WO2024032600A1 - Dérivé hétérocyclique, et composition à base de celui-ci et utilisation pharmaceutique associée - Google Patents

Dérivé hétérocyclique, et composition à base de celui-ci et utilisation pharmaceutique associée Download PDF

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WO2024032600A1
WO2024032600A1 PCT/CN2023/111710 CN2023111710W WO2024032600A1 WO 2024032600 A1 WO2024032600 A1 WO 2024032600A1 CN 2023111710 W CN2023111710 W CN 2023111710W WO 2024032600 A1 WO2024032600 A1 WO 2024032600A1
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alkyl
alkoxy
substituted
halogen
methyl
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PCT/CN2023/111710
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English (en)
Chinese (zh)
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张晨
王健民
黄正刚
唐平明
黄安邦
余彦
李瑶
严庞科
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西藏海思科制药有限公司
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Publication of WO2024032600A1 publication Critical patent/WO2024032600A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in EGFR related diseases such as cancer diseases.
  • Epidermal growth factor receptor is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis, and angiogenesis.
  • EGFR gene Overexpression, mutation or amplification of the EGFR gene in the human body leads to an abnormal increase in EGFR activity, which can lead to many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer.
  • malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer.
  • NSCLC Cells, 2019, 8, 350-361.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • Such compounds can be recognized by the proteasome of cells, causing the degradation of targeted proteins, and can effectively reduce the target protein. The protein content in cells.
  • the purpose of the present invention is to provide a compound with a novel structure, good efficacy, high bioavailability, safety, and the ability to inhibit and degrade EGFR for the treatment of EGFR-related diseases such as cancer.
  • the present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I),
  • R b1 is each independently selected from halogen, OH, CN, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3
  • R b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl Or cyclohexyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally selected from 1 to 4 F, Cl, Br, Substituted by I, OH, CN, methyl, and ethyl substituents;
  • each R b1 is independently selected from F, Cl, Br, I, CF 3 , cyclopropyl, cyclobutyl,
  • R b2 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy is optionally substituted by 1 to 4 selected from halogen, CN, OH , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
  • R b2 is selected from H, F, Cl, Br, I, methyl, ethyl, and the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C Substituted with substituents of 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
  • R b2 is selected from H, F, Cl, Br, I, methyl, and ethyl, and the methyl or ethyl group is optionally replaced by 1 to 4 selected from F, Cl, Br, I , CN, OH, methyl or ethyl substituent;
  • R b2 is selected from F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, ethyl;
  • R b3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy is optionally replaced by 1 to 4 selected from halogen, CN , OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
  • R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy Optionally substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, said methyl, ethyl, methoxy or ethoxy Optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl or ethyl;
  • R b3 is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;
  • R b4 is selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, or 5- to 6-membered heteroaryl
  • the alkyl group, alkoxy group or heteroaryl group is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, CN, OH, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkyl Substituted with oxygen group and C 3-6 cycloalkyl substituent, the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, and N;
  • R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally selected from 1 to 4 Substituted from halogen, CN, OH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
  • R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally selected from 1 to 4 Substituted from substituents of F, Cl, Br, I, CN, OH, CH 2 F, CHF 2 , CF 3 , methyl, and ethyl;
  • R b4 is selected from
  • R b5 is each independently selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally replaced by 1 to Substituted by 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy
  • the base or ethoxy group is optionally substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy
  • the base or ethoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl, and ethyl;
  • R a and R b are each independently selected from H, halogen, and C 1-4 alkyl;
  • R a and R b are each independently selected from H or F;
  • Ra , Rb are selected from H
  • Cy1 and Cy2 are each independently selected from
  • R k1 is each independently selected from H, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, Alkyl, alkoxy, and cycloalkyl are optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl. replaced;
  • each R k1 is independently selected from H, F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, ethyl;
  • R k1 is selected from F, Cl, Br;
  • Rk2 is each independently selected from H, halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, Alkoxy and cycloalkyl are optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • b1 and b5 are each independently selected from 0, 1, 2 or 3;
  • b1 is selected from 0, 1 or 2;
  • b5 is selected from 0, 1;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • p2 is 0;
  • p1 is selected from 0 or 1;
  • the compound represented by general formula (I) contains more than 1 F;
  • the compound represented by general formula (I) contains more than 2 F;
  • At least one of R b2 , R b3 , R b4 , Cy1 and Cy2 contains F means that at least one of R b2 , R b3 , R b4 , Cy1 and Cy2 is selected from F, substituted by F or substituted by F Substituted by substituents (such as CF 3 );
  • R b1 is each independently selected from halogen, OH, CN, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl
  • R b2 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C 1-4 alkyl Substituted with substituents of base, C 1-4 alkoxy group, and C 3-6 cycloalkyl group;
  • R b3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl or alkoxy group optionally has 1 to 4 selected from halogen, CN, OH, C 1- Substituted with substituents of 4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
  • R b4 is selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy or 5 to 6-membered heteroaryl, and the alkyl, alkoxy or heteroaryl is optional Substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl , the heteroaryl group contains 1 to 3 heteroatoms selected from O, S, and N;
  • R b5 is each independently selected from H, halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy groups are optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R a and R b are each independently selected from H, halogen, and C 1-4 alkyl;
  • Cy1 and Cy2 are each independently selected from the group consisting of 4-7 membered nitrogen-containing heteromonocyclic rings, 4-10-membered nitrogen-containing heterocyclic rings, and 5-12-membered nitrogen-containing heterospirocyclic rings.
