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WO2022078259A1 - 一种氘代的喜树碱衍生物及其抗体药物偶联物 - Google Patents

一种氘代的喜树碱衍生物及其抗体药物偶联物 Download PDF

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Publication number
WO2022078259A1
WO2022078259A1 PCT/CN2021/122813 CN2021122813W WO2022078259A1 WO 2022078259 A1 WO2022078259 A1 WO 2022078259A1 CN 2021122813 W CN2021122813 W CN 2021122813W WO 2022078259 A1 WO2022078259 A1 WO 2022078259A1
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Prior art keywords
antibody
deuterated
alkyl
cycloalkyl
substituted
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PCT/CN2021/122813
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English (en)
French (fr)
Inventor
朱义
万维李
卓识
于天姿
朱贵莉
杨秀娟
Original Assignee
四川百利药业有限责任公司
成都百利多特生物药业有限责任公司
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Application filed by 四川百利药业有限责任公司, 成都百利多特生物药业有限责任公司 filed Critical 四川百利药业有限责任公司
Priority to AU2021361938A priority Critical patent/AU2021361938A1/en
Priority to JP2023546377A priority patent/JP2023545580A/ja
Priority to EP21879304.0A priority patent/EP4227309A1/en
Priority to US18/030,757 priority patent/US20230381332A1/en
Priority to IL302053A priority patent/IL302053A/en
Publication of WO2022078259A1 publication Critical patent/WO2022078259A1/zh

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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
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    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6879—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • the present invention relates to deuterated camptothecin derivatives and their antibody drug conjugates.
  • Antibody-drug conjugates as new targeted drugs, generally consist of three parts: antibodies or antibody-like ligands, small-molecule drugs, and linkers that couple the ligands and drugs.
  • Antibody-drug conjugates utilize the specific recognition of antigens by antibodies to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes.
  • FDA U.S. Food and Drug Administration
  • Adecteis TM developed by Seattle Genetics for the treatment of Hodgkin lymphoma and relapsed anaplastic large cell lymphoma (ALCL), and its clinical application has been proven. safety and efficacy of these drugs.
  • ADC Antibody Drug Conjugates
  • Camptothecins as small molecule compounds with anti-tumor properties, are known to exhibit anti-tumor effects by inhibiting DNA topoisomerase I, including irinotecan, ixitecan, SN38, etc.
  • Many camptothecin drugs have been widely used in clinic, the main indications are bone cancer, prostate cancer, breast cancer, pancreatic cancer and so on.
  • ixitecan does not require activation by the use of enzymes.
  • SN-38 which is the main body of irinotecan, and topotecan used in the clinic, topoisomerase I inhibitory activity is stronger, and it has stronger damage to various cancer cells in vitro. cell activity.
  • Deuterium is a non-radioactive isotope of hydrogen in a stable form in nature. Due to its larger atomic mass than hydrogen, C-D bonds are more stable (6-9 times) than C-H bonds. Replacing the hydrogen in the drug molecule with deuterium may block the metabolic site and reduce the generation of toxic metabolites.
  • deuterated drugs can remain stable under various metabolic enzymes, slowing down the systemic clearance rate and prolonging the half-life of the drug in the body. Therefore, deuterated drug therapy can achieve the goal of reducing the toxic and side effects of the drug by reducing the single dose of the drug without affecting the pharmacological activity of the drug.
  • Austedo is a deuterated version of tetrabenazine. Its prototype drug, tetrabenazine, has been the mainstream drug for the treatment of Huntington's disease, but it has defects such as short half-life and low patient dependence.
  • Deuterated tetrabenazine significantly reduces the rate of drug metabolism by replacing the hydrogen atoms in the two methoxy groups on the benzene ring of tetrabenazine with deuterium atoms, thereby increasing the half-life of the drug, thereby reducing the dosage of the drug. At the same time, it also inhibits the withdrawal reaction caused by the decrease of the blood concentration of the drug.
  • the technical problem to be solved by this patent is to combine deuterated technology with camptothecin ADCs to discover better deuterated camptothecin ADCs, which have higher safety, efficacy, and better satisfaction clinical needs.
  • the inventors designed a series of deuterium atom-substituted camptothecin-based antibody-drug conjugates by introducing deuterium atoms into the linker-drug compounds containing camptothecin. It is found through experiments that the molecule exhibits high drug activity and safety in vitro and in vivo, and has achieved unexpected technical effects.
  • the present invention provides a deuterated camptothecin derivative represented by general formula D, or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 , R 7 , R 10 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, one or more deuterated C 1-6 alkyl, substituted alkyl, aryl, one or more deuterated aryl, heteroaryl, one or more deuterated heteroaryl;
  • R 2 , R 3 , R 4 , R 5 , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • X is selected from -C(O) -CRaRb- ( CRcRd ) n -O-, -C(O) -CRaRb- ( CRcRd ) n - NH- or -C ( O)-CR a R b -(CR c R d ) n -S-;
  • R a and R b are independently selected from hydrogen atom, deuterium, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, cycloalkylalkyl , one or more deuterium substituted cycloalkylalkyl, alkoxyalkyl, one or more deuterium substituted alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R a , R b together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, or C 3-6 cycloalkyl substituted with one or more deuterium atoms, cycloalkylalkyl, one or more deuterium atoms substituted cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • R c and R d are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 alkyl group, a haloalkyl group, one or more deuterated C 1-6 alkyl groups, an alkoxy group, a one or more deuterated alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, one or more deuterated cycloalkyl, heterocyclyl, one or more deuterated heterocycle base;
  • R c , R d together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkanes ylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • n is selected from an integer from 0 to 4.
  • X is -C(O)-CR a R b -(CR 3 R 4 ) n -O-;
  • Ra is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkyl group substituted with one or more deuterium atoms, a cycloalkylalkyl group, one or more deuterium atoms substituted cycloalkylalkyl, alkoxyalkyl, alkoxyalkyl substituted with one or more deuterium atoms, heterocyclyl, aryl, substituted aryl, or heteroaryl;
  • R b is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkyl group substituted with one or more deuterium atoms, a cycloalkylalkyl group, one or more deuterium atoms substituted cycloalkylalkyl, alkoxyalkyl, alkoxyalkyl substituted with one or more deuterium atoms, heterocyclyl, aryl, substituted aryl, or heteroaryl;
  • R a , R b together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkane Alkyl or heterocyclyl, one or more deuterated heterocyclyls;
  • R c and R d are the same or different, and are each independently a hydrogen atom, a deuterium atom, an alkyl group, one or more deuterated alkyl groups, alkoxy groups, one or more deuterated alkoxy groups, hydroxyl groups, amino groups, cyano, nitro, hydroxyalkyl, cycloalkyl or heterocyclyl;
  • R c , R d together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkanes base alkyl;
  • n is selected from 0 or 1.
  • At least one of R 1 , R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 7 , R 8 , R 9 , R 10 and X is included deuterium atom.
  • camptothecin derivatives comprise the structure shown in formula D 2 :
  • R 10 is selected from hydrogen atoms, one or more deuterated C 1-6 alkyl groups
  • R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • Ra is selected from a hydrogen atom, a deuterium atom, an alkyl group, one or more deuterated deuterated alkyl groups;
  • R b is selected from a hydrogen atom, a deuterium atom, an alkyl group, one or more deuterated deuterated alkyl groups;
  • R a , R b together with the carbon atoms to which they are attached constitute perhydro-substituted or one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkylalkyl, Heterocyclyl, one or more deuterated heterocyclyl;
  • the wavy line in formula D 2 either represents a hydrogen atom, or is covalently linked to a linker unit or to a ligand unit that binds to an antigen expressed by a target cell.
  • X is non-limitingly selected from:
  • Y is selected from hydrogen or deuterium atoms.
  • it includes its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof.
  • the present invention also provides a drug-linker compound represented by the general formula (-LXD 2 ) or a pharmaceutically acceptable salt or solvate thereof;
  • R 1 , R 7 , R 10 are selected from hydrogen, deuterium, one or more deuterated C 1-6 alkyl, C 1-6 alkyl, substituted alkyl, aryl, one or more deuterated deuterated aryl radical, heteroaryl, one or more deuterated heteroaryl;
  • R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • X is -C(O)-CR a R b -(CR c R d ) n -O-;
  • R a , R b are independently selected from hydrogen atom, deuterium, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, perhydrogen substitution or one or more deuterated cycloalkyl, cycloalkyl alkyl, one or more deuterated cycloalkylalkyl, alkoxyalkyl, one or more deuterated alkoxyalkyl, heterocyclyl, one or more deuterated heterocyclyl, aryl, one or more deuterated aryl, substituted aryl, heteroaryl, one or more deuterated heteroaryl;
  • R a , R b together with the carbon atom to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated C 3-6 cycloalkyl cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • R c and R d are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a perhydrogen substitution, or one or more deuterated or perdeuterated C 1-6 alkyl groups, alkanes oxy, one or more deuterated alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, one or more deuterated cycloalkyl, heterocyclyl, one or more a deuterated heterocyclyl;
  • R c , R d together with the carbon atom to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated C 3-6 cycloalkyl cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • n is selected from an integer from 0 to 4.
  • At least one of R 1 , R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 7 , R 8 , R 9 , R 10 and X is included deuterium atom.
  • the wavy line in formula -LXD 2 either represents a hydrogen atom, or is covalently linked to a linker unit or to an antibody that binds to an antigen expressed by a target cell.
  • the O end of X is connected with the connecting unit L.
  • connecting unit -L- is -L 1 -L 2 -L 3 -L 4 -, and its L 1 end is connected to the antibody, and the L 4 end is connected to X;
  • L 1 is selected from: -(succinimide-3-yl-N)-YC(O)-, -CH 2 -C(O)-NR 5 -YC(O)- or -C(O)-YC (O)-,
  • Y is selected from C 1-8 alkyl, C 1-8 alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl of 1-8 atoms;
  • the heteroalkyl comprises a group selected from N 1-3 atoms of , O or S, the C 1-8 alkyl, cycloalkyl, straight-chain or straight-chain cyclic heteroalkyl are independently selected from deuterated atoms, halogen, hydroxyl, cyano , nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy or one or more substituents of cycloalkyl;
  • L 2 is selected from: -NR 6 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 6 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p C(O)- or chemical bond, wherein p is selected from the integer of 0-20;
  • L3 is selected from: peptide residues consisting of 2-7 amino acids, wherein optional amino acids are further selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy substituted with one or more substituents in cycloalkyl or substituted cycloalkyl;
  • L 4 is selected from: -NR 7 (CR 8 R 9 ) q -, -C(O)NR 7 , -C(O)NR 7 (CH 2 ) q - or a chemical bond, wherein q is selected from an integer of 0-6 ;
  • R 5 , R 6 and R 7 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkoxy group alkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R 8 and R 9 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, Heterocyclyl, aryl, substituted aryl or heteroaryl.
  • L 1 is selected from: -(succinimide-3-yl-N)-YC(O)-, -CH 2 -C(O)-NR 5 -YC(O)- or -C( O)-YC(O)-,
  • Y is selected from C 1-8 alkyl, C 1-8 alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl of 1-8 atoms;
  • the heteroalkyl comprises a group selected from N, 1-3 atoms of O or S, the C 1-8 alkyl, cycloalkyl, straight-chain or straight-chain cyclic heteroalkyl are each independently selected from deuterated atoms, halogen, hydroxyl, cyano, substituted with one or more substituents of nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy or cycloalkyl;
  • L 2 is selected from: -NR 6 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 6 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p C(O)- or a chemical bond, where p is selected from an integer of 0-20.
  • L3 is selected from phenylalanine (F), glycine (G), valine (V), lysine (K), citrulline, serine ( S ), glutamic acid (E) or aspartic acid
  • L 4 is -NR 7 CR 8 R 9 -; preferably -NHCH 2 -;
  • R 5 , R 6 and R 7 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkoxy group alkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R 8 and R 9 are the same or different, and each independently hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocycle aryl, aryl, substituted aryl, or heteroaryl.
  • the present invention provides a drug-linker compound represented by the general formula (LXD 2 ) or a pharmaceutically acceptable salt or solvate thereof;
  • Z is selected from: -YC(O)-, -CH2 -C(O)-NR5-YC(O)- or -C(O) -YC (O)-, wherein Y is selected from C without limitation 1-8 alkyl, C 1-8 alkyl-cycloalkyl or linear or linear-cyclic heteroalkyl of 1-8 atoms containing 1 selected from N, O or S -3 atoms, the C 1-8 alkyl, cycloalkyl, straight-chain or straight-chain cyclic heteroalkyl are each independently selected from deuterium atoms, halogen, hydroxyl, cyano, nitro, amino, substituted with one or more substituents of alkyl, heteroalkyl, substituted alkyl, alkoxy, carboxyl or cycloalkyl;
  • L 2 is selected from: -NR 6 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 6 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p C(O)- or chemical bond, wherein p is selected from the integer of 0-20, and any alkyl group in the structure is substituted by one or more deuterium atoms;
  • L3 is selected from: peptide residues consisting of 2-7 amino acids, wherein optional amino acids are further selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy substituted with one or more substituents in cycloalkyl or substituted cycloalkyl;
  • R is selected from deuterium atom, C 1-6 alkyl or substituted alkyl, aryl, substituted aryl or heteroaryl;
  • R 11 is selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R 12 is selected from hydrogen atom, deuterium atom, halogen, alkyl, haloalkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or Heteroaryl;
  • R 11 , R 12 together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, cycloalkylalkyl or heterocyclyl;
  • R 5 and R 6 are respectively selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R 1 , R 7 , R 10 and R 15 are respectively selected from hydrogen atoms, alkyl groups, and one or more deuterated C 1-4 alkyl groups;
  • R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • R 11 and R 12 are independently selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, one or more deuterated cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl, aryl, one or more deuterated aryl, substituted aryl, heteroaryl, a or more deuterated heteroaryl groups;
  • R 11 , R 12 together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated C 3-6 cycloalkyl cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • R 1 , R 7 , R 10 , and R 15 are respectively selected from hydrogen atoms, alkyl groups, one or more deuterated or per-deuterated C 1-4 alkyl groups or substituted alkyl groups;
  • R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • Ac is a hydrophilic structural unit represented by formula c, and the structure contains both amino and carboxyl groups, X is a scaffold connecting amino and carboxyl groups, and is a C 1-10 hydrocarbylene or substituted hydrocarbylene, and the hydrocarbylene or substituted hydrocarbylene
  • the hydrocarbon group can be substituted by one or more deuterium atoms;
  • Ac is connected to the 2-position methylene carbon indicated in the structural formula L b -XD 2 through the amino functional group;
  • deuterated camptothecin derivatives or their pharmaceutically acceptable salts or solvates are selected from the following structures:
  • the present invention provides a camptothecin derivative or a camptothecin-linker compound or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt or solvate thereof, linked with a ligand unit to form an antibody-drug conjugate of the general formula (Ab-L-X-Dr) or a pharmaceutically acceptable salt or solvent thereof Compound:
  • R 1 , R 7 , R 10 are independently selected from hydrogen, deuterium, one or more deuterated C 1-6 alkyl, C 1-6 alkyl, substituted alkyl, aryl, one or more deuterated aryl, heteroaryl, one or more deuterated heteroaryl;
  • R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' , R 8 , R 9 are independently selected from hydrogen or deuterium;
  • X is -C(O)-CR a R b -(CR c R d ) n -O-;
  • R a and R b are independently selected from hydrogen atom, deuterium, halogen, alkyl, deuterated alkyl, substituted alkyl, cycloalkyl, cycloalkyl substituted with one or more deuterium atoms, cycloalkylalkyl , one or more deuterium substituted cycloalkylalkyl, alkoxyalkyl, one or more deuterium substituted alkoxyalkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R a , R b together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, or C 3-6 cycloalkyl substituted with one or more deuterium atoms, cycloalkylalkyl, one or more deuterium atoms substituted cycloalkylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • R c and R d are the same or different, and are each independently a hydrogen atom, a deuterium atom, a halogen, a C 1-6 alkyl group, a haloalkyl group, one or more deuterated C 1-6 alkyl groups, an alkoxy group, a one or more deuterated alkoxy, hydroxy, amino, cyano, nitro, hydroxyalkyl, cycloalkyl, one or more deuterated cycloalkyl, heterocyclyl, one or more deuterated heterocycle base;
  • R c , R d together with the carbon atoms to which they are attached constitute C 3-6 cycloalkyl, one or more deuterated C 3-6 cycloalkyl, cycloalkylalkyl, one or more deuterated cycloalkanes ylalkyl, heterocyclyl, one or more deuterated heterocyclyl;
  • n is selected from an integer from 0 to 4.
