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WO2025153015A2 - Conjugué d'inhibiteur de la traduction des protéines et son utilisation - Google Patents

Conjugué d'inhibiteur de la traduction des protéines et son utilisation

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Publication number
WO2025153015A2
WO2025153015A2 PCT/CN2025/072722 CN2025072722W WO2025153015A2 WO 2025153015 A2 WO2025153015 A2 WO 2025153015A2 CN 2025072722 W CN2025072722 W CN 2025072722W WO 2025153015 A2 WO2025153015 A2 WO 2025153015A2
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WIPO (PCT)
Prior art keywords
alkyl
membered
alkylene
hydrogen
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/072722
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English (en)
Chinese (zh)
Other versions
WO2025153015A3 (fr
Inventor
李冰
林圣超
张禹
花海清
朱忠远
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Duality Biologics Suzhou Co Ltd
Original Assignee
Duality Biologics Suzhou Co Ltd
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Publication of WO2025153015A2 publication Critical patent/WO2025153015A2/fr
Publication of WO2025153015A3 publication Critical patent/WO2025153015A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes

Definitions

  • mRNA translation Aberrant messenger RNA (mRNA) translation is a common feature of malignant tumors, manifested by upregulation of oncoproteins, growth factors, and signal transduction proteins associated with proliferation, survival, and metastasis.
  • the expression of oncogenic drivers is under strict translational control and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex, which mediates the recruitment of ribosomes to mRNA and initiates the mRNA-to-protein translation process.
  • the eIF4F complex consists of three subunits: the mRNA 5' cap binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A.
  • the first aspect of the present invention provides a ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the ligand-drug conjugate is composed of a ligand, a linker and a drug group, and the drug group is selected from the structure shown in formula IA, II-A', III-A', IV-A or VA
  • M is selected from -N(R m )-, -O-, -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R m )-, said -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R m )- being optionally substituted with one or more (e.g.
  • W is absent or selected from -(C 1 -C 6 )alkylene-, -O- and -N(R w )-, said -(C 1 -C 6 )alkylene- being optionally substituted with one or more (e.g. 1, 2, 3, 4, 5, 6 or 7) groups selected from hydrogen, halogen, -OH, -O-(C 1 -C 4 )alkyl, -NH 2 , -NH(C 1 -C 4 )alkyl and -N[(C 1 -C 4 )alkyl] 2 ;
  • U is selected from -(C 1 -C 6 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-10 membered)heterocyclylene-, wherein -(C 1 -C 6 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-10 membered)heterocyclylene- are optionally substituted by one or more (e.g.
  • Y is absent or selected from -O-, -N(R y )- and -N + (R y ) 2 -
  • R y is selected from hydrogen, -(C 1 -C 6 )alkyl, -O(C 1 -C 6 )alkyl, -(C 1 -C 6 )haloalkyl and -O-(C 1 -C 6 )haloalkyl, or R y and Z form -(4-10 membered)heterocyclylene-, said -(4-10 membered)heterocyclylene- optionally substituted with one or more (e.g.
  • T is selected from -N(R t )-, -O-, -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R t )-, said -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R q )- being optionally substituted with one or more (e.g.
  • R c is selected from hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )haloalkyl, -O-(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )haloalkyl, -(C 3 -C 6 )cycloalkyl, -O-(C 3 -C 6 )cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C 6 -C 10 )aryl, -O-(C 6 -C 10 )aryl, -(5-12 membered)heteroaryl and -O-(5-12 membered)heteroaryl;
  • Ring C is selected from -(C 6 -C 10 )aryl and -(5-12 membered)heteroaryl, or, Ring C is selected from -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene-, wherein -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more R 7 ;
  • n 1, 2, 3, 4 or 5;
  • R 9a and R 9b are combined to form oxo, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl or -(4-10 membered)heterocyclyl,
  • R 8a and R 9a together with the carbon atom to which they are attached form a (C 3 -C 6 )cycloalkyl, a (4-10 membered)heterocyclyl or a (5-10 membered)heteroaryl, which are optionally substituted by one or more groups selected from hydrogen, halogen, -OH, -O-(C 1 -C 4 )alkyl, -NH 2 , -NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 , -(C 3 -C 6 )cycloalkyl, -(4-8 membered)heterocyclyl, -(5-6 membered)heteroaryl and -(C 6 -C 10 )aryl,
  • M is selected from -N(R m )-, -O-, -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R m )-, said -(C 1 -C 6 )alkylene-O- and -(C 1 -C 6 )alkylene-N(R m )- being optionally substituted with one or more (e.g.
  • U is selected from -(C 1 -C 6 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-10 membered)heterocyclylene-, wherein -(C 1 -C 6 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-10 membered)heterocyclylene- are optionally substituted by one or more (e.g.
  • Y is absent or selected from -O- and -N(R y )-
  • R y is selected from hydrogen, -(C 1 -C 6 )alkyl, -O(C 1 -C 6 )alkyl, -(C 1 -C 6 )haloalkyl and -O-(C 1 -C 6 )haloalkyl, or R y and Z form -(4-10 membered)heterocyclylene-, said -(4-10 membered)heterocyclylene- optionally substituted with one or more (e.g.
  • R m , R w , R q and R t are each independently selected from hydrogen, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, -(C 1 -C 6 )haloalkyl and -O-(C 1 -C 6 )haloalkyl;
  • X1 is selected from N and C( R1 ), R1 is selected from hydrogen, halogen, cyano, -OH, -( C1 - C6 )alkyl and -O-( C1 - C6 )alkyl;
  • Ra and Rb are each independently selected from hydrogen, halogen, cyano, -ORc , -SRc , -N( Rc ) Rc , -( C1 - C6 )alkyl and -( C1 - C6 )haloalkyl;
  • R c is selected from hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )haloalkyl, -O-(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )haloalkyl, -(C 3 -C 6 )cycloalkyl, -O-(C 3 -C 6 )cycloalkyl, -(4-10 membered)heterocyclyl, -O-(4-10 membered)heterocyclyl, -(C 6 -C 10 )aryl, -O-(C 6 -C 10 )aryl, -(5-12 membered)heteroaryl and -O-(5-12 membered)heteroaryl;
  • Ring B is selected from -(C 6 -C 10 )aryl and -(5-12 membered)heteroaryl, or, Ring B is selected from -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene-, wherein -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted by one or more groups selected from R 5 and R 6 ;
  • Ring C is selected from -(C 6 -C 10 )aryl and -(5-12 membered)heteroaryl, or, Ring C is selected from -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene-, wherein -(C 6 -C 10 )arylene- and -(5-12 membered)heteroarylene- are optionally substituted with one or more R 7 ;
  • R 8a and R 8b , and R 9a and R 9b independently combine to form oxo, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )cycloalkyl or -(4-10 membered)heterocyclyl,
  • the drug group is selected from the structure shown in Formula IA
  • said R m is selected from hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl.
  • said R m is hydrogen
  • the M is selected from -NH-, -O-, -(C 1 -C 6 )alkylene-O-, and -(C 1 -C 6 )alkylene-NH-.
  • the M is selected from -NH-, -O-, -(C 1 -C 4 )alkylene-O-, and -(C 1 -C 4 )alkylene-NH-.
  • said M is selected from -NH-, -O-, -CH2O- , and -CH2NH- .
  • the M is selected from -NH-, -O-, *-CH 2 O-, and *-CH 2 NH-, wherein the * end is connected to the ring C.
  • said M is selected from -NH-.
  • the ring C is selected from -(C 6 -C 10 )arylene- and -(5-10 membered)heteroarylene-, wherein the -(C 6 -C 10 )arylene- and -(5-10 membered)heteroarylene- are optionally substituted with 1, 2 or 3 R 7 .