  • the heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heterocyclic groups selected from O, S, N atom;
  • R k1 is each independently selected from H, halogen, OH, NH 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy , cycloalkyl is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • Rk2 is each independently selected from H, halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy, cycloalkyl
  • the base is optionally substituted by 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • b1 and b5 are each independently selected from 0, 1, 2 or 3;
  • p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • the condition is when Selected from When, R b2 , R b3 , R b4 , At least one of Cy1 and Cy2 contains F;
  • R b2 is selected from H, F, Cl, Br, I, methyl, and ethyl, and the methyl or ethyl group is optionally substituted by 1 to 4 selected from halogen, CN, OH, C 1-4 alkyl, Substituted with substituents of C 1-4 alkoxy and C 3-6 cycloalkyl;
  • R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from halogen, CN, OH , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
  • R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Substituted by 1 to 4 substituents selected from halogen, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
  • R a and R b are each independently selected from H or F;
  • R k1 is each independently selected from H, F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, and ethyl;
  • p2 is 0
  • R b1 is each independently selected from F, Cl, Br, I, OH, CN, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl or cyclohexyl, the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally selected from 1 to 4 Substituted by F, Cl, Br, I, OH, CN, methyl, and ethyl substituents;
  • R b2 is selected from H, F, Cl, Br, I, methyl, and ethyl.
  • the methyl or ethyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, CN, OH, methane, etc. Substituted with ethyl or ethyl substituents;
  • R b3 is selected from H, F, Cl, Br, I, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is optionally replaced by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, CN, OH, methyl or ethyl;
  • R b4 is selected from pyrazolyl, imidazolyl, pyrrolyl, and triazolyl, and the pyrazolyl, imidazolyl, pyrrolyl, and triazolyl are optionally substituted by 1 to 4 selected from F, Cl, Br , I, CN, OH, CH 2 F, CHF 2 , CF 3 , methyl, ethyl substituents;
  • R b5 is each independently selected from H, F, Cl, Br, I, OH, methyl, ethyl, methoxy or ethoxy, and the methyl, ethyl, methoxy or ethoxy is any Replaced by 1 to 4 substituents selected from F, Cl, Br, I, CN, OH, methyl, and ethyl;
  • R b1 is each independently selected from F, Cl, Br, I, CF 3 , cyclopropyl, cyclobutyl,
  • R b2 is selected from F, Cl, Br, I, CF 3 , CHF 2 , CH 2 F, methyl, and ethyl;
  • R b3 is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;
  • R b4 is selected from
  • Cy1 and Cy2 are each independently selected from
  • R a and R b are selected from H;
  • R k1 is selected from F, Cl, Br;
  • b1 is selected from 0, 1 or 2;
  • b5 is selected from 0 and 1;
  • p1 is chosen from 0 or 1.
  • the present invention relates to a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.
  • the present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and pharmaceutical acceptable carrier.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (e.g., inhibit or degrade EGFR-related diseases such as One or more symptoms of cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-
  • the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 320mg, 400mg, 480mg, 500mg, 600mg, 800mg, 1000mg of the compound of the invention or Its stereoisomers, deuterated products, solvates, pro
  • a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable
  • the salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably renal disease.
  • a method for treating diseases in mammals includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1500 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose.
