WO2022171115A1 - 用于adc制备的喜树碱衍生物 - Google Patents

用于adc制备的喜树碱衍生物 Download PDF

Info

Publication number
WO2022171115A1
WO2022171115A1 PCT/CN2022/075626 CN2022075626W WO2022171115A1 WO 2022171115 A1 WO2022171115 A1 WO 2022171115A1 CN 2022075626 W CN2022075626 W CN 2022075626W WO 2022171115 A1 WO2022171115 A1 WO 2022171115A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
general formula
cycloalkyl
acceptable salt
Prior art date
Application number
PCT/CN2022/075626
Other languages
English (en)
French (fr)
Inventor
谢雨礼
曹刚
钱立晖
樊后兴
Original Assignee
微境生物医药科技(上海)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 微境生物医药科技(上海)有限公司 filed Critical 微境生物医药科技(上海)有限公司
Priority to CN202280012945.8A priority Critical patent/CN116888123A/zh
Publication of WO2022171115A1 publication Critical patent/WO2022171115A1/zh

Links

Images

Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic

Definitions

  • the present invention relates to the field of medicinal chemistry, more particularly, to a new class of camptothecin derivatives, a preparation method thereof and the use of such compounds in preparing antibody drug conjugates.
  • DNA topoisomerase is located in the nucleus, its substrate is DNA, and then it participates in cell replication, transcription and mitosis.
  • the main function of topoisomerase is to help the DNA supercoiled structure unwind and promote the transcription and replication of DNA strands.
  • Topoisomerases are divided into topoisomerase I (Topo I) and topoisomerase II (Topo II). Inhibition of topoisomerase inhibitors results in the accumulation of a large number of fragmented DNA in tumor cells and induces tumor cell death.
  • DNA topoisomerase I inhibitors including camptothecin and its derivatives, are clinically used for the treatment of malignant tumors.
  • Camptothecin was first isolated from the dovetaceae plant, Camptotheca, and has strong cytotoxicity. Have better curative effect.
  • the main disadvantage of camptothecin is its poor solubility and stability, and its high toxicity, so its clinical application is limited. Camptothecin derivatives can increase water solubility or improve their drug metabolism by introducing water-soluble groups or preparing prodrugs, thereby improving druggability.
  • camptothecin derivatives with greatly improved solubility have been approved for marketing, such as topotecan and irinotecan, the carbamate prodrug of 7-ethyl-10-hydroxycamptothecin.
  • ADCs antibody drug conjugates
  • cytotoxic small molecule is camptothecin derivatives.
  • DS-8201a (Trastuzumab Deruxtecan) is an ADC developed by Japan's Daiichi Sankyo and has been approved for marketing. This ADC selects camptothecin derivative Deruxtecan as a small molecule Toxins use a GGFG tetrapeptide hydrolyzable by cathepsin B and a self-cleaving structure as a linker.
  • camptothecin derivatives Due to the relatively low cell proliferation inhibitory activity of camptothecin derivatives, ADCs using camptothecin derivatives as small-molecule toxins generally require a large drug/antibody ratio (DAR), which is likely to cause ADC instability.
  • DAR drug/antibody ratio
  • the above disadvantages can be improved by the type selection and optimization of the linker.
  • the present invention provides a class of camptothecin derivatives modified with different types of linkers, and ADCs can be conveniently prepared by using these derivatives.
  • the present invention provides a compound represented by the general formula (1), or its various optical isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L1 is selected from
  • L 2 is selected from Wherein m is an integer from 0 to 5, wherein "a" means connected to L 1 ;
  • L3 is Wherein "b” indicates that it is connected to -C(O)-;
  • L 4 is selected from Wherein "c" indicates that it is connected to L 3 ;
  • R 1 and R 2 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, NH 2 , NO 2 or CN, or R 1 and R 2 are cyclized together with the attached benzene ring to form R 3 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl.
  • the present invention also provides a compound represented by the general formula (2), or its various optical isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L 5 is selected from
  • L 6 is selected from Wherein m is an integer from 0 to 5, wherein "d" means connected to L 5 ;
  • L7 is Wherein "e” means connected to -C(O)-;
  • L 8 is selected from Wherein "f” indicates that it is connected to -NH-;
  • R 1 and R 2 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, NH 2 , NO 2 or CN, or R 1 and R 2 are cyclized together with the attached benzene ring to form R 3 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl.
  • the present invention also provides a compound represented by the general formula (3), or its various optical isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L 9 is selected from
  • L 10 selected from Where m is an integer from 0 to 5, where "g" means connected to S;
  • L 11 is selected from Wherein "h” indicates that it is connected to -C(O)-;
  • L 12 selected from Wherein "i" indicates that it is connected to L 11 ;
  • R 1 and R 2 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, NH 2 , NO 2 or CN, or R 1 and R 2 are cyclized together with the attached benzene ring to form R 3 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl.
  • the present invention also provides a compound represented by general formula (4) or general formula (4A), or each of its optical isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L 13 is selected from
  • L 14 selected from Wherein m is an integer from 0 to 5, wherein "j" means connected to L 13 ;
  • L 15 is Wherein "k” indicates that it is connected to -C(O)-;
  • R 1 and R 2 are independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, NH 2 , NO 2 or CN, or R 1 and R 2 are cyclized together with the attached benzene ring to form R 3 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl.
  • An object of the present invention is to provide the compounds described in the present invention, or their respective optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates in the preparation of antibody-drug conjugates (ADCs) applications in .
  • ADCs antibody-drug conjugates
  • the compound of the present invention can realize the covalent connection between the drug and the antibody in the following ways:
  • the disulfide bond existing in the antibody is reduced by tris(2-chloroethyl) phosphate to generate free sulfhydryl group, and the small molecule drug can be combined with the maleimide in Linker-Drug by bioorthogonal reaction.
  • the coupling is realized through an amide bond or other covalent bond.
  • n is any number between 1-8, preferably 4-8.
  • n is any number between 1-8, preferably 2-6, more preferably 3-4.
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable excipient or carrier, and the compound of the present invention, or each of its optical isomers, pharmaceutically acceptable inorganic or organic compounds Salt as active ingredient.
  • Another object of the present invention is to provide the compounds of the present invention, or their respective optical isomers, pharmaceutically acceptable inorganic or organic salts, or the pharmaceutical compositions used in the preparation of medicines for the treatment of tumors and other related diseases Applications.
  • Another object of the present invention is to provide an antibody-drug conjugate (ADC), characterized in that, the antibody-drug conjugate comprises an antibody, a small molecule toxin and a linker; the small molecule toxin and the linker part are The compounds described in the general formulae (1), (2), (3), (4), (4A) of the present invention; and the antibody are linked by a covalent bond.
  • ADC antibody-drug conjugate
  • the antibodies to which the small molecules are linked in the antibody drug conjugate described in the present invention are mainly anti-HER2 monoclonal antibodies, anti-HER3 monoclonal antibodies, anti-Trop2 monoclonal antibodies, anti-B7H3 monoclonal antibodies, and the like.
  • the anti-HER2 antibody described in the present invention is trastuzumab, the amino acid sequence of its light chain is preferably as shown in SEQ ID No. 1 in the sequence listing, and the amino acid sequence of the heavy chain is preferably as shown in SEQ ID No. 1 in the sequence listing .2 shown.
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable stabilizer, pH adjuster or carrier, etc., and an antibody-drug conjugate formed by the compound of the present invention and the corresponding antibody as an activity Element.
  • Figure 1 shows the results of in vivo antitumor activity of the antibody-drug conjugate of Example 15 of the present invention.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the solvents, temperatures and other reaction conditions mentioned herein may vary.
  • Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources.
  • the compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999).
  • the general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a preparation method of the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following reaction method:
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting compounds of the general formula with acids, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, nitric, phosphoric and other inorganic acids, formic, acetic, propionic , oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids And acidic amino acids such as aspartic acid and glutamic acid.
  • acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, nitric,
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of the general formula are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the general formula is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds of the general formula are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • compounds of the general formula include crystalline forms and may also be used as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of the general formula may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and in the form of cis-trans isomers.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of the cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • Substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered is meant to denote the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule.
  • a chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • Active ingredient refers to the compound represented by the general formula, as well as the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula.
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of treating diseases, including but not limited to cancer, using the compounds, antibody-drug conjugates or pharmaceutical compositions of the invention.
  • a method for cancer treatment comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition of any of the foregoing compounds, antibody-drug conjugates.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • 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 safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling 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 can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmacologically acceptable excipients or 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 ), 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
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • the ADC prepared from the compound of the present invention is administered, it is mainly administered by intravenous injection. Its preparation form is mainly freeze-dried powder injection, or its solution form.
  • the dosage form components for intravenous injection mainly include antibody-drug conjugates, histidine buffered saline solution, stabilizers such as sucrose or trehalose, and surfactants such as polysorbate.
  • Histidine buffer salt is used as pH stabilizer, and its concentration is preferably 5-100 mM, pH is 5.5-6.5, more preferably 10-25 mM, pH 6.0-6.5.
  • the stabilizer is sucrose or trehalose, etc., the content of which is preferably 1-30%, preferably sucrose, and the concentration is 5-15%, more preferably 6%.
  • the surfactant is polysorbate, preferably polysorbate 20 (Tween 20), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), polyoxyethylene, etc., and more preferably polysorbate Sorbitan 80.
  • the polysorbate concentration is preferably 0-2 mg, more preferably 0.2 or 0.3 mg per 20 mg of antibody-drug conjugate.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for a mammal (such as a human) in need of treatment, and the dose is a pharmaceutically effective dose when administered, and for a 60kg body weight, the dose is given.
  • the dosage is usually 1-10 mg/kg, administered once every 3 weeks.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are all within the skill of a skilled physician.
  • 1 H-NMR was recorded with a Vian Mercury 400 nuclear magnetic resonance apparatus, and chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh not specified, and the proportions of eluents were all volume ratios.
  • RT room temperature
  • PE petroleum ether
  • EA ethyl acetate
  • DCM dichloromethane
  • MeOH 1,4-dioxane
  • MTBE methyl tert-butyl ether
  • EtOH ethanol
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • DMSO Sulfoxide
  • TAA triethylamine
  • DIPEA diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • palladium carbon (Pd/C) ; Eaton's reagent (Eaton's reagent, 7.7wt% phosphorus pentoxide in methanesulfonic acid solution); iron powder (Fe); zinc powder (Zn); Raney nickel (
  • D 4 in Table 4 is D 4A is
  • D 6 in Table 6 is D 6A is
  • D 7 in Table 7 is D 7A is
  • Experimental procedure Take an appropriate amount of the mixture of 41 and 42, dissolve in DMF, and prepare a test solution with a concentration of 10 mg/mL. Take the above-mentioned test solution, inject it into a preparative liquid chromatograph, detect and record data according to the chromatographic conditions of the present invention, and repeat the sample injection for many times.
  • Step 1 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexamido) Synthesis of -3-methylbutyrylamino)-5-ureidopentanamido)benzyl(4-nitrophenyl)carbonate
  • Step 2 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoamido) -3-Methylbutyrylamino)-5-ureidopentanamido)benzyl((1R,9S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1, 2,9,10,13,15-Hexahydro-12H-pyran[3',4':6,7]indolizine[1,2-b]thiopyran[4,3,2-de] Synthesis of quinolin-1-yl)carbamate
  • D 5 in Table 10 is D5A is
  • D 6 in Table 11 is D 6A is
  • Example 5 4-((3-((3-((((R)-1-(2-(((1R,9S)-9-ethyl-5-fluoro-9-hydroxy-10,13-di) Oxo-1,2,9,10,13,15-hexahydro-12H-pyran[3',4':6,7]indolizine[1,2-b]thiopyran[4,3 ,2-de]quinolin-1-yl)amino)-2-oxoethoxy)-1-oxopropyl-2-yl)(methyl)amino)-3-oxopropyl)sulfur Synthesis of pentafluorophenyl)-2,5-oxopyrrol-1-yl)methyl)cyclohexyl-1-carboxylate
  • D 1 in Table 12 is D1A is
  • D 5 in Table 14 is D5A is
  • D 6 in Table 15 is D 6A is
  • Example 6 4-((3-((3-(((R)-1-(2-(((1R,9S)-9-ethyl-5-fluoro-9-hydroxy-10,13-di Oxo-1,2,9,10,13,15-hexahydro-12H-pyran[3',4':6,7]indolizine[1,2-b]thiopyran[4,3 ,2-de]quinolin-1-yl)amino)-2-oxoethoxy)-1-oxopropyl-2-yl)(methyl)amino)-3-oxopropyl)sulfur Synthesis of pentafluorophenyl)-2,5-oxopyrrol-1-yl)methyl)cyclohexyl-1-carboxylate
  • D 1 in Table 16 is D1A is
  • D 6 in Table 19 is D 6A is
  • the antibody Trastuzumab 10mM, 0.082mL
  • the antibody Trastuzumab 10mM, 0.082mL
  • the antibody Trastuzumab 10mM, 0.082mL
  • aqueous solution (10mM, 0.082mL) was placed in a water bath shaker, and the reaction was shaken at 37°C for 3 hours to stop the reaction; the reaction solution was cooled to 25°C in a water bath and diluted to 5.0 mg/mL.
  • aqueous solution (10mM, 0.082mL) was placed in a water bath shaker, and the reaction was shaken at 37°C for 3 hours to stop the reaction; the reaction solution was cooled to 25°C in a water bath and diluted to 5.0 mg/mL.
  • aqueous solution (10mM, 0.082mL) was placed in a water bath shaker, and the reaction was shaken at 37°C for 3 hours to stop the reaction; the reaction solution was cooled to 25°C in a water bath and diluted to 5.0 mg/mL.
  • SK-BR-3 and NCI-N87 cells with high expression of HER2 were selected as cell lines for in vitro activity detection in this experiment to evaluate the dose-response situation of the antibody-drug conjugates of the present invention on cell killing ability.
  • the seeding density of each cell 1500-2000 cells/well, the final concentration of the antibody-drug conjugate was set to 25nM as the initial concentration, and a series of concentrations (3-10 times dilution) were designed, and the cells were observed after 144 hours
  • the survival rate of tumor cells was measured by CellTiter-Glo@Luminescent Cell Viability Assay chemiluminescence staining, and the IC 50 was calculated after reading the fluorescence data.
  • Antibody-drug conjugates of the present invention inhibit proliferation of SK-BR-3 and NCI-N87 cells
  • Example 15 In vivo antitumor activity of the antibody-drug conjugates of the present invention
  • mice 6-8 week old female Balb/c nude mice were subcutaneously injected with human gastric cancer cells (NCI-N87) dissolved in 100 ⁇ L of PBS solution on the right side of the back of the neck.
  • human gastric cancer cells NCI-N87
  • the average tumor volume is about 150-200mm3
  • 30 nude mice were randomly divided into 6 groups, 5 animals in each group, grouped by tail vein injection: 01 was the blank control group, 02 was the control group.
  • DS-8201a (3.0mg/kg)
  • 03 is ADC-1 (3.0mg/kg)
  • 04 is ADC-2 (3.0mg/kg)
  • 05 is ADC-3 (3.0mg/kg)
  • 06 is ADC- 4 (3.0 mg/kg)
  • the body weight and tumor volume of the experimental animals were measured twice a week and the survival status of the animals during the experiment was observed.
  • the specific results of the changes in tumor volume in each group are shown in Figure 1.
  • FIG. 1 It can be seen from FIG. 1 that several ADC samples in the present invention all showed in vivo anti-tumor activity comparable to DS-8201a, or even better than DS8201a.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了用于ADC制备的喜树碱衍生物。具体的，本发明提供了一类喜树碱衍生物及其制备方法和用途。具体而言，本发明提供了如通式(1)、(2)、(3)、(4)所示的化合物及其制备方法，以及如通式(1)、(2)、(3)、(4)所示化合物及其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物在制备抗体药物偶联物(antibody drug conjugate,ADC)中的用途。