  • the wavy line in formula -LXD 2 either represents a hydrogen atom, or is covalently linked to a linker unit or to an antibody that binds to an antigen expressed by a target cell.
  • the connecting unit -L- is -L 1 -L 2 -L 3 -L 4 -, the L 1 end is connected to the antibody, and the L 4 end is connected to X;
  • L 1 is selected from: -(succinimide-3-yl-N)-YC(O)-, -CH 2 -C(O)-NR 5 -YC(O)- or -C(O)-YC (O)-,
  • Y is selected from C 1-8 alkyl, C 1-8 alkyl-cycloalkyl, or straight-chain or straight-chain-cyclic heteroalkyl of 1-8 atoms;
  • the heteroalkyl comprises a group selected from N 1-3 atoms of , O or S, the C 1-8 alkyl, cycloalkyl, straight-chain or straight-chain cyclic heteroalkyl are independently selected from deuterated atoms, halogen, hydroxyl, cyano is substituted with one or more substituents of radical, nitro, amino, alkyl, carboxyl, heteroalkyl, substituted alkyl, alkoxy or cycloalkyl;
  • L 2 is selected from: -NR 6 (CH 2 CH 2 O) p CH 2 CH 2 C(O)-, -NR 6 (CH 2 CH 2 O) p CH 2 C(O)-, -S(CH 2 ) p C(O)- or chemical bond, wherein p is selected from the integer of 0-20;
  • L3 is selected from: peptide residues consisting of 2-7 amino acids, wherein optional amino acids are further selected from deuterium atoms, halogen, hydroxyl, cyano, amino, nitro, alkyl, substituted alkyl, alkoxy substituted with one or more substituents in cycloalkyl or substituted cycloalkyl;
  • L 4 is selected from: -NR 7 (CR 8 R 9 ) q -, -C(O)NR 7 , -C(O)NR 7 (CH 2 ) q - or a chemical bond, wherein q is selected from an integer of 0-6 ;
  • R 5 , R 6 and R 7 are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a haloalkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkoxy group alkyl, heterocyclyl, aryl, substituted aryl or heteroaryl;
  • R 8 and R 9 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, Heterocyclyl, aryl, substituted aryl or heteroaryl.
  • n is selected from an integer or decimal from 1 to 10;
  • Ab is an antibody, antibody fragment, targeting protein or Fc-fusion protein
  • L is the connection unit.
  • Ab is an antibody, which can form a linking bond with a linking unit through its heteroatom, and the antibody is selected from the group consisting of murine antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, antibody fragments, bispecific antibodies and multispecific antibodies.
  • its antibody is selected from the antibody targeting one or more of the following targets: anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody, anti-ENPP3 antibody, anti-TDGF1 antibody, Anti-ETBR Antibody, Anti-MSLN Antibody, Anti-TIM-1 Antibody, Anti-LRRC15 Antibody, Anti-LIV-1 Antibody, Anti-CanAg/AFP Antibody, Anti-cladin 18.2 Antibody, Anti-Mesothelin Antibody, Anti-HER2(ErbB2) Antibody, Anti-EGFR Antibody, Anti-c-MET Antibody, Anti-SLITRK6 Antibody, Anti-KIT/CD117 Antibody, Anti-STEAP1 Antibody, Anti-SLAMF7/CS1 Antibody, Anti-NaPi2B/SLC34A2 Antibody, Anti-GPNMB Antibody, Anti-HER3(ErbB3) Antibody, Anti-MUC1/CD227 Antibody, Antibody A
  • the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is selected from the following structures without limitation:
  • n is selected from an integer or decimal from 1 to 10;
  • Ab is an antibody, antibody fragment, targeting protein, Fc-fusion protein, and the like.
  • the present invention provides a method for preparing a compound (LXD 2 ), which comprises the following synthesis steps:
  • the present invention provides a method for preparing an antibody-drug conjugate represented by the general formula (Ab-L a -X-Dr) or a pharmaceutically acceptable salt or solvate thereof, comprising the following steps:
  • the general formula (Ab-L a -XD 2 ) is obtained by coupling reaction of antibodies, antibody fragments, targeting proteins, Fc-fusion proteins, etc. with the general formula (La-XD 2 ).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a compound comprising camptothecin derivatives or their antibody-drug conjugates or their tautomers, mesomers, racemates, enantiomers and diastereomers Use in the form of a mixture thereof, or a pharmaceutically acceptable salt or solvate compound thereof, and a pharmaceutically acceptable carrier, diluent or excipient, in the preparation of a medicament for treating or preventing tumors.
  • the tumor is selected from, without limitation, 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, lung cancer, colon cancer, rectal cancer, colorectal cancer, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioblastoma multiforme, sarcoma , solid tumors such as lymphoma and leukemia or hematological tumors.
  • trade name includes the product formulation, generic drug and active pharmaceutical ingredient of the trade name product.
  • ligand is a macromolecular compound capable of recognizing and binding 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 to which the ligand binds, including but not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells.
  • the ligand is represented as Ab, and the ligand can form a linking bond with the connecting unit through the heteroatom on the ligand, preferably an antibody or an antigen-binding fragment thereof, the antibody is selected from chimeric antibodies, human-derived antibody, fully human antibody or murine antibody; preferably a monoclonal antibody.
  • Ligand units are targeting agents that specifically bind to the target moiety.
  • the ligands are capable of specifically binding to cellular components or to cellular components or to other target molecules of interest.
  • the target moiety or target is usually on the cell surface.
  • the function of the Ligand unit is to deliver the Drug unit to a specific target cell population with which the Ligand unit interacts.
  • Ligands include, but are not limited to, proteins, polypeptides and peptides, as well as non-proteins such as sugars.
  • Suitable Ligand units include, for example, antibodies, such as full-length (intact) antibodies and antigen-binding fragments thereof.
  • the Ligand unit is a non-antibody targeting agent
  • it may be a peptide or polypeptide, or a non-proteinaceous molecule.
  • targeting agents include interferons, lymphokines, hormones, growth and colony stimulating factors, vitamins, nutrient transport molecules, or any other cell binding molecule or substance.
  • the linker is covalently attached to the sulfur atom of the ligand.
  • the sulfur atom is that of a cysteine residue, which forms an interchain disulfide bond of the antibody.
  • the sulfur atom is one that has been introduced into a cysteine residue of the Ligand unit, which forms an interchain disulfide bond of the antibody.
  • the sulfur atom is one that has been introduced into a cysteine residue of the Ligand unit (eg, by site-directed mutagenesis or chemical reaction).
  • the sulfur atom to which the linker binds is selected from cysteine residues that form interchain disulfide bonds of the antibody or frontal cysteine residues that have been introduced into the Ligand unit (eg, by site-directed mutagenesis or chemical reaction).
  • the EU according to the EU in Kabat ⁇ [Kabat E.A et al., (1991)] Sequences of proteins of Immunological Interest, Fifth Edition, NIH publication 91-3242 ⁇ Index numbering system.
  • an "antibody” or “antibody unit” is within its scope to include any portion of an antibody structure. This unit may bind, reactively associate, or complex with a receptor, antigen or other receptor unit possessed by the targeted cell population.
  • An antibody can be any protein or protein-like molecule that can bind, complex or react with a portion of the cell population to be treated or bioengineered. The antibody constituting the antibody-drug conjugate in the present invention maintains the antigen-binding ability of the original wild state. Therefore, the antibody of the present invention can specifically bind to the antigen.
  • Antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional), lymphokines, cytokines, molecules involved in the regulation of the cell cycle, molecules involved in angiogenesis, and molecules involved in angiogenesis (as known or predicted to be functional).
  • TAAs tumor-associated antigens
  • cell surface receptor proteins and other cell surface molecules regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional)
  • lymphokines cytokines
  • molecules involved in the regulation of the cell cycle molecules involved in angiogenesis
  • angiogenesis as known or predicted to be functional
  • the tumor-associated factor can be a cluster differentiation factor (eg, CD protein).
  • Antibodies for use in antibody drug conjugates include, but are not limited to, antibodies directed against cell surface receptors and tumor-associated antigens. Such tumor-associated antigens are well known in the art and can be prepared by methods and information well known in the art for preparing antibodies.
  • tumor-associated antigens are well known in the art and can be prepared by methods and information well known in the art for preparing antibodies.
  • To develop effective cellular-level targets for cancer diagnosis and therapy researchers seek to find transmembrane or other tumor-associated polypeptides. These targets can be specifically expressed on the surface of one or more cancer cells with little or no expression on the surface of one or more non-cancer cells. Typically, such tumor-associated polypeptides are more overexpressed on the surface of cancer cells relative to the surface of non-cancer cells. Identifying such tumor-associated factors could greatly improve the specific targeting properties of antibody-based cancer therapy.
  • tumor-associated antigens For convenience, antigen-related information that is well known in the industry is indicated below, including name, other names, and GenBank accession numbers. Nucleic acid and protein sequences corresponding to tumor-associated antigens can be found in public databases such as Genbank. Antibodies targeting corresponding tumor-associated antigens include all amino acid sequence variants and isotypes that are at least 70%, 80%, 85%, 90%, or 95% homologous to sequences identified in references, or have The tumor-associated antigen sequences in the literature have completely identical biological properties and characteristics.
  • inhibitor refers to reducing by a detectable amount, or preventing completely.
  • cancer refers to a physiological condition or disease characterized by unregulated cell growth.
  • Tumor includes cancer cells.
  • autoimmune disease is a disease or disorder that results from targeting an individual's own tissues or proteins.
  • drug refers to a cytotoxic drug, where drug designates D, a chemical molecule capable of strongly disrupting normal growth within tumor cells.
  • cytotoxic drugs can kill tumor cells at a high enough concentration, but due to the lack of specificity, when killing tumor cells, they can also lead to apoptosis of normal cells, resulting in serious side effects.
  • toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, radioisotopes (eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 ) , P 32 and Lu 176 radioisotopes), toxic drugs, chemotherapeutic drugs, antibiotics and nucleolysins, preferably toxic drugs.
  • radioisotopes eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212
  • P 32 and Lu 176 radioisotopes radioisotopes
  • toxic drugs eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212
  • antibiotics and nucleolysins preferably toxic drugs.
  • linker or “linker fragment” or “linker unit” refers to a chemical structural fragment or bond that is linked to a ligand at one end and a drug at the other end, and can also be linked to a drug after other linkers are attached.
  • Linkers including stretchers, spacers and amino acid units, can be synthesized by methods known in the art, such as those described in US2005-0238649A1.
  • the linker can be a "cleavable linker" that facilitates the release of the drug in the cell.
  • acid-labile linkers eg, hydrazones
  • protease-sensitive linkers eg, peptidase-sensitive linkers
  • photolabile linkers eg, dimethyl linkers, or disulfide-containing linkers
  • linkers or “linkers of antibody drug conjugates” can be divided into two categories: non-cleavable linkers and cleavable linkers.
  • the drug release mechanism is as follows: after the conjugate binds to the antigen and is endocytosed by the cell, the antibody is enzymatically hydrolyzed in the lysosome to release the small molecule drug , linker, and the active molecule composed of antibody amino acid residues.
  • the resulting changes in the molecular structure of the drug do not reduce its cytotoxicity, but because the active molecule is charged (amino acid residues), it cannot penetrate into adjacent cells.
  • active drugs cannot kill adjacent tumor cells that do not express the target antigen (antigen-negative cells) (bystander effect) (Ducry et al., 2010, Bioconjugate Chem. 21:5-13).
  • ligand-drug conjugate refers to an antibody linked to a biologically active drug through a stable linking unit.
  • ligand-drug conjugate is preferably antibody-drug conjugate (antibody drug conjugate, ADC), which refers to linking a monoclonal antibody or antibody fragment with a biologically active toxic drug through a stable linking unit .
  • 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 1 to 10 carbon atoms atomic alkyl groups, most preferably those containing 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 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, 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.
  • substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclo
  • R', R" and R"' each independently refers to hydrogen, unsubstituted C 1-8 alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, unsubstituted C 1-8 alkyl, C 1- 8 alkoxy or C 1-8 thioalkoxy, or unsubstituted aryl-C 1-4 alkyl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may form together with the nitrogen atom 3-, 4-, 5-, 6- or 7-membered rings.
  • -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl.
  • heteroalkyl refers to an alkyl group containing one or more heteroatoms selected from N, O, or S, wherein alkyl is as defined above.
  • alkylene refers to a saturated straight or branched aliphatic hydrocarbon group having 2 residues derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane, which are A straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- , 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH2CH ) 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 -), etc.
  • the alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkyne group, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy substituted with one or more of the substituents among the radicals, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl or cycloalkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, 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 containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms 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
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. 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 monospiroheterocyclyl group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably the cycloalkyl ring contains 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • cycloalkylalkyl refers to an alkyl group substituted with one or more cycloalkyl groups, preferably one cycloalkyl group, wherein alkyl is as defined above, wherein cycloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • amido refers to -C(O)N(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • carboxylate refers to -C(O)O(alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • the present invention also includes various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated products. In the preparation of deuterated products, commercially available deuterated starting materials can be used, or synthesized by conventional techniques using deuterated reagents, non-limiting examples of deuterated reagents include: deuterated water, deuterated methanol, deuterated borane , trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • antibody refers to an immunoglobulin, which is a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds.
  • the amino acid composition and sequence of the immunoglobulin heavy chain constant region are different, so their antigenicity is also different. Accordingly, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, whose corresponding heavy chains are ⁇ , ⁇ , and ⁇ chains, respectively. , alpha chains and epsilon chains.
  • IgG can be divided into different subclasses according to the difference in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified into kappa chains or lambda chains by the difference in the constant region.
  • Each of the five classes of Ig can have a kappa chain or a lambda chain.
  • the antibodies of the present invention are preferably specific antibodies against cell surface antigens on target cells, non-limiting examples are the following antibodies: anti-EGFRvIII antibody, anti-DLL-3 antibody, anti-PSMA antibody, anti-CD70 antibody, anti-MUC16 antibody , Anti-ENPP3 Antibody, Anti-TDGF1 Antibody, Anti-ETBR Antibody, Anti-MSLN Antibody, Anti-TIM-1 Antibody, Anti-LRRC15 Antibody, Anti-LIV-1 Antibody, Anti-CanAg/AFP Antibody, Anti-cladin 18.2 Antibody, Anti-Mesothelin Antibody, Anti-HER2 (ErbB2) Antibody, Anti-EGFR Antibody, Anti-c-MET Antibody, Anti-SLITRK6 Antibody, Anti-KIT/CD117 Antibody, Anti-STEAP1 Antibody, Anti-SLAMF7/CS1 Antibody, Anti-NaPi2B/SLC34A2 Antibody, Anti-GPNMB Antibody, Anti-HER3(ErbB3) Antibody,
  • solvate refers to the ligand-drug conjugates of the invention forming pharmaceutically acceptable solvates with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile , isopropanol, DMSO, ethyl acetate.
  • drug loading refers to the average amount of cytotoxic drug loaded on each antibody in formula I, and can also be expressed as the ratio of drug amount to antibody amount, and the drug loading range can be that each antibody (Ab) connects 0. -12, preferably 1-10 cytotoxic drugs (D).
  • the drug load is expressed as n, and an exemplary value may be the mean value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the average amount of drug product per ADC molecule after the coupling reaction can be characterized by conventional methods such as UV/Vis spectroscopy, mass spectrometry, ELISA assay and HPLC.
  • 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 conjugate loading can be controlled by the following non-limiting methods, including:
  • pharmaceutically acceptable salt refers to salts of the ligand-drug conjugates of the present invention, or salts of the compounds described in the present invention, when such salts are used in mammals With safety and efficacy, and with due biological activity, the ligand-drug conjugate compound of the present invention contains at least one carboxyl group, so it can form a salt with a base.
  • pharmaceutically acceptable salts include: sodium salt, potassium salt, calcium salt or magnesium salt, etc.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable salts” refers to salts of the antibody-drug conjugates of the present invention, or salts of the compounds described in the present invention, which when used in mammals have Safe and effective, and have due biological activity, the ligand-drug conjugate compound of the present invention contains at least one amino group, so it can form a salt with an acid.
