ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci et une application de celui-ci. L'invention concerne spécifiquement un composé représenté par la formule générale (D) ou un conjugué ligand-médicament de celui-ci, un procédé de préparation de celui-ci, une application du conjugué ligand-médicament et une composition pharmaceutique de celui-ci dans la préparation d'un médicament pour le traitement du cancer ou de maladies infectieuses virales.
PCT/CN2020/118837 2019-09-29 2020-09-29 Dérivé de pyrrolo hétéroaryle ou conjugué de celui-ci, son procédé de préparation et son application WO2021058027A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022194257A1 (fr) * 2021-03-17 2022-09-22 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de camptothécine
WO2022262516A1 (fr) * 2021-06-18 2022-12-22 北京海步医药科技有限公司 Lieur et conjugué correspondant
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US11806405B1 (en) 2021-07-19 2023-11-07 Zeno Management, Inc. Immunoconjugates and methods
WO2024095964A1 (fr) * 2022-10-31 2024-05-10 アステラス製薬株式会社 Complexe anticorps-médicament contenant un composé agoniste double du récepteur 7/8 de type toll

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WO2022262516A1 (fr) * 2021-06-18 2022-12-22 北京海步医药科技有限公司 Lieur et conjugué correspondant
US11806405B1 (en) 2021-07-19 2023-11-07 Zeno Management, Inc. Immunoconjugates and methods
WO2023207710A1 (fr) * 2022-04-29 2023-11-02 四川科伦博泰生物医药股份有限公司 Conjugué anticorps-médicament, composition pharmaceutique de celui-ci et son utilisation
WO2024095964A1 (fr) * 2022-10-31 2024-05-10 アステラス製薬株式会社 Complexe anticorps-médicament contenant un composé agoniste double du récepteur 7/8 de type toll

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