Description

用于ADC制备的喜树碱衍生物
本申请要求申请日为2021年2月9日的中国申请CN202110182363.1的优先权。本申请引用上述中国申请的全文。
技术领域
本发明涉及药物化学领域，更具体而言，涉及一类新型喜树碱衍生物，及其制备方法和该类化合物在制备抗体药物偶联物中的用途。
背景技术
DNA拓扑异构酶位于细胞核，其作用底物为DNA，继而参与细胞的复制、转录及有丝分裂。拓扑异构酶的主要作用为帮助DNA超螺旋结构解旋，促进DNA链的转录与复制。拓扑异构酶分为拓扑异构酶Ⅰ(Topo Ⅰ)和拓扑异构酶Ⅱ(Topo Ⅱ)。抑制拓扑异构酶抑制剂致使肿瘤细胞内积累大量断裂DNA，诱发肿瘤细胞死亡。DNA拓扑异构酶Ⅰ抑制剂包括喜树碱及其衍生物，临床上用于恶性肿瘤的治疗。
喜树碱最早是从珙桐科植物喜树中分离得到的，具有较强的细胞毒性，对消化道肿瘤(胃癌、结肠癌、直肠癌)、肝癌、乳腺癌、膀胱癌和白血病等恶性肿瘤有较好的疗效。喜树碱的主要缺点是溶解性和稳定性较差，毒性较大，因此临床应用受到限制。喜树碱衍生物通过引入水溶性基团或制备前药，可以增加水溶性或改善其药物代谢情况，从而改善成药性。已有多个溶解度大幅提高的喜树碱衍生物获批上市，例如拓扑替康和7-乙基-10-羟基喜树碱的氨基甲酸酯型前药伊立替康。
癌症治疗的一种策略是利用抗体作为载体，通过共价连接的方式将细胞毒性分子携带进入癌细胞，然后利用偶联物在肿瘤中特殊环境中解离下来的小分子杀伤癌细胞，使用这种策略的偶联物被称为抗体药物偶联物(antibody drug conjugate,ADC)。其中常见的一类细胞毒性小分子是喜树碱衍生物，DS-8201a(Trastuzumab Deruxtecan)是日本第一三共研发的ADC，已经被批准上市，该ADC选择喜树碱衍生物Deruxtecan作为小分子毒素，用可被组织蛋白酶B水解的GGFG四肽和自裂解结构作为连接子(linker)。
拓扑替康、伊立替康和Deruxtecan的结构式如下:
Figure PCTCN2022075626-appb-000001
因喜树碱类衍生物细胞增殖抑制活性相对较低，以喜树碱衍生物为小分子毒素的ADC一般需要较大的药物/抗体比(DAR)，容易造成ADC不稳定。通过连接子的类型选择和优化可以改善以上缺点。本发明提供一类修饰了不同类型连接子的喜树碱衍生物，用这些衍生物可以方便的制备ADC。
发明内容
本发明提供了一种通式(1)所示的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022075626-appb-000002
通式(1)中：
L 1选自
Figure PCTCN2022075626-appb-000003
Figure PCTCN2022075626-appb-000004
L 2选自
Figure PCTCN2022075626-appb-000005
Figure PCTCN2022075626-appb-000006
其中m为0至5的整数，其中“a”表示和L 1相连；
L 3为
Figure PCTCN2022075626-appb-000007
其中“b”表示和-C(O)-相连；
L 4选自
Figure PCTCN2022075626-appb-000008
Figure PCTCN2022075626-appb-000009
Figure PCTCN2022075626-appb-000010
其中“c”表示和L 3相连；
D选自
Figure PCTCN2022075626-appb-000011
其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2、NO 2或CN，或R 1和R 2与所相连的 苯环一起环合形成
Figure PCTCN2022075626-appb-000012
R 3选自H、C 1-6烷基或C 3-6环烷基。
本发明同时提供了一种通式(2)所示的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022075626-appb-000013
通式(2)中：
L 5选自
Figure PCTCN2022075626-appb-000014
Figure PCTCN2022075626-appb-000015
L 6选自
Figure PCTCN2022075626-appb-000016
Figure PCTCN2022075626-appb-000017
其中m为0至5的整数，其中“d”表示和L 5相连；
L 7为
Figure PCTCN2022075626-appb-000018
其中“e”表示和-C(O)-相连；
L 8选自
Figure PCTCN2022075626-appb-000019
其中“f”表示和-NH-相连；
D选自
Figure PCTCN2022075626-appb-000020
其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2、NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
Figure PCTCN2022075626-appb-000021
R 3选自H、C 1-6烷基或C 3-6环烷基。
本发明同时提供了一种通式(3)所示的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022075626-appb-000022
通式(3)中：
L 9选自
Figure PCTCN2022075626-appb-000023
L 10选自
Figure PCTCN2022075626-appb-000024
其中m为0至5的整数，其中“g”表示和S相连；
L 11选自
Figure PCTCN2022075626-appb-000025
Figure PCTCN2022075626-appb-000026
其中“h”表示和-C(O)-相连；
L 12选自
Figure PCTCN2022075626-appb-000027
Figure PCTCN2022075626-appb-000028
其中“i”表示和L 11相连；
D选自
Figure PCTCN2022075626-appb-000029
其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2、NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
Figure PCTCN2022075626-appb-000030
R 3选自H、C 1-6烷基或C 3-6环烷基。
本发明同时提供了一种通式(4)或通式(4A)所示的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022075626-appb-000031
通式(4)或通式(4A)中：
L 13选自
Figure PCTCN2022075626-appb-000032
Figure PCTCN2022075626-appb-000033
L 14选自
Figure PCTCN2022075626-appb-000034
Figure PCTCN2022075626-appb-000035
其中m为0至5的整数，其中“j”表示和L 13相连；
L 15为
Figure PCTCN2022075626-appb-000036
其中“k”表示和-C(O)-相连；
L 16选自
Figure PCTCN2022075626-appb-000037
Figure PCTCN2022075626-appb-000038
Figure PCTCN2022075626-appb-000039
其中“l”表示和-NH-相连；
D选自
Figure PCTCN2022075626-appb-000040
其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2、NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
Figure PCTCN2022075626-appb-000041
R 3选自H、C 1-6烷基或C 3-6环烷基。
在另一优选例中，如通式(1)所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
Figure PCTCN2022075626-appb-000042
Figure PCTCN2022075626-appb-000043
其中D选自
Figure PCTCN2022075626-appb-000044
Figure PCTCN2022075626-appb-000045
在另一优选例中，如通式(2)所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
Figure PCTCN2022075626-appb-000046
Figure PCTCN2022075626-appb-000047
Figure PCTCN2022075626-appb-000048
其中D选自
Figure PCTCN2022075626-appb-000049
Figure PCTCN2022075626-appb-000050
在另一优选例中，如通式(3)所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
Figure PCTCN2022075626-appb-000051
Figure PCTCN2022075626-appb-000052
Figure PCTCN2022075626-appb-000053
Figure PCTCN2022075626-appb-000054
D选自
Figure PCTCN2022075626-appb-000055
Figure PCTCN2022075626-appb-000056
在另一优选例中，如通式(4)所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
Figure PCTCN2022075626-appb-000057
其中D选自
Figure PCTCN2022075626-appb-000058
Figure PCTCN2022075626-appb-000059
在另一优选例中，如通式(4A)所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
Figure PCTCN2022075626-appb-000060
Figure PCTCN2022075626-appb-000061
其中D选自
Figure PCTCN2022075626-appb-000062
Figure PCTCN2022075626-appb-000063
本发明的一个目的是提供本发明所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物在制备抗体-药物偶联物(ADC)中的应用。
其中，本发明所述的化合物可通过以下方式实现药物与抗体之间的共价连接：
其一，通过磷酸三(2-氯乙基)酯将抗体中存在的二硫键还原，产生游离的巯基，通过与Linker-Drug中马来酰亚胺进行生物正交反应实现小分子药物与抗体之间的共价连接；
其二，通过Linker-Drug与抗体中游离氨基进行取代反应，通过酰胺键或其他共价键形式实现偶联。
Figure PCTCN2022075626-appb-000064
其中，n为1-8间任意数，优选为4-8。
其二，通过与抗体中赖氨酸残基上的游离氨基发生反应，实现抗体与小分子间的偶 联，其具有以下结构：
Figure PCTCN2022075626-appb-000065
其中，n为1-8间任意数，优选为2-6，更优选为3-4。
本发明的另一个目的是提供一种药物组合物，其含有药学上可接受的赋形剂或载体，以及本发明所述化合物、或其各光学异构体、药学上可接受的无机或有机盐作为活性成分。
本发明的再一个目的是提供本发明所述化合物、或其各光学异构体、药学上可接受的无机或有机盐、或所述的药物组合物用于制备治疗肿瘤等相关疾病的药物中的应用。
本发明的再一个目的是提供一种抗体药物偶联物(ADC)，其特征在于，所述抗体药物偶联物包括抗体、小分子毒素和连接子；所述小分子毒素和连接子部分为本发明通式(1)、(2)、(3)、(4)、(4A)所述的化合物；和抗体通过共价键连接。
本发明中所述的抗体药物偶联物中小分子所连接的抗体主要为抗HER2单克隆抗体，抗HER3单克隆抗体，抗Trop2单克隆抗体，抗B7H3单克隆抗体等。
本发明中所述的抗HER2抗体为曲妥珠单抗，其轻链的氨基酸序列优选为如序列表中SEQ ID No.1所示，重链的氨基酸序列优选为如序列表中SEQ ID No.2所示。
本发明的再一个目的是提供一种药物组合物，其含有药学上可接受的稳定剂、pH调节剂或载体等，以及含有本发明所述化合物与相应抗体形成的抗体药物偶联物作为活性成分。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