  • the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1200 mg/day, 10 -1000mg/day, 10-800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 100-1000mg/day, 200-1000mg/day, 200-800mg/day, 25-400mg /day, 50-400mg/day, 100-400mg/day, 200-400mg/day, in some embodiments, the daily dosage includes but is not limited to 10mg/day, 20mg/day, 25mg/day, 50mg/day, 100mg /day, 125mg/day, 150mg/day, 200mg/day, 400mg/day, 600mg/day, 800mg/day, 1000mg/day, 1200mg/day, 1400mg/day.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Application in drugs for diseases related to EGFR activity or expression.
  • the present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatments and Applications in drugs that inhibit or degrade EGFR-related diseases.
  • the present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions. Selected from cancer.
  • the present invention relates to a kit, which may include a composition in a single dose or multiple dose form.
  • the kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical
  • the amount of the compound of the present invention or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as that in the above pharmaceutical composition. The amount is the same.
  • the present invention relates to a preparation method of compound MH, which is prepared through the following reaction:
  • Compound M-G reacts in the presence of a reducing agent to obtain compound M-H.
  • the reducing agent is preferably ammonium chloride/zinc or ammonium chloride/iron.
  • the present invention relates to a preparation method of compound MG, which is prepared through the following reaction:
  • Compound M-F and compound M-F-1 react in the presence of an alkaline reagent to obtain compound M-G.
  • the alkaline reagent is preferably N,N-diisopropylethylamine.
  • the present invention relates to a preparation method of compound MF, which is prepared through the following reaction:
  • Compound M-E is reacted in the presence of a deamination protecting reagent to obtain compound M-F.
  • the deamination protecting reagent is preferably hydrogen chloride.
  • the present invention relates to a preparation method of compound ME, which is prepared through the following reaction:
  • Compound M-C and compound M-D react in the presence of a palladium-containing metal catalyst to obtain compound M-E.
  • the palladium-containing metal catalyst is preferably [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride. Methyl chloride complex.
  • the present invention relates to a preparation method of compound 1E, which is prepared through the following reaction:
  • Compound M-A and compound M-B react in the presence of an alkaline reagent to obtain compound M-C.
  • the alkaline reagent is preferably potassium carbonate.
  • the present invention relates to a compound shown below,
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • Halogen refers to F, Cl, Br or I.
  • Halo-substituted means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted” is simply referred to as "halogenated.”
  • Alkyl refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition.
  • Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Hydrocarbyl refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms.
  • the hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10). Examples of alkylene include but are not Limited to methylene, ethylene, propylene, butylene, etc.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or
  • the heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms
  • alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 -Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl
  • alkynyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • Carbocyclyl or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Bicyclic or 10 to 15-membered tricyclic system the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Sexually substituted N and S can be oxidized into various oxidation states.
  • the heterocyclyl group can be connected to a heteroatom or a carbon atom.
  • the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl
  • Spirocyclic or “spirocyclyl” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Spiro or “spiryl” may be monovalent, divalent, trivalent or tetravalent.
  • Ring ring group refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or un
  • the number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include: "And ring" or "and ring group” can be monovalent, divalent, trivalent or tetravalent.
  • the "bridging ring” or “bridging ring base” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
  • Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • Heteromonocycle refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system
  • Heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
  • Heterospirocycle refers to a “spirocycle” containing heteroatoms.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • Aryl or "aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring.
  • the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms.
  • the aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include benzene ring, naphthalene ring, "Aryl” or “aryl ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzene Pyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Non-limiting examples include Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
  • Consing 1 to X heteroatoms selected from O, S, and N means containing 1, 2, 3...X heteroatoms selected from O, S, and N.
  • Substituted by 0 to X substituents selected from means substituted by 0, 1, 2, 3...
  • substituted with 0 to 4 substituents selected from means substituted with 0, 1, 2, 3 or 4 substituents selected from...
  • substituted with 0 to 5 substituents selected from means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from...
  • the hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from H or F means that the hetero-bridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.
  • Rings of ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
  • “497-membered heteromonocyclic ring” refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring
  • "5910-membered heterocyclic ring” refers to a 5-, 6-, 7-, 8-, or 9-membered heterocyclic ring. 10-membered heterocyclic ring.
  • Alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
  • the prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as ketone- Enol isomerism and amide-iminoalcohol isomerism, etc.
  • IC 50 is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).