  • the ring C is selected from phenylene, naphthylene and (5-6 membered) heteroarylene, wherein the phenylene, naphthylene and (5-6 membered) heteroarylene are optionally substituted with 1 or 2 R 7 .
  • each of the R 7 is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH 2 , -(C 1 -C 4 )alkyl, -(C 2 -C 4 )alkenyl, -(C 2 -C 4 )alkynyl, -(C 1 -C 4 )haloalkyl, -O-(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )haloalkyl, -S-(C 1 -C 4 )alkyl, -NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 , -(C 3 -C 6 )cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C 3 -C 6 )cycloalkyl, and -O-(4-8
  • the R 7 are each independently selected from hydrogen, halogen, cyano, -OH, -NH 2 , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-NH(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 , and -(C 1 -C 4 )alkylene-NH 2 .
  • each of the R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH 2 , -CH 2 OH, and -CH 2 NH 2 .
  • the ring C is The * terminal is connected to M.
  • the drug group is selected from the structure shown in formula II-A'
  • X, X 1 , X 2 , ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , m, W, U, Z and Y are as defined in any embodiment of the present invention, and n is 0 or 1.
  • said R w is selected from hydrogen and methyl.
  • W is absent or is selected from -(C 1 -C 6 )alkylene-, -NH-, -N[(C 1 -C 6 )alkyl]-, and -N[O(C 1 -C 6 )alkyl]-.
  • said W is absent, or is selected from -NH- and -N(Me)-.
  • said Z is absent or is selected from methylene, ethylene, cyclopropylene, azetidinylene, and pyrrolidinylene.
  • Y is absent or is selected from -O-, -N(R y )-, and -N + (R y ) 2 -, and R y is selected from hydrogen, methyl, ethyl, and -O-methyl.
  • Y is selected from -O-, -NH-, -N(CH 3 )-, and -N + (CH 3 ) 2 -.
  • the structural unit -WUZY- is selected from -N( Rw )-( C1 - C6 )alkylene-N( Ry )-, -N( Rw )-( C1 - C6 )alkylene-N + ( Ry ) 2- , -N( Rw )-( C1 - C6 )alkylene-O-, -( C1 - C6 )alkylene-N( Ry )-, -( C1 - C6 )alkylene-O-, -( C3 - C6 )cycloalkylene-N( Ry )-, -( C1 - C6 )alkylene-N + ( Ry ) 2- , -( C3 - C6 )cycloalkylene-O-, -(4-6 membered)heterocyclylene-O-, -(4-6 membered)heterocyclylene-N(Ry ) -, -
  • the structural unit -WUZY- is selected from -N( Rw )-( C1 - C6 )alkylene-N( Ry )-, -N( Rw )-( C1 - C6 )alkylene-N + ( Ry ) 2- , -N( Rw )-( C1 - C6 )alkylene-O-, -( C1 - C6 )alkylene-N( Ry )-, -( C1 - C6 )alkylene-N + ( Ry ) 2- , -( C1 - C6 )alkylene-O-, -(4-6 membered)heterocyclylene-O-, -(4-6 membered)heterocyclylene-N( Ry )-, and -N( Rw )-(4-6 membered)heterocyclylene-.
  • the structural unit -WUZY- is selected from *-NH- CH2 - CH2 -NH-, *-N( CH3 )-CH2-CH2-NH-, *-NH- CH2 - CH2 -O-, *-CH2-O-, * -CH2 -NH-, *-CH2-N ( CH3)-, *-CH2- N +(CH3)2-, *-NH-CH2 ...O-, * -CH2 -NH-, * -CH2- N( CH3 )-, *-CH2-N + (CH3) 2- , *-NH-CH2 - CH2-O-, *-CH2-O-, * -CH2- NH-, *-CH2- Among them, the * end is connected to the carbonyl group.
  • the structural unit -WUZY- is selected from -N( Rw )-( C1 - C6 )alkylene-N(Ry)-, -N( Rw )-(C1-C6)alkylene-O-, -( C1 - C6 )alkylene-N( Ry )-, -(C1-C6)alkylene-O-, -( C3 - C6 )cycloalkylene-N( Ry )-, -( C3 - C6 )cycloalkylene-O-, -(4-6 membered)heterocyclylene-O-, -( 4-6 membered )heterocyclylene-N(Ry)-, and -N(Rw)-(4-6 membered)heterocyclylene-, wherein -N( Rw )-( C1 - C6 )alkylene-N(Ry)-, -N(Rw)-(
  • the structural unit -WUZY- is selected from *-NH- CH2 - CH2 -NH-, *-N( CH3 )-CH2 -CH2 - NH- , *-NH-CH2- CH2 -O- , *-CH2 - O-, * -CH2- NH-, Wherein, the * end is connected to the carbonyl group.
  • the structural unit -WUZY- is selected from *-NH-CH 2 -CH 2 -NH- and Among them, the * end is connected to the carbonyl group.
  • the drug group is selected from the structure shown in formula III-A'
  • X, X 1 , X 2 , ring B, ring C, L, R 3 , R 4 , R 5 , R 6 , R 7 , m, R 8a , R 8b and R 12 are as defined in any embodiment of the present invention.
  • the drug group is selected from the structure shown in formula III-A
  • X, X 1 , X 2 , ring B, ring C, R 3 , R 4 , R 5 , R 6 , R 7 , m, R 8a , R 8b and R 12 are as defined in any embodiment of the present invention.
  • R 12 is selected from hydrogen, -(C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl, -(C ⁇ O)-(C 1 -C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, -O-(C 3 -C 6 )cycloalkyl, -(4-10 membered)heterocyclyl, and -O-(4-10 membered)heterocyclyl.
  • the R 12 is selected from hydrogen, -(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )alkyl, -(C ⁇ O)-(C 1 -C 4 )alkyl, -(C 3 -C 6 )cycloalkyl, and -O-(C 3 -C 6 )cycloalkyl.
  • said R 12 is selected from hydrogen, -(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )alkyl, and -(C 3 -C 6 )cycloalkyl.
  • said R 12 is selected from hydrogen and -(C 1 -C 4 )alkyl.
  • said R 12 is selected from hydrogen, methyl, and ethyl.
  • said R 12 is selected from hydrogen and methyl.
  • said R 12 is selected from hydrogen.
  • said L is absent.
  • the drug group is selected from the structure shown in Formula IV-A
  • the R q is selected from hydrogen, -(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )alkyl, -(C 1 -C 4 )haloalkyl, and -O-(C 1 -C 4 )haloalkyl.
  • said Rq is selected from hydrogen, methyl, ethyl, propyl, -O-methyl, -O-ethyl, and -O-propyl.
  • Q is selected from -NH-, -O-, -CH2O- , and -CH2NH- .
  • said R 6 is selected from hydrogen, fluoro, chloro, bromo, cyano, -OH, -NH 2 , -O-methyl, and cyclopropyl.
  • said R3 is selected from
  • said R3 is selected from
  • said R3 is selected from
  • said R 4 is selected from hydrogen, fluoro, chloro, cyano, -OH, -NH 2 and methyl.
  • the Ra and Rb are each independently selected from hydrogen, fluoro, chloro, cyano , -OH, -O-methyl, -SH, -S-methyl, -NH2, -N(methyl)2 , -N(methyl)-ethyl, -N(ethyl) 2 , methyl, ethyl, propyl, halomethyl, haloethyl, and halopropyl.
  • X is selected from O, S, NH and N[(C 1 -C 4 )alkyl].
  • said X is selected from O, S and NH.
  • said X is selected from O.
  • the ring B is selected from phenyl, naphthyl, and (5-6 membered) heteroaryl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, -OH, -NH 2 , -(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkyl-OH, -(C 1 -C 4 )alkyl-NH 2 , -(C 1 -C 4 )haloalkyl, -O-(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )haloalkyl and -(C 3 -C 6 )cycloalkyl.