附图说明
图1是本发明实施例15的抗体-药物偶联物的体内抗肿瘤活性结果。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，Advanced Organic Chemistry 4 th Ed.,(Wiley 1992)；Carey和Sundberg，Advanced Organic Chemistry 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，Protective Groups in Organic Synthesis 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下述反应方法制备：
Figure PCTCN2022075626-appb-000066
Figure PCTCN2022075626-appb-000067
其中，L 1、L 2、L 3、L 4、L 5、L 6、L 7、L 8、L 9、L 10、L 11、L 12、L 13、L 14、L 15、L 16和D(Drug)的定义如前所述。
以化合物I为起始原料，经过缩合反应反应得到通式(1)化合物。
以化合物II为起始原料，经过亲核取代反应得到通式(2)化合物。
以化合物III为起始原料，经过缩合反应反应得到通式(3)化合物。
以化合物IV为起始原料，经过缩合反应反应得到通式(4)化合物。
以化合物IVA为起始原料，经过缩合反应反应得到通式(4A)化合物。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)、氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。
除非另有规定，“环烷基”是指非芳香族烃环系统(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子 基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2022075626-appb-000068
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片段”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
除非另有说明，用楔形实线键
Figure PCTCN2022075626-appb-000069
和楔形虚线键
Figure PCTCN2022075626-appb-000070
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022075626-appb-000071
和直形虚线键
Figure PCTCN2022075626-appb-000072
表示立体中心的相对构型，用波浪线
Figure PCTCN2022075626-appb-000073
表示楔形 实线键
Figure PCTCN2022075626-appb-000074
或楔形虚线键
Figure PCTCN2022075626-appb-000075
或用波浪线
Figure PCTCN2022075626-appb-000076
表示直形实线键
Figure PCTCN2022075626-appb-000077
或直形虚线键
Figure PCTCN2022075626-appb-000078
除非另有说明，用
Figure PCTCN2022075626-appb-000079
表示单键或双键。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式所示化合物，以及通式化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本 说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明所述化合物、抗体-药物偶联物或药物组合物治疗疾病的方法，所述疾病包括但不限于癌症。
在一些实施方案中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的化合物、抗体-药物偶联物的药物组合物。在其它实施方案中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、前列腺癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理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。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”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与本发明的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。药理上可以接受的赋形剂或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
Figure PCTCN2022075626-appb-000080
)、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。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
施用本发明化合物所制备的ADC时，主要以静脉注射进行给药。其制剂形态主要为冻干粉针，或其溶液形式。
用于静脉注射的剂型成分主要包括抗体-药物偶联物，组氨酸缓冲盐溶液，蔗糖或海藻糖等稳定剂，聚山梨酯等表面活性剂。
组氨酸缓冲盐作为pH稳定剂，其浓度优选为5-100mM，pH为5.5-6.5，更优选为 10-25mM，pH 6.0-6.5。
稳定剂为蔗糖或海藻糖等，其含量优选为1-30％，优选为蔗糖，浓度为5-15％，更优选为6％。
表面活性剂为聚山梨酯，优选为聚山梨酯20(吐温20)、聚山梨酯60(吐温60)、聚山梨酯80(吐温80)、聚氧乙烯等，并且更优选为聚山梨酯80。
聚山梨酯浓度为每20mg抗体-药物偶联物优选0-2mg，更优选为0.2或0.3mg。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。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，给药剂量通常为1-10mg/kg,每3周给药一次当然，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。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
所有实施例中， 1H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。本发明采用下述缩略词：室温(RT，rt)；水溶液(aq.)；石油醚(PE)；乙酸乙酯(EA)；二氯甲烷(DCM)；1,4-二氧六环(dioxane)；甲醇(MeOH)；甲基叔丁基醚(MTBE)；乙醇(EtOH)；四氢呋喃(THF)；二甲基甲酰胺(DMF)；N-甲基吡咯烷酮(NMP)；二甲基亚砜(DMSO)；三乙胺(TEA)；二异丙基乙胺(DIPEA)；4-二甲基氨基吡啶(DMAP)；四氯化碳(CCl 4)；钯碳(Pd/C)；Eaton’s reagent(伊顿试剂，7.7wt％五氧化二磷的甲磺酸溶液)；铁粉(Fe)；锌粉(Zn)；兰尼镍(Ranyi Ni)；乙酰氯(AcCl)；乙酸(AcOH)；乙酸酐(Ac 2O)；间氯过氧苯甲酸(m-CPBA)；亚硝酸 正丁酯(n-BuNO)；亚硝酸钠(NaNO 2)；氢化钠(NaH)；硫酸镁(MgSO 4)；N-溴代丁二酰亚胺(NBS)；一水合对甲基苯磺酸(TsOH·H 2O)；碳酸钠(Na 2CO 3)；碳酸钾(K 2CO 3)；当量(eq)；克/毫克(g/mg)；摩尔/毫摩尔(mol/mmol)；升/毫升(L/mL)；分钟(min(s))；小时(h,hr,hrs)；氮气(N 2)；核磁共振(NMR)；液相-质谱仪(LC-MS)；薄层色谱(TLC)；制备液相色谱仪(pre-HPLC)。
实施例1 N-((S)-10-苄基-1-(((1R,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫吡喃[4,3,2-de]喹啉-1-基)氨基)-1,6,9,12,15-五氧代-3-氧杂-5,8,11,14-四氮杂十六烷基-16-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺的合成
Figure PCTCN2022075626-appb-000081
于50mL单口瓶中加入LA1(76mg,0.12mmol,1.0eq)，D2(60.4mg,0.12mmol,1.0eq)，NMI(50.6mg,0.62mmol,5.0eq)和DMF(2mL)，搅拌均匀并冷却至0℃。向反应液中加入TCFH(41.5mg,0.15mmol,1.2eq)，搅拌30min。LC-MS检测，反应完毕。反应液经反相C18柱层析(MeCN/water＝0～60％)纯化，目标组分经冻干得黄色固体80mg，收率61.5％。LC-MS:1052.1[M+H] +；1050.1[M-H] -。
1H-NMR(400MHz,DMSO-d 6)δ:8.56(t,J＝6.4Hz,1H),8.30(dd,J＝14.0,8.3Hz,2H),8.11(d,J＝7.9Hz,1H),8.06(t,J＝5.7Hz,1H),7.99(t,J＝5.7Hz,1H),7.76(d,J＝10.7Hz,1H), 7.31(d,J＝2.8Hz,1H),7.27-7.12(m,5H),6.98(s,2H),6.54(d,J＝1.8Hz,1H),5.84-5.83(m,1H),5.49-5.31(m,3H),5.27-5.21(m,1H),4.66-4.53(m,2H),4.48-4.41(m,1H),3.98(s,2H),3.75-3.54(m,6H),3.42(s,2H),3.36-3.35(m,2H),3.04-2.98(m,1H),2.80-2.74(m,1H),2.42(s,3H),2.08(t,J＝7.4,2H),1.93-1.79(m,2H),1.50-1.41(dd,J＝13.2,5.9Hz,4H),1.25-1.12(m,2H),0.88-0.84(m,3H).
类似化合物27的合成，可以得到表1-7所列的化合物：
表1.化合物1-26A
Figure PCTCN2022075626-appb-000082
Figure PCTCN2022075626-appb-000083
Figure PCTCN2022075626-appb-000084
Figure PCTCN2022075626-appb-000085
注：表1中D 1为
Figure PCTCN2022075626-appb-000086
D 1A为
Figure PCTCN2022075626-appb-000087
表2.化合物27-52
Figure PCTCN2022075626-appb-000088
Figure PCTCN2022075626-appb-000089
Figure PCTCN2022075626-appb-000090
注：表2中D 2为
Figure PCTCN2022075626-appb-000091
表3.化合物53-78
Figure PCTCN2022075626-appb-000092
Figure PCTCN2022075626-appb-000093
Figure PCTCN2022075626-appb-000094
注：表3中D 3为
Figure PCTCN2022075626-appb-000095
表4.化合物79-104A
Figure PCTCN2022075626-appb-000096
Figure PCTCN2022075626-appb-000097
Figure PCTCN2022075626-appb-000098
Figure PCTCN2022075626-appb-000099
Figure PCTCN2022075626-appb-000100
注：表4中D 4为
Figure PCTCN2022075626-appb-000101
D 4A为
Figure PCTCN2022075626-appb-000102
表5.化合物105-130A
Figure PCTCN2022075626-appb-000103
Figure PCTCN2022075626-appb-000104
Figure PCTCN2022075626-appb-000105
Figure PCTCN2022075626-appb-000106