  • Non-limiting examples of pharmaceutically acceptable salts include: hydrochloric acid Salt, Hydrobromide, Hydroiodide, Sulfate, Hydrogen Sulfate, Citrate, Acetate, Succinate, Ascorbate, Oxalate, Nitrate, Pearate, Hydrogen Phosphate, Phosphoric Acid Dihydrogenate, Salicylate, Hydrogencitrate, Tartrate, Maleate, Fumarate, Formate, Benzoate, Mesylate, Ethanesulfonate, Besylate , p-toluenesulfonate.
  • Acid amino acid means that the isoelectric point of the amino acid is less than 7, and the acidic amino acid molecule often has one or more acid groups such as carboxyl groups, which can be effectively ionized into negative ions in the structure to increase hydrophilicity. Acidic amino acids may be natural or unnatural amino acids.
  • Natural amino acid refers to an amino acid that is biosynthesized. Natural amino acids are generally L-form, but there are a few exceptions, such as glycine, both natural and biosynthetic.
  • Unnatural amino acid refers to an amino acid obtained by synthetic means.
  • the No. 1 1000ml three-necked flask was replaced with nitrogen and protected with a nitrogen balloon, and there was a constant pressure dropping funnel device, and heavy water (25ml, 1.25mol) was added to the flask using a syringe, and stirred at 0°C for later use.
  • the No. 2 500ml three-neck flask was protected by a nitrogen balloon, 1.0M LiHMDS in THF solution (300ml, 0.30mol) was added, and the mixture was stirred and cooled at 0°C.
  • DSM1-1 (12.00g, 54.0mmol) was slowly added dropwise thereto, and the reaction was performed for 5min after the addition was completed. The syringe was drawn out, slowly added to the constant pressure dropping funnel of No.
  • the progress of the reaction was detected by HPLC, the reaction was about 3 hours, the raw material was less than 5%, the liquid phase of the reaction system was prepared and separated, and lyophilized to obtain a yellow solid D-D1: 64.0 mg, with a yield of 69%.
  • the No. 1 1000ml three-necked bottle was replaced with nitrogen and protected with a nitrogen balloon, equipped with a constant pressure dropping funnel, and heavy water (20ml, 1.00mol) was added to the bottle using a syringe, and stirred at 0°C for later use.
  • the No. 2 500ml three-neck flask was protected by a nitrogen balloon, 1.0M LiHMDS in THF solution (200ml, 0.20mol) was added, and the mixture was stirred and cooled at 0°C.
  • DSM2-1 (10.00g, 42.3mmol) was slowly added dropwise to it, and the reaction was performed for 5min after the addition was completed. The syringe was drawn out, slowly added to the constant pressure dropping funnel of No.
  • the No. 1 1000ml three-necked bottle was replaced with nitrogen and protected with a nitrogen balloon, equipped with a constant pressure dropping funnel, and heavy water (30ml, 1.50mol) was added to the bottle using a syringe, and stirred at 0°C for later use.
  • the No. 2 500ml three-necked flask was protected by a nitrogen balloon, 1.0M LiHMDS in THF solution (350ml, 0.35mol) was added, and the mixture was stirred and cooled at 0°C.
  • DSM3-1 (20.32g, 70.0mmol) was slowly added dropwise to it, and the reaction was performed for 5min after the addition was completed. The syringe was drawn out, slowly added to the No.
  • the No. 1 1000ml three-necked bottle was replaced with nitrogen and protected with a nitrogen balloon, equipped with a constant pressure dropping funnel, and heavy water (30ml, 1.50mol) was added to the bottle using a syringe, and stirred at 0°C for later use.
  • the No. 2 500ml three-necked flask was protected by a nitrogen balloon, 1.0M LiHMDS in THF solution (350ml, 0.35mol) was added, and the mixture was stirred and cooled at 0°C.
  • DSM4-1 (18.36g, 70.0mmol) was slowly added dropwise to it, and the reaction was performed for 5min after the addition was completed. The syringe was drawn out, slowly added to the constant pressure dropping funnel of No.
  • the No. 1 500ml three-necked bottle was replaced with nitrogen and protected with a nitrogen balloon, equipped with a constant pressure dropping funnel, and heavy water (20ml, 1.0mol) was added to the bottle using a syringe, and stirred at 0°C for later use.
  • the No. 2 250ml three-neck flask was protected by a nitrogen balloon, 1.0M LiHMDS solution in THF (125ml, 0.125mol) was added, and the mixture was stirred and cooled at 0°C.
  • DSM5-1 (5.99g, 25.0mmol) was slowly added dropwise thereto, and the reaction was performed for 5min after the addition was completed. The syringe was drawn out, slowly added to the constant pressure dropping funnel of No.
  • the deuterated state was judged by the integral number of hydrogens at the ⁇ -position of the carbonyl group, and it was found that the hydrogen at the ⁇ -position of the carbonyl group almost disappeared, and it was confirmed that the undeuterated portion was about 1.5%.
  • reaction solution is purified by the preparation liquid phase to obtain the product preparation solution, the preparation solution is extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 2b ( 4.58 g), 68% yield.
  • reaction solution is purified by preparation liquid phase to obtain product preparation solution, the preparation solution is extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 3b ( 3.52 g), yield 48%.
  • M4 (4.57g, 11.0mmol, purchased from outside), PyBOP (6.26g, 12.0mmol), HOBt (1.65g, 12.0mmol) and 10mL DMF were added, and DIEA (2.00mL, 12.0mL) was added in an ice-water bath. mmol), continue to stir for 30min, add the above-mentioned standing reaction solution to the reaction flask, and raise to room temperature for reaction.
  • reaction solution is purified by the preparation liquid phase to obtain the product preparation solution, the preparation solution is extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 4b ( 4.68 g), 71% yield.
  • Example 34 With reference to the synthetic route and method of Example 21, the following compounds were synthesized:
  • Example 35 General method for preparing ADC drug by coupling
  • the antibody molecule Ab with a monomer rate greater than 95% after preliminary purification was changed into a phosphate buffer using an ultrafiltration centrifuge tube at a concentration of 10 mg/ml.
  • use an ultrafiltration centrifuge tube with a molecular weight cut-off of 30KDa to change the medium to PBS, and remove the uncoupled payload.
  • the ADC samples after the liquid change were filtered through a 0.22-micron sterile filter before use.
  • the coupling payload compounds L-D1, L-D2, L-D3, L-D4, L-D5, L-D6, L-D7, L-D8, L-D9, L-D10, L-D11, L-H1, L-H2, L-H3, L-H4, L-H5, L-H6, L-H7 and L-H8 were coupled with the antibody molecule Ab (Ab A: Trastuzumab antibody; B: Cetuximab antibody).
  • the average drug/antibody ratio (DAR) value of the conjugated product was determined by reversed-phase high performance liquid chromatography.
  • the obtained ADC drug molecule related information and the corresponding situation with the payload molecule are as follows:
  • Preparation of stock solution Weigh an appropriate amount of the test substance or positive control compound into an appropriate container, and prepare a 10 mM stock solution with DMSO (or other suitable organic solvent).
  • Preparation of working solution dilute 10 mM stock solution with acetonitrile (or other suitable solvent) to 1.0 mM as working solution for use.
  • Liver microsome stock solution (20 mg/mL) was diluted with 100 mM potassium phosphate buffer (pH 7.4) to the concentration required to incubate the sample (1.12 mg/mL).
  • the NADPH coenzyme solution contains 10 mM NADPH, which is obtained by dissolving and diluting NADPH in 100 mM potassium phosphate buffer solution. It is prepared and used immediately before sample incubation.
  • A431, Fadu, Bxpc-3, SW620 and N87 are used as research systems for in vitro drug efficacy detection.
  • Appropriate number of tumor cells were evenly seeded into 96-well plates and incubated in a carbon dioxide incubator. After 24 hours, the cells were confirmed to be in normal state under the microscope, and drug addition treatment was performed. Dilute the drug with the medium (the initial concentration of the ADC drug is 500nM, the dilution factor is 7 times, there are 8 concentration points in total, the theoretical coupling ratio (DAR) of toxin and antibody is 8:1, and the actual coupling ratio is roughly 7.5: 1.
  • DAR theoretical coupling ratio
  • the initial concentration of the toxin is 4.0 ⁇ M, 7-fold concentration gradient dilution, 8 concentration points), after mixing, add it to the corresponding cell wells, where the last two columns are the control group (ie cells + medium, no drug) treatment) and blank group (ie, no cells, containing only medium, for background subtraction), put into a carbon dioxide incubator at 37°C for 5 days. After 5 days, 20 ⁇ L of MTS (Promega, G3581) was added to each well to react for 2 hours, and the absorbance value at a wavelength of 490 nm was read with a microplate reader (Molecular Device, model: SpectraMAX190). By detecting the activity of dehydrogenase in mitochondria, IC50 was calculated to evaluate the inhibitory effect of ADC drugs on tumor cell proliferation. The result is as follows
  • the deuterated camptothecin drug of the present invention shows good antitumor activity in multiple antigen-positive tumor cell lines after coupling with the antibody through the linking unit L, and has great of clinical application value.
  • Example 38 ADC in vivo efficacy test
  • an A431 tumor-bearing nude mouse model is established to evaluate the in vivo efficacy of the deuterated camptothecin derivative ADC conjugated drug and the non-deuterated ADC conjugate. That is, 3 ⁇ 10 6 A431 cells were subcutaneously injected into the right shoulder of 4-6 weeks old BALB/c nude mice, and when the average size of the tumor volume of the mice grew to 140-150 mm 3 , they were randomly divided into groups, 5 mice in each group , On the 0th, 7th, 14th, and 21st days, intravenous injection of blank control (buffer solution blank) and 10 mg/kg dose of antibody drug conjugates ADC-1, ADC-3, ADC-5, ADC-10, ADC- 12.
