WO2024017258A1 - Inhibiteur à petites molécules egfr, composition pharmaceutique le contenant et son utilisation - Google Patents

Inhibiteur à petites molécules egfr, composition pharmaceutique le contenant et son utilisation Download PDF

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Publication number
WO2024017258A1
WO2024017258A1 PCT/CN2023/107949 CN2023107949W WO2024017258A1 WO 2024017258 A1 WO2024017258 A1 WO 2024017258A1 CN 2023107949 W CN2023107949 W CN 2023107949W WO 2024017258 A1 WO2024017258 A1 WO 2024017258A1
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alkyl
halogenated
cycloalkyl
alkoxy
alkylene
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PCT/CN2023/107949
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English (en)
Chinese (zh)
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白海云
苏明波
楼洋
高安慧
钟利
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百极弘烨(南通)医药科技有限公司
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Publication of WO2024017258A1 publication Critical patent/WO2024017258A1/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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and specifically to an EGFR small molecule inhibitor, pharmaceutical compositions containing the same and uses thereof.
  • Epidermal growth factor receptor (EGFR, also known as HER-1 or c-erbB-1) is a transmembrane glycoprotein composed of 1186 amino acids and 170kDa.
  • EGFR is a member of the c-erbB family of receptor tyrosine kinases, which regulates cell proliferation, survival, adhesion, migration and differentiation.
  • EGFR consists of three parts: extracellular receptor region; transmembrane region; intracellular tyrosine kinase region.
  • Ligands that have been confirmed to bind to EGFR include: epidermal growth factor (EGF), transforming growth factor ⁇ (TGF ⁇ ), bidirectional regulatory factor, heparin-binding EGF, cytoregulin, etc.
  • EGFR is overactivated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer, etc.
  • the EGFR-TKI small molecule inhibitors that have been marketed include the first-generation Iressa, Tarceva, and Kemena, the second-generation afatinib and dacomitinib, and the third-generation osimertinib.
  • the EGFR-TKI small molecule inhibitors that have been marketed include the first-generation Iressa, Tarceva, and Kemena, the second-generation afatinib and dacomitinib, and the third-generation osimertinib.
  • patients with non-small cell lung cancer benefit from EGFR-TKI treatment.
  • drug-resistant mutations in tumors and the development of resistance are inevitable problems.
  • approximately 60% of patients will develop T790M resistance mutation, causing the first- and second-generation drugs to lose their therapeutic effect.
  • osimertinib As a third-generation EGFR-TKI, osimertinib has very good inhibitory activity against T790M, thus bringing better therapeutic effects and survival benefits to patients.
  • the EGFR C797S or C796S triple mutation has emerged, resulting in the inability of the third-generation inhibitors to covalently bind to protein kinases, thereby rendering these inhibitors ineffective.
  • the latest research shows that HER-2 amplification and c-MET amplification are also highly related to third-generation EGFR-TKI resistance.
  • HER-2 Human epidermal growth factor receptor 2
  • ERBB2 Human epidermal growth factor receptor 2
  • HER-2 consists of an extracellular ligand-binding region, a single-chain transmembrane region, and an intracellular protein tyrosine kinase region.
  • HER-2 proteins bind to their respective ligands primarily by forming heterodimers with other members of the family, including HER-1 (EGFR), HER-3, and HER-4.
  • HER-2 protein is often the preferred partner of heterodimers and is often more active than other heterodimers.
  • HER-2 When HER-2 binds to its ligand, it activates tyrosine kinase activity mainly by causing receptor dimerization and autophosphorylation of the tyrosine kinase region in the cytoplasm.
  • Mutated forms of HER-2 include overexpression, mutation, and amplification. The incidence rate of HER-2 overexpression is highest in breast cancer, and the positive rate decreases in order in gastric cancer and colon cancer.
  • standard EGFR-TKIs such as osimertinib
  • studies have shown that combined use of HER-2 inhibitors can inhibit tumor growth in osimertinib-resistant patients.
  • Mesenchymal epithelial transition factor (cellular-mesenchymal epithelial transition factor, c-MET) encodes a synthetic protein c-MET, which is a receptor tyrosine kinase that can bind to hepatocyte growth factor (HGF).