注：表5中D 5为
Figure PCTCN2022075626-appb-000107
D 5A为
Figure PCTCN2022075626-appb-000108
表6.化合物131-156A
Figure PCTCN2022075626-appb-000109
Figure PCTCN2022075626-appb-000110
Figure PCTCN2022075626-appb-000111
Figure PCTCN2022075626-appb-000112
Figure PCTCN2022075626-appb-000113
注：表6中D 6为
Figure PCTCN2022075626-appb-000114
D 6A为
Figure PCTCN2022075626-appb-000115
表7.化合物157-182A
Figure PCTCN2022075626-appb-000116
Figure PCTCN2022075626-appb-000117
Figure PCTCN2022075626-appb-000118
Figure PCTCN2022075626-appb-000119
注：表7中D 7为
Figure PCTCN2022075626-appb-000120
D 7A为
Figure PCTCN2022075626-appb-000121
实施例2 N-((S)-10-苄基-2-环丙基-1-(((1R,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]吲哚嗪[1,2-b]硫吡喃[4,3,2-de]喹啉-1-基)氨基)-1,6,9,12,15-五氧代-3-氧杂-5,8,11,14-四氮杂十六烷基-16-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺的合成
Figure PCTCN2022075626-appb-000122
向50mL单口瓶中加入LA2(80mg,0.12mmol,1.0eq)和D2(58.8mg,0.12mmol,1.0eq)，NMI(50.6mg,0.62mmol,5.0eq)和DMF(2mL)，搅拌均匀并冷却至0℃。向反应液中加入TCFH(41.5mg,0.15mmol,1.2eq)，搅拌30min。LC-MS检测，反应完毕后，反应液经反相C18柱层析纯化，分得两个馏分，保留时间较短的为化合物41，保留时间较长的为42。目标馏分经冻干得黄色固体41(20mg)，42(25mg)
LC-MS:1092.4[M+H] +。
色谱条件：采用赛默飞半制备液相色谱仪U3000；色谱柱：Welch Ultimate XB-Phenyl；流动相：0.1％甲酸/乙腈-0.1％甲酸/水溶液＝50:50；流速：30.0mL/min；检测波长：370nm；进样量：100μL。
实验步骤：取41和42混合物适量，DMF溶解，配制浓度为10mg/mL的供试品溶液。取上述供试品溶液，注入制备液相色谱仪，按照本发明色谱条件进行检测并记录数据，多次重复进样。
结果：经制备分离得到化合物41和42，两个组分的保留时间分别是5.29min和5.87min，纯度分别是99.38％和99.21％。
实施例3 N-((S)-10-苄基-1-(((1S,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫吡喃[4,3,2-de]喹啉-1-基)氨基)-1,6,9,12,15-五氧代-3-氧杂-5,8,11,14-四氮杂十六烷基-16-基)-6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺的合成
Figure PCTCN2022075626-appb-000123
于50mL单口瓶中加入LA1(76mg,0.12mmol,1.0eq)，D3(60.4mg,0.12mmol,1.0eq)，NMI(50.6mg,0.62mmol,5.0eq)和DMF(2mL)，搅拌均匀并冷却至0℃。向反应液中加入TCFH(41.5mg,0.15mmol,1.2eq)，搅拌30min。经LC-MS检测，反应完毕。反 应液经反相C18柱层析(MeCN/water＝0～60％)纯化，目标组分经冻干得黄色固体80mg，收率61.5％。LC-MS:1052.1[M+H] +；1050.1[M-H] -。
实施例4 4-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰氨基)-3-甲基丁酰氨基)-5-脲基戊酰胺基)苄基((1R,9S)-9-乙基-5-氟-9-羟基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫代吡喃[4,3,2-de]喹啉-1-基)氨基甲酸酯的合成
Figure PCTCN2022075626-appb-000124
步骤1：4-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰氨基)-5-脲基戊酰胺基)苄基(4-硝基苯基)碳酸酯的合成
Figure PCTCN2022075626-appb-000125
于50mL三口瓶中加入B1-a(572mg，1mmol，1eq)，DIEA(387mg，3mmol，3eq)，DMF(10mL)和双(4-硝基苯)碳酸酯(664mg，2mmol，2eq)，氩气保护下，15℃搅拌1h，原料反应完全。浓缩，粗品柱层析(MeOH/DCM＝1/20-1/10)分离得淡黄色固体B1-b(241mg，收率32％)。LC-MS:752.2[M+H] +。
步骤2：4-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰氨基)-3-甲基丁酰氨基)-5-脲基戊酰胺基)苄基((1R,9S)-9-乙基-5-氟-9-羟基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫代吡喃[4,3,2-de]喹啉-1-基)氨基甲酸酯的合成
Figure PCTCN2022075626-appb-000126
于50mL三口瓶中加入B1-b(75mg,0.1mmol,1eq)，D1(44mg,0.1mmol,1eq)，DIEA(26mg,0.2mmol,2eq)和DMF(10mL)，氩气保护下，15℃搅拌1h，原料反应完全。体系由Pre-HPLC(ACN/0.5％TFA,30/70-50/50)分离得淡黄色固体产物(32mg,收率32％)。LC-MS:1038.2[M+H] +。
类似化合物183的合成，可以得到表8-11所列的化合物。
表8.化合物183-198A
Figure PCTCN2022075626-appb-000127
Figure PCTCN2022075626-appb-000128
Figure PCTCN2022075626-appb-000129
Figure PCTCN2022075626-appb-000130
Figure PCTCN2022075626-appb-000131
注：表8中D 1为
Figure PCTCN2022075626-appb-000132
D 1A为
Figure PCTCN2022075626-appb-000133
表9.化合物199-214A
Figure PCTCN2022075626-appb-000134
Figure PCTCN2022075626-appb-000135
Figure PCTCN2022075626-appb-000136
Figure PCTCN2022075626-appb-000137
Figure PCTCN2022075626-appb-000138
注：表9中D 2为
Figure PCTCN2022075626-appb-000139
D 3为
Figure PCTCN2022075626-appb-000140
表10.化合物215-230A
Figure PCTCN2022075626-appb-000141
Figure PCTCN2022075626-appb-000142
Figure PCTCN2022075626-appb-000143
Figure PCTCN2022075626-appb-000144
Figure PCTCN2022075626-appb-000145
注：表10中D 5为
Figure PCTCN2022075626-appb-000146
D 5A为
Figure PCTCN2022075626-appb-000147
表11.化合物231-246A
Figure PCTCN2022075626-appb-000148
Figure PCTCN2022075626-appb-000149
Figure PCTCN2022075626-appb-000150
Figure PCTCN2022075626-appb-000151
Figure PCTCN2022075626-appb-000152
注：表11中D 6为
Figure PCTCN2022075626-appb-000153
D 6A为
Figure PCTCN2022075626-appb-000154
实施例5 4-((3-((3-(((R)-1-(2-(((1R,9S)-9-乙基-5-氟-9-羟基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫代吡喃[4,3,2-de]喹啉-1-基)氨基)-2-氧代乙氧基)-1-氧代丙基-2-基)(甲基)氨基)-3-氧代丙基)硫代)-2,5-氧代吡咯-1-基)甲基)环己基-1-甲酸五氟苯酯的合成
Figure PCTCN2022075626-appb-000155
于25mL三口瓶中加入D1-SH(100mg，0.15mmol，1.0eq)，LC1(90.2mg，0.22mmol，1.5eq)和DMF(2mL)，体系溶清后加入TEA(22.6mg，0.22mmol，1.5eq)，室温氩气保护下搅拌，LCMS监测至Drug1-SH反应完毕，反应液反相柱层析(MeCN/water＝20～100％)，相应组分冻干，得黄色固体247(120mg,收率74.9％)。LC-MS:1074.2[M+H] +。
类似化合物247的合成，可以得到表12-15所列的化合物。
表12.化合物248-264A
Figure PCTCN2022075626-appb-000156
Figure PCTCN2022075626-appb-000157
Figure PCTCN2022075626-appb-000158
Figure PCTCN2022075626-appb-000159
Figure PCTCN2022075626-appb-000160
注：表12中D 1为
Figure PCTCN2022075626-appb-000161
D 1A为
Figure PCTCN2022075626-appb-000162
表13.化合物265-282A
Figure PCTCN2022075626-appb-000163
Figure PCTCN2022075626-appb-000164
Figure PCTCN2022075626-appb-000165
Figure PCTCN2022075626-appb-000166
Figure PCTCN2022075626-appb-000167
Figure PCTCN2022075626-appb-000168
注：表13中D 2为
Figure PCTCN2022075626-appb-000169
D 3为
Figure PCTCN2022075626-appb-000170
表14.化合物283-300A
Figure PCTCN2022075626-appb-000171
Figure PCTCN2022075626-appb-000172
Figure PCTCN2022075626-appb-000173
Figure PCTCN2022075626-appb-000174
Figure PCTCN2022075626-appb-000175
Figure PCTCN2022075626-appb-000176
注：表14中D 5为
Figure PCTCN2022075626-appb-000177
D 5A为
Figure PCTCN2022075626-appb-000178
表15.化合物301-318A
Figure PCTCN2022075626-appb-000179
Figure PCTCN2022075626-appb-000180
Figure PCTCN2022075626-appb-000181
Figure PCTCN2022075626-appb-000182
Figure PCTCN2022075626-appb-000183
Figure PCTCN2022075626-appb-000184
注：表15中D 6为
Figure PCTCN2022075626-appb-000185
D 6A为