  • said R 5 is selected from hydrogen, fluoro, chloro, bromo, cyano, -OH, -NH 2 , and -CH 2 NH 2 .
  • said R 5 is selected from hydrogen.
  • said R 6 is selected from hydrogen, fluoro, chloro, bromo, cyano, -OH, -NH 2 , -O-methyl, and cyclopropyl.
  • said R 6 is selected from hydrogen, cyano and -O-methyl.
  • said R 6 is selected from cyano and -O-methyl.
  • said R 6 is cyano
  • the atoms to which R 5 and R 6 are attached form The * indicates the positions of connected atoms.
  • the ring C is selected from -(C 6 -C 10 )aryl and (5-10 membered)heteroaryl.
  • the ring C is selected from phenyl, naphthyl, and (5-6 membered) heteroaryl.
  • -(C 1 -C 4 )alkyl, -(C 2 -C 4 )alkenyl, -(C 2 -C 4 )alkynyl, -(C 1 -C 4 )haloalkyl, -O-(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )haloalkyl, -S-(C 1 -C 4 )alkyl, -NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 , -(C 3 -C 6 )cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C 3 -C 6 )cycloalkyl, -O-(4-8 membered)heterocyclyl and -NHC( ⁇ O)-(C 1 -C 4 )alkyl are optionally substituted by 1,
  • each of the R 7 is independently selected from hydrogen, halogen, cyano, nitro, -OH, -SH, -NH 2 , -(C 1 -C 4 )alkyl, -(C 2 -C 4 )alkenyl, -(C 2 -C 4 )alkynyl, -(C 1 -C 4 )haloalkyl, -O-(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )haloalkyl, -S-(C 1 -C 4 )alkyl, -NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 , -(C 3 -C 6 )cycloalkyl, -(4-8 membered)heterocyclyl, -O-(C 3 -C 6 )cycloalkyl, and -O-(4-8
  • the R 7 are each independently selected from hydrogen, halogen, cyano, -OH, -NH 2 , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-NH(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 , and -(C 1 -C 4 )alkylene-NH 2 .
  • each of the R 7 is independently selected from hydrogen, fluorine, chlorine, bromine, -OH, -NH 2 , -CH 2 OH, and -CH 2 NH 2 .
  • said R 7 are each independently selected from hydrogen.
  • m is 1, 2 or 3.
  • n 1
  • the R is each independently selected from hydrogen, -OH, -NH2 , -( C1 - C4 )alkyl, -O-( C1 - C4 )alkyl and -(4-8 membered)heterocyclyl, and the -( C1 - C4 )alkyl, -O-( C1 - C4 )alkyl and -(4-8 membered)heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, halogen, -OH, -NH2 , -NH( C1 - C4 )alkyl, -N[( C1 - C4 )alkyl] 2 and -O-( C1 - C4 )alkyl.
  • said R 9a is selected from hydrogen
  • said R 9a is selected from hydrogen
  • said R 9a is selected from hydrogen
  • said R 9a is selected from hydrogen
  • said R 9a is hydrogen
  • said R 9a is
  • said R 9b is selected from hydrogen and
  • said R 9b is -OH.
  • said R 9b is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • said R 9b is selected from hydrogen
  • R 8a and R 9a , R 8b and R 9b together with the carbon atom to which they are attached form (C 3 -C 6 )cycloalkyl, (4-8 membered)heterocyclyl or (5-9 membered)heteroaryl, the foregoing groups being optionally substituted with 1, 2, 3, 4, 5, 6 or 7 groups selected from hydrogen, halogen, -OH, -O-(C 1 -C 4 )alkyl, -NH 2 , -NH(C 1 -C 4 )alkyl, -N[(C 1 -C 4 )alkyl] 2 , -(C 3 -C 6 )cycloalkyl and -(C 6 -C 10 )aryl.
  • R 8b and R 9b together with the carbon atom to which they are attached form a (4-8 membered) heterocyclyl or a (5-9 membered) heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 groups selected from hydrogen, fluorine, chlorine, -OH, -O-methyl, -O-ethyl, -NH 2 , -NH-methyl, -NH-ethyl, -N(methyl) 2 , -N(methyl)-ethyl, -N(ethyl) 2 , cyclopropyl, cyclobutyl, cyclopentyl, phenyl and naphthyl.
  • the atoms to which R 10 and R 9a are attached form The * indicates the positions of connected atoms.
  • said R 10 is -OH.
  • said R 10 is
  • the drug group is selected from the structure shown in Formula IA-1, II-A-1', II-A-1, III-A-1', III-A-1, IV-A-1 or VA-1:
  • the drug group is selected from the structure shown in Formula IA-2, II-A-2', II-A-2, III-A-2', III-A-2, IV-A-2 or VA-2:
  • X, X1 , X2 , Ring A, R3 , R4 , R5 , R6 , R7, R8a , R8b , R9a , R9b , R10 , R12 , m, n, M, W, U, Z, Y, L , Q and T are as defined in any embodiment of the present invention.
  • the drug group is selected from the structures shown in Formula IA-3, III-A-3', III-A-3, IV-A-3 or VA-3:
  • X, X 1 , X 2 , Ring A, R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , R 9b , R 12 , m, M, L, Q and T are as defined in any embodiment of the present invention.
  • the drug group is selected from the structure shown in formula IA-4, II-A-4', II-A-4, III-A-4', III-A-4, IV-A-4 or VA-4:
  • M is selected from -NH-, -O-, -(C 1 -C 4 )alkylene-O- and -(C 1 -C 4 )alkylene-NH-;
  • n 0 or 1
  • W is absent or is selected from -(C 1 -C 4 )alkylene, -NH- and -N[-(C 1 -C 4 )alkyl]-;
  • U is selected from -(C 1 -C 4 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-6 membered)heterocyclylene-;
  • Z is absent or is selected from -(C 1 -C 4 )alkylene-, -(C 3 -C 6 )cycloalkylene- and -(4-6 membered)heterocyclylene-;
  • R 12 is selected from hydrogen, -(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )alkyl and -(C 3 -C 6 )cycloalkyl;
  • Q is selected from -NH-, -O-, -(C 1 -C 4 )alkylene-O- and -(C 1 -C 4 )alkylene-NH-;
  • T is selected from -NH-, -O-, -(C 1 -C 4 )alkylene-O- and -(C 1 -C 4 )alkylene-NH-;
  • X 1 is selected from N and C(R 1 ), R 1 is selected from hydrogen, halogen, cyano, -OH, -(C 1 -C 4 )alkyl and -O-(C 1 -C 4 )alkyl;
  • X 2 is selected from C(R 2 ), R 2 is selected from hydrogen, halogen, cyano, -OH, -(C 1 -C 4 )alkyl and -O-(C 1 -C 4 )alkyl;
  • R 3 is selected from -(5-9 membered)heteroaryl, -(C 3 -C 6 )cycloalkyl and -(4-6 membered)heterocyclyl, said R 3 being optionally substituted by 1, 2, 3 or 4 R 31 ;
  • Ring A is selected from -(5-9 membered)heteroarylene-, said ring A is optionally substituted by 1, 2, 3 or 4 R 31 ,
  • R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH, -NH 2 , methyl, halomethyl, -O-methyl, -NH-methyl and cyclopropyl;
  • X is selected from O, S, NH and N[(C 1 -C 4 )alkyl];
  • Ring B is phenyl or phenylene, and the phenylene is optionally substituted by one R 5 or R 6 ;
  • R 5 and R 6 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH 2 , -(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkyl-OH, -(C 1 -C 4 )alkyl-NH 2 , -(C 1 -C 4 )haloalkyl, -O-(C 1 -C 4 )alkyl, -O-(C 1 -C 4 )haloalkyl and -(C 3 -C 6 )cycloalkyl; or R 5 and R 6 and the atoms to which they are attached form Where * indicates the connected atomic positions;
  • Q is selected from -NH-, -O-, -CH2O- and -CH2NH- ;
  • X 1 is selected from N and C(R 1 ), R 1 is selected from hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl;
  • R 31 is selected from oxo, hydrogen, fluoro, chloro, cyano, -OH, -SH, -NH 2 , methyl, halomethyl, -O-methyl, -CH 2 OH, -CH 2 NH 2 and -CH 2 CH 2 N(CH 3 ) 2 ;
  • R is selected from cyclopropyl, oxetanyl, morpholinyl, morpholinonyl, piperidinyl, piperazinyl, piperazinonyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridazinoimidazolyl, pyrazinoimidazolyl and pyrimidonyl, said R being optionally substituted with 1, 2 or 3 R ;