  • the compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXIA (Shanghai) ) Chemical Industrial Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Commercially available chemicals” are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, etc. company.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
  • THP Boc: tert-butoxycarbonyl
  • Ms TBS: MTBE: methyl tert-butyl ether
  • Bn DIPEA: N,N-diisopropylethylamine
  • DMAc N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • Cbz NMP: N-methylpyrrolidone
  • PE petroleum ether.
  • Test Example 1 Proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells
  • NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC.
  • the culture media were RPMI1640+10%FBS and DMEM+10%FBS respectively, in a 37°C, 5% CO 2 incubator. nourish.
  • NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase were collected, and viable cells were counted using an automatic cell analyzer (countstar).
  • V sample is the reading of the drug treatment group
  • V vehicle control is the average value of the solvent control group.
  • origin9.2 software a nonlinear regression model was used to draw a S-type dose-survival rate curve and calculate the IC 50 value.
  • the compounds of the present invention have good proliferation inhibitory activity on NCI-H1975 (EGFR-L858R-T790M) cells; they have poor inhibitory activity on A431 (EGFR-WT) cells and have good selectivity.
  • test substance was administered intravenously and intragastrically to ICR mice in a single dose, to measure the concentration of the test substance in the plasma of the mice, and to evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the mice.
  • mice male ICR mice, 20 to 25 g. Purchased from Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008; or Chengdu Dashuo Experimental Animal Co., Ltd. (SCXK (Sichuan) 2020-030); or Hunan Slack King Da Experimental Animal Co., Ltd. (SCXK (Hunan) 2019-0004).
  • Test method On the day of the test, ICR mice were randomly divided into groups according to body weight. The patient was fasted for 12 to 14 hours on the day before administration and resumed food 4 hours after administration.
  • the dosage is based on free base, and the dosage for intravenous administration is either 2.5 mg/kg or 1 mg/kg;
  • Time points for collecting plasma in G1&G2 group 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;
  • Time points for plasma collection in group G3 0, 5min, 15min, 30min, 1, 2, 4, 7, 24h;
  • Test animals male SD rats, about 220g, 6 to 8 weeks old. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline;
  • Intragastric administration vehicle 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD)
  • Test Example 4 hERG potassium ion channel function test
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology.
  • the glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument.
  • the tip resistance after infusion of the electrode liquid is about 2-5M ⁇ .
  • the glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier.
  • Clamp voltage and data recording were controlled and recorded via computer using pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz.
  • the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV.
  • This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ⁇ 2).
  • Inhibition% represents the inhibition percentage of the hERG potassium current by the compound
  • I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
  • X is the Log value of the detection concentration of the test product
  • Y is the inhibition percentage at the corresponding concentration
  • the compounds of the present invention have poor inhibitory activity on hERG potassium ion channels.
  • the experiment used five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substances.
  • LC-MS/ The MS method detects the concentration of the test substance in the sample, and calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and the liver intrinsic clearance rate CL int(Liver) .
  • the compounds of the present invention such as the example compounds, have good liver microsome stability.
  • the purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
  • CYP human liver microsomal cytochrome P450
  • the specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the compounds of the present invention such as the example compounds, have weak CYP inhibitory activity.
  • Test Example 7 EGFR protein degradation activity in cells H1975-EGFR-T790M-L858R-C797S
  • Protein sample preparation Cells NCI-H1975EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO 2 incubator, and the culture medium was RPMI1640+10% FBS+100 ⁇ g/mL hygromycin. Collect cells in the exponential growth phase, adjust the cell suspension to an appropriate concentration with hygromycin-free culture medium, and then plate it into a 6-well plate with a plating density of 200,000 cells/well and a plating volume of 2 mL. Cultivate overnight at 37°C and 5 % CO2 incubator. The next day, add different concentrations of compounds and set up DMSO control wells to ensure that the DMSO concentration in all wells is 0.1%.
  • Western detection Add 20 ⁇ g protein sample to each well, perform polyacrylamide gel electrophoresis and transfer to membrane. After transfer, add diluted anti-EGFR (CST, Cat. 4267S) and NADPH (Kangchen, Cat. KC-5G4) antibodies and incubate at 4°C overnight. After washing the membrane, add diluted goat anti-rabbit (Licor, Cat. 926-32211) and goat anti-mouse (Licor, Cat. 926-68070) antibodies and incubate in the dark for 45 minutes. A far-infrared imaging system (Odyssey) was used to scan and detect at wavelengths of 700 nm and 800 nm.