  • ADC-13 and ADC-15 Tumor volumes were tested at 0, 7, 14, 21, 24, 28, 32, and 36 days, respectively, and the measured data were shown as the mean tumor volume at the time of measurement. At the same time, the body weight changes of mice were recorded to observe the preliminary toxicity of ADC drugs in vivo. The result is as follows:
  • the deuterated camptothecin drug of the present invention exhibits clear anti-tumor activity in tumor-bearing mice after coupling with the antibody through the linking unit L, and the average tumor
  • the body was significantly lower than the blank control, the inhibitory effect was obvious, no obvious rebound was observed during the observation period, and the drug effect was lasting.
  • the deuterated camptothecin drug of the present invention has good safety.

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Abstract

公开了一种氘代的喜树碱衍生物及其抗体药物偶联物，将氘代技术与喜树碱类ADC结合，发现更优的氘代喜树碱类ADC药物，使其具有更高的安全性、有效性，更好满足临床需求。

Description

一种氘代的喜树碱衍生物及其抗体药物偶联物 技术领域
本发明涉及氘代的喜树碱衍生物及其抗体药物偶联物。
背景技术
抗体药物偶联物(ADC)作为新型的靶向药物，一般由三部分组成：抗体或抗体类配体，小分子药物以及将配体和药物偶联起来的连接子。抗体药物偶联物利用抗体对抗原的特异性识别，将药物分子运输至靶细胞附近并有效释放药物分子，达到治疗目的。2011年8月，美国食品药品监督管理局(FDA)批准西雅图基因公司研制的用于治疗霍奇金淋巴瘤以及复发性变性大细胞淋巴瘤(ALCL)的ADC新药Adecteis TM上市，临床应用已经证明了此类药物的安全性和有效性。
抗体药物偶联物(ADC)类药物的优势在于增加水溶性，提高靶向性，特异性抗体与抗原的结合，将药物携带至靶细胞周围，通过在靶细胞附近释放药物，有效杀灭肿瘤细胞，降低毒副作用。喜树碱类药物在ADC药物中具有可观的应用前景，目前以依喜替康为毒素的抗体偶联药物trastuzumab deruxtecan(商品名为Enhertu)已于2019年12月20日被美国FDA获批上市，作为第一个上市的喜树碱类ADC药物，很好证明了此类药物在ADC领域的成药能力和应用前景。
喜树碱类药物作为抗肿瘤性的小分子化合物，已知作为抑制DNA拓扑异构酶I而呈现抗肿瘤作用，包括伊立替康，依喜替康，SN38等。许多喜树碱类药物已在临床中广泛应用，主要适应症为骨癌、前列腺癌、乳腺癌、胰腺癌等。与目前临床使用的伊立替康不同，依喜替康不需要通过利用酶进行活化。另外，与作为伊立替康的药效本体的SN-38、同在临床中使用的拓扑替康相比，拓扑异构酶I抑制活性更强，在体外针对多种癌细胞具有更强的伤细胞活性。尤其是，对于通过P-糖蛋白的表达面对SN-38等显示耐性的癌细胞也显示效果。依喜替康作为单独化疗药物尚未成功上市，推测与其较高的细胞活性相关，导致治疗窗口窄。同时，喜树碱类药物在血浆中半衰期短，在临床使用中维持药效需要增加给药剂量或增大给药频次，因此可能给病人带来耐受性问题。
氘为氢在自然界中的一种稳定形态的非放射性同位素，由于具有比氢更大的原子质量使得C-D键比C-H键更加稳定(6-9倍)。将药物分子中的氢用氘取代后，可能封闭代谢位点、减少有毒代谢物的生成。此外，氘代药物在多种代谢酶下可以保持稳定，减缓系统清除速率从而延长药物在体内的半衰期。因此，氘代药物治疗可以通过降低单次 给药剂量，同时在不影响药物的药理活性情况下实现降低药物的毒副作用的目标。在2017年，美国FDA批准了历史上第一款氘代药物上市——Teva的Austedo，并于2020年5月在中国获准上市。Austedo是氘代版的丁苯那嗪，其原型药丁苯那嗪此前一直是治疗亨廷顿舞蹈症的主流药物，但存在半衰期短、患者依存性低等缺陷。氘代丁苯那嗪通过将丁苯那嗪苯环上的两个甲氧基中的氢原子用氘原子置换，显著降低了药物代谢的速度，提高药物半衰期，从而减少药物的给药量，同时还抑制了由于药物血液浓度下降产生的戒断反应。
发明内容
本专利所需要解决的技术问题，就是将氘代技术与喜树碱类ADC结合，发现更优的氘代喜树碱类ADC药物，使其具有更高的安全性、有效性，更好满足临床需求。
发明人在对ADC类药物综合理解的基础上，通过将氘原子引入至含喜树碱的连接子-药物化合物中，从而设计出一系列氘原子取代的喜树碱类抗体药物偶联物，通过实验发现，所述的分子在体内外表现出很高的药物活性和安全性，取得了预料不到的技术效果。
本发明提供了一种通式D所示的氘代喜树碱类衍生物，或其药学上可接受的盐或溶剂化物：
Figure PCTCN2021122813-appb-000001
其中：
R 1、R 7、R 10分别独立选自氢、氘、C 1-6烷基、一个或多个氘代的C 1-6烷基、取代烷基、芳基、一个或多个氘代的芳基、杂芳基、一个或多个氘代的杂芳基；
R 2、R 3、R 4、R 5、R 8、R 9分别选自氢或氘；
X选自-C(O)-CR aR b-(CR cR d) n-O-、-C(O)-CR aR b-(CR cR d) n-NH-或-C(O)-CR aR b-(CR cR d) n-S-；
R a、R b分别独立的选自氢原子、氘、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、或一个或多个氘原子取代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、C 1-6烷基、卤代烷基、一个或多个氘代C 1-6烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代环烷基、杂环基、一个或多个氘代的杂环基；
或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
n选自0至4的整数。
作为优选方式，X为-C(O)-CR aR b-(CR 3R 4) n-O-；
R a选自氢原子、氘原子、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代的烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
R b选自氢原子、氘原子、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代的烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、个或多个氘代环烷基烷基或杂环基、一个或多个氘代杂环基；
R c、R d相同或者不同，且分别独立地为氢原子、氘原子、烷基、一个或多个氘代烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基；
或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基；
n选自0或1。
R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10和X中有且至少含有一个氘原子。
进一步优选，所述喜树碱类衍生物包含式D 2所示的结构：
Figure PCTCN2021122813-appb-000002
其中：
R 10选自氢原子、一个或多个氘代的C 1-6烷基；
R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
R a选自氢原子、氘原子、烷基、一个或多个氘代的氘代烷基；
R b选自氢原子、氘原子、烷基、一个或多个氘代的氘代烷基；
或者，R a、R b连同其所连接碳原子构成全氢取代或一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
其中，式D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的配体单元共价连接。
作为优选方式，X非限制性地选自：
Figure PCTCN2021122813-appb-000003
其中Y选自氢或氘原子。
作为优选方式，包括其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式。
作为优选方式，其非限制性地选自以下所示的化合物或其药学上接受的盐或溶剂化物：
Figure PCTCN2021122813-appb-000004
本发明还提供了一种通式如(-L-X-D 2)所示的药物-连接子化合物或者其药学上可接受的盐或溶剂化物；
Figure PCTCN2021122813-appb-000005
其中：
R 1、R 7、R 10选自氢、氘、一个或多个氘代C 1-6烷基、C 1-6烷基、取代烷基、芳基、一个或多个氘代氘代芳基、杂芳基、一个或多个氘代杂芳基；
R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
X为-C(O)-CR aR b-(CR cR d) n-O-；
R a、R b分别独立的选自氢原子、氘、卤素、烷基、氘代烷基、取代烷基、环烷基、全氢取代或一个或多个氘代环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、烷氧基烷基、一个或多个氘代的烷氧基烷基、杂环基、一个或多个氘代的杂环基、芳基、一个或多个氘代的芳基、取代芳基、杂芳基、一个或多个氘代的杂芳基；
或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、烷基、卤代烷基、全氢取代或一个或多个氘代或全氘代C 1-6烷基、烷氧基、一个或多个氘代的烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代的环烷基、杂环基、一个或多个氘代的杂环基；
或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
n选自0至4的整数。
R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10和X中有且至少含有一个氘原子。
L为连接单元；
其中，式-L-X-D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的抗体共价连接。
作为优选方式，其中X的O端与连接单元L相连。
进一步优选，其中连接单元-L-为-L 1-L 2-L 3-L 4-,，其L 1端与抗体相连，L 4端与X相连；
其中:
L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或-C(O)-Y-C(O)-，
其中，Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链 或者直链环状杂烷基各自独立地选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数；
L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
L 4选自：-NR 7(CR 8R 9) q-、-C(O)NR 7、-C(O)NR 7(CH 2) q-或者化学键，其中q选自0-6的整数；
R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
R 8和R 9相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
更进一步优选，L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或者-C(O)-Y-C(O)-，
其中Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或者直链环状杂烷基各自独立地选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数。
L 3选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)或者天冬氨酸(D)中的氨基酸形成的多肽残基；优选为由一个、两个或者多个选自苯丙氨酸和甘氨酸的氨基酸形成的氨基酸残基；最优选的为甘氨酸-甘氨酸-苯丙氨酸-甘氨酸组成的四肽残基；
L 4为-NR 7CR 8R 9-；优选为-NHCH 2-；
R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
R 8和R 9相同或者不同，且各自独立地氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
本发明提供了一种通式(L-X-D 2)所示的药物-连接子化合物或者其药学上可接受的盐或溶剂化物；
Figure PCTCN2021122813-appb-000006
其中：
Z选自：-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或者-C(O)-Y-C(O)-，其中Y非限制性地选自C 1-8烷基、C 1-8烷基-环烷基或1-8个原子的直链或直链-环状杂烷基，所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或直链环状杂烷基各自独立地被选自氘原子、卤素、羟基、氰基、硝基、氨基、烷基、杂烷基、取代烷基、烷氧基、羧基或环烷基的一个或者多个取代基所取代；
L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或化学键，其中p选自0-20的整数，结构中任意烷基被一个或多个氘原子取代；
L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
R选自氘原子、C 1-6烷基或取代烷基、芳基、取代芳基或杂芳基；
R 11选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、杂环基、芳基、取代芳基或杂芳基；
R 12选自氢原子、氘原子、卤素、烷基、卤代烷基、氘代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
或者，R 11、R 12连同其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基；
R 5、R 6分别选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
R 1、R 7、R 10、R 15分别选自氢原子、烷基、一个或多个氘代的C 1-4烷基；
R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10、R 11和R 12中有且至少含有一个氘原子。
作为优选方式，其为通式(L b-X-D 2)所示的化合物，或其药学上可接受的盐或溶剂化物；
Figure PCTCN2021122813-appb-000007
其中：
R 11、R 12分别独立选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘代的环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基、芳基、一个或多个氘代的芳基、取代芳基、杂芳基、一个或多个氘代的杂芳基；
或者，R 11、R 12连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
R 1、R 7、R 10、R 15分别选自氢原子、烷基、一个或多个氘代或全氘代的C 1-4烷基或取代烷基；
R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
Ac为具有式c所示的亲水结构单元，该结构中同时含有氨基和羧基，X为连接氨基和羧基的支架，为C 1-10亚烃基或取代亚烃基，所述亚烃基或取代亚烃基可被一个或多个氘原子取代；Ac通过氨基官能团与结构式L b-X-D 2中已标示的2位亚甲基碳相连；
Figure PCTCN2021122813-appb-000008
进一步优选，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，其中Ac选自甘氨酸，α-丙氨酸，β-丙氨酸，(D/L)谷氨酸组成的组。
作为优选方式，氘代喜树碱类衍生物或者其药学上可接受的盐或溶剂化物，选自以下结构：
Figure PCTCN2021122813-appb-000009
Figure PCTCN2021122813-appb-000010
Figure PCTCN2021122813-appb-000011
Figure PCTCN2021122813-appb-000012
Figure PCTCN2021122813-appb-000013
本发明提供了一种喜树碱衍生物或喜树碱-连接子化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或混合物形式，或其药学上可接受的盐或溶剂化物，与配体单元连接形成如通式(Ab-L-X-Dr)所示的抗体-药物偶联物或其药学上可接受的盐或溶剂化物：
Figure PCTCN2021122813-appb-000014
其中：
R 1、R 7、R 10分别选自氢、氘、一个或多个氘代的C 1-6烷基、C 1-6烷基、取代烷基、芳基、一个或多个氘代的芳基、杂芳基、一个或多个氘代的杂芳基；
R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
X为-C(O)-CR aR b-(CR cR d) n-O-；
R a、R b分别独立的选自氢原子、氘、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、或一个或多个氘原子取代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、C 1-6烷基、卤代烷基、一个或多个氘代C 1-6烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代环烷基、杂环基、一个或多个氘代的杂环基；
或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
n选自0至4的整数；
L为连接单元；
其中，式-L-X-D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的抗体共价连接。
作为优选方式，其中连接单元-L-为-L 1-L 2-L 3-L 4-,，其L 1端与抗体相连，L 4端与X相连；
其中:
L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或-C(O)-Y-C(O)-，
其中，Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或者直链环状杂烷基各自独立地被选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数；
L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
L 4选自：-NR 7(CR 8R 9) q-、-C(O)NR 7、-C(O)NR 7(CH 2) q-或者化学键，其中q选自0-6的整数；
R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
R 8和R 9相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
m选自1-10的整数或小数；
Ab为抗体、抗体片段、靶向蛋白或Fc-融合蛋白；
L为连接单元。
进一步优选，Ab为抗体，可通过其杂原子与连接单元形成连接键，所述抗体选自鼠源抗体、嵌合抗体、人源化抗体、全人源抗体、抗体片段、双特异性抗体及多特异性抗体。
更进一步优选，其抗体选自靶向以下一个或多个靶点的抗体：抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin 4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体、抗CD47抗体。
作为优选方式，抗体-药物偶联物或其药学上可接受的盐或溶剂化物，非限制性地选自以下结构：
Figure PCTCN2021122813-appb-000015
Figure PCTCN2021122813-appb-000016
Figure PCTCN2021122813-appb-000017
Figure PCTCN2021122813-appb-000018
Figure PCTCN2021122813-appb-000019
其中：
m选自1-10的整数或小数；
Ab为抗体、抗体片段、靶向蛋白、Fc-融合蛋白等。
本发明提供一种制备化合物(L-X-D 2)的方法，其包括以下合成步骤：
Figure PCTCN2021122813-appb-000020
本发明提供一种制备通式(Ab-L a-X-Dr)所示抗体-药物偶联物或其药学上可接受的盐或溶剂化物的方法，包括如下步骤：
Figure PCTCN2021122813-appb-000021
通过抗体、抗体片段、靶向蛋白、Fc-融合蛋白等与通式(La-X-D 2)偶联反应，得到通式(Ab-L a-X-D 2)。
本发明提供一种药物组合物，其含有治疗有效量的抗体-药物偶联物或其药学上可接受的盐或溶剂化物，以及药学上可接受的载体、稀释剂或赋形剂。
本发明提供一种包括喜树碱类衍生物或其抗体-药物偶联物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其药学上可接受的盐或溶剂化合物，以及药学上可接受的载体、稀释剂或者赋形剂，在制备用于治疗或预防肿瘤的药物中的用途。
作为优选方式，所述的肿瘤非限制性地选自：乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液肿瘤。
具体实施方式
缩写和定义
除非另有限定，本文所用的所有技术和科学术语均与本发明所属领域普通技术人员的通常理解一致。虽然也可采用与本文所述相似或等同的任何方法和材料实施或测试本发明，但本文描述了优选的方法和材料。描述和要求保护本发明时，依据以下定义使用下列术语。
当本发明中使用商品名时，申请人旨在包括该商品名产品的制剂、该商品名产品的 非专利药和活性药物部分。
除非另有说明，否则如本文所用的以下术语和短语旨在具有以下含义。当本文中使用商标名称时，除非上下文中另有指明，否则商标名称包括所述商标名称产品的产品配方、通用药物和活性药物成分。
