WO2022161479A1 - 适用于抗体-药物偶联物的毒素分子 - Google Patents

适用于抗体-药物偶联物的毒素分子 Download PDF

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WO2022161479A1
WO2022161479A1 PCT/CN2022/074825 CN2022074825W WO2022161479A1 WO 2022161479 A1 WO2022161479 A1 WO 2022161479A1 CN 2022074825 W CN2022074825 W CN 2022074825W WO 2022161479 A1 WO2022161479 A1 WO 2022161479A1
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compound
alkyl
group
pharmaceutically acceptable
hydrate
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PCT/CN2022/074825
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English (en)
French (fr)
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李傲
陈以乐
曹国庆
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明慧医药（杭州）有限公司
明慧医药（上海）有限公司
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Application filed by 明慧医药（杭州）有限公司, 明慧医药（上海）有限公司 filed Critical 明慧医药（杭州）有限公司
Priority to KR1020237029395A priority Critical patent/KR20230162595A/ko
Priority to AU2022212854A priority patent/AU2022212854A1/en
Priority to EP22745351.1A priority patent/EP4286389A1/en
Priority to CN202280012708.1A priority patent/CN116848124A/zh
Priority to CA3206519A priority patent/CA3206519A1/en
Priority to US18/274,905 priority patent/US20240132515A1/en
Priority to JP2023546115A priority patent/JP2024504489A/ja
Publication of WO2022161479A1 publication Critical patent/WO2022161479A1/zh
Priority to IL304779A priority patent/IL304779A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular, the present invention provides a toxin molecule with tumor cell proliferation inhibitory activity.
  • Antibody-drug conjugates link monoclonal antibodies or antibody fragments to biologically active cytotoxins through stable chemical linker compounds, making full use of the specificity of antibodies for binding to normal and tumor cell surface antigens
  • ADCs Antibody-drug conjugates
  • Kadcyla is an ADC drug formed by trastuzumab targeting Her2 and DM1.
  • Kadcyla is an ADC drug formed by trastuzumab targeting Her2 and DM1.
  • B7H3 is also patent reports on antibodies and ADC drugs targeting B7H3.
  • camptothecin derivatives which have antitumor effects by inhibiting topoisomerase I.
  • camptothecin derivative ixatecan to antibody-drug conjugates (ADC) has been reported in the literature, but there is still a need for further development of ADC drugs with better efficacy in this field.
  • Topoisomerase is a class of essential enzymes widely existing in organisms, involved in all key nuclear processes such as DNA replication, transcription, recombination, and repair. According to the different forms of topoisomerases that cause transient DNA strand breaks, topoisomerases can be divided into two categories: topoisomerase I and topoisomerase II. Topoisomerase I and topoisomerase II together catalyze the unwinding of supercoiled DNA during DNA replication, but topoisomerase II involves double-strand breaks, while topoisomerase I only causes single-strand breaks break.
  • Camptothecin and its analogs reversibly bind to the DNA topoisomerase I-DNA complex to form a ternary complex of camptothecin and its analogs-DNA topoisomerase I-DNA, which terminates the progressive unwinding , eventually causing the replication fork to hit the ternary complex, resulting in irreparable DNA breaks and cell death.
  • the object of the present invention is to provide a toxin molecule suitable for antibody conjugated drugs.
  • the first aspect of the present invention provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof:
  • X is selected from the group consisting of H, OH, NH2 , NHR0 ;
  • Y is selected from the group consisting of (CR 1 R 2 ) n ;
  • Z is selected from the group consisting of: chemical bond, C(O), C(S), C(NH), S(O) 2 , S(O);
  • R 0 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 deuterated alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl , C 3 -C 8 cycloalkyl or 3-12 membered heterocyclyl;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 deuterated alkyl, C 1 - C 8 alkoxy, hydroxyl, amino, cyano, nitro, C 1 -C 8 hydroxyalkyl, C 3 -C 8 cycloalkyl or 3-12 membered heterocyclyl;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 8 cycloalkyl or 3-12 membered heterocyclyl;
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 deuterated alkyl;
  • the carbon atoms to which R and R are attached together form a structure selected from the group consisting of saturated or unsaturated 5-12 membered rings, saturated or unsaturated 5-12 membered heterocycles;
  • n is selected from 0, 1, 2 or 3 (preferably 0, 1 or 2);
  • each CR 1 R 2 may be the same or different.
  • the groups of the present invention can be substituted by substituents selected from the group consisting of halogen, nitrile, nitro, hydroxyl, amino, C 1 -C 6 alkyl-amino, C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl , C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C 3
  • the R 3 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, and C 1 -C 8 deuterated alkyl.
  • the R 4 is selected from the group consisting of hydrogen atom, deuterium atom and halogen.
  • the compound has the structure shown in the following formula:
  • the Z is a chemical bond, C(O).
  • the X is H, OH, or NH 2 .
  • the Y is selected from the following group: (CR 1 R 2 ) n ;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen atom, deuterium atom, halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 deuterated alkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl; alternatively, R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or 3- 6-membered heterocyclyl; and C 1 -C 8 alkyl may be optionally substituted with substituents selected from the group consisting of C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 ring Alkyl, 3-6 membered heterocyclic group.
  • n is selected from 0, 1, 2 or 3;
  • each CR 1 R 2 can be the same or different;
  • the compound has the structure shown in the following formula:
  • the compound has the structure shown in the following formula:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I according to any one of the second aspect of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and one or more a pharmaceutically acceptable excipient, diluent or carrier.
  • the third aspect of the present invention provides a use of the compound of formula I according to the first aspect of the present invention for preparing a pharmaceutical composition for treating diseases related to tumor cell proliferation.
  • the disease is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, lung cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, and endometrial cancer , salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, pharyngeal cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreas Cancer, lymphoma.
  • the fourth aspect of the present invention provides a use of the compound of formula I as described in the first aspect of the present invention, characterized in that it is used as a toxin in an antibody-drug conjugate to prepare an antibody-drug conjugate .
  • the present inventors found a compound represented by formula I unexpectedly.
  • the compounds have unexpected activity in inhibiting tumor cell proliferation and can be used to treat diseases associated with tumor cell proliferation. Based on the above findings, the inventors have completed the present invention.
  • alkyl includes straight or branched chain alkyl groups.
  • C 1 -C 8 alkyl means straight or branched chain alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C 2 -C 6 alkenyl refers to straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -butenyl, or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C2 - C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C3 - C10 cycloalkyl refers to a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible.
  • C 1 -C 8 alkylamino refers to an amine group substituted with a C 1 -C 8 alkyl group, which may be mono- or di-substituted; for example, methylamino, ethylamino, Propylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine, diisobutylamine tert-Butylamine, etc.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having 1-8 carbon atoms; eg, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, tert-butoxy, etc.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O” refers to a heterocycloalkyl having 3-10 atoms and wherein 1-3 atoms are A saturated or partially saturated cyclic group of heteroatoms selected from the following groups N, S and O. It may be monocyclic or bicyclic, eg bridged or spirocyclic. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • C6 - C10 aryl refers to an aryl group having 6-10 carbon atoms, eg, phenyl or naphthyl and the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the following groups N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from Cyclic aromatic groups of heteroatoms of the following groups N, S and O. It may be a single ring or a fused ring form.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • substituted or unsubstituted the groups described in the present invention can be substituted by substituents selected from the following group: halogen, nitrile, nitro, hydroxyl, amino , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkynyl-
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halo” means substituted with an atom selected from F, Cl, Br, and I.