  • HGF hepatocyte growth factor
  • the c-MET pathway When the c-MET pathway is expressed normally, it can promote tissue differentiation and repair. When it is abnormally expressed or exon 14 skipping mutations occur, it can promote the proliferation and metastasis of tumor cells.
  • Abnormal activation of the c-MET pathway exists in many solid tumors, including brain tumors, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, lung cancer, liver cancer, skin cancer, prostate cancer and soft tissue sarcoma.
  • Abnormal activation of the c-MET pathway can occur through HGF-independent mechanisms, mainly including c-MET exon 14 skipping mutations, c-MET amplification, rearrangement, and c-MET protein overexpression.
  • c-MET mutations were detected in 7.8% of non-small cell lung cancer patients who relapsed after treatment with standard EGFR-TKIs such as osimertinib. Therefore, inhibiting c-MET can not only be used to treat a variety of primary tumors. cancer, and can also be used to treat EGFR-TKI-resistant non-small cell lung cancer.
  • a new generation of multi-target inhibitors is developed to simultaneously target EGFR C797S mutation, HER-2 amplification and c-MET.
  • Amplification and other drug-resistant mutations can be used to treat diseases caused by EGFR mutations, HER-2 amplification, c-MET amplification, etc., and can also be used to treat EGFR-TKI-resistant non-small cell lung cancer caused by the above mutations. , is a matter of great significance.
  • the first aspect of the present invention provides a compound represented by formula I, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate,
  • X is selected from: NR 5 , CR 5 Ra or O;
  • Y is selected from: absent, NRa, CRaRb or O;
  • R 1 , R 2 and the atoms connected to them together form a C5-C6 cycloalkyl group, a 5-6 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group; wherein, H in each of the above groups optionally substituted by 1, 2 or 3 Ra;
  • R, R' and R" are each independently selected from the following group: H, D, halogen, cyano, nitro, hydroxyl, amino, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2.
  • substitution means being selected from the following Substitution of 1, 2 or 3 groups of the group: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1 -C6 alkoxy, C3-C12 cycloalkyl, 3-12 membere
  • n is independently selected from: 1 or 2;
  • R 3 , R 4 and the atoms connected to them together form a 5-6 membered heterocyclic group; wherein H in the above group is optionally substituted by 1, 2 or 3 Ra;
  • ring A2 is C5-C6 cycloalkyl or 5-6 membered heterocyclyl, and H in ring A2 is optionally replaced by 1 , 2 or 3 Ra substitutions; R 5 , R 6 and the atoms connected to them together form ring A3, ring A3 is C5-C6 cycloalkyl or 5-6 membered heterocyclyl, H in ring A3 is optional Substituted by 1, 2 or 3 Ra; and among ring A1, ring A2 and ring A3, 1 ring, 2 rings or 3 rings are present.
  • the compound is represented by formula II,
  • X, Y, L, R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 and R 11 are as defined above.
  • R 1 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H or halogen, more preferably H, F, Cl or Br, further H is more preferred.
  • R 1 is selected from: methyl.
  • R 2 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, -C(O)OH, -C(O)OC1-C3 alkyl, C1-C6 alkyl group (such as methyl or ethyl), halogenated C1-C6 alkyl group (such as CF 3 ), C1-C6 alkoxy group (such as methoxy group), halogenated C1-C6 alkoxy group (such as OCF 3 ), C2-C6 alkenyl (such as vinyl, allyl or propenyl), C2-C6 alkynyl (such as ethynyl or propynyl), C3-C6 cycloalkyl (such as cyclopropyl), 3-6 yuan Heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably halogen, more F, Cl or Br is preferred, and Cl or Br is more preferred.
  • R 11 is selected from: H, D, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkoxy.
  • Selected from: H in this group is optionally substituted by 1, 2 or 3 Ra, as defined above.
  • X is O, for H in this group is optionally substituted by 1, 2 or 3 R, wherein R 6 , R 7 , R 12 and R are as defined above.
  • X is NR 5 , for H in this group is optionally substituted by 1, 2 or 3 R, wherein R 3 , R 6 , R 7 , R 12 and R are as defined above.
  • X is CR 5 Ra, for H in this group is optionally substituted by 1, 2 or 3 R, wherein R3 , R4 , R6 , R7 , R12 and R are as defined above.