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“配体”是能识别和结合目标细胞相关的抗原或受体的大分子化合物。配体的作用是将药物呈递给与配体结合的目标细胞群，这些配体包括但不限于蛋白类激素、凝集素、生长因子、抗体或其他能与细胞结合的分子。在本发明实施方式中，配体表示为Ab，配体可通过配体上的杂原子与连接单元形成连接键，优选为抗体或其抗原结合片段，所述抗体选自嵌合抗体、人源化抗体、全人抗体或鼠源抗体；优选为单克隆抗体。
配体单元是与靶标部分特异性结合的靶向剂。所述配体能够特异性结合至细胞组分或结合至细胞组分或结合至其他感兴趣的靶标分子。靶标部分或靶标通常在细胞表面上。在一些方面中，配体单元的作用是将药物单元递送至配体单元与之相互作用的特定靶细胞群。配体包括但不限于蛋白质、多肽和肽，以及非蛋白质如糖。合适的配体单元包括，例如，抗体，例如全长(完整)抗体及其抗原结合片段。在配体单元是非抗体靶向试剂的实施方式中，其可以是肽或多肽，或非蛋白质分子。这类靶向试剂的示例包括干扰素、淋巴因子、激素、生长因子和集落刺激因子、维生素、营养转运分子、或任何其他细胞结合分子或物质。在一些实施方式中，连接子共价连接至配体的硫原子。在一些方面中，硫原子是半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子(例如，通过定点诱变或化学反应)。在其他方面中，连接子结合的硫原子选自形成抗体的链间二硫键的半胱氨酸残基或已经引入配体单元的额半胱氨酸残基(例如，通过定点诱变或化学反应)。在一些实施方式中，按照Kabat{[Kabat E.A等，(1991)]《免疫学感兴趣的蛋白质序列》(Sequences of proteins of Immunological Interest)，第五版，NIH出版物91-3242}中的EU索引编号系统。
如本文所用，“抗体”或“抗体单元”在其所属的范围内，包括抗体结构的任何部分。这一单元可以结合，反应性关联，或者络合一个受体，抗原或者靶向细胞群体具有的其它受体单元。抗体可以是任何蛋白或蛋白类分子，它可以结合、络合或者与待治疗或生 物改造的细胞群体的一部分发生反应。本发明中组成抗体药物偶联物的抗体保持其原有野生状态时的抗原结合能力。因此，本发明中的抗体能够专一性地与抗原结合。涉及的抗原包括，例如，肿瘤相关抗原(TAA)，细胞表面受体蛋白和其他细胞表面分子，细胞存活调节因子，细胞增殖调节因子，与组织生长与分化相关的分子(如已知或预知的具有功能性的)，淋巴因子，细胞因子，参与细胞循环调节的分子，参与血管生成的分子，以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。
应用在抗体药物偶联物中的抗体包括，但不局限于，针对细胞表面受体和肿瘤相关抗原的抗体。这样的肿瘤相关抗原是业内所熟知的，可以通过业内熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物，研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性的表达在一种或多种癌细胞表面，而在一种或多种非癌细胞表面表达很少或不表达。通常，相对于非癌细胞表面而言，这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子，可大大提高基于抗体治疗癌症的专一靶向特性。为方便起见，为业内所熟知的抗原相关信息标示如下，包括名称，其他名称，基因库登录号。与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库，例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种，与参考文献中确认的序列具有至少70％,80％,85％,90％或者95％的同源性，或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
术语“抑制”或“的抑制”指，减少了可检测的量，或完全阻止。
术语“癌症”指的是以失调的细胞生长为特征的生理病症或疾病。“肿瘤”包括癌细胞。
术语“自身免疫疾病”是源自针对个体自身的组织或蛋白质的疾病或紊乱。
术语“药物”是指细胞毒性药物，药物表示D，能在肿瘤细胞内具有较强破坏其正常生长的化学分子。细胞毒性药物原则上在足够高的浓度下都可以杀死肿瘤细胞，但是由于缺乏特异性，在杀伤肿瘤细胞的同时，也会导致正常细胞的凋亡，导致严重的副作用。该术语包括毒素，如细菌、真菌、植物或动物来源的小分子毒素或酶活性毒素，放射性同位素(例如At 211、I 131、I 125、Y 90、Re 186、Re 188、Sm 153、Bi 212、P 32和Lu 176的放射性同位素)，毒性药物，化疗药物，抗生素和核溶酶，优选为毒性药物。
术语“连接子”或“连接片段”或“连接单元”是指一端与配体连接而另一端与药物相连的化学结构片段或键，也可以连接其他接头后再与药物相连。
接头，包括延伸物、间隔物和氨基酸单元，可以通过本领域己知方法合成，诸如US2005-0238649A1中所记载的。接头可以是便于在细胞中释放药物的“可切割接头”。例如，可使用酸不稳定接头(例如腙)、蛋白酶敏感(例如肽酶敏感)接头、光不稳定接头、二甲基接头、或含二硫化物接头(Chari等Cancer Research 52:127-131,1992)；美国专利No.5,208,020。
按照在细胞内药物释放的机制，如本文所用，“连接子”或“抗体药物偶联物的连接子”可被分为两类：不可断裂连接子和可断裂连接子。对于含有不可断裂连接子的配体-药物偶联物，其药物释放机制为：偶联物与抗原结合并被细胞内吞后，抗体在溶酶体中被酶解，释放出由小分子药物，连接子，和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性，但由于活性分子是带电荷的(氨基酸残基)，从而导致其不能渗入邻近细胞。因此，此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应，bystander effect)(Ducry等，2010，Bioconjugate Chem.21:5-13)。
术语“配体-药物偶联物”，指抗体通过稳定的连接单元与具有生物活性的药物相连。在本发明中“配体-药物偶联物”优选为抗体-药物偶联物(antibody drug conjugate,ADC)，指把单克隆抗体或者抗体片段通过稳定的连接单元与具有生物活性的毒性药物相连。
本公开所用氨基酸三字母代码和单字母代码如J.boil.Chem.1968,243,3558.中所述。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至10个碳原子的烷基，最优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2- 二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基。
术语“取代烷基”指烷基中的氢被取代基团取代，除非文中另有说明，烷基的取代基可以是选自下组的多种基团：-卤素、-OR’、-NR’R”、-SR’、-SiR’R”R”’、-OC(O)R’、-C(O)R’、-CO 2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R”’、-NR”C(O) 2R’、-NH-C(NH 2)＝NH、-NR’C(NH 2)＝NH、-NH-C(NH 2)＝NR’、-S(O)R’、-S(O) 2R’、-S(O) 2NR’R”、-NR’S(O) 2R”、-CN和-NO 2，取代基数量为0至(2m’+1)，其中m’为该基团中碳原子的总数。R’、R”和R”’各自独立的指代氢、未取代的C 1-8烷基、未取代的芳基、由1-3个卤素取代的芳基、未取代的C 1-8烷基、C 1-8烷氧基或C 1-8硫代烷氧基、或未取代的芳基-C 1-4烷基。R’和R”连接于同一个氮原子时，它们可与该氮原子一起形成3-，4-，5-，6-或7-元环。例如，-NR’R”包括1-吡咯烷基和4-吗啉基。
术语“杂烷基”指含有一个或多个选自N、O或S的杂原子的烷基，其中烷基如上所定义。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)和1,5-亚丁基(-CH 2CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、 卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(环烷基)，其中烷基或环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至10个碳原子，最优选包含3至8个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺杂环基"指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的兀电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中 m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选环烷基环包含3至10个环原子。单环杂环基的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，优选被一个环烷基取代，其中烷基如上所定义，其中环烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。术语“硝基”指-NO 2。
术语“酰胺基"指-C(O)N(烷基)或(环烷基)，其中烷基、环烷基如上所定义。
术语“羧酸酯基"指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基如上所定义。
本发明还包括各种氘代形式。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘代产物。在制备氘代产物时，可使用市售的氘代起始物质，或通过常规技术采用氘代试剂合成，氘代试剂的非限制性实例包括:氘代水、氘代甲醇、氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
术语“抗体”指免疫球蛋白，是由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE，其相应的重链分别为μ链、δ链、γ链、α链和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。本发明所述的抗体优选为针对靶细胞上细胞表面抗原的特异性抗体，非限制性实施例为以下抗体：抗EGFRvIII抗体、抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin 4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗 CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体中一个或多个；优选为曲妥珠单抗(Trastuzumab,商品名Herceptin)、帕妥珠单抗(Pertuzumab,也被称作2C4，商品名Perjeta)、尼妥珠单抗(Nimotuzumab，商品名泰欣生)、Enoblituzumab、Emibetuzumab、Inotuzumab、Pinatuzumab、Brentuximab、Gemtuzumab、Bivatuzumab、Lorvotuzumab、cBR96和Glematumamab。
术语“溶剂化物”或“溶剂化合物”指本发明的配体-药物偶联物与一种或多种溶剂分子形成可药用的溶剂化物，溶剂分子的非限制性实例包括水、乙醇、乙腈、异丙醇、DMSO、乙酸乙酯。
术语“载药量”是指式Ⅰ中每个抗体上加载的细胞毒性药物平均数量，也可以表示为药物量和抗体量的比值，药物载量的范围可以是每个抗体(Ab)连接0-12个，优选1-10个细胞毒性药物(D)。在本发明的实施方式中，载药量表示为n,示例性的可以为1,2,3,4,5,6,7,8,9,10的均值。可用常规方法如UV/可见光光谱法，质谱，ELISA试验和HPLC特征鉴定偶联反应后每个ADC分子的药物品均数量。
本发明的一个实施方式中，细胞毒性药物通过连接单元偶联在配体的N端氨基和/或赖氨酸残基的ε-氨基上，一般地，偶联反应中能与抗体偶联的药物分子数将小于理论上的最大值。
可以用以下非限制性方法控制配体细胞毒性药物偶联物的载量，包括：
(1)控制连接试剂和单抗的摩尔比，
(2)控制反应时间和温度，
(3)选择不同的反应试剂。
常规的药物组合物的制备见中国药典。
术语“药学上可接受的盐”或“可药用盐”是指本发明配体-药物偶联物的盐，或本发明中所述的化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性，本发明配体-药物偶联化合物至少含有一个羧基，因此可以与碱形成盐，药学上可接受的盐的非限制性实例包括：钠盐、钾盐、钙盐或镁盐等。
术语“药学上可接受的盐”或“可药用盐”是指本发明抗体-药物偶联物的盐，或本发明中所述的化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性，本发明配体-药物偶联化合物至少含有一个氨基，因此可以与酸形成盐，药 学上可接受的盐的非限制性实例包括：盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。
“酸性氨基酸”指氨基酸的等电点小于7，酸性氨基酸分子中往往带有一个或多个羧基等酸性基团，在结构中可有效电离为负离子形式而增加亲水性。酸性氨基酸可以为天然的，也可为非天然的氨基酸。
“天然氨基酸”指由生物合成的氨基酸。天然氨基酸一般情况下是L-型的，但也有少数例外，比如甘氨酸，包括天然的和生物体合成的。
“非天然氨基酸”指通过合成手段所获得的氨基酸。
下面结合具体实施例，进一步阐述本发明，应理解，这些实施例只用于说明本发明，而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比例、比率、或份数按重量计。
除非另行定义，文中所使用的所有专业和科学用于与本领域熟练人员所熟悉的意义相同。
此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1：化合物1和iso-1的合成
Figure PCTCN2021122813-appb-000022
向1L的圆底烧瓶中称入化合物SM-1(N-(8-氨基-6-氟-5-甲基-1-氧代-1,2,3,4-四氢萘-2-基)乙酰胺，外购)(6.26g,25.0mmol)、SM-2((S)-4-乙基-4-羟基-7,8-二氢-1H-吡喃O[3,4-F]吲哚嗪-3,6,10(4H)-酮，外购)(7.90g,30.0mmol)、对甲苯磺酸吡啶盐(1.26g,5.0mmol)，加入500mL甲苯，加热回流分水，反应6小时，HPLC监测反应至SM-2消失，停止反应。降温，冰水浴搅拌析晶2h，过滤，真空烘干，得到化合物Ac-1:11.02g，92％。LC-MS得到[M+H] +:478.2。
将Ac-1(11.02g，23.0mmol)、甲磺酸(55mL)、水(110mL)和甲苯(55mL)混合于1L圆底烧瓶中，加热回流。6小时后，TLC监测反应，原料消失，室温下向体系中缓慢滴加500mL甲醇，并持续搅拌，待滴加完毕，搅拌过夜，将反应体系直接抽滤，甲醇洗涤滤饼，收集滤液，将滤饼烘干，得到灰白色固体化合物1(6.58g,54％)，LC-MS得到[M+H] +:436.2。将滤液减压浓缩，液相制备纯化(MeCN/H 2O作为流动相)，冻干，得到浅棕色固体化合物iso-1(3.71g，37％)，LC-MS得到[M+H] +:436.2。
实施例2：化合物D-D1的合成
Figure PCTCN2021122813-appb-000023
将1号1000ml三口瓶氮气置换并用氮气球保护，并且有恒压滴液漏斗装置，使用注射器往瓶中加入重水(25ml，1.25mol)，置于0℃下搅拌备用。将2号500ml三口瓶氮气球保护，加入1.0M LiHMDS的THF溶液(300ml，0.30mol)，置于0℃下搅拌降温。向其中缓慢滴加DSM1-1(12.00g，54.0mmol)，滴加完毕后反应5min，注射器抽出，缓慢加入至1号瓶恒压滴液漏斗中并滴加至已冷却的重水中，滴加时间约15min。滴加完毕后搅拌5min，向反应体系中加入饱和氯化铵300ml，乙酸乙酯萃取3次，合并有机 相，清水洗涤有机相1次，无水硫酸钠干燥，浓缩后进行柱层析分离。分离得8.33g无色油状液体DSM1-2，收率69％。 1H-NMR检测，通过羰基α位氢的积分个数判断氘代情况，确认未氘代部分约1.7％。
向250ml单口瓶中加入50ml二氯甲烷和DSM1-2(8.33g，37.3mmol)，置于0℃下搅拌，加入50ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入100ml甲醇溶解，加入10％Pd/C(5.00g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到浅黄色油状液体DSM-1(2.85g，99％)直接使用。
向25ml圆底烧瓶中加入化合物1(100.3mg，0.19mmol)、DSM-1(43.0mg，0.56mmol)、HATU(107.2mg，0.28mmol)、HOBt(38.1mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体D-D1：64.0mg，收率69％。
LC-MS结果显示[M+H]+：495.2。
1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝9.2Hz,1H),7.64(d,J＝11.2Hz,1H),7.25(s,1H),6.51(s,1H),5.60-5.41(m,2H),5.39(s,2H),5.09(d,J＝18.8Hz,1H),4.92(d,J＝18.8Hz,1H),3.97(s,1H),3.22-2.98(m,2H),2.29(s,3H),2.22-2.08(m,2H),1.95-1.73(m,2H),0.86(t,J＝7.2Hz,3H).
实施例3：化合物D-D2的合成
Figure PCTCN2021122813-appb-000024
向25ml圆底烧瓶中加入化合物iso-1(82.5mg，0.19mmol)、DSM-1(43.1mg，0.56mmol)、HATU(107.2mg，0.28mmol)、HOBt(38.2mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室 温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体D-D2：67.8mg，收率73％。
LC-MS结果显示[M+H]+：495.1。
1H NMR(400MHz,DMSO-d6)δ8.38(d,J＝9.0Hz,1H),7.65(d,J＝10.9Hz,1H),7.25(s,1H),6.51(s,1H),5.53(dt,J＝9.1,6.0Hz,1H),5.41(s,2H),5.12(d,J＝19.1Hz,1H),4.92(d,J＝18.9Hz,1H),3.99(s,1H),3.10(qt,J＝16.7,6.1Hz,2H),2.29(d,J＝1.8Hz,3H),2.16(q,J＝6.4Hz,2H),2.00–1.81(m,2H),0.91(t,J＝7.3Hz,3H).
实施例4：化合物D-D3的合成
Figure PCTCN2021122813-appb-000025
将1号1000ml三口瓶氮气置换并用氮气球保护，并装备恒压滴液漏斗，使用注射器往瓶中加入重水(20ml，1.00mol)，置于0℃下搅拌备用。将2号500ml三口瓶氮气球保护，加入1.0M LiHMDS的THF溶液(200ml，0.20mol)，置于0℃下搅拌降温。向其中缓慢滴加DSM2-1(10.00g，42.3mmol)，滴加完毕后反应5min，注射器抽出，缓慢加入至1号瓶恒压滴液漏斗中并滴加至已冷却的重水中，滴加时间约12min。滴加完毕后搅拌5min，向反应体系中加入饱和氯化铵200ml，乙酸乙酯萃取3次，合并有机相，清水洗涤有机相1次，无水硫酸钠干燥，浓缩后进行柱层析分离。分离得5.07g无色油状液体DSM2-2，收率50％。 1H-NMR检测，通过羰基α位氢的积分个数判断氘代情况，发现羰基α位氢几乎消失，确认未氘代部分约1％。
向150ml单口瓶中加入40ml二氯甲烷和DSM2-2(5.07g，21.4mmol)，置于0℃下搅拌，加入20ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应 液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入50ml甲醇溶解，加入10％Pd/C(2.00g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到浅黄色油状液体DSM-2(1.84g，94％)直接使用。
向25ml圆底烧瓶中加入化合物1(100.4mg，0.19mmol)、DSM-2(51.3mg，0.56mmol)、HATU(107.1mg，0.28mmol)、HOBt(38.3mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体75.9mg，收率79％。
LC-MS结果显示[M+H]+：509.2。
1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝8.8Hz,1H),7.64(d,J＝10.8Hz,1H),7.26(s,1H),6.53(s,1H),5.56(d,J＝5.2Hz,1H),5.48(dd,J＝14.0,6.4Hz,1H),5.40(s,2H),5.09(d,J＝18.8Hz,1H),4.89(d,J＝18.8Hz,1H),3.22-3.11(m,1H),3.11-3.00(m,1H),2.29(s,3H),2.22-2.09(m,2H),1.92-1.78(m,2H),1.32(s,3H),0.87(t,J＝7.2Hz,3H).
实施例5：化合物D-D4的合成
Figure PCTCN2021122813-appb-000026
向25ml圆底烧瓶中加入化合物iso-1(82.8mg，0.19mmol)、DSM-2(50.9mg，0.56mmol)、HATU(107.4mg，0.28mmol)、HOBt(38.0mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体70.7mg，收率74％。
LC-MS结果显示[M+H]+：509.3。
1HNMR(400MHz,DMSO-d6)δ8.46(d,J＝9.2Hz,1H),7.71(d,J＝10.9Hz,1H),7.29(s,1H),6.53(s,1H),5.68(d,J＝4.9Hz,1H),5.54(q,J＝7.3Hz,1H),5.42(s,2H),5.20(d,J＝ 19.0Hz,1H),4.93(d,J＝18.9Hz,1H),3.25–3.01(m,2H),2.32(s,3H),2.14(q,J＝6.5Hz,2H),1.96–1.80(m,J＝7.1Hz,2H),1.42(s,3H),0.90(t,J＝7.2Hz,3H).