  • the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • tautomer means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting.
  • proton tautomers ie, protonation
  • Valence tautomers include interconversion by some bonding electron recombination.
  • hydrate refers to a complex formed by the coordination of a compound of the present invention with water.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of specific embodiments and other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of this application.
  • the solvents used in this application can be obtained commercially, and the compounds are artificially or Software naming, commercially available compounds use supplier catalog names.
  • the compounds of the present invention can be prepared by the following general methods:
  • the compound of formula I is obtained by reacting the compound of formula Ia with phosphorus pentasulfide or Lawson's reagent.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent tumor cell proliferation inhibitory activity
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as containing the compound of the present invention are the main activities
  • the pharmaceutical composition of the ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) a disease associated with tumor cell proliferation.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 1-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition are capable of admixture with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents.
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with the compounds of the present invention for prophylaxis and/or treatment Cytokine and/or Interferon-mediated diseases.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 1 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • reaction system was quenched with water (15 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to preparative thin layer chromatography ( methanol: dichloromethane) was purified to give compound 10 (30 mg), yield: 51%.
  • the crude product 14a (125 mg) was dissolved in ethyl acetate (4 mL), hydrogen chloride ethyl acetate solution (4.0 M, 4 mL) was added dropwise to the above solution, and the reaction was stirred at room temperature for 17 hours.
  • the residue was slurried with acetonitrile (2 mL) to obtain 14 (60 mg), two-step yield: 54%.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain compound 15 (3 mg), yield: 21%.
  • reaction system was quenched by adding water (15mL), extracted with dichloromethane (150mL ⁇ 1), the organic phases were combined, the organic phase was washed with saturated brine (15mL ⁇ 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue , the residue was separated and purified by preparative HPLC to obtain compound 17 (12 mg), yield: 10%.
  • reaction system was quenched with water (10 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was subjected to preparative thin layer chromatography ( methanol:dichloromethane) was purified to give compound 20 (5 mg), yield: 13%.
  • KPL-4 tumor cells in logarithmic growth phase were taken, resuspended in fresh RPMI1640 medium, counted and adjusted to 2 ⁇ 10 4 cells/mL.
  • the cell suspension was inoculated into a 96-well cell culture plate, 100 ⁇ L/well, and cultured overnight in a carbon dioxide incubator (37° C., 5% CO 2 ).
  • a carbon dioxide incubator 37° C., 5% CO 2 .
  • one of the 96-well plates inoculated with cells was taken out, equilibrated to room temperature, and 100 ⁇ L of CellTiter-Glo reagent (Promega, USA) pre-equilibrated to room temperature and mixed well was added to each well of the test plate, and incubated in the dark for 30 minutes.
  • the luminescence value (marked as G 0 value) in the microplate reader; take another parallel plate and add different concentrations of the test compound or DMSO (final concentration 0.5%) to the corresponding wells of the test plate, and place in a carbon dioxide incubator After culturing in medium for 72 h, the test plate was equilibrated to room temperature and the cell viability was detected by CellTiter - Glo reagent, which was recorded as the G3 value.
  • Inhibition curves were fitted using Graphpad Prism software and GI50 values were calculated (see table below).
  • the compounds of the present invention exhibited higher anti-proliferation activities in the above-mentioned tumor cell proliferation inhibition experiments, and the activities were better than DXd (Exatecan derivatives, the structure is as follows). Since the compound of the present invention has excellent tumor cell proliferation inhibitory activity, it can be used as a tumor therapeutic drug, or as a toxin molecule for preparing an antibody-drug conjugate for tumor treatment.

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Abstract

本发明提供了一种适用于抗体-药物偶联物的毒素分子，具体地，本发明提供了一种如下式(I)所示的化合物，或其药学上可接受的盐或水合物。本发明的化合物可以用于制备治疗与肿瘤细胞增殖相关的疾病的药物组合物。

Description

适用于抗体-药物偶联物的毒素分子 技术领域
本发明涉及药物化学领域，具体地，本发明提供了一种具有肿瘤细胞增殖抑制活性的毒素分子。
背景技术
抗体-药物偶联物(antibody drug conjugate,ADC)将单克隆抗体或者抗体片段通过稳定的化学接头化合物与具有生物活性的细胞毒素相连，充分利用了抗体对正常细胞和肿瘤细胞表面抗原结合的特异性和细胞毒性物质的高效性，同时又避免了前者疗效偏低和后者毒副作用过大等缺陷。这也就意味着，与以往传统的化疗药物相比，抗体-药物偶联物能更精准地结合肿瘤细胞并降低将对正常细胞的影响。
目前已有多种ADC药物被用于临床或临床研究，如Kadcyla，是靶向Her2的曲妥珠单抗与DM1形成的ADC药物。同时，也有靶向B7H3的抗体及ADC药物的专利报道。
用于抗体药物偶联物的具有细胞毒性的小分子有几类；其中有一类是喜树碱衍生物，它们通过抑制拓扑异构酶I而具有抗肿瘤作用的。喜树碱衍生物依沙替康应用于抗体偶联药物(ADC)已有文献报道，但本领域仍需进一步开发疗效更好的ADC药物。