Figure PCTCN2022075626-appb-000186
实施例6 4-((3-((3-(((R)-1-(2-(((1R,9S)-9-乙基-5-氟-9-羟基-10,13-二氧代-1,2,9,10,13,15-六氢-12H-吡喃[3',4':6,7]氮茚[1,2-b]硫代吡喃[4,3,2-de]喹啉-1-基)氨基)-2-氧代乙氧基)-1-氧代丙基-2-基)(甲基)氨基)-3-氧代丙基)硫代)-2,5-氧代吡咯-1-基)甲基)环己基-1-甲酸五氟苯酯的合成
Figure PCTCN2022075626-appb-000187
Figure PCTCN2022075626-appb-000188
于50mL单口瓶中加入LD1(50mg,0.13mmol,1.0eq)，D2(57mg,0.13mmol,1.0eq)，NMI(54.8mg,0.67mmol,5.0eq)和DMF(2mL)，搅拌均匀并冷却至0℃。向反应液中加入TCFH(45mg,0.16mmol,1.2eq)，搅拌30min。LC-MS检测，反应完毕。反应液经反相C18柱层析(MeCN/water＝0～60％)纯化，目标馏分经冻干得黄色固体77mg，收率73.2％。LC-MS：803.3，[M+H] +；801.2，[M-H] -。
1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),8.48(s,1H),8.11(s,1H),7.34-7.42(m,1H),7.106-7.14(m,3H),7.09(s,1H),7.05(s,1H),5.67(t,J＝14.8Hz,1H),5.41(s,1H),5.32(s,1H),5.08-5.13(m,2H),4.71-4.87(m,3H),3.77-4.12(m,3H),3.11-3.32(m,1H),2.52-2.81(m,1H),1.88-2.03(m,3H),1.71-1.92(m,1H),1.56-1.77(m,2H),1.32-1.46(m,3H),1.19-1.27(m,4H),0.79-1.01(m,9H).
类似化合物335的合成，可以得到表16-19所列的化合物。
表16.化合物319-334A
Figure PCTCN2022075626-appb-000189
Figure PCTCN2022075626-appb-000190
Figure PCTCN2022075626-appb-000191
Figure PCTCN2022075626-appb-000192
注：表16中D 1为
Figure PCTCN2022075626-appb-000193
D 1A为
Figure PCTCN2022075626-appb-000194
表17.化合物335-350A
Figure PCTCN2022075626-appb-000195
Figure PCTCN2022075626-appb-000196
Figure PCTCN2022075626-appb-000197
注：表17中D 2为
Figure PCTCN2022075626-appb-000198
D 3为
Figure PCTCN2022075626-appb-000199
表18.化合物351-366A
Figure PCTCN2022075626-appb-000200
Figure PCTCN2022075626-appb-000201
Figure PCTCN2022075626-appb-000202
Figure PCTCN2022075626-appb-000203
注：表18中D 5为
Figure PCTCN2022075626-appb-000204
D 5A为
Figure PCTCN2022075626-appb-000205
表19.化合物367-382A
Figure PCTCN2022075626-appb-000206
Figure PCTCN2022075626-appb-000207
Figure PCTCN2022075626-appb-000208
Figure PCTCN2022075626-appb-000209
注：表19中D 6为
Figure PCTCN2022075626-appb-000210
D 6A为
Figure PCTCN2022075626-appb-000211
实施例7 抗体-药物偶联物(ADC-1)的制备
Figure PCTCN2022075626-appb-000212
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，封闭反应管并置于水浴振荡器，于37℃振荡反应3小时，停止反应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物27(1.03mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用SephadexG25凝胶柱脱盐纯化(洗脱相：pH为6.0的0.05M的组氨酸缓冲盐溶液，含6％蔗糖)，得到的ADC(5.0mg/mL,1.1mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.2。
类似于化合物27的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例8 抗体-药物偶联物(ADC-2)的制备
Figure PCTCN2022075626-appb-000213
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，封闭反应管并置于水浴振荡器，于37℃振荡反应3小时，停止反应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物41(1.06mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.0的25mM的组氨酸缓冲盐溶液，含6％蔗糖)，得到的ADC(4.6mg/mL,1.2mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.2。
实施例9 抗体-药物偶联物(ADC-3)的制备
Figure PCTCN2022075626-appb-000214
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，封闭反应管并置于水浴振荡器，于37℃振荡反应3小时，停止反 应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物42(1.05mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.0的25mM的组氨酸缓冲盐溶液，含6％蔗糖)，得到的ADC(4.8mg/mL,1.2mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.2。
类似于化合物41、42的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例10 抗体-药物偶联物(ADC-4)的制备
Figure PCTCN2022075626-appb-000215
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，置于水浴振荡器，于37℃振荡反应3小时，停止反应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物53(1.03mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.0的25mM的组氨酸缓冲盐溶液，含6％蔗糖)，得到的ADC-4(5.0mg/mL,1.1mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.2。
类似于化合物53的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例11 抗体-药物偶联物(ADC-5)的制备
Figure PCTCN2022075626-appb-000216
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，置于水浴振荡器，于37℃振荡反应3小时，停止反应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物183(1.05mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.0的25mM的组氨酸缓冲盐溶液，含6％蔗糖)，得到的ADC-5(4.6mg/mL,1.2mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.3。
类似于化合物183的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例12 抗体-药物偶联物(ADC-6)的制备
Figure PCTCN2022075626-appb-000217
在37℃条件下，向含有抗体Trastuzumab的缓冲溶液(pH＝7.0的0.05M PBS缓冲水溶液，抗体浓度2-10mg/mL)加入适当比例的化合物247，于25℃振荡反应0.5-6小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.5的0.05M的PBS缓冲水溶液，含0.001M的EDTA)，得到的ADC-6(5.0mg/mL,1.1mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝3.2。
类似于化合物247的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例13 抗体-药物偶联物(ADC-7)的制备
Figure PCTCN2022075626-appb-000218
在37℃条件下，向含有抗体Trastuzumab的PBS缓冲盐溶液(pH＝7.0的0.05M PBS缓冲水溶液；2.5mL,9.96mg/mL,0.168μmol)加入配置好的三(2-羧乙基)膦的水溶液(10mM,0.082mL)，置于水浴振荡器，于37℃振荡反应3小时，停止反应；将反应液用水浴降温至25℃，稀释至5.0mg/mL。
将化合物335(0.83mg)溶解于DMSO(0.10mL)中，加入到上述2.0mL溶液中，置于水浴振荡器，于25℃振荡反应3小时，停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相：pH为6.5的0.05M的PBS缓冲水溶液，含0.001M的EDTA)，得到的ADC-7(4.4mg/mL,1.2mL)于4℃冷藏储存。UV-HPLC计算平均值：n＝7.3。
类似于化合物335的其它化合物可以用同样的方法和抗体Trastuzumab或其他类似的抗体来制备包含本申请中的喜树碱衍生物为小分子毒素的抗体-药物偶联物。
实施例14 本发明抗体-药物偶联物的体外抗肿瘤活性
选择高表达HER2的SK-BR-3及NCI-N87细胞作为本次实验体外活性检测用细胞株，用于评价本发明中的抗体-药物偶联物对细胞杀伤能力的量效情况。每种细胞的种板密度：1500-2000cells/孔，抗体-药物偶联物加样后终浓度设定25nM为起始浓度，设计系列浓度(3-10倍比稀释)，观察144小时后细胞的存活情况，通过CellTiter-Glo@ Luminescent Cell Viability Assay化学发光染色测定肿瘤细胞存活率，读取荧光数据后计算其IC 50。
表20.本发明中抗体-药物偶联物对SK-BR-3及NCI-N87细胞的增殖抑制活性
Figure PCTCN2022075626-appb-000219
从活性测试结果看，所有的ADC均表现出一定的抗肿瘤活性，部分ADC的活性与DS-8201a相当。
实施例15 本发明抗体-药物偶联物的体内抗肿瘤活性
6-8周大的雌性Balb/c nude小鼠颈背部右侧皮下注射溶于100μLPBS溶液的人源胃癌细胞(NCI-N87)。待肿瘤平均体积约150-200mm 3时，根据肿瘤大小随机分组，将所述裸鼠30只随机分成6组，每组5只动物，分组尾静脉注射给药：01为空白对照组,02为DS-8201a(3.0mg/kg),03为ADC-1(3.0mg/kg),04为ADC-2(3.0mg/kg)，05为ADC-3(3.0mg/kg)，06为ADC-4(3.0mg/kg)，每周两次测量实验动物体重和肿瘤体积并观察实验过程中动物生存状态，其中各组的肿瘤体积变化情况的具体结果见图1。
从图1可以看出，本发明中的数个ADC样品均表现出与DS-8201a相当，甚至优于DS8201a的体内抗肿瘤活性。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (14)