  • X is O, for H in this group is optionally substituted by 1, 2 or 3 R, wherein R 6 and R are as defined above.
  • X is NR 5 , for Should H in the group is optionally substituted by 1, 2 or 3 R, wherein R3 , R6 and R are as defined above.
  • X is CR 5 Ra, for H in this group is optionally substituted by 1, 2 or 3 R, wherein R 3 , R 4 , R 6 and R are as defined above.
  • X is selected from: NR 5 , CR 5 Ra or O, wherein R 5 and Ra are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1- C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered Heteroaryl, preferably, X is selected from: O, CH2 or NH.
  • R 2 is selected from: bromine, chlorine, cyano, hydrogen, isoallyl, isopropyl, carboxyl, trifluoromethyl, cyclopropyl, ethyl, methoxycarbonyl, ethylene base, isopropoxycarbonyl or methyl.
  • Y is selected from: CH 2 or oxygen.
  • R 9 is selected from: or H.
  • R 10 is selected from: H, F,
  • R 11 is selected from: methoxy, hydrogen, chlorine or methyl.
  • L is selected from:
  • the compound has the structure shown in formula III
  • Z 1 and Z 2 are each independently selected from: CH or N;
  • Y, L, R 1 , R 2 , R 10 and R 11 are defined as above;
  • Y is selected from: CH 2 or O;
  • L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,
  • Z 2 is N, and Z 1 is CH;
  • Y is selected from: CH2 or O; and L is selected from: -( CH2 ) 3- .
  • Y is selected from: CRaRb, wherein Ra and Rb are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably, Y Selected from: CH 2 .
  • L is selected from: C1-C4 alkylene, -C1-C3 alkylene-O-, -C1-C3 alkylene-NH-, methylene, ethylene, -NH-CH 2 -, -NH-CH 2 -CH 2 -CH 2 -,
  • R 6 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
  • R 7 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H.
  • R 8 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H.
  • R 9 is selected from: H in this group is optionally substituted by 1, 2 or 3 R, where R is as defined above.
  • R 9 is selected from:
  • R 9 is selected from:
  • R 10 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen Substitute C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C3-C6 cycloalkyl-O-, 3-6 membered heterocycle Base-O-, phenyl-O-, 5-6 membered heteroaryl-O-, C3-C6 cycloalkyl C3-C6 cycloalkylene-O-, C3-C6 cycloalkyl 3-6 membered Heterocyclyl-O-, preferably H,
  • R 10 is selected from: -L m1 -L m2 -L m3 -L m4 , (C1-C6 alkyl)HNC1-C6 alkylene-O-, (C1-C6 alkyl)HNC1 -C6 alkylene-N(C1-C6 alkyl)-, Among them, L m1 , L m2 and L m3 are each independently selected from: bond, -O-, C1-C6 alkylene, C3-C6 cycloalkylene, 3-6 membered heterocyclylene, 7-10 membered Bicycloheterocyclylene, 5-6 membered heteroarylene or phenylene; L m4 is selected from: C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 7-10 membered bicyclic heterocyclyl, 5-6 membered heteroaryl or phenyl; preferably,
  • R 11 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen Substitute C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably C1-C6 alkoxy, such as methoxy, ethoxy , n-propoxy or isopropoxy.
  • R 11 is selected from: H in this group is optionally substituted by 1, 2 or 3 R, where R is as defined above.
  • R 12 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably C1-C6 alkyl, such as methyl.
  • R 12 is methyl, ethyl or propyl.
  • R 13 is each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl group, preferably H.
  • R' 13 is each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl Oxy group, halogenated C1-C6 alkoxy group, C3-C6 cycloalkyl group, 3-6 membered heterocyclyl group, phenyl or 5-6 membered heteroaryl group, preferably H.
  • the compound has the structure shown in formula IV
  • Z 1 and Z 2 are each independently selected from: CH or N;
  • Y is selected from: CH 2 or O;
  • L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -,
  • R 11 is H or methyl
  • R 2 is selected from: H, D, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C2-C6 alkenyl or Halogenated C2-C6 alkenyl; preferably, R 2 is selected from: H, halogen, cyano, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 ring Alkyl, C2-C3 alkenyl or halogenated C2-C3 alkenyl; more preferably, R 2 is bromine, hydrogen, cyano, isoallyl, isopropyl, trifluoromethyl, cyclopropyl, chlorine , ethyl, vinyl, methyl, iodine or fluorine.