  • EGFR compound is the fluorescence value of EGFR protein after incubation with the compound
  • EGFR vehicle is the fluorescence value of EGFR protein in the DMSO control group.
  • EGFR% EGFR compound /EGFR vehicle ⁇ 100% Formula (7-1)
  • Protein sample preparation Cells NCI-H1975EGFR-L858R-T790M-C797S were cultured in a 37°C, 5% CO 2 incubator, and the culture medium was RPMI1640+10% FBS+100 ⁇ g/mL hygromycin. Collect cells in the exponential growth phase, adjust the cell suspension to an appropriate concentration with hygromycin-free culture medium, and then plate it into a 6-well plate with a plating density of 350,000 cells/well and a plating volume of 2 mL. Cultivate overnight at 37°C and 5 % CO2 incubator. The next day, add different concentrations of compounds and set up DMSO control wells to ensure that the DMSO concentration in all wells is 0.1%.
  • Western detection Add 20 ⁇ g protein sample to each well, perform polyacrylamide gel electrophoresis and transfer to membrane. After transfer, add diluted anti-EGFR (CST, Cat. 4267S) and NADPH (Kangchen, Cat. KC-5G4) antibodies and incubate at 4°C overnight. After washing the membrane, add diluted goat anti-rabbit (Licor, Cat. 926-32211) and goat anti-mouse (Licor, Cat. 926-68070) antibodies and incubate in the dark for 45 minutes. A far-infrared imaging system (Odyssey) was used to scan and detect at wavelengths of 700 nm and 800 nm.
  • EGFR compound is the fluorescence value of EGFR protein after incubation with the compound
  • EGFR vehicle is the fluorescence value of EGFR protein in the DMSO control group.
  • the compounds of the present invention such as the example compounds, have good EGFR degradation activity.

Abstract

L'invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un composé deutéré, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci, un intermédiaire correspondant, et une utilisation associée dans des maladies liées à l'EGFR, telles que le cancer.
PCT/CN2023/111710 2022-08-08 2023-08-08 Dérivé hétérocyclique, et composition à base de celui-ci et utilisation pharmaceutique associée WO2024032600A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109912655A (zh) * 2017-12-13 2019-06-21 上海科技大学 Alk蛋白降解剂及其抗肿瘤应用
WO2022055181A1 (fr) * 2020-09-11 2022-03-17 제이투에이치바이오텍 주식회사 Composés destinés à éliminer le cancer mutant de l'egfr et leur utilisation pharmaceutique
CN114286678A (zh) * 2019-08-23 2022-04-05 北京泰德制药股份有限公司 抑制并诱导降解egfr和alk的化合物
WO2022194269A1 (fr) * 2021-03-19 2022-09-22 上海齐鲁制药研究中心有限公司 Nouvel agent de dégradation de l'egfr
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
WO2023278325A1 (fr) * 2021-06-28 2023-01-05 Dana-Farber Cancer Institute, Inc. Composés bifonctionnels dégradant alk et leurs utilisations
WO2023066350A1 (fr) * 2021-10-22 2023-04-27 标新生物医药科技(上海)有限公司 Composé ligand de ligase e3 crbn, agent de dégradation de protéine développé sur la base d'un composé de ligand, et leurs utilisations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109912655A (zh) * 2017-12-13 2019-06-21 上海科技大学 Alk蛋白降解剂及其抗肿瘤应用
CN114286678A (zh) * 2019-08-23 2022-04-05 北京泰德制药股份有限公司 抑制并诱导降解egfr和alk的化合物
WO2022055181A1 (fr) * 2020-09-11 2022-03-17 제이투에이치바이오텍 주식회사 Composés destinés à éliminer le cancer mutant de l'egfr et leur utilisation pharmaceutique
WO2022194269A1 (fr) * 2021-03-19 2022-09-22 上海齐鲁制药研究中心有限公司 Nouvel agent de dégradation de l'egfr
WO2022228547A1 (fr) * 2021-04-30 2022-11-03 四川海思科制药有限公司 Dérivé de phosphonyle, et composition et application pharmaceutique de celui-ci
WO2023278325A1 (fr) * 2021-06-28 2023-01-05 Dana-Farber Cancer Institute, Inc. Composés bifonctionnels dégradant alk et leurs utilisations
WO2023066350A1 (fr) * 2021-10-22 2023-04-27 标新生物医药科技(上海)有限公司 Composé ligand de ligase e3 crbn, agent de dégradation de protéine développé sur la base d'un composé de ligand, et leurs utilisations

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