DNA拓扑异构酶(Topoisomerase,Topo)是生物体内广泛存在的一类必需酶，参与DNA复制、转录、重组、修复等所有关键的核内过程。根据拓扑异构酶引起瞬间DNA链断裂形式的不同，可将拓扑异构酶分为两大类：拓扑异构酶I和拓扑异构酶II。拓扑异构酶I和拓扑异构酶II共同催化了DNA复制过程中的超螺旋的DNA的解旋，但拓扑异构酶II涉及了双链的断裂，而拓扑异构酶I只引起单链的断裂。喜树碱及其类似物通过与DNA拓扑异构酶I-DNA复合物可逆结合，形成喜树碱及其类似物-DNA拓扑异构酶I-DNA三元复合物，使进行性解旋终止，最终导致复制叉撞上三元复合物，发生不可修复的DNA断裂，使细胞死亡。
发明内容
本发明的目的是提供一种适用于抗体偶联药物的毒素分子。
本发明的第一方面，提供了一种如下式(I)所示的化合物，或其药学上可接受的盐或水合物：
Figure PCTCN2022074825-appb-000001
Figure PCTCN2022074825-appb-000002
X选自下组：H、OH、NH 2、NHR 0；
Y选自下组：(CR 1R 2) n；
Z选自下组：化学键、C(O)、C(S)、C(NH)、S(O) 2，S(O)；
R 0选自下组：C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 3-C 8环烷基或3-12元杂环基；
R 1和R 2各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8烷氧基、羟基、氨基、氰基、硝基、C 1-C 8羟烷基、C 3-C 8环烷基或3-12元杂环基；
或者，R 1和R 2与其相连接的碳原子一起形成C 3-C 8环烷基或3-12元杂环基；
R 3和R 4各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基；
或者，R 3和R 4与其相连接的碳原子共同形成选自下组的结构：饱和或不饱和的5-12元环、饱和或不饱和的5-12元杂环；
n选自0、1、2或3(优选为0、1或2)；
且当n为2、3时，各个CR 1R 2可相同或不同。
除非特别说明，本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基。
在另一优选例中，所述的R 3选自下组：C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基。
在另一优选例中，所述的R 4选自下组：氢原子、氘原子、卤素。
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2022074825-appb-000003
在另一优选例中，所述的Z为化学键、C(O)。
在另一优选例中，所述的X为H、OH、NH 2。
在另一优选例中，所述的Y选自下组：(CR 1R 2) n；
其中R 1和R 2各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8羟烷基、C 3-C 6环烷基或3-6元杂环基；或者，R 1和R 2与其相连接的碳原子一起形成C 3-C 6环烷基或3-6元杂环基；且C 1-C 8烷基可任选地被选自下组的取代基取代：C 6-C 10芳基、5-10元杂芳基、C 3-C 6环烷基、3-6元杂环基。 n选自0、1、2或3；
且当n为2、3时，各个CR 1R 2可相同或不同；
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2022074825-appb-000004
在另一优选例中，所述的化合物具有如下式所示的结构：
Figure PCTCN2022074825-appb-000005
Figure PCTCN2022074825-appb-000006
Figure PCTCN2022074825-appb-000007
本发明的第二方面，提供了一种药物组合物，其包含本发明第二方面中任一项所述的式I化合物，或其药学上可接受的盐或水合物，以及一种或多种药学上可接受的赋形剂、稀释剂或载体。
本发明的第三方面，提供了一种如本发明第一方面所述的式I化合物的用途，用于制备治疗与肿瘤细胞增殖相关的疾病的药物组合物。
在另一优选例中，所述的疾病选自下组：乳腺癌、卵巢癌、宫颈癌、肺癌、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、黑色素瘤、神经胶质瘤、神经母细胞瘤、肉瘤、咽头癌、肺癌、结肠癌、直肠癌、结直肠癌、白血病、骨癌、皮肤癌、甲状腺癌、胰腺癌、淋巴瘤。
本发明的第四方面，提供了一种如本发明第一方面中所述的式I化合物的用途，其特征在于，用作抗体-药物偶联物中的毒素从而制备抗体-药物偶联物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体 描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一种如式I所示的化合物。所述的化合物对抑制肿瘤细胞增殖具有出乎意料的活性，可用于治疗与肿瘤细胞增殖相关的疾病。基于上述发现，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“C 3-C 10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C 1-C 8烷胺基”是指被C 1-C 8烷基所取代的胺基，可以是单取代或双取代的；例如，甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6 炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、具体实施方式与其他化学合成方法的结合所形成的实施方式、以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请所使用的溶剂可以经市售获得，化合物经人工或者
Figure PCTCN2022074825-appb-000008
软件命名，市售化合物采用供应商目录名称。
化合物的制备
本发明的化合物可以通过以下通用方法制备：
制备方法1：
Figure PCTCN2022074825-appb-000009
用式Ia化合物与五硫化二磷或者劳森试剂反应，得到式I化合物。
制备方法2：
Figure PCTCN2022074825-appb-000010
将式IIa化合物中的羟基用保护基(PG 1)保护后，与五硫化二磷或者劳森试剂反应，得到式IIc化合物。然后IIc和IId经脱水缩合以及脱保护基(PG 1和PG 2)反应，得到式IIf化合物。最终，由IIf转化从而得到式I化合物。
药物组合物和施用方法
由于本发明化合物具有优异的肿瘤细胞增殖的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)治疗与肿瘤细胞增殖相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有1-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022074825-appb-000011
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基 甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的治疗剂联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗细胞因子和/或干扰素介导的疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选1～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅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实验方法，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，否则百分比和份数按重量计算。
实施例
实施例1
Figure PCTCN2022074825-appb-000012
Figure PCTCN2022074825-appb-000013
第一步
依次将1a(1.95g，7.40mmol)，咪唑(2.52g，37.00mmol)置于三口瓶(100mL)内，氮气置换后，向三口瓶中加入无水N,N-二甲基甲酰胺(30mL)，降温至0℃，向反应体系中依次加入三乙基氯硅烷(4.45g，29.60mmol)和4-二甲氨基吡啶(0.90g，7.40mmol)，在0℃继续反应2小时，反应体系用乙酸乙酯(200mL)稀释，并用饱和食盐水(25mL x 4)洗涤，有机相经无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经硅胶柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到1b-1(0.90g)，1b-2(1.50g)，总收率：73％。
1b-1：
MS-ESI计算值[M+H] +378，实测值为378。
1b-2：
MS-ESI计算值[M+H] +492，实测值为378(脱一分子TES)。
第二步
依次将1b-2(1.10g，2.20mmol)，劳森试剂(1.80g，4.40mmol)置于三口瓶(100mL)内，氮气置换后，向三口瓶中加入无水甲苯(30mL)，混合体系升温至90℃搅拌反应5-6小时。反应体系用乙酸乙酯(200mL)稀释，有机相经饱和食盐水(25mL x 2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经硅胶柱层析(乙酸乙酯：石油醚＝0-100％)纯化得到1c(620mg)，收率：51％。
MS-ESI计算值[M+H] +394，实测值为394。
第三步
依次将1c(620mg，1.10mmol)，1d(380mg，1.54mmol)，吡啶对甲苯磺酸盐(166mg，0.66mmol)置于单口瓶(100mL)内，加入无水甲苯(30mL)，置换氮气后，升温至120℃反应24小时后，向反应体系中补加1d(60mg)和吡啶对甲苯磺酸盐(90mg)，继续升温至120℃反应20小时，反应体系减压浓缩得到残余物，残 余物经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到1e(260mg)，收率：48％。
MS-ESI计算值[M+H] +494，实测值为494。
第四步
将1e(80mg，0.16mmol)称入单口瓶(100mL)内，向反应体系中加入6N盐酸水溶液(27mL)，升温至110℃反应4小时，反应体系过滤除去不溶物，滤液减压浓缩得到粗产物1f(50mg)。
MS-ESI计算值[M+H] +452，实测值为452。
第五步
向单口瓶(25mL)中依次加入1f(20mg，0.04mmol)和1.2mg/mL的羟乙酸的N,N-二甲基甲酰胺溶液(2.00mL，0.032mmol)，反应体系降温至0℃，向反应体系中依次加入N,N-二异丙基乙胺(11mg，0.08mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(16mg，0.04mmol)，反应0.5小时后补加1.2mg/mL的羟乙酸的N,N-二甲基甲酰胺溶液(0.20mL，0.003mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(1mg)，继续反应1小时后，反应体系经乙酸乙酯(80mL)稀释，有机相依次经0.5N稀盐酸(5mL x 1)、饱和碳酸氢钠溶液(10mL x 2)和饱和食盐水(10mL x 5)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物1-1(2mg)和1-2(5mg)，总收率：34％。
1-1：
MS-ESI计算值[M+H] +510，实测值为510。
1H NMR(400MHz,DMSO-d 6)δ8.54(d,J＝8.8Hz,1H),7.82(d,J＝10.8Hz,1H),7.80(s,1H),5.92(d,J＝16.8Hz,1H),5.69–5.60(m,1H),5.53(d,J＝20.4Hz,1H),5.52(d,J＝16.4Hz,1H),5.35(d,J＝20.0Hz,1H),4.15–3.98(m,2H),3.30–3.22(m,1H),3.19–3.09(m,1H),2.40(s,3H),2.26–2.14(m,2H),1.96–1.84(m,2H),0.86(t,J＝7.2Hz,3H).