  • the compound has the structure represented by formula V
  • R 11 is H or methyl
  • R 2 is selected from: H, D, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C3-C6 Cycloalkyl, C2-C6 alkenyl or halogenated C2-C6 alkenyl; preferably, R 2 is selected from: H, halogen, cyano, C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6 Cycloalkyl, halogenated C3-C6 cycloalkyl, C2-C3 alkenyl or halogenated C2-C3 alkenyl; more preferably, R 2 is bromine, hydrogen, cyano, isoallyl, isopropyl, Trifluoromethyl, cyclopropyl, chlorine, ethyl, vinyl, methyl, iodine or fluorine.
  • the compound is selected from:
  • a second aspect of the present invention provides a pharmaceutical composition, which contains the compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvent compound; and a pharmaceutically acceptable carrier.
  • a method for preparing a pharmaceutical composition including the steps of: combining a pharmaceutically acceptable carrier with the compound of the present invention, its stereoisomers, its optical isomers, and its pharmaceutically acceptable
  • the accepted salts, prodrugs thereof, or solvates thereof are mixed to form a pharmaceutical composition.
  • the pharmaceutical composition also contains other therapeutic agents.
  • Other therapeutic agents may be EGFR monoclonal antibodies or MEK inhibitors.
  • the EGFR monoclonal antibody is selected from the following group: cetuximab, panitumumab, nexituzumab, nimotuzumab, or a combination thereof.
  • the MEK inhibitor is selected from the following group: selumetinib, trametinib, PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), or a combination thereof.
  • the third aspect of the present invention provides a compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as in the second aspect Use of the pharmaceutical composition described in the aspect in the preparation of drugs that inhibit EGFR kinase or drugs for EGFR-mediated diseases.
  • the compound, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or the pharmaceutical combination as described in the second aspect The use of substances in the preparation of drugs for EGFR-mediated diseases.
  • the EGFR is a mutant EGFR, preferably L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, or a combination thereof; more preferably, it is L858R, T790M, C797S, Del19, or a combination thereof.
  • Combinations; further more preferred are L858R/T790M double mutation, T790M/C797S double mutation, L858R/T790M/C797S triple mutation or Del19/T790M/C797S triple mutation.
  • the drug that inhibits EGFR kinase is a drug used to treat cancer.
  • the cancer is selected from the following group: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, Pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal cancer, head and neck tumors, colon cancer, rectal cancer, glioma , or a combination thereof.
  • the lung cancer for which the drug is used to treat is selected from the following group:
  • the fourth aspect of the present invention provides a compound as described in the first aspect, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as in the second aspect
  • the EGFR mutation is L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, exon 20 mutation, or a combination thereof; preferably, it is L858R, T790M, C797S, Del19, D770_N771insSVD, A763_Y764insFQEA, V769_D770insASV, H773_V774insNPH, or combinations thereof; more preferably L858R/T790M double mutation, T790M/C797S double mutation, Del19/C797S double mutation, L858R/C797S double mutation, L858R/T790M/C797S triple mutation or Del 19/T790M/C797S Three mutations.
  • the HER-2 amplification results in abnormal protein expression due to abnormal gene copy number.
  • the amplification of c-MET results in abnormal protein expression due to abnormal copy number of its gene.
  • the drug is a drug for treating cancer; preferably, the cancer is selected from the following group: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer Carcinoma, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal cancer, head and neck neoplasms, colon cancer, rectal cancer, glioma, or combinations thereof ;
  • the tumor for which the drug is used to treat is selected from the group consisting of:
  • Tumors caused by EGFR L858R mutation preferably lung cancer
  • Tumors caused by EGFR Del19 mutations preferably lung cancer
  • Tumors caused by EGFR C797S mutation preferably lung cancer
  • Tumors caused by EGFR T790M mutation preferably lung cancer
  • Tumors caused by EGFR L858R/T790M/C797S mutations preferably lung cancer
  • Tumors caused by EGFR Del19/T790M/C797S mutations are preferably lung cancer;
  • the present invention provides a method for treating cancer, which includes the steps of: administering an effective amount of a compound as described in the first aspect, its stereoisomer, its optical isomer, and its pharmaceutical composition to a subject in need of treatment. an acceptable salt thereof, a prodrug thereof or a solvate thereof, or a pharmaceutical composition as described in the second aspect.