  • Ring A is selected from the group consisting of oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, triazolylene, tetrazolylene, pyridinylene, pyrazinylene, pyridazinylene, pyrimidinylene, pyridazinoimidazolylene, pyrazinoimidazolylene and pyrimidinonylene, and the ring A is optionally substituted with 1, 2 or 3 R 31 ;
  • R 4 is selected from hydrogen, fluorine, chlorine, cyano, -OH and -NH 2 ;
  • X is selected from O;
  • R 5 is selected from hydrogen, -OH, -NH 2 and -CH 2 NH 2 ;
  • R 6 is selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH 2 , cyclopropyl and -O-methyl;
  • ring B is * terminal is connected to Q;
  • R 7 is each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, -OH, -NH 2 , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-NH(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkylene-N[(C 1 -C 4 )alkyl] 2 and -(C 1 -C 4 )alkylene-NH 2 ;
  • n 1, 2 or 3;
  • ring C is * end is connected to M;
  • M is selected from -NH-, -O-, -CH2O- and -CH2NH- ;
  • ring B is * terminal is connected to Q;
  • R4 is hydrogen
  • X is O
  • R 5 and R 6 and the atoms to which they are attached form Where * indicates the connected atomic positions;
  • ring C is * end is connected to M;
  • R 8b is selected from hydrogen
  • the drug group is selected from the structures shown in Formula IA-5, II-A-5, III-A-5, IV-A-5 or VA-5:
  • X, R 1 , Ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , n, M, W, U, Z, Y, L, Q and T are as defined in any embodiment of the present invention.
  • M is selected from -NH-, -O-, *-CH 2 O- and *-CH 2 NH-, wherein the * end is connected to the ring C;
  • n 0 or 1
  • W is absent or selected from -NH- and -N(Me)-;
  • U is selected from methylene, ethylene and
  • Y is selected from -O-, -NH-, -N(CH 3 )- and -N + (CH 3 ) 2 -;
  • the structural unit -WUZY- is selected from *-NH- CH2 - CH2 -NH-, *-NH- CH2 - CH2 -O-, *-CH2 - O-, * -CH2 -NH-, * -CH2- N(CH3 ) -, * -CH2 -N + ( CH3 ) 2- , Among them, the * end is connected to the carbonyl group;
  • R 12 is selected from hydrogen and methyl
  • Q is selected from -NH-
  • X is O
  • R 1 is selected from hydrogen, halogen, cyano, -OH, -(C 1 -C 4 )alkyl and -O-(C 1 -C 4 )alkyl, in certain embodiments, said R 1 is selected from hydrogen, fluorine, chlorine, cyano, -OH, methyl, ethyl, propyl, -O-methyl, -O-ethyl and -O-propyl;
  • R3 is selected from oxazolyl, pyrazolyl and pyrimidinyl. In certain embodiments, said R3 is selected from R 3 is optionally substituted with 1, 2 or 3 R 31 ;
  • Ring A is selected from -(5-6 membered)heteroarylene-, wherein the -(5-6 membered)heteroarylene- is optionally substituted with 1, 2, 3 or 4 R 31 ;
  • R 31 is each independently selected from hydrogen, fluorine, chlorine, cyano, -OH, -SH, -NH 2 , -CH 2 OH, -CH 2 NH 2 , -CH 3 , -CF 3 and -OCH 3 ;
  • R3 is selected from
  • ring A is selected from The * end is connected to T;
  • R 5 is hydrogen or -NH 2 ;
  • R 7 is each independently selected from hydrogen, fluorine, chlorine, bromine, -OH and -NH 2 ;
  • R 9a is selected from hydrogen,
  • the drug group is selected from the structures shown in Formula IA-6 and IA-7:
  • R 8b and R 9a are hydrogen, and R 9b is as described in any embodiment of the present invention.
  • R 8b and R 9b are hydrogen, and R 9a is as described in any embodiment of the present invention.
  • R 9a is hydrogen
  • R 8b and R 9b are as described in any embodiment of the present invention, and R 8b and R 9b are not hydrogen.
  • said R 31 is hydrogen
  • the drug group is selected from the structures shown in Table A:
  • L2 is absent or selected from a linker fragment
  • L1 is a connection unit.
  • the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate wherein the linking group is -Tr-L 3 -L 2 -L 1 -, wherein:
  • Tr does not exist or Tr is an arbitrary group
  • L 3 is absent or selected from a polypeptide fragment
  • L2 is absent or selected from a linker fragment
  • L1 is a connection unit.
  • the linker group and the drug group are connected to form a structure selected from the group consisting of:
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 8a , R 8b , R 9a , R 9b , R 10 , M, Tr, L 3 , L 2 and L 1 are as defined in any embodiment of the present invention;
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • the linker group and the drug group are connected to form a structure selected from the group consisting of:
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , m, n, W, U, Z, Y, Tr, L 3 , L 2 and L 1 are as defined in any embodiment of the present invention
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • the linker group and the drug group are connected to form a structure selected from Formula II-B,
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , m, W, U, Z, Y, Tr, L 3 , L 2 and L 1 are as defined in any embodiment of the present invention
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 12 , L, m, Tr, L 3 , L 2 and L 1 are as defined in any embodiment of the present invention;
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • the linker group and the drug group are connected to form a structure selected from the group consisting of:
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • the linker group and the drug group are connected to form a structure selected from the group consisting of:
  • X, X 1 , X 2 , Ring A, Ring B, Ring C, R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , m, T, Tr, L 3 , L 2 and L 1 are as defined in any embodiment of the present invention;
  • the wavy line indicates that the ligand is connected through the nitrogen atom or carbon atom on the L1 group.
  • the linker group and the drug group are connected to form a structure wherein:
  • L 1 is the connection unit
  • L2 is -(C(R L21 ) 2 ) r -, r is a natural number between 0 and 50,
  • -Cy- is selected from -phenylene-, -(5-8 membered)heteroarylene-, -(4-10 membered)heterocyclylene- and -(C 3 -C 10 )cycloalkylene-, wherein said -Cy- is unsubstituted or each independently substituted by one or more R Cx ,
  • s and y are each independently a natural number between 0 and 50,
  • Tr does not exist or is selected from and any combination of the foregoing groups,
  • R Tr , R Tr1 and R Tr2 are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH 2 , -SH, -OC( ⁇ O)NH 2 , -C( ⁇ O)OH, -C( ⁇ O)NH 2 , -S( ⁇ O) 2 OH, -S( ⁇ O) 2 NH 2 , -CH 2 C( ⁇ O)-(N(Me)CH 2 C( ⁇ O)) z -OR Tra , -CH 2 C( ⁇ O)-(N(Me)CH 2 C( ⁇ O)) z -NHR Tra , -(CH 2 CH 2 O) z -R Tra , -C( ⁇ O)NH-(CH 2 CH 2 O) z -R Tra , -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 3 -C 6 )alkyny
  • each R Tra is independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH 2 , -SH, -N(Me) 2 , -C( ⁇ O)OH, -C( ⁇ O)NH 2 , -S( ⁇ O) 2 OH, -S( ⁇ O) 2 NH 2 , -S( ⁇ O) 2 Me, -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C 6 -C 10 )aryl, and -(5-10 membered)heteroaryl,
  • each R Tra is independently hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH 2 , -SH, -N(Me) 2 , -C( ⁇ O)OH, -C( ⁇ O)NH 2 , -S( ⁇ O) 2 OH, -S( ⁇ O) 2 NH 2 , -S( ⁇ O) 2 Me, -(C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, -(C 3 -C 8 )cycloalkyl, -(4-10 membered)heterocycloalkyl, -(C 6 -C 10 )aryl, and -(5-10 membered)heteroaryl,
  • Each z is independently a natural number between 0 and 50.