1-2：
MS-ESI计算值[M+H] +510，实测值为510。
1H NMR(400MHz,DMSO-d 6)δ8.54(d,J＝9.2Hz,1H),7.81(d,J＝11.2Hz,1H),7.80(s,1H),6.69(s,1H),5.92(d,J＝16.8Hz,1H),5.69–5.62(m,1H),5.62–5.56(m,1H),5.55–5.47(m,2H),5.33(d,J＝20.0Hz,1H),4.16–3.98(m,2H),3.30–3.20(m,1H),3.16–3.07(m,1H),2.39(s,3H),2.26–2.15(m,2H),1.95–1.85(m,2H),0.86(t,J＝7.2Hz,3H).
实施例2
Figure PCTCN2022074825-appb-000014
Figure PCTCN2022074825-appb-000015
第一步
将粗产品1f(15.00g)经制备HPLC分离纯化得到2-1(2.80g)和2-2(4.00g)，制备收率：45％。
2-1：
MS-ESI计算值[M+H] +452，实测值为452。
1H NMR(400MHz,DMSO-d 6)δ7.82–7.73(m,2H),6.70(s,1H),5.92(d,J＝16.8Hz,1H),5.86(d,J＝20.4Hz,1H),5.59(d,J＝20.4Hz,1H),5.52(d,J＝16.4Hz,1H),4.45–4.37(m,1H),3.30–3.19(m,1H),3.10–2.98(m,1H),2.40(s,3H),2.25–2.12(m,1H),2.08–1.96(m,1H),1.95–1.82(m,2H),0.86(t,J＝7.2Hz,3H).
2-2：
MS-ESI计算值[M+H] +452，实测值为452。
1H NMR(400MHz,DMSO-d 6)δ8.51(d,J＝4.4Hz,1H),7.92(d,J＝10.4Hz,1H),7.84(s,1H),6.02(d,J＝20.0Hz,1H),5.95(d,J＝16.4Hz,1H),5.70(d,J＝20.0Hz,1H),5.53(d,J＝16.8Hz,1H),5.23–5.15(m,1H),3.36–3.25(m,1H),3.20–3.07(m,1H),2.60–2.51(m,1H),2.42(s,3H),2.25–2.12(m,1H),1.98–1.82(m,1H),0.86(t,J＝7.2Hz,3H).
实施例3
Figure PCTCN2022074825-appb-000016
第一步
向单口瓶(25mL)中依次加入2-1(20mg，0.04mmol)、二氯甲烷(2mL)、三乙胺(25μL，0.18mmol)，再逐滴加入醋酸酐(19μL，0.20mmol)，室温下搅拌反应1小时。将反应液直接过滤，滤饼用二氯甲烷溶液(5mL)淋洗，收集滤饼，干燥得到化合物3(10mg)，收率：46％。
MS-ESI计算值[M+H] +494，实测值为494。
1H NMR(400MHz,DMSO-d 6)δ8.59(d,J＝8.8Hz,1H),7.84(d,J＝10.8Hz,1H),7.79 (s,1H),6.71(s,1H),5.91(d,J＝16.8Hz,1H),5.62–5.57(m,1H),5.56–5.48(m,2H),5.41(d,J＝20.0Hz,1H),3.26–3.12(m,2H),2.41(s,3H),2.22–2.10(m,2H),2.00(s,3H),1.92–1.86(m,2H),0.85(t,J＝7.2Hz,3H).
实施例4
Figure PCTCN2022074825-appb-000017
第一步
向单口瓶(100mL)中依次加入2-2(4.00g，8.86mmol)，无水二氯甲烷(30mL)和三乙胺(3.58g，35.44mmol)，醋酸酐(3.70g，36.28mmol)逐滴加入至上述反应液中，室温下搅拌反应1.5小时。将反应液直接过滤，滤饼用二氯甲烷(20mL)淋洗，收集滤饼，干燥得化合物4(4.26g)，收率：96％。
MS-ESI计算值[M+H] +494，实测值为494。
1H NMR(400MHz,DMSO-d 6)δ8.58(d,J＝8.8Hz,1H),7.83–7.77(m,2H),6.70(s,1H),5.91(d,J＝16.8Hz,1H),5.61–5.55(m,1H),5.55–5.51(m,1H),5.49(d,J＝12.0Hz,1H),5.32(d,J＝19.6Hz,1H),3.28–3.07(m,2H),2.37(s,3H),2.26–2.04(m,2H),2.01(s,3H),1.96–1.84(m,2H),0.88(t,J＝7.2Hz,3H).
实施例5
Figure PCTCN2022074825-appb-000018
Figure PCTCN2022074825-appb-000019
第一步
向单口瓶(25mL)中依次加入2-1(20mg，0.04mmol)、2-羟基-2-苯基乙酸(13mg，0.09mmol)和N,N-二甲基甲酰胺(2mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(21μL，0.12mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(23mg，0.06mmol)，继续搅拌反应1.5小时。反应体系加水(50mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，15mL x 4)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物5(5mg)，收率：19％。
MS-ESI计算值[M+H] +586，实测值为586。
1H NMR(400MHz,DMSO-d 6)δ8.76–8.70(m,1H),7.88–7.82(m,1H),7.803(s,0.5H),7.800(s,0.5H),7.56(d,J＝7.2Hz,1H),7.46(d,J＝6.8Hz,1H),7.35–7.31(m,2H),7.29–7.26(m,1H),6.72(s,1H),6.33–6.18(m,1H),5.93(d,J＝16.8Hz,0.5H),5.92(d,J＝16.4Hz,0.5H),5.56–5.47(m,4H),5.17–5.02(m,1H),3.17–3.13(m,2H),2.41(s,3H),2.17–2.10(m,2H),1.94–1.87(m,2H),0.87(t,J＝7.2Hz,3H).