  • a new macrocyclic multi-target inhibitor which can be used to treat EGFR mutations, HER-2 amplification, c-MET amplification and other gene mutation-mediated related diseases.
  • Diseases such as cancer
  • Drug-induced diseases such as cancer
  • the present invention was completed.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left.
  • the term "about” when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “contains” or “includes” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
  • alkyl includes straight or branched chain alkyl groups.
  • C1-C8 alkyl represents a straight-chain or branched alkyl group having 1 to 8 (eg, 1, 2, 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C1-C6 alkyl or C1-C4 alkyl, examples of alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
  • alkenyl includes straight or branched chain alkenyl groups.
  • C2-C8 alkenyl refers to a straight-chain or branched alkenyl group with 2-8 (for example, 2, 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C2-C6 alkenyl or C2- C4 alkenyl
  • alkenyl include but are not limited to vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.
  • alkynyl includes straight or branched chain alkynyl groups.
  • C2-C8 alkynyl refers to a straight-chain or branched alkynyl group with 2-8 (such as 2, 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C2-C6 alkynyl or C2- C4 alkynyl, examples of alkynyl include but are not limited to ethynyl, propynyl, butynyl, or similar groups.
  • cycloalkyl refers to a cyclic alkyl group containing a specified number of C atoms, such as "C3-C12 cycloalkyl” refers to a cyclic alkyl group having 3 to 12 (e.g., 3, 4, 5, 6, 7 , 8, 9, 10, 11 or 12) cycloalkyl carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic forms, such as bridged or spirocyclic forms, are also possible.
  • the cycloalkyl group can also be condensed on an aryl, heteroaryl, or heterocyclyl ring, where the ring connected to the parent structure is a cycloalkyl group, such as wait.
  • the cycloalkyl group is preferably a C3-C8 cycloalkyl group, and more preferably a C3-C6 cycloalkyl group.
  • Examples of cycloalkyl groups include cycloalkyl groups.
  • cycloalkyl groups are intended to include substituted cycloalkyl groups.
  • C1-C10 alkoxy refers to a straight or branched chain having 1 to 10 carbon atoms (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • chain alkoxy group which has the formula C1-C10 alkyl-O- structure, preferably C1-C6 alkyl-O-, for example, methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy or tert-butoxy, etc.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from the group consisting of N, S and O
  • heterocyclyl refers to having 3-12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) atoms and 1-3 (such as 1, 2 or 3) atoms are selected Saturated or partially saturated cyclic groups of heteroatoms from the group consisting of N, S and O. It can be a single ring or a double ring, such as a bridged ring or a spiro ring.
  • the 3-12-membered heterocyclic group is preferably a 3-8-membered heterocyclic group, and more preferably a 3-6-membered or 6-8-membered heterocyclic group.
  • Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
  • described Heterocyclyl groups can be fused to heteroaryl, aryl or cycloalkyl rings, where the ring attached to the parent structure is heterocyclyl, e.g. wait.
  • aryl refers to an aromatic ring group that does not contain heteroatoms in the ring
  • C6-C12 aryl refers to an aromatic ring group that does not contain heteroatoms in the ring and has 6 to 12 (for example, 6, 7, 8 , 9, 10, 11 or 12) aromatic ring groups of carbon atoms
  • the aryl group can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is Aryl ring.
  • phenyl i.e.
  • C6-C12 aryl group is preferably C6-C10 aryl group.
  • Aryl groups may be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 (eg, 1, 2, or 3) atoms selected from the group consisting of N, S, and O
  • heteroaryl refers to a cyclic aromatic group having 1-3 (eg, 1, 2, or 3) atoms selected from the group consisting of N, S, and O
  • “5-12 membered heteroaryl” "Aryl” means having 5-12 (eg 5, 6, 7, 8, 9, 10, 11 or 12) atoms and 1-3 (eg 1, 2 or 3) atoms are selected from the following
  • the cyclic aromatic group of the heteroatom of groups N, S and O is preferably a 5-10 membered heteroaryl group, more preferably a 5-6 membered heteroaryl group. It can be a single ring or a fused ring.
  • heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc.
  • C1-C10 heteroalkyl refers to a group in which the C atoms (non-terminal C atoms) in the C1-C10 alkyl chain are replaced by heteroatoms such as O, S, NH, etc., preferably C1-C6 heteroalkyl.
  • alkyl, C1-C10 heteroalkyl include but are not limited to: -CH 2 -O-CH 2 CH 3 , -CH 2 -O-(CH 2 ) 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 , -CH 2 -O-CH 2 CH 2 CH 3 , -CH 2 -S-CH 2 CH 3 , -CH 2 -S-(CH 2 ) 2 CH 3 , -CH 2 CH 2 -S- CH 2 CH 3 , -CH 2 -S-CH 2 CH 2 CH 3 , -CH 2 -NH-CH 2 CH 3 , -CH 2 -NH-(CH 2 ) 2 CH 3 , -CH 2 CH 2 -NH -CH 2 CH 3 , -CH 2 -NH-CH 2 CH 3 , etc.
  • an alkyl group removes an H atom and becomes an alkylene group (for example: methylene, ethylene base, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), Ethylene (such as ), heptylene (such as ), etc.); cycloalkyl corresponds to cycloalkylene (such as: etc.); heterocyclyl corresponds to heterocyclylene (such as: ), alkoxy corresponds to alkyleneoxy (such as: -CH 2 O-, -CH 2 CH 2 O-, -OCH 2 CH 2 CH 2 -), heteroalkyl
  • the base corresponds to the heteroalkylene group (such as: -CH 2 -O-CH 2 CH 2 -, -CH 2 -O-(CH 2 ) 2 CH 2 -, -CH 2
  • halogen refers to F, Cl, Br and I. More preferably, the halogen is selected from F, Cl and Br.
  • amino refers to -NH2 .
  • C1-C6 alkylamino refers to C1-C6 alkyl NH2 .
  • C3-C12 cycloalkyl C1-C6 alkyl refers to -C3-C12 cycloalkyl C1-C6 alkyl or C3-C12 cycloalkyl C1-C6 alkyl-; in addition, “3-12 "Membered heterocyclyl C1-C6 alkyl”, “C6-C10 aryl C1-C6 alkyl” and “5-10 membered heteroaryl C1-C6 alkyl” have similar meanings.
  • substituted means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituted or unsubstituted the groups described in the present invention can be substituted with substituents selected from the following group: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl group.
  • substituents selected from the following group: D, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclyl, C3-C12 cycloalkyl, 5-10 membered heteroaryl , C6-C10 aryl group.
  • the term "plurality” independently refers to 2, 3, 4, 5, or a positive integer greater than 5.
  • the structural formulas described in the present invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers and geometric isomers (or conformational isomers)): R and S configurations containing asymmetric centers, (Z) and (E) isomers with double bonds, etc. Therefore, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are within the scope of the invention.
  • solvate refers to a compound of Formula I coordinated with solvent molecules to form a complex in a specific ratio.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
  • compounds of the present invention refer to compounds represented by Formula I, and also include stereoisomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds represented by Formula I.
  • the compounds of the present invention may contain one or more chiral carbon atoms and may therefore give rise to enantiomeric, diastereomeric and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • the weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure” compounds of the invention are here also included as part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixtures.
  • asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain the isomers in various ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds (ie, isotopic derivatives) that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes in the isotope derivatives of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotopic derivatives of the compounds of the present invention are within the scope of the present invention.
  • 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates.
  • Compounds labeled with tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are relatively easy to prepare and detect and are the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e. 2H , may have advantages in certain therapies due to their good metabolic stability, such as increased half-life in the body or reduced dosage, and therefore may be prioritized in certain circumstances.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • pharmaceutically acceptable salts includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include but are not limited to formates, acetates, and 2,2-dichloroacetates.
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Biridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclo
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituted refers to the substitution of a designated structural substituent for a hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substitution includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence.
  • this invention is not intended to be limited in any way to the permitted substituted organic compounds.
  • the present invention considers that the combination of substituents and variable groups is excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • Prodrugs refer to a class of compounds that are inactive or have little activity in vitro, but undergo enzymatic or non-enzymatic transformation in the body to release active drugs and exert medicinal effects.