  • said L is selected from carbonyl, -(C 1 -C 4 )alkylene-C( ⁇ O)-, -(5-6 membered)heterocyclylene-, -(5-6 membered)heteroarylene- and -(C 1 -C 4 )alkylene-(5-6 membered)heteroarylene-, and said -(C 1 -C 4 )alkylene-C( ⁇ O)-, -(5-6 membered)heterocyclylene-, -(5-6 membered)heteroarylene- and -(C 1 -C 4 )alkylene-(5-6 membered)heteroarylene- are optionally substituted with 1, 2 or 3 oxo, -(C 1 -C 4 )alkylene- and -(C 1 -C 4 )alkylene.
  • the L 1 is selected from
  • the L 1 is selected from Among them, the * end is connected to L2 .
  • L 2 is -(C( RL21 ) 2 ) r- , r is a natural number of 0-10 (eg, 1, 2, 3, 4, 5, 6, 7, 8 or 9),
  • said -L 1 -L 2 - is selected from:
  • said -L 1 -L 2 - is selected from: Among them, the * end is connected to L3 .
  • said -L 1 -L 2 - is selected from: Among them, the * end is connected to L3 .
  • said -L 1 -L 2 - is selected from: Among them, the * end is connected to L3 .
  • the amino acid residue is selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg and Ser,
  • the short peptide consisting of 2 to 10 amino acid residues is selected from -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -(D-Ala)-Ala-, -Gly-Glu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-As n-, -Asp-Asp-, -Asp-Glu-, -Ser-Val-, -Ser-Ala-, -Ser-Gly-, -Ser
  • the polyethylene glycol fragment is selected from -(CH 2 CH 2 O) t -R L3 , R L3 is -(C 1 -C 6 ) alkyl, and t is an integer of 6-30.
  • L is selected from Val, D-Val, Phe, Lys, Leu, Ile, Gly, Ala, D-Ala, Cit, Asp, Asn, Glu, Gln, Arg, -Arg-Val-, -Arg-Leu-, -Val-Cit-, -Val-Ala-, -Val-Lys-, -Val-Lys(AC)-, -Phe-Lys-, -Phe-Lys(AC)-, -Leu-Lys-, -Leu-Lys(AC)-, -Ala-Ala-, -Ala-Lys-, -D-Ala-Ala-, -Gly-Glu-, -Gly-Asp-, -Gly-Asn-, -Val-Glu-, -Val-Asp-, -Asn-Asn-, -Asp-Asp-, -Asp-, -
  • L 3 is selected from -Val-Cit-*, *-Ala-Ala-, *-Gly-Glu-, *-Ser-Ala-, *-Ser-Gly-, *-Ser-Glu-, *-Ser-Asp-, -Gly-Gln-*, *-Gly-Ala-Ala-, *-Gly-Gly-Glu-, -Gly-Gly-Phe-Gly-*, *-Ala-Ala-Glu(NH-(CH 2 CH 2 O) 11 -CH 3 )-, wherein the * end is connected to Tr.
  • the L3 is selected from *-Ala-Ala-, *-Gly-Glu- and *-Gly-Gly-Glu-, wherein the * end is connected to Tr.
  • R Tr , R Tr1 and R Tr2 are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -OH, -NH 2 , -SH, -OC( ⁇ O)NH 2 , -C( ⁇ O)OH, -C( ⁇ O)NH 2 , -S( ⁇ O) 2 OH, -S( ⁇ O) 2 NH 2 , -(CH 2 CH 2 O) z -R Tra , -C( ⁇ O)NH-(CH 2 CH 2 O) z -R Tra , gluconolactone, glucuronic acid, -(C 1 -C 4 )alkyl and -(C 2 -C 4 )alkenyl, said -(C 1 -C 4 )alkyl and -(C 2 -C 4 )alkenyl being optionally substituted with 1, 2, 3, 4 or 5 R Tra ,
  • Each z is independently an integer from 6 to 30.
  • Each z is independently an integer from 6 to 30.
  • Each z is independently an integer from 6 to 30 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 20, 21, 22, 23, 24, 25).
  • the Tr is absent or is selected from
  • the Tr is absent or is selected from
  • the Tr is absent or is selected from Among them, the * end is connected to L3 .
  • said -L 3 -L 2 -L 1 - is selected from:
  • said -L 3 -L 2 -L 1 - is selected from:
  • the -L 3 -L 2 -L 1 - is selected from
  • the -L 3 -L 2 -L 1 - is selected from
  • the -Tr-L 3 -L 2 -L 1 - is selected from
  • the -Tr-L 3 -L 2 -L 1 - is
  • the linker group and the drug group are connected to form a structure selected from the group consisting of IB-2, II-B-2', II-B-2, III-B-2', III-B-2, IV-B-2 or VB-2,
  • X, X1 , X2 , Ring A, R3 , R4 , R5 , R6 , R7, R8a , R8b , R9a , R9b , R10 , R12 , m, n, M, W, U, Z, Y, L , Q, T, Tr, L1 , L2 and L3 are as defined in any embodiment of the present invention.
  • X, R 1 , Ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , n, M, W, U, Z, Y, L, Q, T, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the linker group and the drug group are connected to form a structure selected from the group consisting of Formula IB-6 and IB-7,
  • R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b , M, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the linker group and the drug group are connected to form a structure selected from the following Table B:
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 8a , R 8b , R 9a , R 9b , R 10 , M, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention;
  • Ab is the ligand that binds to the target
  • k is the drug loading amount, which is an integer or decimal between 1 and 16.
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , m, W, U, Z, Y, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention.
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 12 , m, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention;
  • Ab is the ligand that binds to the target
  • k is the drug loading amount, which is an integer or decimal between 1 and 16.
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , m, Q, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention;
  • Ab is the ligand that binds to the target
  • X, X 1 , X 2 , Ring A, Ring B, Ring C, R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , m, T, Tr, L 1 , L 2 and L 3 are as defined in any embodiment of the present invention;
  • Ab is the ligand that binds to the target
  • k is the drug loading amount, which is an integer or decimal between 1 and 16.
  • the Ab is coupled to L1 via the S atom
  • the antibody is selected from one or more of the following:
  • the antigen-binding fragment is selected from the group consisting of an antigen-binding fragment of a Fab, Fab', F(ab') 2 , Fv, scFv, Fd, dAb, VHH, and a complementarity determining region (CDR) fragment.
  • the Ab comprises a heavy chain variable region sequence as shown in SEQ ID NO:24 and/or a light chain variable region sequence as shown in SEQ ID NO:23.
  • the Ab comprises a heavy chain variable region sequence as shown in SEQ ID NO:34 and/or a light chain variable region sequence as shown in SEQ ID NO:33.
  • the Ab comprises a heavy chain variable region sequence as shown in SEQ ID NO:44 and/or a light chain variable region sequence as shown in SEQ ID NO:43.
  • the Ab comprises a heavy chain variable region sequence as shown in SEQ ID NO:60 and/or a light chain variable region sequence as shown in SEQ ID NO:59.
  • amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:1
  • amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:2.
  • amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:3, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:4.
  • amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:25, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:26.
  • amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:35, and the amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:36.
  • amino acid sequence of the heavy chain of the Ab is as shown in SEQ ID NO:15
  • amino acid sequence of the light chain of the Ab is as shown in SEQ ID NO:16.
  • the Ab is an anti-CEACAM5 antibody or an antigen-binding fragment thereof, such as Tusamitamab or an antigen-binding fragment thereof or a variant thereof.
  • the Ab comprises a heavy chain and a light chain of an anti-CEACAM5 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:1 or as shown in SEQ ID NO:1, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:2 or as shown in SEQ ID NO:2.
  • the Ab is an anti-HER3 antibody or an antigen-binding fragment thereof, such as DB1001 or an antigen-binding fragment thereof or a variant thereof.
  • the Ab is an anti-GPC-3 antibody or an antigen-binding fragment thereof, such as DB1002 or an antigen-binding fragment thereof or a variant thereof.
  • the Ab comprises a heavy chain and a light chain of an anti-GPC-3 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:5 or as shown in SEQ ID NO:5, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:6 or as shown in SEQ ID NO:6.
  • the Ab is an anti-ADAM9 antibody or an antigen-binding fragment thereof, such as DB1003 or an antigen-binding fragment thereof or a variant thereof.
  • the Ab comprises a heavy chain and a light chain of an anti-ADAM9 antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:25 or as shown in SEQ ID NO:25, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:26 or as shown in SEQ ID NO:26.
  • the Ab is an anti-BCMA antibody or an antigen-binding fragment thereof, such as DB1004 or an antigen-binding fragment thereof or a variant thereof.
  • the Ab comprises a heavy chain and a light chain of an anti-BCMA antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:35 or as shown in SEQ ID NO:35, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO:36 or as shown in SEQ ID NO:36.
  • the Ab is an anti-c-met antibody or an antigen-binding fragment thereof, such as DB1005 or an antigen-binding fragment thereof or a variant thereof.
  • the Ab comprises a heavy chain and a light chain of an anti-c-met antibody or an antigen-binding fragment thereof, wherein the amino acid sequence of the heavy chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO: 15 or as shown in SEQ ID NO: 15, and the amino acid sequence of the light chain is a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity with SEQ ID NO: 16 or as shown in SEQ ID NO: 16.
  • the k is an integer or decimal selected from 1-10.
  • k is an integer or decimal selected from 2-9.
  • k is an integer or decimal selected from 2-8.
  • k is selected from an integer or decimal of 4-8 (eg, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8).
  • k is selected from an integer or decimal of 6-8 (e.g., about 6.1, about 6.3, about 6.5, about 6.7, about 6.9, about 7.1, about 7.3, about 7.5, about 7.7, about 8).
  • k is selected from an integer or decimal of 7-9 (e.g., about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5).
  • k is selected from an integer or decimal between 7.5 and 8.1 (e.g., 7.81, 7.82, 7.83, 7.84, 7.85, 7.86, 7.87, 7.88, 7.89, 7.90, 7.91, 7.92, 7.93, 7.94, 7.95, 7.96, 7.97, 7.98, 7.99, 8.00, 8.01, 8.02, 8.03, 8.04, 8.05, 8.06, 8.07, 8.08, 8.09, 8.10).
  • k is selected from an integer or decimal of 7-8 (e.g., about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8).
  • the k is an integer or decimal selected from 7.5-8.
  • said k is selected from a number of 2-8, for example, 2, 3, 4, 5, 6, 7, 8. In certain embodiments, said k is selected from 6 and 8.
  • the ligand-drug conjugate is selected from the compounds represented by formula IC-1, II-C-1', II-C-1, III-C-1', III-C-1, IV-C-1 or VC-1;
  • the ligand-drug conjugate is selected from the compounds represented by formula IC-2, II-C-2', II-C-2, III-C-2', III-C-2, IV-C-2 or VC-2,
  • the ligand-drug conjugate is selected from the compounds represented by formula IC-3, III-C-3', III-C-3, IV-C-3 or VC-3,
  • X, X 1 , X 2 , Ring A, R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , R 9b , R 12 , m, M, L, Q, T, Tr, L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.
  • the ligand-drug conjugate is selected from the compounds represented by formula IC-5, II-C-5, III-C-5, IV-C-5 or VC-5,
  • R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b , M, Tr, L 1 , L 2 , L 3 , Ab and k are as defined in any embodiment of the present invention.
  • the ligand-drug conjugate is selected from the structures shown in Table C:
  • the second aspect of the present invention provides a mixture of ligand-drug conjugates, which comprises the aforementioned ligand-drug conjugates, their tautomers, their enantiomers, their diastereomers, their pharmaceutically acceptable salts or solvates thereof or consists of them, wherein the ligand-drug conjugates have one, two or more k values.
  • X, X 1 , X 2 , Ring A, Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 12 , m, n, M, W, U, Z, Y, L, Q, T, Tr, L 2 and L 3 are as defined in any embodiment of the first aspect of the present invention
  • L 1a is a connecting unit.
  • the compound is selected from the group consisting of the structure shown in formula III-D
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 12 , m, Tr, L 1a , L 2 and L 3 are as defined in any embodiment of the present invention.
  • X, X 1 , X 2 , Ring B, Ring C, R 3 , R 4 , R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , m, Q, Tr, L 1a , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the compound is selected from the group consisting of the structures shown in formula VD
  • the L 1a is selected from
  • the L 1a is selected from
  • said L 1a -L 2 - is selected from:
  • said L 1a -L 2 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • the L 1a -L 2 -L 3 -Tr- is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • said L 1a -L 2 -L 3 - is selected from:
  • the compound is selected from the structure shown in formula ID-3, III-D-3', III-D-3, IV-D-3 or VD-3,
  • X, X 1 , X 2 , Ring A, R 3 , R 4 , R 5 , R 6 , R 7 , R 8b , R 9b , R 12 , m, M, L, Q, T, Tr, L 1a , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the compound is selected from the structure shown in formula ID-4, II-D-4', II-D-4, III-D-4', III-D-4, IV-D-4 or VD-4,
  • the compound is selected from the structure shown in formula ID-5, II-D-5, III-D-5, IV-D-5 or VD-5,
  • X, R 1 , Ring A, R 3 , R 5 , R 6 , R 7 , R 8b , R 9a , R 9b , R 12 , n, M, W, U, Z, Y, Q, T, Tr, L, L 1a , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the compound is selected from the structures shown in formula ID-6 and ID-7,
  • R 1 , R 31 , R 5 , R 6 , R 8b , R 9a , R 9b , M, Tr, L, L 1a , L 2 and L 3 are as defined in any embodiment of the present invention.
  • the compound is selected from the structures shown in Table D:
  • the fourth aspect of the present invention provides the use of the compound described in any embodiment of the third aspect of the present invention or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate in the preparation of the ligand-drug conjugate described in any embodiment of the first aspect of the present invention.
  • the fifth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one ligand-drug conjugate described in any embodiment of the first aspect of the present invention or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or at least one compound described in any embodiment of the third aspect of the present invention or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the sixth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mixture of at least one ligand-drug conjugate as described in any embodiment of the second aspect of the present invention, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the seventh aspect of the present invention provides the use of the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, as described in any embodiment of the first aspect of the present invention, or the compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, as described in any embodiment of the third aspect of the present invention, or the pharmaceutical composition as described in any embodiment of the fifth aspect of the present invention in the preparation of a medicament for treating and/or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.
  • the seventh aspect of the present invention also provides the use of the mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the pharmaceutical composition described in any embodiment of the sixth aspect of the present invention in the preparation of a medicament for treating and/or preventing a disease or condition or alleviating the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.