实施例6
Figure PCTCN2022074825-appb-000020
第一步
向单口瓶(25mL)中依次加入2-2(60mg，0.13mmol)、2-羟基-2-苯基乙酸(40mg，0.27mmol)和无水N,N-二甲基甲酰胺(2mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(52mg，0.40mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(76mg，0.20mmol)，搅拌反应1.5小时。反应体系加水(10 mL)淬灭，乙酸乙酯(200mL x 1)萃取，有机相经饱和食盐水(25mL x 4)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物6(65mg)，收率：83％。
MS-ESI计算值[M+H] +586，实测值为586。
1H NMR(400MHz,DMSO-d 6)δ8.80–8.70(m,1H),7.87–7.81(m,1H),7.81(s,0.5H),7.80(s,0.5H),7.57(d,J＝7.2Hz,1H),7.46(d,J＝7.2Hz,1H),7.37–7.30(m,2H),7.30–7.23(m,1H),6.71(s,1H),6.35–6.17(m,1H),5.95(d,J＝16.4Hz,0.5H),5.93(d,J＝16.4Hz,0.5H),5.65–5.35(m,4H),5.15–5.02(m,1H),3.22–3.06(m,2H),2.39(s,3H),2.19–2.05(m,2H),1.96–1.85(m,2H),0.87(t,J＝7.2Hz,3H).
实施例7
Figure PCTCN2022074825-appb-000021
第一步
向单口瓶(25mL)中依次加入2-1(20mg，0.04mmol)、2-羟基-3-苯基丙酸(15mg，0.09mmol)和N,N-二甲基甲酰胺(2mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(21μL，0.12mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(23mg，0.06mmol)，搅拌反应1.5小时。向反应体系加入水(50mL)，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，15mL x 4)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物7(15mg)，收率：56％。
MS-ESI计算值[M+H] +600，实测值为600。
1H NMR(400MHz,DMSO-d 6)δ8.57(d,J＝8.8Hz,0.5H),8.39(d,J＝8.8Hz,0.5H),7.85–7.82(m,1H),7.80(d,J＝8.0Hz,1H),7.30–7.28(m,1H),7.25–7.22(m,1H),7.20–7.15(m,3H),7.13–7.07(m,1H),6.72(d,J＝4.0Hz,1H),5.94–5.89(m,1H),5.56–5.51(m,2H),5.43–5.38(m,2H),4.36–4.31(m,0.5H),4.24–4.19(m,0.5H),3.18–3.05(m,4H),2.40(s,3H),2.17–2.12(m,2H),1.93–1.87(m,2H),0.88–0.85(m,3H).
实施例8
Figure PCTCN2022074825-appb-000022
第一步
向单口瓶(25mL)中依次加入2-2(65mg，0.14mmol)，2-羟基-3-苯基丙酸(48mg，0.29mmol)和无水二氯甲烷(2mL)，继续向反应液中依次加入N,N-二异丙基乙胺(55mg,0.43mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(84mg，0.22mmol)，室温下搅拌反应1.5小时。反应体系加水(10mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，150mL x 1)萃取，有机相经饱和食盐水(25mL x 2)洗，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物8(55mg)，收率：64％。
MS-ESI计算值[M+H] +600，实测值为600。
1H NMR(400MHz,DMSO-d 6)δ8.60(d,J＝9.2Hz,0.5H),8.39(d,J＝8.8Hz,0.5H),7.85–7.76(m,2H),7.34–7.07(m,6H),6.71(s,0.5H),6.70(s,0.5H),5.98–5.87(m,1H),5.75–5.50(m,3H),5.42–5.38(m,1H),4.40–4.30(m,0.5H),4.26–4.15(m,0.5H),3.21–3.04(m,4H),2.38(s,3H),2.20–2.00(m,2H),1.96–1.82(m,2H),0.91–0.81(m,3H).
实施例9
Figure PCTCN2022074825-appb-000023
第一步
向单口瓶(25mL)中依次加入2-1(40mg，0.09mmol)，2-甲基-2-羟基丙酸(14mg，0.13mmol)，无水二氯甲烷(5mL)，N,N-二异丙基乙胺(29mg，0.22mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(51mg，0.13mmol)，室温下搅拌反应1小时。反应体系加水(10mL)淬灭，二氯甲烷(20mL x5)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物9(10mg)，收率：21％。
MS-ESI计算值[M+H] +538，实测值为538。
1H NMR(400MHz,DMSO-d 6)δ8.45(d,J＝9.2Hz,1H),7.82(d,J＝11.2Hz,1H),7.79(s,1H),6.71(s,1H),5.90(d,J＝16.4Hz,1H),5.62–5.50(m,4H),5.36–5.28(m,1H),3.32–3.20(m,1H),3.18–3.04(m,1H),2.39(s,3H),2.24–2.13(m,2H),1.93–1.79(m,2H),1.53(s,3H),1.37(s,3H),0.90–0.81(m,3H).
实施例10
Figure PCTCN2022074825-appb-000024
第一步
向单口瓶(25mL)中依次加入2-2(50mg，0.11mmol)，2-甲基-2-羟基丙酸(17mg，0.17mmol)，无水二氯甲烷(5mL)，N,N-二异丙基乙胺(36mg，0.28mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(63mg，0.17mmol)，室温下搅拌反应1小时。反应体系加水(15mL)淬灭，二氯甲烷(30mL x 3)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物10(30mg)，收率：51％。
MS-ESI计算值[M+H] +538，实测值为538。
1H NMR(400MHz,DMSO-d 6)δ8.46(d,J＝9.2Hz,1H),7.83–7.74(m,2H),6.71(s,1H),5.91(d,J＝16.4Hz,1H),5.64–5.44(m,4H),5.24(d,J＝20.0Hz,1H),3.29–3.18(m,1H),3.17–3.08(m,1H),2.37(s,3H),2.22–2.09(m,2H),1.96–1.85(m,2H),1.55(s,3H),1.37(s,3H),0.87(t,J＝7.2Hz,3H).
实施例11
Figure PCTCN2022074825-appb-000025
第一步
向单口瓶(25mL)中依次加入2-1(20mg，0.04mmol)、3,3,3-三氟-2-甲基丙酸(13mg，0.09mmol)和N,N-二甲基甲酰胺(2mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(21μL，0.12mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(23mg，0.06mmol)，搅拌反应1.5小时。反应体系加水(30mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，15mL x 4)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物11-1(2mg)(小极性)和11-2(5mg)(大极性)，总收率：27％。
11-1：
MS-ESI计算值[M+H] +578，实测值为578。
11-2：
MS-ESI计算值[M+H] +578，实测值为578。
实施例12
Figure PCTCN2022074825-appb-000026
第一步
向单口瓶(25mL)中依次加入2-2(50mg，0.11mmol)，3,3,3-三氟-2-羟基丙酸(23.9mg，0.17mmol)和无水二氯甲烷(4mL)，向反应溶液中依次加入N,N-二异丙基乙胺(35.8mg，0.28mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷 酸盐(75mg，0.19mmol)，室温下搅拌反应4小时。反应体系加水(15mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，10mL x 6)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物12-1(15mg)(小极性)和12-2(6mg)(大极性)，总收率：32％。
12-1：
MS-ESI计算值[M+H] +578，实测值为578。
1H NMR(400MHz,DMSO-d 6)δ9.01(d,J＝8.8Hz,1H),7.83(d,J＝10.8Hz,1H),7.81(s,1H),7.36(br s,1H),6.70(br s,1H),5.92(d,J＝16.4Hz,1H),5.67–5.59(m,2H),5.52(d,J＝16.4Hz,1H),5.41(s,2H),4.73–4.61(m,1H),3.18(t,J＝6.4Hz,2H),2.40(s,3H),2.31–2.21(m,1H),2.20–2.10(m,1H),1.96–1.84(m,2H),0.87(t,J＝7.2Hz,3H).