实施例6：化合物D-D5的合成
Figure PCTCN2021122813-appb-000027
将1号1000ml三口瓶氮气置换并用氮气球保护，并装备恒压滴液漏斗，使用注射器往瓶中加入重水(30ml，1.50mol)，置于0℃下搅拌备用。将2号500ml三口瓶氮气球保护，加入1.0M LiHMDS的THF溶液(350ml，0.35mol)，置于0℃下搅拌降温。向其中缓慢滴加DSM3-1(20.32g，70.0mmol)，滴加完毕后反应5min，注射器抽出，缓慢加入至1号瓶恒压滴液漏斗中并滴加至已冷却的重水中，滴加时间约12min。滴加完毕后搅拌5min，向反应体系中加入饱和氯化铵350ml，乙酸乙酯萃取3次，合并有机相，清水洗涤有机相1次，无水硫酸钠干燥，浓缩后进行柱层析分离。分离得7.15g浅黄色油状液体DSM3-2，收率35％。 1H-NMR检测，通过羰基α位氢的积分个数判断氘代情况，发现羰基α位氢几乎消失，确认未氘代部分约1％。
向150ml单口瓶中加入40ml二氯甲烷和DSM3-2(7.15g，24.5mmol)，置于0℃下搅拌，加入20ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入50ml甲醇溶解，加入10％Pd/C(3.50g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到浅黄色油状液体DSM-3(3.54g，97％)直接使用。
向25ml圆底烧瓶中加入化合物1(100.8mg，0.19mmol)、DSM-3(81.3mg，0.56mmol)、HATU(106.8mg，0.28mmol)、HOBt(38.5mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体63.1mg，收率59％。
LC-MS结果显示[M+H]+：562.1。
实施例7：化合物D-D6的合成
Figure PCTCN2021122813-appb-000028
向25ml圆底烧瓶中加入化合物iso-1(82.3mg，0.19mmol)、DSM-3(81.5mg，0.56mmol)、HATU(107.2mg，0.28mmol)、HOBt(38.3mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体66.1mg，收率62％。
LC-MS结果显示[M+H]+：562.2。
实施例8：化合物D-D7的合成
Figure PCTCN2021122813-appb-000029
Figure PCTCN2021122813-appb-000030
将1号1000ml三口瓶氮气置换并用氮气球保护，并装备恒压滴液漏斗，使用注射器往瓶中加入重水(30ml，1.50mol)，置于0℃下搅拌备用。将2号500ml三口瓶氮气球保护，加入1.0M LiHMDS的THF溶液(350ml，0.35mol)，置于0℃下搅拌降温。向其中缓慢滴加DSM4-1(18.36g，70.0mmol)，滴加完毕后反应5min，注射器抽出，缓慢加入至1号瓶恒压滴液漏斗中并滴加至已冷却的重水中，滴加时间约12min。滴加完毕后搅拌5min，向反应体系中加入饱和氯化铵350ml，乙酸乙酯萃取3次，合并有机相，清水洗涤有机相1次，无水硫酸钠干燥，浓缩后进行柱层析分离。分离得7.58g浅黄色油状液体DSM4-2，收率41％。 1H-NMR检测，通过羰基α位氢的积分个数判断氘代情况，发现羰基α位氢几乎消失，确认未氘代部分约0.7％。
向150ml单口瓶中加入60ml二氯甲烷和DSM4-2(7.58g，28.8mmol)，置于0℃下搅拌，加入20ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入50ml甲醇溶解，加入10％Pd/C(4.01g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到几乎无色油状液体DSM-4(3.27g，97％)直接使用。
向25ml圆底烧瓶中加入化合物1(100.7mg，0.19mmol)、DSM-4(65.9mg，0.56mmol)、HATU(107.8mg，0.28mmol)、HOBt(38.9mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体71.3mg，收率70％。
LC-MS结果显示[M+H]+：535.2。
实施例9：化合物D-D8的合成
Figure PCTCN2021122813-appb-000031
向25ml圆底烧瓶中加入化合物iso-1(82.7mg，0.19mmol)、DSM-4(65.6mg，0.56mmol)、HATU(107.3mg，0.28mmol)、HOBt(38.9mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体65.3mg，收率64％。
LC-MS结果显示[M+H]+：535.2。
实施例10：化合物D-D9的合成
Figure PCTCN2021122813-appb-000032
将1L三口瓶用氮气球保护，加入300mL新蒸THF和1.0M LiHMDS的THF溶液(200ml，0.20mol)，置于-78℃下搅拌降温。向其中缓慢滴加DSM1-1(22.23g，0.10mol)，滴加完毕后反应30min，向其中加入CD 3I(10mL,0.20mol)。滴加完毕后搅拌15min，将反应提至室温再搅拌15min，向反应体系中加入饱和氯化铵300ml淬灭反应，乙酸乙 酯萃取3次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离。分离得13.88g浅黄色油状液体DSM5-1，收率58％。
向150ml单口瓶中加入40ml二氯甲烷和DSM5-1(4.79g，20.0mmol)，置于0℃下搅拌，加入20ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入50ml甲醇溶解，加入10％Pd/C(2.56g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到几乎无色油状液体DSM-5(1.83g，98％)直接使用。
向25ml圆底烧瓶中加入化合物1(100.5mg，0.19mmol)、DSM-5(52.6mg，0.56mmol)、HATU(107.6mg，0.28mmol)、HOBt(38.7mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体66.9mg，收率69％。
LC-MS结果显示[M+H]+：511.2。
实施例11：化合物D-D10的合成
Figure PCTCN2021122813-appb-000033
向25ml圆底烧瓶中加入化合物iso-1(82.6mg，0.19mmol)、DSM-5(52.3mg，0.56mmol)、HATU(107.4mg，0.28mmol)、HOBt(38.2mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体70.8mg，收率73％。
LC-MS结果显示[M+H]+：511.1。
实施例12：化合物D-D11的合成
Figure PCTCN2021122813-appb-000034
将1号500ml三口瓶氮气置换并用氮气球保护，并装备恒压滴液漏斗，使用注射器往瓶中加入重水(20ml，1.0mol)，置于0℃下搅拌备用。将2号250ml三口瓶氮气球保护，加入1.0M LiHMDS的THF溶液(125ml，0.125mol)，置于0℃下搅拌降温。向其中缓慢滴加DSM5-1(5.99g，25.0mmol)，滴加完毕后反应5min，注射器抽出，缓慢加入至1号瓶恒压滴液漏斗中并滴加至已冷却的重水中，滴加时间约12min。滴加完毕后搅拌5min，向反应体系中加入饱和氯化铵150ml，乙酸乙酯萃取3次，合并有机相，清水洗涤有机相1次，无水硫酸钠干燥，浓缩后进行柱层析分离。分离得3.11g浅黄色油状液体DSM5-2，收率52％。 1H-NMR检测，通过羰基α位氢的积分个数判断氘代情况，发现羰基α位氢几乎消失，确认未氘代部分约1.5％。
向100ml单口瓶中加入30ml二氯甲烷和DSM5-2(3.11g，12.6mmol)，置于0℃下搅拌，加入10ml TFA，提至室温搅拌约1h，TLC检测反应完全，30℃下减压浓缩反应液，并用DCM带出残余TFA，油泵减压干燥15min，得到油状物粗品，直接用于下一步。向该粗品中加入30ml甲醇溶解，加入10％Pd/C(1.50g)，氢气置换并增加氢气球装置，置于室温反应约2h，TLC检测原料消失，抽滤，滤饼甲醇洗涤2次。合并滤液，减压浓缩，油泵减压干燥，得到几乎无色油状液体DSM-6(1.15g，97％)直接使用。
向25ml圆底烧瓶中加入化合物1(101.1mg，0.19mmol)、DSM-6(52.7mg，0.56mmol)、HATU(108.1mg，0.28mmol)、HOBt(38.7mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC 检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体66.1mg，收率68％。
LC-MS结果显示[M+H]+：512.2。
实施例13：化合物D-D12的合成
Figure PCTCN2021122813-appb-000035
向25ml圆底烧瓶中加入化合物iso-1(82.7mg，0.19mmol)、DSM-6(52.9mg，0.56mmol)、HATU(107.4mg，0.28mmol)、HOBt(38.2mg，0.28mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(95uL，0.57mmol)，并提至室温搅拌。HPLC检测反应进度，反应约3h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体70.8mg，收率73％。
LC-MS结果显示[M+H]+：512.2。
实施例14：化合物D-D13的合成
Figure PCTCN2021122813-appb-000036
向25mL圆底烧瓶中称入化合物1(319.1mg，0.60mmol)，氩气保护，加入8mL新蒸的THF，-78℃冷却。将14.8mg NaH溶于2.0mL新蒸THF，缓慢滴加至化合物1的低温溶液中，低温搅拌5min，向其中加入CD 3I(50uL，0.80mmol)，加毕将反应提至室温搅拌1h，HPLC监测反应无明显进展，停止反应。向体系中加入5mL HCl(3M)溶液，室温搅拌过夜，直接浓缩，液相制备纯化，得到黄色固体CD-1：172.0mg，63％。LC-MS结果显示[M+H]+：453.2。
向25ml圆底烧瓶中加入化合物CD-1(67.5mg，0.15mmol)、DSM-7(35.2mg，0.45mmol)、HATU(114.2mg，0.30mmol)、HOBt(41.0mg，0.30mmol)和5ml超干DMF， 瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(78uL，0.45mmol)，并提至室温搅拌。HPLC检测反应进度，反应约6h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体35.7mg，收率47％。
LC-MS结果显示[M+H]+：511.2。
实施例15：化合物D-D14的合成
Figure PCTCN2021122813-appb-000037
向25ml圆底烧瓶中加入化合物CD-1(67.9mg，0.15mmol)、DSM-8(40.5mg，0.45mmol)、HATU(113.9mg，0.30mmol)、HOBt(41.4mg，0.30mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(78uL，0.45mmol)，并提至室温搅拌。HPLC检测反应进度，反应过夜，原料小于5％，反应体系液相制备分离，冻干，得黄色固体38.9mg，收率49％。
LC-MS结果显示[M+H]+：525.2。
实施例16：化合物D-D15和D-D16的合成
Figure PCTCN2021122813-appb-000038
参照实施例14的合成路线和方法，得到化合物D-D15(33.5mg)，LC-MS结果显示[M+H]+：511.2。
Figure PCTCN2021122813-appb-000039
参照实施例15的合成路线和方法，得到化合物D-D16(37.5mg)，LC-MS结果显示[M+H]+：525.1。
实施例17：化合物D-D17的合成
Figure PCTCN2021122813-appb-000040
向25mL圆底烧瓶中称入化合物1(320.5mg，0.60mmol)，氩气保护，加入8mL新蒸的THF，-78℃冷却。将15.5mg NaH溶于2.0mL新蒸THF，缓慢滴加至化合物1的低温溶液中，低温搅拌5min，向其中加入CH 3I(50uL，0.80mmol)，加毕，将反应提至室温搅拌1h，HPLC监测反应无明显进展，停止反应。向体系中加入5mL HCl(3M)溶液，室温搅拌过夜，直接浓缩，液相制备纯化，得到黄色固体CH-1：174.6mg，65％。LC-MS结果显示[M+H]+：450.2。
向25ml圆底烧瓶中加入化合物CH-1(66.8mg，0.15mmol)、DSM-5(42.2mg，0.45mmol)、HATU(114.2mg，0.30mmol)、HOBt(41.0mg，0.30mmol)和5ml超干DMF，瓶口液封。将其冰水浴下搅拌10分钟，然后加入DIEA(78uL，0.45mmol)，并提至室温搅拌。HPLC检测反应进度，反应约5h，原料小于5％，反应体系液相制备分离，冻干，得黄色固体38.7mg，收率49％。
LC-MS结果显示[M+H]+：525.2。
实施例18：化合物D-D18、D-D19和D-D20的合成
Figure PCTCN2021122813-appb-000041
参照实施例17的合成路线和方法，得到化合物D-D18(39.5mg)，LC-MS结果显示[M+H]+：576.1。
Figure PCTCN2021122813-appb-000042
参照实施例17的合成路线和方法，得到化合物D-D19(37.5mg)，LC-MS结果显示[M+H]+：525.1。
Figure PCTCN2021122813-appb-000043
参照实施例17的合成路线和方法，得到化合物D-D16(38.9mg)，LC-MS结果显示[M+H]+：576.2。
实施例19：化合物M1的合成
Figure PCTCN2021122813-appb-000044
于5000mL单口瓶中加入N-芴甲氧羰基-甘氨酸-甘氨酸(100g,282mmol,1.0eq，外购)，四乙酸铅(175g,553mmol,1.4eq)，2000mL干燥四氢呋喃和670mL甲苯，搅拌均匀，氮气保护，加热至85℃反应2.5h。TLC监控，原料反应完后，冷却至室温，过滤，滤液减压浓缩，残余物经柱色谱纯化，得化合物M1(87g)。LC-MS：[M+NH 4] +386.0。
实施例20：化合物M2的合成
Figure PCTCN2021122813-appb-000045
于1000mL单口瓶，加入化合物SM-3(49.9g，100.0mmol,1.0eq，参照本公司专利申请CN108452321公开的方法合成)、五氟苯酚(18.5g,110.0mmol,1.1eq)、DCC(20.64g,110.0mmol,1.1eq)及THF(500mL)，室温反应1h(采用TLC监测反应完全)，过滤滤去不溶物，将此滤液记为滤液A，2-8℃保存，以备后用(直接取用溶剂，按照0.2M计算使用)。LC-MS：[M+H] +565.2。
实施例21：化合物L-D1的合成
Figure PCTCN2021122813-appb-000046
Figure PCTCN2021122813-appb-000047
第一步：化合物1a的合成
于250mL单口瓶中，加入M1(7.37g,20.0mmol)，100mL THF，对甲苯磺酸一水合物(0.38g,2.00mmol)，搅拌冷却至0℃，滴加DSM-5的合成中间体苄酯(7.33g,40.0mmol)，滴毕，自然升温至室温反应(反应约2-4h)，TLC监控。反应结束，加入饱和NaHCO 3溶液淬灭反应，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化(PE:EA＝10:1-5:1-1:1)得1a(5.32g)，收率54％。LC-MS：[M+H]+492.2。
第二步：化合物1b的合成
于50mL单口瓶，加入1a(5.00g,10.2mmol)，20mL DMF，0℃搅拌，加入DBU(1.64mL,11.0mmol)，反应1h，TLC监测Fmoc脱保护完成后，静置，待用；
另取50mL单口瓶中加入M4(4.55g,11.0mmol，外购)、PyBOP(6.25g,12.0mmol)，HOBt(1.62g,12.0mmol)及10mL DMF，冰水浴下加入DIEA(2.00mL,12.0mmol)，继续搅拌30min，将上述静置反应液加至反应瓶中，升至室温反应。HPLC监测反应结束后，反应液经制备液相纯化，得到产品制备液，制备液冷冻干燥得到固体1b(4.61g)，收率68％。LC-MS：[M+H]+为665.3。
第三步：化合物1c的合成
于50mL单口瓶中加入1b(4.32g,6.50mmol)，15mL DMF溶清后，加入4.2g 5％Pd/C，氢化反应2h，反应完毕，过滤，得滤液，得粗产品1c直接用于下一步反应。
第四步：化合物1d的合成
将粗产品1c置于冰水浴中，加入DIPEA(1.22mL,7.00mmol)，再加入化合物 M2(35mL,7.0mmol)，加毕升至室温反应1h。HPLC监测反应完毕，液相纯化，得制备液，冻干得到1d(3.62g)。LC-MS：[M+H]+821.4。
第五步：化合物1e的合成
于50mL单口瓶中加入1d(500.0mg,0.60mmol)，化合物1(310.6mg,0.58mmol)，PyBOP(448.3mg,0.94mmol)，HOBt(127.0mg,0.94mmol)及15mL DMF，冰水浴下加入DIEA(418uL,2.40mmol)，升至室温反应3h。HPLC监测反应完毕后，反应液经液相制备纯化，得化合物1e的制备液，冻干得到1e(497.9mg，67％)。LC-MS：[M+H] +1238.6；
第六步：化合物L-D1的合成
于25mL单口瓶中加入1e(100mg,0.081mmol)，溴化锌(368mg,1.63mmol)及5mL硝基甲烷，40℃下反应1h。HPLC监测反应完毕后，减压浓缩除去溶剂，得粗品。粗品经液相制备纯化，得到产品制备液，冻干得到固体化合物L-D1(63.1mg)。LC-MS：[M+H] +1082.3。
实施例22：化合物L-D2的合成
Figure PCTCN2021122813-appb-000048
参照实施例21合成路线和方法，得到化合物L-D2(59.8mg)。LC-MS：[M+H] +1082.4。
实施例23：化合物L-D3的合成
Figure PCTCN2021122813-appb-000049
Figure PCTCN2021122813-appb-000050
第一步：化合物2a的合成
于250mL单口瓶中，加入M1(7.36g,20.0mmol)，100mL THF，对甲苯磺酸一水合物(0.38g,2.00mmol)，搅拌冷却至0℃，滴加DSM-2的合成中间体苄酯(7.25g,40.0mmol)，滴毕，自然升温至室温反应(反应约2-4h)，TLC监控。反应结束，加入饱和NaHCO 3溶液淬灭反应，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化(PE:EA＝10:1-5:1-1:1)得2a(5.12g)，收率52％。LC-MS：[M+H] +490.2。
第二步：化合物2b的合成
于50mL单口瓶，加入2a(5.00g,10.2mmol)，20mL DMF，0℃搅拌，加入DBU(1.64mL,11.0mmol)，反应1h，TLC监测Fmoc脱保护完成后，静置，待用；
另取50mL单口瓶中加入M4(4.56g,11.0mmol，外购)、PyBOP(6.26g,12.0mmol)，HOBt(1.64g,12.0mmol)及10mL DMF，冰水浴下加入DIEA(2.00mL,12.0mmol)，继续搅拌30min，将上述静置反应液加至反应瓶中，升至室温反应。HPLC监测反应结束后，反应液经制备液相纯化，得到产品制备液，制备液经二氯甲烷萃取，饱和氯化钠溶液洗 涤，无水硫酸钠干燥，过滤，减压浓缩，得到固体2b(4.58g)，收率68％。LC-MS：[M+H] +为663.3。
第三步：化合物2c的合成
于50mL单口瓶中加入2b(4.31g,6.50mmol)，15mL DMF溶清后，加入4.0g 5％Pd/C，氢化反应2h，反应完毕，过滤，得滤液，得粗产品2c直接用于下一步反应。
第四步：化合物2d的合成