  • the seventh aspect of the present invention also provides the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or solvate as described in any embodiment of the first aspect of the present invention, or the compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or mixture thereof as described in any embodiment of the third aspect of the present invention, or the pharmaceutical composition as described in any embodiment of the fifth aspect of the present invention, which is used to treat and/or prevent a disease or condition or reduce the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.
  • the seventh aspect of the present invention also provides a mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the drug combination described in any embodiment of the sixth aspect of the present invention, which is used to treat and/or prevent a disease or condition or alleviate the severity of the disease or condition, wherein the disease or condition is a tumor or cancer.
  • the seventh aspect of the present invention also provides a method for treating and/or preventing a disease or condition or reducing the severity of the disease or condition, which comprises administering to an individual in need an effective amount of the ligand-drug conjugate or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof as described in any embodiment of the first aspect of the present invention, or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt or solvate, or the compound or its racemate, tautomer, stereoisomer, enantiomer, diastereomer, or a mixture thereof as described in any embodiment of the third aspect of the present invention, or the pharmaceutical composition as described in any embodiment of the fifth aspect of the present invention, wherein the disease or condition is a tumor or cancer.
  • the seventh aspect of the present invention also provides a method for treating and/or preventing a disease or condition or reducing the severity of the disease or condition, which comprises administering to an individual in need an effective amount of a mixture of the ligand-drug conjugate described in any embodiment of the second aspect of the present invention, or the drug combination described in any embodiment of the sixth aspect of the present invention.
  • the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma, gastric cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, liver cancer and lung cancer.
  • the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, liver cancer and lung cancer.
  • the tumor or cancer is selected from gastric cancer, colorectal cancer, breast cancer, ovarian cancer and liver cancer.
  • the colorectal cancer is selected from colorectal adenocarcinoma and colon cancer.
  • the tumor or cancer is selected from leukemia, malignant lymphoma, multiple myeloma.
  • Tusamitamab The complementary determining region and variable region sequences of Tusamitamab are shown in the table below.
  • the complementary determining region and variable region sequences of the anti-ADAM9 antibody DB1003 are shown in the table below.
  • Anti-BCMA antibody DB1004 (Belantamab) heavy chain amino acid sequence
  • Anti-BCMA antibody DB1004 (Belantamab) light chain amino acid sequence
  • the CDR region sequences in the above table are defined using the Kabat numbering system. Any other CDR region sequence determination method known in the art may also be used to identify the amino acid residues in the CDR region within the variable region.
  • the complementary determining region and variable region sequences of the anti-c-met antibody DB1005 are shown in the following table.
  • X represents norvaline (Nva).
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids or with organic acids, or coordination compounds formed by acidic protons present on the parent compound being substituted with metal ions or with organic bases.
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention can exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, and any combination or any mixture thereof.
  • a single enantiomer for example, a single diastereomer, or a mixture thereof.
  • the compounds of the present invention contain an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions, such as keto-enol tautomers, imine-enamine tautomers, etc. If tautomers exist for the compounds of the present invention, they may exist in the form of a single tautomer or a mixture thereof, preferably in the form of a relatively stable tautomer as the main component.
  • racemate includes “racemate”, the term “racemate” refers to an equimolar mixture of an optically active chiral molecule and its enantiomer; the term “enantiomer” refers to one of a pair of molecular entities that are mirror images of each other and cannot be superimposed, and a mixture of enantiomers can be separated under conditions such as chiral resolution; the term “diastereomer” refers to stereoisomers that are unrelated to each other in mirror image, and diastereomers are characterized by some differences in physical and chemical properties. A mixture of diastereomers can be separated under conditions such as chromatography or crystallization.
  • solvate refers to a substance formed by the association of a compound of the present invention with a solvent molecule.
  • the solvent may be an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.), for example, the compound of the present invention may form an ethanolate with ethanol.
  • the compound of the present invention may also form a hydrate with water.
  • the amount of the solvent may be present in a stoichiometric ratio or a non-stoichiometric ratio.
  • substituted means that a hydrogen atom in a group is replaced by a corresponding substituent, for example, -CH2- in A- CH2 -B is replaced by one -NH2 , thus obtaining A-CH( NH2 )-B. It should be understood that the substituents are only in their possible chemical positions.
  • replacement means that the group itself is replaced by a corresponding group, for example, -CH 2 - in A-CH 2 -B is replaced by -NH- to obtain A-NH-B.
  • R is selected from -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) alkyl and -NH(C 1 -C 6 ) alkyl, and the -(C 1 -C 6 ) alkyl is optionally substituted by halogen", means that the (C 1 -C 6 ) alkyl in -(C 1 -C 6 ) alkyl, -O-(C 1 -C 6 ) alkyl, and the (C 1 -C 6 ) alkyl in -NH(C 1 -C 6 ) alkyl.
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • alkyl refers to a linear or branched monovalent saturated hydrocarbon group, for example, (C 1 -C 6 ) alkyl refers to a group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms; (C 1 -C 4 ) alkyl refers to a group having 1 to 4 carbon atoms, such as 1, 2, 3 or 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, etc.
  • alkylene refers to a straight or branched divalent saturated hydrocarbon group, for example, (C 1 -C 6 )alkylene refers to a group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms; (C 1 -C 4 )alkylene refers to a group having 1 to 4 carbon atoms, such as 1, 2, 3 or 4 carbon atoms.
  • alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, etc.
  • halo means that the group it modifies is substituted by one or more halogens, for example, substituted by 1, 2, 3, 4, 5 or 6 halogens.
  • (C 1 -C 6 )haloalkyl means that (C 1 -C 6 )alkyl as defined above is substituted by one or more halogens, non-limiting examples include but are not limited to CF 3 , CHF 2 or CF 2 CF 3 , etc.
  • alkenyl refers to a straight or branched unsaturated hydrocarbon group containing at least one double bond.
  • (C2 - C6 )alkenyl refers to a group having 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, including (C2 - C5 )alkenyl, (C2 - C4 )alkenyl, (C2 - C3 )alkenyl, etc.
  • alkynyl refers to a straight or branched unsaturated hydrocarbon group containing at least one triple bond
  • (C2 - C6 )alkynyl refers to a group having 2 to 6 (such as 2, 3, 4, 5 or 6) carbon atoms, including (C2 - C5 )alkynyl, (C2 - C4 )alkynyl, (C2 - C3 )alkynyl, etc.
  • Non-limiting examples include but are not limited to ethynyl or propynyl, etc.
  • cycloalkyl refers to a monovalent saturated hydrocarbon group consisting of carbon atoms, for example, a (C 3 -C 6 )cycloalkyl group is composed of 3-6 (e.g., 3, 4, 5, or 6) carbon atoms.
  • the cycloalkyl group includes a monocyclic, bicyclic, or polycyclic ring, including a spirocyclic, fused, or bridged ring.
  • Non-limiting examples include, but are not limited to, cyclobutyl, cyclopentyl, or cyclohexyl, etc.
  • cycloalkylene refers to a divalent saturated hydrocarbon group consisting of carbon atoms, for example, (C 3 -C 6 )cycloalkylene refers to a group consisting of 3-6 (e.g., 3, 4, 5 or 6) carbon atoms.
  • the cycloalkylene includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, fused or bridged ring.
  • Non-limiting examples include, but are not limited to, cyclobutylene, cyclopentylene or cyclohexylene, etc.
  • arylene refers to a divalent unsaturated carbocyclic group having a conjugated ⁇ electron system, for example, (C 6 -C 10 )arylene consists of 6 to 10 (eg, 6, 7, 8, 9 or 10) carbon atoms.
  • Non-limiting examples include, but are not limited to, phenylene and the like.
  • amino acids have meanings known in the art.