12-2：
MS-ESI计算值[M+H] +578，实测值为578。
1H NMR(400MHz,DMSO-d 6)δ8.97(d,J＝8.4Hz,1H),7.85(d,J＝10.8Hz,1H),7.80(s,1H),7.17–7.09(m,1H),6.72(br s,1H),5.91(d,J＝16.4Hz,1H),5.68–5.59(m,1H),5.58–5.33(m,3H),4.66–4.55(m,1H),3.20–3.12(m,2H),2.40(s,3H),2.28–2.09(m,2H),1.93–1.83(m,2H),0.86(t,J＝7.2Hz,3H).
实施例13
Figure PCTCN2022074825-appb-000027
第一步
向单口瓶(25mL)中依次加入2-1(20mg，0.04mmol)、N-叔丁氧基羰基甘氨酸(16mg，0.09mmol)和N,N-二甲基甲酰胺(2mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(21μL，0.12mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(23mg，0.06mmol)，搅拌反应1.5小时。反应体系加水(40mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，15mL x 4)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物13a(15mg)，收率：56％。
MS-ESI计算值[M+H] +609，实测值为609。
第二步
依次将13a(15mg，0.02mmol)、乙酸乙酯(2mL)加入单口瓶(25mL)中， 向反应体系中逐滴加入氯化氢乙酸乙酯溶液(4.0M,2mL)，室温下搅拌反应7小时后，再逐滴加入氯化氢二氧六环溶液(4.0M,1mL)，室温下继续搅拌反应1小时。将反应液缓慢加入冰的饱和碳酸氢钠水溶液中(50mL)，直至无气泡产生，用二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，30mL x 6)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备HPLC纯化得到化合物13(2mg)，收率：15％。
MS-ESI计算值[M+H] +509，实测值为509。
实施例14
Figure PCTCN2022074825-appb-000028
第一步
向单口瓶(25mL)中依次加入2-2(100mg，0.22mmol)、N-叔丁氧基羰基甘氨酸(77mg，0.44mmol)和无水二氯甲烷(4mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(85mg，0.66mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(100mg，0.26mmol)，搅拌反应1小时。反应体系加水(10mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，150mL x 1)萃取，有机相经饱和食盐水(25mL x 2)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩得到粗产物14a(140mg)。
MS-ESI计算值[M+H] +609，实测值为609。
第二步
将粗产品14a(125mg)溶于乙酸乙酯(4mL)中，滴加氯化氢乙酸乙酯溶液(4.0M，4mL)至上述溶液中，室温下搅拌反应17小时。将反应液缓慢加入冰的饱和碳酸氢钠水溶液中调节pH至8-9，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，200mL x 3)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经乙腈(2mL)打浆得到14(60mg)，两步收率：54％。
MS-ESI计算值[M+H] +509，实测值为509。
1H NMR(400MHz,DMSO-d 6)δ8.60(br s,1H),7.82(d,J＝10.8Hz,1H),7.79(s,1H),6.71(br s,1H),5.90(d,J＝16.8Hz,1H),5.66–5.58(m,1H),5.56–5.45(m,2H),5.41–5.37(m,1H),3.30–3.10(m,4H),2.38(s,3H),2.24–2.14(m,2H),1.96–1.82(m,2H),0.86(t,J＝7.2Hz,3H).
实施例15
Figure PCTCN2022074825-appb-000029
第一步
向单口瓶(25mL)中依次加入2-1(30mg，0.07mmol)、4-(叔丁氧羰基氨基)丁酸(28mg，0.14mmol)和N,N-二甲基甲酰胺(3mL)，室温下，向反应体系中依次加入N,N-二异丙基乙胺(37μL，0.21mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(40mg，0.11mmol)，搅拌反应1.5小时。反应体系加水(50mL)，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，15mL x 4)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物15a(17mg)，收率：40％。
MS-ESI计算值[M+H] +637，实测值为637。
第二步
依次将15a(17mg，0.03mmol)、二氧六环(1mL)加入单口瓶(25mL)中，向反应体系中逐滴加入氯化氢二氧六环溶液(4M,4mL)，室温下搅拌反应1小时。将反应液缓慢加入冰的饱和碳酸氢钠水溶液中(60mL)，直至无气泡产生，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，30mL x 6)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到残余物，残余物经制备HPLC纯化得到化合物15(3mg)，收率：21％。
MS-ESI计算值[M+H] +537，实测值为537。
1H NMR(400MHz,DMSO-d 6)δ8.67(d,J＝8.8Hz,1H),8.37(s,1H),7.85(d,J＝10.8Hz,1H),7.80(s,1H),6.73(br s,1H),5.91(d,J＝16.8Hz,1H),5.64–5.59(m,1H),5.53–5.45(m,3H),3.25–3.10(m,2H),2.79–2.75(m,2H),2.41(s,3H),2.35–2.32(m,2H),2.24–2.11(m,2H),1.92–1.80(m,4H),0.85(t,J＝7.2Hz,3H).
实施例16
Figure PCTCN2022074825-appb-000030
Figure PCTCN2022074825-appb-000031
第一步
向单口瓶(25mL)中依次加入2-2(100mg，0.22mmol)和4-(叔丁氧羰基氨基)丁酸(90mg，0.44mmol)和无水二氯甲烷(5mL)，向反应溶液中依次加入N,N-二异丙基乙胺(86mg，0.66mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(121mg，0.32mmol)，室温下搅拌反应4小时。反应体系加水(30mL)淬灭，二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，50mL x 4)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经硅胶柱层析(甲醇：二氯甲烷＝0-100％)纯化得到16a(106mg)，收率：75％。
MS-ESI计算值[M+H] +637，实测值为637。
第二步
向单口瓶(25mL)中依次加入16a(106mg，0.17mmol)和乙酸乙酯(5mL)，滴加氯化氢乙酸乙酯溶液(4.0M,5mL)至上述溶液中，室温下搅拌反应17小时。反应液减压浓缩得到残余物。残余物加入饱和碳酸钠溶液调节pH至碱性，水相用二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，50mL x 4)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC分离纯化得到化合物16(4mg)，收率：4％。
MS-ESI计算值[M+H] +537，实测值为537。
1H NMR(400MHz,DMSO-d 6)δ8.73(d,J＝8.8Hz,1H),8.39(br s,1H),7.83(d,J＝10.8Hz,1H),7.80(s,1H),5.91(d,J＝16.4Hz,1H),5.64–5.56(m,1H),5.55–5.34(m,3H),3.19–3.10(m,2H),2.80(t,J＝7.6Hz,2H),2.39(s,3H),2.35(t,J＝7.2Hz,2H),2.25–2.05(m,2H),2.04–1.93(m,1H),1.94–1.80(m,3H),0.86(t,J＝7.2Hz,3H).