将粗产品2c置于冰水浴中，加入DIPEA(1.22mL,7.00mmol)，再加入化合物M2(35mL,7.0mmol)，加毕升至室温反应1h。HPLC监测反应完毕，液相纯化，得制备液，冻干得到2d(3.57g)。LC-MS：[M+H]+819.4。
第五步：化合物2e的合成
于50mL单口瓶中加入2d(500.0mg,0.61mmol)，化合物1(320.1mg,0.60mmol)，PyBOP(448.5mg,0.94mmol)，HOBt(127.3mg,0.94mmol)及15mL DMF，冰水浴下加入DIEA(418uL,2.40mmol)，升至室温反应3h。HPLC监测反应完毕后，反应液经液相制备纯化，得化合物2e的制备液，冻干得到2e(482.3mg，64％)。LC-MS：[M+H] +1236.5。
第六步：化合物L-D3的合成
于25mL单口瓶中加入2e(100mg,0.081mmol)，溴化锌(370mg,1.63mmol)及5mL硝基甲烷，40℃下反应1h。HPLC监测反应完毕后，减压浓缩除去溶剂，得粗品。粗品经液相制备纯化，得到产品制备液，冻干得到固体化合物L-D3(48.3mg)。LC-MS：[M+H] +1080.4。
实施例24：化合物L-D4的合成
Figure PCTCN2021122813-appb-000051
参照实施例23合成路线和方法，得到化合物L-D4(49.8mg)。LC-MS：[M+H] +1080.4。
实施例25：化合物L-D5的合成
Figure PCTCN2021122813-appb-000052
第一步：化合物3a的合成
于250mL单口瓶中，加入M1(11.05g,30.0mmol)，150mL THF，对甲苯磺酸一水合物(0.57g,3.00mmol)，搅拌冷却至0℃，滴加DSM-3的合成中间体苄酯(9.41g,40.0mmol)，滴毕，自然升温至室温反应(反应约2-4h)，TLC监控。反应结束，加入饱和NaHCO 3溶液淬灭反应，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化(PE:EA＝10:1-5:1-1:1)得3a(8.04g)，收率37％。LC-MS：[M+H] +544.2。
第二步：化合物3b的合成
于50mL单口瓶，加入3a(5.54g,10.2mmol)，20mL DMF，0℃搅拌，加入DBU(1.64mL,11.0mmol)，反应1h，TLC监测Fmoc脱保护完成后，静置，待用；
另取50mL单口瓶中加入M4(4.55g,11.0mmol，外购)、PyBOP(6.27g,12.0mmol)，HOBt(1.66g,12.0mmol)及10mL DMF，冰水浴下加入DIEA(2.00mL,12.0mmol)，继续搅拌30min，将上述静置反应液加至反应瓶中，升至室温反应。HPLC监测反应结束后，反应液经制备液相纯化，得到产品制备液，制备液经二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到固体3b(3.52g)，收率48％。LC-MS：[M+H] +为717.3。
第三步：化合物3c的合成
于50mL单口瓶中加入3b(3.22g,4.50mmol)，10mL DMF溶清后，加入3.0g 5％Pd/C，氢化反应2h，反应完毕，过滤，得滤液，得粗产品3c直接用于下一步反应。
第四步：化合物3d的合成
将粗产品3c置于冰水浴中，加入DIPEA(1.22mL,7.00mmol)，再加入化合物M2(25mL,5.0mmol)，加毕升至室温反应1h。HPLC监测反应完毕，液相纯化，得制备液，冻干得到3d(3.17g)。LC-MS：[M+H] +873.3。
第五步：化合物3e的合成
于50mL单口瓶中加入3d(500.2mg,0.57mmol)，化合物1(319.5mg,0.60mmol)，PyBOP(447.3mg,0.94mmol)，HOBt(126.9mg,0.94mmol)及15mL DMF，冰水浴下加入DIEA(418uL,2.40mmol)，升至室温反应3h。HPLC监测反应完毕后，反应液经液相制备纯化，得化合物3e的制备液，冻干得到3e(492.3mg，67％)。LC-MS：[M+H] +1290.5。
第六步：化合物L-D5的合成
于25mL单口瓶中加入3e(100mg,0.077mmol)，溴化锌(370mg,1.63mmol)及5mL硝基甲烷，40℃下反应1h。HPLC监测反应完毕后，减压浓缩除去溶剂，得粗品。粗品经液相制备纯化，得到产品制备液，冻干得到固体化合物L-D5(42.4mg，48％)。LC-MS：[M+H] +1134.4。
实施例26：化合物L-D6的合成
Figure PCTCN2021122813-appb-000053
参照实施例25合成路线和方法，得到化合物L-D6(41.8mg)。LC-MS：[M+H] +1134.4。
实施例27：化合物L-D7的合成
Figure PCTCN2021122813-appb-000054
参照实施例23的合成路线和方法，得到化合物L-D7(45.7mg)。LC-MS：[M+H] +1083.4。
实施例28：化合物L-D8的合成
Figure PCTCN2021122813-appb-000055
Figure PCTCN2021122813-appb-000056
第一步：化合物4a的合成
于250mL单口瓶中，加入M1(7.36g,20.0mmol)，100mL THF，对甲苯磺酸一水合物(0.38g,2.00mmol)，搅拌冷却至0℃，滴加羟基乙酸苄酯(6.65g,40.0mmol)，滴毕，自然升温至室温反应(反应约2-4h)，TLC监控。反应结束，加入饱和NaHCO 3溶液淬灭反应，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析纯化(PE:EA＝10:1-5:1-1:1)得4a(5.29g)，收率56％。LC-MS：[M+H] +475.2。
第二步：化合物4b的合成
于50mL单口瓶，加入4a(5.00g,10.5mmol)，20mL DMF，0℃搅拌，加入DBU(1.64mL,11.0mmol)，反应1h，TLC监测Fmoc脱保护完成后，静置，待用；
另取50mL单口瓶中加入M4(4.57g,11.0mmol，外购)、PyBOP(6.26g,12.0mmol)，HOBt(1.65g,12.0mmol)及10mL DMF，冰水浴下加入DIEA(2.00mL,12.0mmol)，继续搅拌30min，将上述静置反应液加至反应瓶中，升至室温反应。HPLC监测反应结束后，反应液经制备液相纯化，得到产品制备液，制备液经二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到固体4b(4.68g)，收率71％。LC-MS：[M+H] + 为648.3。
第三步：化合物4c的合成
于50mL单口瓶中加入4b(3.00g,4.63mmol)，15mL DMF溶清后，加入2.0g 5％Pd/C，氢化反应2h，反应完毕，过滤，得滤液，得粗产品4c直接用于下一步反应。
第四步：化合物4d的合成
将粗产品4c置于冰水浴中，加入DIPEA(1.22mL,7.00mmol)，再加入化合物M2(25mL,5.0mmol)，加毕升至室温反应1h。HPLC监测反应完毕，液相纯化，得制备液，冻干得到4d(2.57g)。LC-MS：[M+H] +804.3。
第五步：化合物4e的合成
于50mL单口瓶中加入4d(500.0mg,0.62mmol)，化合物CD-1(289.1mg,0.64mmol)，PyBOP(448.5mg,0.94mmol)，HOBt(127.3mg,0.94mmol)及15mL DMF，冰水浴下加入DIEA(418uL,2.40mmol)，升至室温反应3h。HPLC监测反应完毕后，反应液经液相制备纯化，得化合物4e的制备液，冻干得到4e(412.3mg，48％)。LC-MS：[M+H] +1238.5。
第六步：化合物L-D8的合成
于25mL单口瓶中加入4e(100mg,0.081mmol)，溴化锌(370mg,1.63mmol)及5mL硝基甲烷，40℃下反应1h。HPLC监测反应完毕后，减压浓缩除去溶剂，得粗品。粗品经液相制备纯化，得到产品制备液，冻干得到固体化合物L-D8(48.7mg)。LC-MS：[M+H] +1082.4。
实施例29：化合物L-D9的合成
Figure PCTCN2021122813-appb-000057
参照实施例21、28的合成路线和方法，得到化合物L-D9(45.1mg)。LC-MS：[M+H] +1096.4。
实施例30：化合物L-D10的合成
Figure PCTCN2021122813-appb-000058
参照实施例21的合成路线和方法，得到化合物L-D10(45.9mg)。LC-MS：[M+H] +1066.4。
实施例31：化合物L-D11的合成
Figure PCTCN2021122813-appb-000059
参照实施例23的合成路线和方法，得到化合物L-D11(55.2mg)。LC-MS：[M+H] +1106.4。
实施例32：用于对照的化合物合成
参照专利CN111689980和WO2020063676中的方法合成得到下列化合物：
Figure PCTCN2021122813-appb-000060
Figure PCTCN2021122813-appb-000061
Figure PCTCN2021122813-appb-000062
实施例33：化合物L-H1的合成
Figure PCTCN2021122813-appb-000063
第一步：化合物1f的合成
于50mL单口瓶中加入1b(500.0mg，0.772mmol)、5％Pd/C(500.0mg，100％m)和10ml DMF，添加氢气球并置换氢气，室温下反应约3h。HPLC监测反应完全后，超声除氢气。过滤，得滤液，得粗产品1c。冰水浴下，向滤液中依次加入MC(280.1mg，0.9mmol)，DIEA(235mg，1.8mmol)，氮气保护，加完后升至室温反应1h，HPLC监控，液相制备纯化，冻干得化合物1f(268.9mg，86％)，MS：[M+H] +617.2。
第二步：化合物L-H1的合成
10ml单口瓶中加入1f(268.9mg，0.44mmol)、依喜替康甲磺酸盐(233.8mg，0.44mmol，外购)、HATU(190.5mg，0.50mmol)、HOBt(67.8mg，0.50mmol)和5ml DMF，置于 冰水浴下搅拌10min，滴加DIEA(140uL，0.84mmol)继续反应，HPLC监测反应完全后制备分离，制备液冻干得254.3mg黄色固体,收率56％。LC-MS：[M+H] +1034.4。
实施例34：参照实施例21的合成路线和方法，合成下列化合物：
Figure PCTCN2021122813-appb-000064
Figure PCTCN2021122813-appb-000065
实施例35：偶联制备ADC药物通法
将通过初步的纯化后单体率大于95％的抗体分子Ab，使用超滤离心管换液至磷酸盐缓冲液中，浓度10mg/ml。加入20倍于抗体摩尔分子数的TCEP，室温下反应4h以打开抗体链间二硫键。加入20倍于抗体摩尔分子数的payload，室温下反应2h。反应结束后，使用截留分子量为30KDa的超滤离心管换液至PBS中，并去除未偶联的payload。换液后的ADC样品使用0.22微米除菌过滤器过滤后备用。
将偶联用payload化合物L-D1、L-D2、L-D3、L-D4、L-D5、L-D6、L-D7、L-D8、L-D9、L-D10、L-D11、L-H1、L-H2、L-H3、L-H4、L-H5、L-H6、L-H7和L-H8采用本实施例35所述偶联通法，与抗体分子Ab偶联(Ab分别为A：Trastuzumab抗体；B：Cetuximab抗体)。偶联产物经反相高效液相色谱测定其平均药物/抗体比(DAR)值。所得ADC药物分子相关信息及与payload分子的对应情况如下：
Figure PCTCN2021122813-appb-000066
Figure PCTCN2021122813-appb-000067
Figure PCTCN2021122813-appb-000068
Figure PCTCN2021122813-appb-000069
Figure PCTCN2021122813-appb-000070
实施例36：氘代喜树碱药物的清除半衰期测试
材料
肝微粒体：
人肝微粒体(供应商Xenotech)
化学试剂：
名称 供应商 批号
NADPH Sigma SLCC8498
KH2PO4 国药集团化学试剂有限公司 20180816
K2HPO4·3H 2O 国药集团化学试剂有限公司 P1359845
MgCl2·6H2O 国药集团化学试剂有限公司 20180813
甲酸(FA) Aladdin L1903097
DMSO Sigma BCBW5664
乙腈(ACN) Merck I0928430749
甲醇(MeOH) Merck I1074607006
设备仪器
液相系统         Waters ACQUITY UPLC I-Class
质谱：           Waters Xevo G2-XS QTOF
水浴装置：       BSG-24
离心机：         Thermo Fisher ST40R
净水系统：       Milli-Q IQ7000
孵育体系
肝微粒体蛋白浓度 1.0mg/mL
种属 人
供试品和阳性对照浓度 10μM
NADPH浓度 1.0mM
氯化镁浓度 3.0mM
孵育介质 100mM磷酸钾钾盐缓冲液(pH＝7.4)
孵育条件 37℃
孵育体积 200μl
实验流程
磷酸盐缓冲液的制备
磷酸盐缓冲液的配制：分别称取适量的KH 2PO 4(MW＝136.09)、K 2HPO 4·3H 2O(MW＝228.22)和MgCl 2·6H 2O(MW＝203.3)充分溶解于适当体积的去离子水中，配制成100mM的pH＝7.4±0.05的磷酸钾缓冲液含3mM MgCl 2，必要时采用HCl调节pH值。
储备液和工作液配制
储备液的配制：称取适量供试品或阳性对照化合物至适当容器中，用DMSO(或者其它适合的有机溶剂)配制为10mM的储备液。
工作液的配制：将10mM的储备液用乙腈(或者其它合适的溶剂)稀释至1.0mM 作为工作液，备用。
微粒体供试品/阳性对照品工作液的配制
肝微粒体原液(浓度为20mg/mL)用浓度为100mM的磷酸钾缓冲液(pH 7.4)稀释至孵育样品所需的浓度(浓度为1.12mg/mL)为止。
NADPH溶液的制备
NADPH辅酶溶液中包含10mM NADPH，由100mM的磷酸钾缓冲溶液溶解稀释NADPH所得，样品孵育前现配现用。
终止液的制备
甲醇和乙腈按等体积混合(MeOH:ACN＝1:1,v:v)作为终止液，置于4℃冰箱中备用。
样品的孵育与处理
1.将供试品工作液加入肝微粒体工作液中37℃预孵育5分钟后，加入配制好的NADPH工作溶液，混匀。使得孵育体系反应体积达到200μL,且孵育体系中肝微粒蛋白浓度和供试品孵育浓度为1.0mg/mL和10μM。孵育管将于37℃的水浴箱中孵育120分钟。供试品孵育体系中，总有机溶剂(DMSO和乙腈或者其它的有机溶剂)的最小体积含量要求≤1％，而且DMSO含量≤0.1％。所有操作均在湿冰上进行。
2.对于空白样品，加入相应体积的磷酸缓冲液代替供试品工作液，对于0min样品，先加入终止液和肝微粒体溶液混匀，再加入供试品工作液。
3.孵育结束时，加入400μL的终止液终止反应，从水浴箱中取出孵育样品。
4.反应终止后，样品经过振摇之后以4700g的离心力离心10分钟。离心之后，移取200μL上清液于96孔板中直接用于LC-MS分析进样，分析代谢产物与主药比例。
测试结果如下：
Figure PCTCN2021122813-appb-000071
Figure PCTCN2021122813-appb-000072
Figure PCTCN2021122813-appb-000073
Figure PCTCN2021122813-appb-000074
实验结果表明，氘代药物在肝微粒中代谢稳定性明显提高。
实施例37：ADC药物抗肿瘤细胞活性测试
本发明中采用A431、Fadu、Bxpc-3、SW620和N87作为体外药效检测的研究体系。均匀接种适当数量肿瘤细胞系于96孔板中，放入二氧化碳培养箱孵育。24小时后，镜下确认细胞状态正常，进行药物加药处理。用培养基稀释药物(ADC药物起始浓度为500nM，稀释倍数为7倍，共8个浓度点，毒素与抗体的理论偶联比例(DAR)为8:1，实际偶联比例大致为7.5:1，因此毒素的起始浓度4.0μM，7倍浓度梯度稀释，8个浓度点)，混匀后加入对应的细胞孔中，其中最后两列分别为对照组(即细胞+培养基，无药物处理)和空白组(即无细胞，仅含有培养基，用于扣除背景)，放入二氧化碳培养箱37℃孵育5天。5天后，每孔加入20μL MTS(Promega，G3581)反应2小时，用酶标仪(Molecular Device，型号：SpectraMAX190)读取波长为490nm的吸光值读数。通过检测线粒体内的脱氢酶的活性，计算IC50评价ADC药物对肿瘤细胞的增殖抑制作用。结果如下
Figure PCTCN2021122813-appb-000075
Figure PCTCN2021122813-appb-000076
经过以上ADC细胞活性测试，本发明所述的氘代喜树碱药物在通过连接单元L与抗体偶联后，在多个抗原阳性肿瘤细胞系中均表现出良好的抗肿瘤活性，具有极大的临床应用价值。
实施例38：ADC体内药效测试
本发明中建立了A431荷瘤裸鼠模型，以评价氘代喜树碱衍生物ADC偶联药物与未氘代ADC偶联物的体内药效。即以3×10 6个A431细胞通过皮下注射到4～6周龄的BALB/c裸鼠右肩侧皮下，待小鼠肿瘤体积平均大小生长至140～150mm 3，随机分组，每组5只，在第0、7、14、21天分别静脉注射空白对照(缓冲溶液空白)和10mg/kg剂量的抗体药物偶联物ADC-1、ADC-3、ADC-5、ADC-10、ADC-12、ADC-13和ADC-15。在0、7、14、21、24、28、32、36天分别测试肿瘤体积，测量数据显示为测量时肿瘤平均体积。同时记录小鼠体重变化情况，用以观察ADC药物的体内初步毒性。结果如下：
Figure PCTCN2021122813-appb-000077
Figure PCTCN2021122813-appb-000078
Figure PCTCN2021122813-appb-000079
经过以上ADC小鼠体内药效实验，证明本发明所述的氘代喜树碱药物在通过连接单元L与抗体偶联后，在荷瘤小鼠中表现出了明确的抗肿瘤活性，平均瘤体明显低于空白对照，抑制作用明显，在观察周期内未观察到明显的反弹，药效持久。小鼠体重在给药期间无明显变化，除空白对照外，组内小鼠体重无明显变化，无小鼠死亡，本发明所述的氘代喜树碱药物具有良好的安全性。

Claims (27)

  1. 一种通式D所示的氘代喜树碱类衍生物或其药学上可接受的盐或溶剂化物：
    Figure PCTCN2021122813-appb-100001
    其中：
    R 1、R 7、R 10分别独立选自氢、氘、C 1-6烷基、一个或多个氘代的C 1-6烷基、取代烷基；
    R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
    X选自-C(O)-CR aR b-(CR cR d) n-O-、-C(O)-CR aR b-(CR cR d) n-NH-或-C(O)-CR aR b-(CR cR d) n-S-；
    R a、R b分别独立的选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘代的环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、烷氧基烷基、一个或多个氘代的烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、或一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
    R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、C 1-6烷基、卤代烷基、一个或多个氘代C 1-6烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代环烷基、杂环基、一个或多个氘代的杂环基；
    或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
    n选自0至4的整数；
    R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10和X中有且至少含有一个氘原子。
  2. 根据权利要求1中所述的喜树碱类衍生物或其药学上可接受的盐或溶剂化物，其特征在于：X为-C(O)-CR aR b-(CR cR d) n-O-；