  1. 一种如通式(1)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022075626-appb-100001
    通式(1)中：
    L 1选自
    Figure PCTCN2022075626-appb-100002
    Figure PCTCN2022075626-appb-100003
    L 2选自
    Figure PCTCN2022075626-appb-100004
    Figure PCTCN2022075626-appb-100005
    其中m为0至5的整数，其中“a”表示和L 1相连；
    L 3为
    Figure PCTCN2022075626-appb-100006
    其中“b”表示和-C(O)-相连；
    L 4选自
    Figure PCTCN2022075626-appb-100007
    Figure PCTCN2022075626-appb-100008
    Figure PCTCN2022075626-appb-100009
    Figure PCTCN2022075626-appb-100010
    其中“c”表示和L 3相连；
    D选自
    Figure PCTCN2022075626-appb-100011
    其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2或NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
    Figure PCTCN2022075626-appb-100012
    R 3选自H、C 1-6烷基或C 3-6环烷基。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有以下结构之一：
    Figure PCTCN2022075626-appb-100013
    Figure PCTCN2022075626-appb-100014
    其中D选自
    Figure PCTCN2022075626-appb-100015
    Figure PCTCN2022075626-appb-100016
  3. 一种如通式(2)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022075626-appb-100017
    通式(2)中：
    L 5选自
    Figure PCTCN2022075626-appb-100018
    Figure PCTCN2022075626-appb-100019
    L 6选自
    Figure PCTCN2022075626-appb-100020
    Figure PCTCN2022075626-appb-100021
    其中m为0至5的整数，其中“d”表示和L 5相连；
    L 7为
    Figure PCTCN2022075626-appb-100022
    其中“e”表示和-C(O)-相连；
    L 8选自
    Figure PCTCN2022075626-appb-100023
    其中“f”表示和-NH-相连；
    D选自
    Figure PCTCN2022075626-appb-100024
    其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2或NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
    Figure PCTCN2022075626-appb-100025
    R 3选自H、C 1-6烷基或C 3-6环烷基。
  4. 如权利要求3所述的化合物或其药学上可接受的盐，其中所述化合物具有以下结构之一：
    Figure PCTCN2022075626-appb-100026
    Figure PCTCN2022075626-appb-100027
    其中D选自
    Figure PCTCN2022075626-appb-100028
    Figure PCTCN2022075626-appb-100029
  5. 一种如通式(3)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022075626-appb-100030
    通式(3)中：
    L 9选自
    Figure PCTCN2022075626-appb-100031
    L 10选自
    Figure PCTCN2022075626-appb-100032
    其中m为0至5的整数，其中“g”表示和S相连；
    L 11选自
    Figure PCTCN2022075626-appb-100033
    Figure PCTCN2022075626-appb-100034
    其中“h”表示和-C(O)-相连；
    L 12选自
    Figure PCTCN2022075626-appb-100035
    Figure PCTCN2022075626-appb-100036
    其中“i”表示和L 11相连；
    D选自
    Figure PCTCN2022075626-appb-100037
    其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2或NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
    Figure PCTCN2022075626-appb-100038
    R 3选自H、C 1-6烷基或C 3-6环烷基。
  6. 如权利要求5所述的化合物或其药学上可接受的盐，其中所述化合物具有以下结构之一：
    Figure PCTCN2022075626-appb-100039
    Figure PCTCN2022075626-appb-100040
    Figure PCTCN2022075626-appb-100041
    其中D选自
    Figure PCTCN2022075626-appb-100042
    Figure PCTCN2022075626-appb-100043
  7. 一种如通式(4)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022075626-appb-100044
    通式(4)中：
    L 13选自
    Figure PCTCN2022075626-appb-100045
    Figure PCTCN2022075626-appb-100046
    L 14选自
    Figure PCTCN2022075626-appb-100047
    Figure PCTCN2022075626-appb-100048
    其中m为0至5的整数，其中“j”表示和L 13相连；
    L 15为
    Figure PCTCN2022075626-appb-100049
    其中“k”表示和-C(O)-相连；
    D选自
    Figure PCTCN2022075626-appb-100050
    其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2或NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
    Figure PCTCN2022075626-appb-100051
    R 3选自H、C 1-6烷基或C 3-6环烷基。
  8. 如权利要求7所述的化合物或其药学上可接受的盐，其中所述化合物具有以下结构之一：
    Figure PCTCN2022075626-appb-100052
    Figure PCTCN2022075626-appb-100053
    其中D选自
    Figure PCTCN2022075626-appb-100054
    Figure PCTCN2022075626-appb-100055
    Figure PCTCN2022075626-appb-100056
  9. 一种如通式(4A)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2022075626-appb-100057
    通式(4A)中：
    L 13选自
    Figure PCTCN2022075626-appb-100058
    Figure PCTCN2022075626-appb-100059
    L 14选自
    Figure PCTCN2022075626-appb-100060
    Figure PCTCN2022075626-appb-100061
    其中m为0至5的整数，其中“j”表示和L 13相连；
    L 15为
    Figure PCTCN2022075626-appb-100062
    其中“k”表示和-C(O)-相连；
    L 16选自
    Figure PCTCN2022075626-appb-100063
    Figure PCTCN2022075626-appb-100064
    Figure PCTCN2022075626-appb-100065
    其中“l”表示和-NH-相连；
    D选自
    Figure PCTCN2022075626-appb-100066
    其中R 1和R 2独立地选自H、卤素、OH、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、NH 2、NO 2或CN，或R 1和R 2与所相连的苯环一起环合形成
    Figure PCTCN2022075626-appb-100067
    R 3选自H、C 1-6烷基或C 3-6环烷基。
  10. 如权利要求9所述的化合物或其药学上可接受的盐，其中所述化合物具有以下结构 之一：
    Figure PCTCN2022075626-appb-100068
    其中D选自
    Figure PCTCN2022075626-appb-100069
    Figure PCTCN2022075626-appb-100070
  11. 一种如权利要求1-10中任一项所述的化合物或其药学上可接受的盐用于抗体-药物偶 联物的制备中的应用。
  12. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-10中任一项所述的化合物或其药学上可接受的盐作为活性成分。
  13. 一种如权利要求1-10中任一项所述的化合物或其药学上可接受的盐或如权利要求12所述的药物组合物在制备治疗癌症药物中的应用。
  14. 一种抗体药物偶联物(ADC)，其特征在于，所述抗体药物偶联物包括抗体、小分子毒素(payload)和连接子(linker)；所述修饰上连接子的小分子毒素为如权利要求1-10中任一项所述的化合物；和抗体通过共价键连接。
PCT/CN2022/075626 2021-02-09 2022-02-09 用于adc制备的喜树碱衍生物 WO2022171115A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280012945.8A CN116888123A (zh) 2021-02-09 2022-02-09 用于adc制备的喜树碱衍生物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110182363 2021-02-09
CN202110182363.1 2021-02-09