实施例17
Figure PCTCN2022074825-appb-000032
第一步
向单口瓶(25mL)中依次加入1f(100mg，0.22mmol)，1-羟基-1-环丙羧酸(45mg，0.44mmol)，无水二氯甲烷(3mL)，N,N-二异丙基乙胺(85mg，0.66mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(108mg，0.29mmol)，室温下搅拌反应3小时。反应体系加水(15mL)淬灭，二氯甲烷(150mL x1)萃取，合并有机相，有机相用饱和食盐水(15mL x 2)洗，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备HPLC分离纯化得到化合物17(12mg)，收率：10％。
MS-ESI计算值[M+H] +536，实测值为536。
1H NMR(400MHz,DMSO-d 6)δ8.62(d,J＝8.8Hz,1H),7.84–7.79(m,1H),7.79(s,1H),6.70(s,1H),6.27(s,1H),5.91(d,J＝16.8Hz,1H),5.66–5.57(m,1H),5.56–5.46(m,2H),5.35–5.24(m,1H),3.32–3.21(m,1H),3.20–3.05(m,1H),2.39(s,3H),2.35–2.15(m,2H),1.38–1.15(m,2H),1.04–0.90(m,2H),0.85(t,J＝7.2Hz,3H).
实施例18
Figure PCTCN2022074825-appb-000033
第一步
向单口瓶(25mL)中依次加入2-2(70mg，0.16mmol)，1-羟基-1-环丙羧酸(33mg，0.32mmol)和无水N,N-二甲基甲酰胺(2mL)，向混合溶液内依次加入N,N-二异丙基乙胺(60mg，0.47mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(91mg，0.24mmol)，室温下搅拌反应3小时。反应体系加水(15mL)淬灭，乙酸乙酯(150mL x 1)萃取，有机相用饱和食盐水(25mL x 5)洗，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物18(28mg)，收率：34％。
MS-ESI计算值[M+H] +536，实测值为536。
1H NMR(400MHz,DMSO-d 6)δ8.65(d,J＝9.2Hz,1H),7.81(d,J＝11.2Hz,1H),7.79(s,1H),6.70(s,1H),6.29(s,1H),5.92(d,J＝16.8Hz,1H),5.66–5.58(m,1H),5.56–5.46(m,2H),5.92(d,J＝20.0Hz,1H),3.32–3.20(m,1H),3.20–3.05(m,1H),2.39(s,3H),1.95–1.84(m,2H),1.38–1.16(m,2H),1.05–0.90(m,2H),0.86(t,J＝7.2Hz,3H).
实施例19
Figure PCTCN2022074825-appb-000034
第一步
向单口瓶(25mL)中依次加入2-1(30mg，0.07mmol)，3-环丙基-2-羟基丙酸(22mg，0.17mmol)，无水二氯甲烷(3mL)，N,N-二异丙基乙胺(23mg，0.18mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(42mg，0.11mmol)，室温下搅拌反应1小时。反应液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物19(6mg)，收率：16％。
MS-ESI计算值[M+H] +564，实测值为564。
1H NMR(400MHz,DMSO-d 6)δ8.50(d,J＝8.8Hz,1H),7.81(d,J＝10.8Hz,1H),7.79(s,1H),6.71(s,1H),5.90(d,J＝16.4Hz,1H),5.63–5.55(m,1H),5.62–5.46(m,3H),5.35(d,J＝20.0Hz,1H),4.27–4.05(m,1H),3.29–3.20(m,1H),3.19–3.05(m,1H),2.40(s,3H),2.29–2.08(m,2H),1.74–1.63(m,2H),1.72–1.62(m,1H),1.62–1.49(m,1H),0.97–0.89(m,1H),0.85(t,J＝7.4Hz,3H),0.50–0.28(m,2H),0.20–0.02(m,2H).
实施例20
Figure PCTCN2022074825-appb-000035
Figure PCTCN2022074825-appb-000036
第一步
向单口瓶(25mL)中依次加入20a(500mg，3.87mmol)，水(4mL)和冰醋酸(930mg，15.48mmol)，混合体系降温至0-5℃，缓慢滴加亚硝酸钠水溶液(2mL，7.7mmol/mL)，滴加完毕后恢复至室温继续搅拌反应3小时。反应体系经乙酸乙酯(20mL x 5)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到粗产品20b(200mg)。
第二步
向单口瓶(25mL)中依次加入2-2(30mg，0.07mmol)，20b(90mg，0.69mmol)，无水二氯甲烷(5mL)，N,N-二异丙基乙胺(15.2mg，0.28mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(34mg，0.09mmol)，室温下搅拌反应1小时。反应体系加水(10mL)淬灭，二氯甲烷(30mL x 3)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物20(5mg)，收率：13％。
MS-ESI计算值[M+H] +564，实测值为564。
1H NMR(400MHz,DMSO-d 6)δ8.51(d,J＝8.8Hz,1H),7.78–7.65(m,2H),6.69(s,1H),5.86(d,J＝16.4Hz,1H),5.66(d,J＝5.6Hz,1H),5.60–5.34(m,3H),5.20(d,J＝20.0Hz,1H),4.10–3.91(m,1H),3.25–3.13(m,1H),3.13–2.99(m,1H),2.31(s,3H),2.12(q,J＝6.8Hz,2H),1.99–1.75(m,3H),1.63–1.42(m,1H),0.95–0.86(m,1H),0.83(t,J＝7.3Hz,3H),0.50–0.26(m,2H),0.19–0.07(m,2H).
实施例21
Figure PCTCN2022074825-appb-000037
Figure PCTCN2022074825-appb-000038
第一步
向单口瓶(25mL)中依次加入21a(800mg，3.72mmol)和乙酸乙酯(4mL)，滴加氯化氢乙酸乙酯溶液(4.0M,7.4mL)至上述溶液中，室温下搅拌反应17小时。将反应液直接过滤，滤饼用乙酸乙酯(5mL)淋洗，收集滤饼，干燥得到化合物21b(570mg)，收率：99％。
1H NMR(400MHz,DMSO-d 6)δ13.63(br s,1H),8.52(s,3H),3.22(d,J＝8.8Hz,1H),1.16–1.02(m,1H),0.68–0.50(m,4H).