    R a选自氢原子、氘原子、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代的烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    R b选自氢原子、氘原子、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代的烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、个或多个氘代环烷基烷基或杂环基、一个或多个氘代杂环基；
    R c、R d相同或者不同，且分别独立地为氢原子、氘原子、烷基、一个或多个氘代烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基或杂环基；
    或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基；
    n选自0或1。
  3. 根据权利要求1或2中所述的喜树碱类衍生物或其药学上可接受的盐或溶剂化物，其特征在于：所述喜树碱类衍生物包含式D 2所示的结构：
    Figure PCTCN2021122813-appb-100002
    其中：
    R 10选自氢原子、一个或多个氘代的C 1-6烷基；
    R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
    R a选自氢原子、氘原子、烷基、一个或多个氘代的氘代烷基；
    R b选自氢原子、氘原子、烷基、一个或多个氘代的氘代烷基；
    或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
    其中，式D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的配体单元共价连接。
  4. 根据权利要求1所述的喜树碱类衍生物或其药学上可接受的盐或溶剂化物，其特征在于：X非限制性地选自：
    Figure PCTCN2021122813-appb-100003
    其中Y选自氢或氘原子。
  5. 根据权利要求1中所述的喜树碱类衍生物或其药学上可接受的盐或溶剂化物，其特征在于：包括其互变异构体、外消旋体、非对映异构体或其混合物形式。
  6. 根据权利要求1中所述的喜树碱类衍生物或其药学上可接受的盐或溶剂化物，其特征在于：其非限制性地选自以下所示的化合物或其药学上接受的盐或溶剂化物：
    Figure PCTCN2021122813-appb-100004
  7. 一种通式如(-L-X-D 2)所示的药物-连接子化合物或者其药学上可接受的盐或溶剂化物；
    Figure PCTCN2021122813-appb-100005
    其中：
    R 1、R 7、R 10选自氢、氘、一个或多个氘代C 1-6烷基、C 1-6烷基、取代烷基、芳基、一个或多个氘代氘代芳基、杂芳基、一个或多个氘代杂芳基；
    R2、R2’、R3、R3’、R4、R4’、R5、R5’、R8、R9分别选自氢或氘；
    X为-C(O)-CR aR b-(CR cR d) n-O-；
    R a、R b分别独立的选自氢原子、氘、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘代环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、烷氧基烷基、一个或多个氘代的烷氧基烷基、杂环基、一个或多个氘代的杂环基、芳基、一个或多个氘代的芳基、取代芳基、杂芳基、一个或多个氘代的杂芳基；
    或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
    R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、烷基、卤代烷基、C 1-6烷基、一个或多个氘代或全氘代C 1-6烷基、烷氧基、一个或多个氘代的烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代的环烷基、杂环基、一个或多个氘代的杂环基；
    或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
    n选自0至4的整数。
    R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10和X中有且至少含有一个氘原子；
    L为连接单元；
    其中，式-L-X-D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的抗体共价连接。
  8. 根据权利要求7中所述的药物-连接子化合物或者其药学上可接受的盐或溶剂化物，其特征在于：其中X的O端与连接单元L相连。
  9. 根据权利要求7或8中所述的药物-连接子化合物或其药学上可接受的盐或者溶剂化物，其特征在于：其中连接单元-L-为-L 1-L 2-L 3-L 4-，其L 1端与抗体相连，L 4端与X相连；
    其中:
    L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或-C(O)-Y-C(O)-，
    其中，Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链 或者直链环状杂烷基各自独立地选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
    L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数；
    L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
    L 4选自：-NR 7(CR 8R 9) q-、-C(O)NR 7、-C(O)NR 7(CH 2) q-或者化学键，其中q选自0-6的整数；
    R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    R 8和R 9相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
  10. 根据权利要求9中任一所述的药物-连接子化合物或其药学上可接受的盐或溶剂化合物，其特征在于：
    L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或者-C(O)-Y-C(O)-，
    其中Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或者直链环状杂烷基各自独立地选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
    L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数。
    L 3选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)或者天冬氨酸(D)中的氨基酸形成的多肽残基；
    L 4为-NR 7CR 8R 9-；
    R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    R 8和R 9相同或者不同，且各自独立地氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
  11. 根据权利要求9中任一所述的药物-连接子化合物或其药学上可接受的盐或溶剂化合物，其特征在于：L3优选为由一个、两个或者多个选自苯丙氨酸和甘氨酸的氨基酸形成的氨基酸残基；最优选的为甘氨酸-甘氨酸-苯丙氨酸-甘氨酸组成的四肽残基；
  12. 根据权利要求9中任一所述的药物-连接子化合物或其药学上可接受的盐或溶剂化合物，其特征在于：L4优选为-NHCH 2-；
  13. 一种通式(L-X-D 2)所示的药物-连接子化合物或者其药学上可接受的盐或溶剂化物；
    Figure PCTCN2021122813-appb-100006
    其中：
    Z选自：-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或者-C(O)-Y-C(O)-，其中Y非限制性地选自C 1-8烷基、C 1-8烷基-环烷基或1-8个原子的直链或直链-环状杂烷基，所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或直链环状杂烷基各自独立地被选自氘原子、卤素、羟基、氰基、硝基、氨基、烷基、杂烷基、取代烷基、烷氧基、羧基或环烷基的一个或者多个取代基所取代；
    L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或化学键，其中p选自0-20的整数，结构中任意烷基被一个或多个氘原子取代；
    L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
    R选自氘原子、C 1-6烷基或取代烷基、芳基、取代芳基或杂芳基；
    R 11选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、杂环基、芳基、取代芳基或杂芳基；
    R 12选自氢原子、氘原子、卤素、烷基、卤代烷基、氘代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    或者，R 11、R 12连同其所连接碳原子构成C 3-6环烷基、环烷基烷基或杂环基；
    R 5、R 6分别选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    R 1、R 7、R 10、R 15分别选自氢原子、烷基、一个或多个氘代的C 1-4烷基；
    R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
    R 1、R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 7、R 8、R 9、R 10、R 11和R 12中有且至少含有一个氘原子。
  14. 根据权利要求13所述的通式(L-X-D 2)所示的化合物或者其药学上可接受的盐或溶剂化物，其特征在于：其为通式(L b-X-D 2)所示的化合物，或其药学上可接受的盐或溶剂化物；
    Figure PCTCN2021122813-appb-100007
    其中：
    R 11、R 12分别独立选自氢原子、氘原子、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘代的环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基、芳基、一个或多个氘代的芳基、取代芳基、杂芳基、一个或多个氘代的杂芳基；
    或者，R 11、R 12连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
    R 1、R 7、R 10、R 15分别选自氢原子、烷基、一个或多个氘代或全氘代的C 1-4烷基或取代烷基；
    R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
    Ac为具有式c所示的亲水结构单元，该结构中同时含有氨基和羧基，X为连接氨基和羧基的支架，为C 1-10亚烃基或取代亚烃基，所述亚烃基或取代亚烃基可被一个或多个氘原子取代；Ac通过氨基官能团与结构式L b-X-D 2中已标示的2位亚甲基碳相连；
    Figure PCTCN2021122813-appb-100008
  15. 如权利要求14中所述的通式为(L-X-D 2)的化合物或其药学上可接受的盐或溶剂化物，其特征在于：其中Ac选自甘氨酸，α-丙氨酸，β-丙氨酸，(D/L)谷氨酸组成的组。
  16. 根据权利要求13中所述的通式为(L-X-D 2)的化合物或者其药学上可接受的盐或溶剂化物，其特征在于：选自以下结构：
    Figure PCTCN2021122813-appb-100009
    Figure PCTCN2021122813-appb-100010
    Figure PCTCN2021122813-appb-100011
    Figure PCTCN2021122813-appb-100012
    Figure PCTCN2021122813-appb-100013
  17. 一种包括权利要求1-15任一所述的喜树碱衍生物或喜树碱-连接子化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或混合物形式，或其药学上可接受的盐或溶剂化物，与配体单元连接形成如通式(Ab-L-X-Dr)所示的抗体-药物偶联物或其药学上可接受的盐或溶剂化物：
    Figure PCTCN2021122813-appb-100014
    其中：
    R 1、R 7、R 10分别选自氢、氘、一个或多个氘代的C 1-6烷基、C 1-6烷基、取代烷基、芳基、一个或多个氘代的芳基、杂芳基、一个或多个氘代的杂芳基；
    R 2、R 2’、R 3、R 3’、R 4、R 4’、R 5、R 5’、R 8、R 9分别选自氢或氘；
    X为-C(O)-CR aR b-(CR cR d) n-O-；
    R a、R b分别独立的选自氢原子、氘、卤素、烷基、氘代烷基、取代烷基、环烷基、一个或多个氘原子取代的环烷基、环烷基烷基、一个或多个氘原子取代的环烷基烷基、烷氧基烷基、一个或多个氘原子取代烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    或者，R a、R b连同其所连接碳原子构成C 3-6环烷基、或一个或多个氘原子取代的C 3-6环烷基、环烷基烷基、一个或多个氘代的环烷基烷基、杂环基、一个或多个氘代的杂环基；
    R c、R d相同或者不同，且分别独立地为氢原子、氘原子、卤素、C 1-6烷基、卤代烷基、一个或多个氘代C 1-6烷基、烷氧基、一个或多个氘代烷氧基、羟基、氨基、氰基、硝基、羟烷基、环烷基、一个或多个氘代环烷基、杂环基、一个或多个氘代的杂环基；
    或者，R c、R d连同其所连接碳原子构成C 3-6环烷基、一个或多个氘代C 3-6环烷基、环烷基烷基、一个或多个氘代环烷基烷基、杂环基、一个或多个氘代杂环基；
    n选自0至4的整数；
    L为连接单元；
    其中，式-L-X-D 2中的波浪线或表示氢原子，或与接头单元或与结合靶细胞所表达抗原的抗体共价连接。
  18. 根据权利要求16中所述的抗体药物偶联物或其药学上可接受的盐或者溶剂化物，其特征在于：其中连接单元-L-为-L 1-L 2-L 3-L 4-,，其L 1端与抗体相连，L 4端与X相连；
    其中:
    L 1选自：-(琥珀酰亚胺-3-基-N)-Y-C(O)-、-CH 2-C(O)-NR 5-Y-C(O)-或-C(O)-Y-C(O)-，
    其中，Y选自C 1-8烷基、C 1-8烷基-环烷基或者1-8个原子的直链或者直链-环状杂烷基；所述杂烷基包含选自N、O或者S的1-3个原子，所述的C 1-8烷基、环烷基、直链或者直链环状杂烷基各自独立地被选自氘代原子、卤素、羟基、氰基、硝基、氨基、烷基、羧基、杂烷基、取代烷基、烷氧基或者环烷基的一个或者多个取代基所取代；
    L 2选自：-NR 6(CH 2CH 2O) pCH 2CH 2C(O)-、-NR 6(CH 2CH 2O) pCH 2C(O)-、-S(CH 2) pC(O)-或者化学键，其中p选自0-20的整数；
    L 3选自：由2-7个氨基酸构成的肽残基，其中任选氨基酸进一步被选自氘原子、卤素、羟基、氰基、氨基、硝基、烷基、取代烷基、烷氧基和环烷基或者取代环烷基中的一个或多个取代基所取代；
    L 4选自：-NR 7(CR 8R 9) q-、-C(O)NR 7、-C(O)NR 7(CH 2) q-或者化学键，其中q选自0-6的整数；
    R 5、R 6和R 7相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基；
    R 8和R 9相同或者不同，且各自独立地选自氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基、环烷基、环烷基烷基、烷氧基烷基、杂环基、芳基、取代芳基或杂芳基。
    m选自1-10的整数或小数；
    Ab为抗体、抗体片段、靶向蛋白或Fc-融合蛋白；
    L为连接单元。
  19. 根据权利要求17中所述的抗体-药物偶联物或其药学上可接受的盐或溶剂化物，其特征在于：Ab为抗体，可通过其杂原子与连接单元形成连接键，所述抗体选自鼠源抗体、嵌合抗体、人源化抗体、全人源抗体、抗体片段、双特异性抗体及多特异性抗体。
  20. 根据权利要求17或18所述的抗体-药物偶联物或其药学上可接受的盐或溶剂化物，其特征在于，其抗体选自靶向以下一个或多个靶点的抗体：抗EGFRvIII抗体、 抗DLL-3抗体、抗PSMA抗体、抗CD70抗体、抗MUC16抗体、抗ENPP3抗体、抗TDGF1抗体、抗ETBR抗体、抗MSLN抗体、抗TIM-1抗体、抗LRRC15抗体、抗LIV-1抗体、抗CanAg/AFP抗体、抗cladin 18.2抗体、抗Mesothelin抗体、抗HER2(ErbB2)抗体、抗EGFR抗体、抗c-MET抗体、抗SLITRK6抗体、抗KIT/CD117抗体、抗STEAP1抗体、抗SLAMF7/CS1抗体、抗NaPi2B/SLC34A2抗体、抗GPNMB抗体、抗HER3(ErbB3)抗体、抗MUC1/CD227抗体、抗AXL抗体、抗CD166抗体、抗B7-H3(CD276)抗体、抗PTK7/CCK4抗体、抗PRLR抗体、抗EFNA4抗体、抗5T4抗体、抗NOTCH3抗体、抗Nectin 4抗体、抗TROP-2抗体、抗CD142抗体、抗CA6抗体、抗GPR20抗体、抗CD174抗体、抗CD71抗体、抗EphA2抗体、抗LYPD3抗体、抗FGFR2抗体、抗FGFR3抗体、抗FRα抗体、抗CEACAMs抗体、抗GCC抗体、抗Integrin Av抗体、抗CAIX抗体、抗P-cadherin抗体、抗GD3抗体、抗Cadherin 6抗体、抗LAMP1抗体、抗FLT3抗体、抗BCMA抗体、抗CD79b抗体、抗CD19抗体、抗CD33抗体、抗CD56抗体、抗CD74抗体、抗CD22抗体、抗CD30抗体、抗CD37抗体、抗CD138抗体、抗CD352抗体、抗CD25抗体或抗CD123抗体、抗CD47抗体。
  21. 根据权利要求17或18中所述的抗体-药物偶联物或其药学上可接受的盐或溶剂化物，其特征在于，非限制性地选自以下结构：
    Figure PCTCN2021122813-appb-100015
    Figure PCTCN2021122813-appb-100016
    Figure PCTCN2021122813-appb-100017
    Figure PCTCN2021122813-appb-100018
    Figure PCTCN2021122813-appb-100019
    其中：
    m选自1-10的整数或小数；
    Ab为抗体、抗体片段、靶向蛋白、Fc-融合蛋白。
  22. 一种制备权利要求14所述化合物(L-X-D 2)的方法，其特征在于，包括以下合成步骤：
    Figure PCTCN2021122813-appb-100020
  23. 一种制备如权利要求17-20任一所述通式(Ab-L a-X-Dr)所示抗体-药物偶联物或其药学上可接受的盐或溶剂化物的方法，其特征在于，包括如下步骤：
    Figure PCTCN2021122813-appb-100021
    通过抗体、抗体片段、靶向蛋白、Fc-融合蛋白等与通式(La-X-D 2)偶联反应，得到通式(Ab-L a-X-D 2)。
  24. 一种药物组合物，其含有治疗有效量的根据权利要求1-20中任一项所述的抗体-药物偶联物或其药学上可接受的盐或溶剂化物，以及药学上可接受的载体、稀释剂或赋形剂。
  25. 一种包括权利要求1-20中任一项所述的喜树碱类衍生物或其抗体-药物偶联物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式， 或其药学上可接受的盐或溶剂化合物，以及药学上可接受的载体、稀释剂或者赋形剂，在制备用于治疗或预防肿瘤的药物中的用途。
  26. 根据权利要求23中所述的用途，其特征在于：所述的肿瘤为实体瘤或血液肿瘤。
  27. 根据权利要求25中所述的用途，其特征在于：所述的肿瘤非限制性地选自：乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤或白血病。
PCT/CN2021/122813 2020-10-12 2021-10-09 一种氘代的喜树碱衍生物及其抗体药物偶联物 WO2022078259A1 (zh)

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