Publications (1)

Publication Number Publication Date
WO2022171115A1 true WO2022171115A1 (zh) 2022-08-18

Family

ID=82838201

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/075626 WO2022171115A1 (zh) 2021-02-09 2022-02-09 用于adc制备的喜树碱衍生物

Country Status (2)

Country Link
CN (1) CN116888123A (zh)
WO (1) WO2022171115A1 (zh)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495432A1 (en) * 1991-01-16 1992-07-22 Daiichi Pharmaceutical Co., Ltd. Hexa-cyclic compound
JPH0687746A (ja) * 1992-07-16 1994-03-29 Dai Ichi Seiyaku Co Ltd 抗腫瘍剤
TW201620554A (zh) * 2014-04-10 2016-06-16 第一三共股份有限公司 抗ｈｅｒ２抗體－藥物結合物
CN105829346A (zh) * 2014-01-31 2016-08-03 第三共株式会社 抗her2抗体－药物偶联物
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
WO2020063673A1 (zh) * 2018-09-30 2020-04-02 江苏恒瑞医药股份有限公司 抗b7h3抗体-依喜替康类似物偶联物及其医药用途
CN111670053A (zh) * 2019-05-20 2020-09-15 烟台迈百瑞国际生物医药有限公司 一种抗体药物偶联物中间体的一锅法制备工艺
WO2020244657A1 (zh) * 2019-06-06 2020-12-10 上海翰森生物医药科技有限公司 抗b7-h4抗体-药物偶联物及其医药用途
CN112125915A (zh) * 2019-09-18 2020-12-25 四川百利药业有限责任公司 一种喜树碱衍生物及其偶联物
WO2020259258A1 (zh) * 2019-06-28 2020-12-30 上海复旦张江生物医药股份有限公司 一种抗体偶联药物、其中间体、制备方法及应用

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0495432A1 (en) * 1991-01-16 1992-07-22 Daiichi Pharmaceutical Co., Ltd. Hexa-cyclic compound
JPH0687746A (ja) * 1992-07-16 1994-03-29 Dai Ichi Seiyaku Co Ltd 抗腫瘍剤
CN105829346A (zh) * 2014-01-31 2016-08-03 第三共株式会社 抗her2抗体－药物偶联物
TW201620554A (zh) * 2014-04-10 2016-06-16 第一三共股份有限公司 抗ｈｅｒ２抗體－藥物結合物
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
WO2020063673A1 (zh) * 2018-09-30 2020-04-02 江苏恒瑞医药股份有限公司 抗b7h3抗体-依喜替康类似物偶联物及其医药用途
CN111670053A (zh) * 2019-05-20 2020-09-15 烟台迈百瑞国际生物医药有限公司 一种抗体药物偶联物中间体的一锅法制备工艺
WO2020244657A1 (zh) * 2019-06-06 2020-12-10 上海翰森生物医药科技有限公司 抗b7-h4抗体-药物偶联物及其医药用途
WO2020259258A1 (zh) * 2019-06-28 2020-12-30 上海复旦张江生物医药股份有限公司 一种抗体偶联药物、其中间体、制备方法及应用
CN112125915A (zh) * 2019-09-18 2020-12-25 四川百利药业有限责任公司 一种喜树碱衍生物及其偶联物

Also Published As

Publication number Publication date
CN116888123A (zh) 2023-10-13

Similar Documents

Publication Publication Date Title
TWI820077B (zh) 治療涉及酸性或缺氧性患病組織之疾病之化合物、組合物及方法
ES2426482T3 (es) Inhibidor de IGF-1R
WO2021203768A1 (zh) 嘧啶并二环类衍生物、其制备方法及其在医药上的应用
WO2020156285A1 (zh) 一种苯并吡啶酮杂环化合物及其用途
WO2020259679A1 (zh) 嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用
KR101627382B1 (ko) 항암 경구 제제
TW202116778A (zh) 作為治療劑之細胞毒素之肽結合物
JP2010523566A (ja) ワートマニン−ラパマイシンコンジュゲートおよびその使用
WO2022121981A1 (zh) 新型喜树碱衍生物、含其的组合物和其用途
WO2021121210A1 (zh) 并环类衍生物、其制备方法及其在医药上的应用
WO2023138541A1 (zh) 吡啶酰胺类parp抑制剂、及其制备方法和医药用途
EP2836493B1 (en) Functionalized thieno-indole derivatives for the treatment of cancer
WO2023061406A1 (zh) 含三并环结构的parp抑制剂、及其制备方法和医药用途
KR20220107018A (ko) Jak 억제제로서의 트리헤테로사이클릭 화합물 및 이의 용도
WO2022063297A1 (zh) 喹唑啉衍生物及其制备方法和用途
TW202116356A (zh) 作為治療劑之微管靶向藥劑之肽結合物
WO2022171115A1 (zh) 用于adc制备的喜树碱衍生物
WO2023125928A1 (zh) Menin抑制剂及其用途
WO2022174765A1 (zh) 作为Wee-1抑制剂的稠环化合物
WO2021104413A1 (zh) 稠合吡啶环衍生物、其制备方法及其在医药上的应用
WO2022171088A1 (zh) 吡唑并[3,4-d]嘧啶-3-酮衍生物
JP2010523565A (ja) ワートマニン−ラパログコンジュゲートおよびその使用
JP2024520283A (ja) 化学的カップリングリンカー及びその使用
WO2024041589A1 (zh) 含氮杂环化合物、其制备方法、其中间体及其应用
WO2024109840A1 (zh) 稠环类化合物及其偶联物和用途

Legal Events

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

Ref document number: 22752275

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280012945.8

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22752275

Country of ref document: EP

Kind code of ref document: A1