第二步
将21b(330mg，2.20mmol)溶于稀硫酸(2.0N，4.4mL)中，混合体系降温至0-5℃，缓慢滴加亚硝酸钠水溶液(5mL，4.4mmol/mL)，滴加完毕后缓慢恢复至室温继续搅拌反应过夜。反应体系加入氯化钠至饱和状态，乙酸乙酯(100mL x 3)萃取，合并有机相，有机相经无水硫酸钠干燥后过滤，滤液减压浓缩得到粗产品21c(150mg)。
第三步
向单口瓶(25mL)中依次加入2-2(100mg，0.22mmol)，粗产品21c(130mg)和无水二氯甲烷(5mL)，向反应体系中依次加入N,N-二异丙基乙胺(113mg，0.88mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(125mg，0.33mmol)，室温下搅拌反应2小时。反应体系加二氯甲烷和甲醇的混合溶剂(V 二氯甲烷:V 甲醇＝10:1，200mL)稀释，有机相依次经稀盐酸(1.0N,20mL x 1)，饱和食盐水(20mL x 2)洗，无水硫酸钠干燥后过滤，滤液减压浓缩得到残余物，残余物经制备薄层色谱(甲醇：二氯甲烷)纯化得到化合物21(5mg)，收率：4％。
MS-ESI计算值[M+H] +550，实测值为550。
1H NMR(400MHz,DMSO-d 6)δ8.75(d,J＝8.8Hz,1H),7.85(d,J＝10.4Hz,1H),7.80(S,1H),6.69(s,1H),5.92(d,J＝16.4Hz,1H),5.64–5.56(m,1H),5.56–5.46(m,2H),5.43–5.34(m,1H),4.66–4.60(m,1H),3.48–3.30(m,1H),3.22–3.12(m,1H),2.41(s,3H),2.26–2.10(m,2H),1.94–1.82(m,2H),1.11–1.05(m,1H),0.90–0.72(m,7H).
生物活性测试
细胞增殖抑制实验
取对数生长期的KPL-4肿瘤细胞，采用新鲜RPMI1640培养液重悬细胞，计数并 将细胞悬液调至2×10 4个/mL。将细胞悬液接种至96孔细胞培养板中，100μL/孔，置于二氧化碳培养箱(37℃，5％CO 2)中培养过夜。第二天取出其中一块接种细胞的96孔板，平衡至室温后向测试板各孔中加入预先平衡至室温并配制混匀的CellTiter-Glo试剂(Promega,USA)100μL，避光孵育30分钟后在酶标仪中读取luminescence数值(记为G 0值)；取另一块平行板并在测试板的相应孔内加入不同浓度的待测化合物或者DMSO(终浓度0.5％)，于二氧化碳培养箱中培养72h后，将测试板平衡至室温并采用CellTiter-Glo试剂检测细胞活性，记为G 3值。
根据以下公式计算细胞增殖率：细胞增殖率(％)＝(待测化合物孔G 3平均值–G 0平均值)/(DMSO对照孔G 3平均值–G 0平均值)*100。采用Graphpad Prism软件拟合抑制曲线并计算GI 50值(见下表)。
实施例 GI 50(nM)
实施例1:1-1 13.9
实施例1:1-2 10.3
实施例2:2-1 <1.52
实施例2:2-2 2.47
实施例3 2.59
实施例4 1.55
实施例5 1.79
实施例6 5.31
实施例7 5.76
实施例8 4.95
实施例9 12.1
实施例10 3.54
实施例11:11-1 17.3
实施例11:11-2 23.5
实施例12:12-1 5.8
实施例12:12-2 6.4
实施例13 7.54
实施例14 6.14
实施例17 1.83
实施例18 3.89
实施例19 2.9
实施例20 4.79
实施例21 34.7
DXd 72
结果表明：本发明的多个化合物在上述肿瘤细胞增殖抑制实验中展现了较高的抑制增殖活性，活性优于DXd(Exatecan衍生物，结构如下)。由于本发明化合物具有 优异的肿瘤细胞增殖抑制活性，因此可以作为肿瘤治疗药物使用，或者作为毒素分子，用于制备治疗肿瘤的抗体-药物偶联物。
Figure PCTCN2022074825-appb-000039
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种如下式(I)所示的化合物，或其药学上可接受的盐或水合物：
    Figure PCTCN2022074825-appb-100001
    X选自下组：H、OH、NH 2、NHR 0；
    Y选自下组：(CR 1R 2) n；
    Z选自下组：化学键、C(O)、C(S)、C(NH)、S(O) 2，S(O)；
    R 0选自下组：C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 3-C 8环烷基或3-12元杂环基；
    R 1和R 2各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8烷氧基、羟基、氨基、氰基、硝基、C 1-C 8羟烷基、C 3-C 8环烷基或3-12元杂环基；
    或者，R 1和R 2与其相连接的碳原子一起形成C 3-C 8环烷基或3-12元杂环基；
    R 3和R 4各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基；
    或者，R 3和R 4与其相连接的碳原子共同形成选自下组的结构：饱和或不饱和的5-12元环、饱和或不饱和的5-12元杂环；
    n选自0、1、2或3；
    且当n为2、3时，各个CR 1R 2可相同或不同；
    除非特别说明，本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐或水合物，其特征在于，所述R 3选自下组：C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基。
  3. 如权利要求1-2所述的化合物，或其药学上可接受的盐或水合物，其特征在于，R 4选自下组：氢原子、氘原子、卤素。
  4. 如权利要求1-3所述的化合物，或其药学上可接受的盐或水合物，其特征在于，所述的化合物具有如下式所示的结构：
    Figure PCTCN2022074825-appb-100002
  5. 如权利要求1-4所述的化合物，或其药学上可接受的盐或水合物，其特征在于，Z为化学键、C(O)。
  6. 如权利要求1-5所述的化合物，或其药学上可接受的盐或水合物，其特征在于，X选自下组：H、OH、NH 2。
  7. 如权利要求1-6所述的化合物，或其药学上可接受的盐或水合物，其特征在于，Y选自下组：(CR 1R 2) n；
    所述的R 1和R 2各自独立地选自下组：氢原子、氘原子、卤素、C 1-C 8烷基、C 1-C 8卤代烷基、C 1-C 8氘代烷基、C 1-C 8羟烷基、C 3-C 6环烷基或3-6元杂环基；或者，R 1和R 2与其相连接的碳原子一起形成C 3-C 6环烷基或3-6元杂环基；且C 1-C 8烷基可任选地被选自下组的取代基取代：C 6-C 10芳基、5-10元杂芳基、C 3-C 6环烷基、3-6元杂环基。
    n选自0、1、2或3；
    且当n为2、3时，各个CR 1R 2可相同或不同；
  8. 如权利要求1-7所述的化合物，或其药学上可接受的盐或水合物，其特征在于，所述的化合物具有如下式所示的结构：
    Figure PCTCN2022074825-appb-100003
  9. 如权利要求1-7所述的化合物，或其药学上可接受的盐或水合物，其特征在于，所述的化合物具有如下式所示的结构：
    Figure PCTCN2022074825-appb-100004
    Figure PCTCN2022074825-appb-100005
    Figure PCTCN2022074825-appb-100006
  10. 一种药物组合物，其包含根据权利要求1-9中任一项所述的式I化合物，或其药学上可接受的盐或水合物，以及一种或多种药学上可接受的赋形剂、稀释剂或载体。
  11. 如权利要求1-9中任一所述的式I化合物的用途，其特征在于，用于制备治疗与肿瘤细胞增殖相关的疾病的药物组合物。
  12. 如权利要求1-9中任一所述的式I化合物的用途，其特征在于，用作抗体-药物偶联物中的毒素从而制备抗体-药物偶联物。
PCT/CN2022/074825 2021-01-29 2022-01-28 适用于抗体-药物偶联物的毒素分子 WO2022161479A1 (zh)

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