  • the amino acids are generally L-type amino acids, and those skilled in the art understand that they can also be replaced by D-type amino acids with similar chemical properties.
  • Val represents valine
  • Ala represents alanine
  • Glu represents glutamic acid
  • Cit represents citrulline
  • Nva represents norvaline
  • Lys (AC) represents acetylated lysine.
  • linking unit refers to a fragment used to link antibodies.
  • any values of the ranges disclosed in this application are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values.
  • the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this application.
  • antibody refers to any form of antibody having the desired biological activity. Therefore, it is used in the broadest sense, specifically including but not limited to monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • the term "monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a large number of antibodies directed against (or specific for) different epitopes.
  • the modifier "monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous antibody population, and should not be construed as requiring the antibody to be produced by any particular method.
  • the term "antigen-binding fragment" of an antibody includes fragments or derivatives of an antibody, typically including at least one fragment of an antigen-binding region or variable region (e.g., one or more CDRs) of a parent antibody, which retains at least some of the binding specificity of the parent antibody.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab') 2 and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as scFv; nanobodies and multispecific antibodies formed by antibody fragments.
  • the binding fragment or derivative When the binding activity of an antigen is expressed on a molar concentration basis, the binding fragment or derivative generally retains at least 10% of its antigen-binding activity.
  • the binding fragment or derivative retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the antigen-binding affinity of the parent antibody. It is also contemplated that the antigen-binding fragment of an antibody may include conservative or non-conservative amino acid substitutions that do not significantly change its biological activity (referred to as “conservative variants” or “functional conservative variants” of antibodies).
  • the term "ligand-conjugated drug” generally refers to a ligand connected to a biologically active cytotoxic drug through a stable linker.
  • the "ligand-conjugated drug” may be an antibody-drug conjugate (ADC), and the ADC may refer to a monoclonal antibody or an antigen-binding fragment connected to a biologically active cytotoxic drug through a stable linker.
  • ADC antibody-drug conjugate
  • the term "ligand” generally refers to small molecules, polypeptides, RNA, DNA, carbohydrates and macromolecular compounds that can recognize and bind to antigens or receptors associated with target cells.
  • the role of the ligand can be to present the drug to the target cell population bound to the ligand.
  • These ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells, receptors and/or antigens.
  • the ligand can be expressed as Ab, and the ligand antigen forms a connection bond with the connecting unit (also called "linker” or "linker”) through the heteroatom on the ligand.
  • the ligand can be an antibody or an antigen-binding fragment thereof, and the antibody can be selected from a chimeric antibody, a humanized antibody, a fully human antibody or a mouse antibody; the antibody can be a monoclonal antibody; the antibody can be a bispecific antibody.
  • the antibody can be an antibody targeting a target selected from the following targets: HER2, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 and EGFR.
  • the antibody can be an antibody targeting a target selected from the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, A SLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CC R7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223 , CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45(PTPRC), CD46,
  • an antibody that specifically binds to an antigen means that the antibody binds to the antigen with an affinity ( KD ) of less than about 10-5 M, such as less than about 10-6 M, 10-7 M, 10-8 M, 10-9 M, or 10-10 M or less.
  • the term "pharmaceutically acceptable carrier and/or excipient” refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995).
  • Pharmaceutically acceptable carriers and/or excipients include, but are not limited to, pH adjusters, surfactants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, preservatives, stabilizers.
  • pH adjusters include, but are not limited to, phosphate buffers.
  • Surfactants include, but are not limited to, cationic, anionic or nonionic surfactants, such as Tween-80.
  • Ionic strength enhancers include, but are not limited to, sodium chloride.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like.
  • Agents that delay absorption include, but are not limited to, monostearate and gelatin.
  • Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), etc.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc.
  • Stabilizers have the meanings commonly understood by those skilled in the art, which can stabilize the desired activity of the active ingredient in the drug, including, but not limited to, sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), etc.
  • sugars such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose
  • amino acids such as glutamic acid, glycine
  • proteins such as dried whey, albumin or casein
  • degradation products such as lactalbumin hydrolysate
  • the term "treatment” is intended to alleviate, mitigate, improve or eliminate the disease state or condition being targeted. If a subject receives a therapeutic amount of the ligand-coupled drug or its racemate, enantiomer, diastereomer, pharmaceutically acceptable salt, or a mixture of the foregoing forms according to the methods described herein, and one or more signs and symptoms of the subject show an observable and/or detectable reduction or improvement, the subject is successfully "treated”. It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment but achieving some biological or medically relevant results.
  • prevention aims to avoid, reduce, prevent or delay the occurrence of a disease or disease-related symptoms, and such disease or disease-related symptoms have not yet appeared before the relevant drug is administered. "Prevention” does not require completely preventing the occurrence of a disease or disease-related symptoms. For example, after the relevant drug is administered, the risk of a subject developing a specific disease or disease-related symptom can be reduced, or the severity of the related symptoms that appear later can be reduced, which can be considered as "preventing" the occurrence or development of the disease.
  • the DMSO solvent used to dissolve compounds in NMR structure identification is deuterated DMSO, namely DMSO-d 6 .
  • FIG1 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on HPAF-II transplanted tumors;
  • FIG3 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate (5 mg/kg) of the present invention on NCI-H929 transplanted tumors;
  • FIG7 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on Calu3 transplanted tumors;
  • FIG8 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on NCI-H1975 transplanted tumors;
  • FIG9 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on NCI-H820 transplanted tumors;
  • FIG. 10 is a graph showing the in vivo inhibitory effect of the ligand-drug conjugate of the present invention on LD1-0038-361928 transplanted tumors.
  • the conjugate has good tumor tissue targeting ability
  • the conjugate has a good therapeutic effect on tumor animal models.
  • the coupling method of the present invention has a wide range of applications and can be widely used for coupling bioactive molecules with antibodies or targeted small molecule ligands.
  • linker and ligand-drug conjugates of the present invention have significant clinical value.
  • the racemic compound of the present invention is dissolved in methanol and separated using a chiral preparative chromatographic column (see the table below) to obtain the product compound.
  • the absolute configuration of the compound can be determined by optical rotation detection, X-ray single crystal diffraction and the like.
  • LCMS [M+H] + 716.5.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne le domaine de la chimie pharmaceutique, et en particulier un conjugué d'un inhibiteur de la traduction des protéines et son utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention d'une maladie.
PCT/CN2025/072722 2024-01-16 2025-01-16 Conjugué d'inhibiteur de la traduction des protéines et son utilisation Pending WO2025153015A2 (fr)

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CN202410063661.2 2024-01-16
CN202410063661 2024-01-16
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CN202411574559.5 2024-11-06
CN202510025596.9 2025-01-07
CN202510025596 2025-01-07

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WO2025153015A3 WO2025153015A3 (fr) 2025-09-04

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Publication number Priority date Publication date Assignee Title
DE102004024504A1 (de) * 2004-05-18 2006-02-16 Bayer Healthcare Ag Neue Cylopenta[b]benzofuran-Derivate und ihre Verwendung
WO2010063471A1 (fr) * 2008-12-05 2010-06-10 Intermed Discovery Gmbh Inhibiteurs de l’accumulation de la protéine hif-1
WO2011140334A2 (fr) * 2010-05-06 2011-11-10 Trustees Of Boston University Composés, méthodes de fabrication ou d'identification de composés et leurs utilisations
CN109476648B (zh) * 2016-06-06 2022-09-13 豪夫迈·罗氏有限公司 司维司群抗体-药物缀合物和使用方法
TW202241897A (zh) * 2020-12-23 2022-11-01 大陸商上海偌妥生物科技有限公司 抗體藥物結合物、醫藥組合物及治療應用
CN115073407A (zh) * 2021-03-10 2022-09-20 上海中医药大学 一种具有合成致死性的药用组合物及其应用

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