  • Metabolites of the compound represented by Formula I and its pharmaceutically acceptable salts, as well as prodrugs that can be converted into the compound represented by Formula I and its pharmaceutically acceptable salts in vivo, are also included in the protection scope of the present invention.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the preparation of the compounds of the invention includes the steps:
  • G is halogen, OMs, OTs, etc.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 , R 11 , X, Y and L are defined as above;
  • compound (II-3) reacts with compound (II-4) to obtain compound (II-5);
  • reaction solvent reaction temperature, reaction time, catalyst, etc.
  • reaction time reaction time, catalyst, etc.
  • compositions and methods of administration are provided.
  • a pharmaceutical composition in which the compound of the present invention is the main active ingredient can be used to prevent and/or treat (stabilize, alleviate, or cure) EGFR.
  • non-small cell lung cancer small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin carcinoma, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma or combinations thereof, etc.
  • the pharmaceutical composition of the present invention contains the compound of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound/dose of the invention, more preferably, 10-200 mg of the compound/dose of the invention.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here refers to the ability of each component of the pharmaceutical composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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, glycerin, mannitol, sorbitol, etc.), milk chemicals (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • talc such as sodium carboxymethylcellulose,
  • the administration mode of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the compounds of the invention are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, For example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Moisturizing (d) disintegrating agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding agents, such as paraffin; ( f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h)
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents, and the release of the compounds of the invention from such pharmaceutical compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the compounds of the present invention may also be in the form of microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol , 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol , 1,3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the compounds of the invention, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances wait.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances wait.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, EGFR inhibitors).
  • other pharmaceutically acceptable compounds eg, EGFR inhibitors.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, EGFR inhibitors).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (eg, EGFR inhibitors) may be used simultaneously, separately, or sequentially with the compounds of the invention. Prevent and/or treat diseases related to the activity or expression of EGFR kinase.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dosage is usually 1-2000 mg, preferably 20-500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the compound of the present invention has a novel structure and has excellent inhibitory effects on EGFR, HER-2, and c-MET kinases;
  • the compounds of the present invention can be used as EGFR kinase inhibitors, especially as mutant EGFR (especially Inhibitors of double or triple mutations, such as L858R/T790M, T790M/C797S, L858R/T790M/C797S, Del19/T790M/C797S, etc.);
  • the compounds of the present invention can be used as HER-2 kinase inhibitors
  • the compound of the present invention can be used as a c-MET kinase inhibitor
  • the compounds of the present invention can be used as inhibitors of the above-mentioned EGFR mutations, HER-2 amplification, and c-MET amplification at the same time, and can be used to treat diseases caused by multiple gene mutations occurring at the same time.
  • v% refers to volume percentage
  • percentages have meanings known to those skilled in the art. For example, for purity and yield, the percentages are mass percentages; when a solid is dissolved to make a solution, the percentages are mass percentages; when a liquid is dissolved into a solution, the percentages are mass percentages; When dissolved to form a solution, the percentage is volume percentage; for gas, the percentage is volume percentage, for example, 5% in 5% CO2 is volume percentage.
  • fraction ratio has the meaning known to those skilled in the art.
  • the fraction ratio of two solids is the mass fraction ratio
  • the fraction ratio of two liquids or two gases is the volume fraction ratio. portion ratio.
  • PTLC or TLC (thin layer chromatography) preparations were performed on 20 ⁇ 20 cm plates (500 ⁇ m thick silica gel); silica gel chromatography was performed using a Biotage flash chromatography system.
  • the liquid chromatography uses the Agilent Technologies 1200 series or 6120 quadrupole spectrometer; for the liquid chromatography, the mobile phase is acetonitrile (A) and water (B) and 0.01% Formic acid, eluent gradient: 6.0 min 5-95% A, 5.0 min 60-95% A, 5.0 min 80-100% A and 10 min 85-100% A, using SBC 1850 mm x 4.6 mm x 2.7 ⁇ m capillary Column; mass spectrometry (MS) was determined by electrospray ion mass spectrometry (ESI).
  • Agilent Technologies 1200 series or 6120 quadrupole spectrometer for the liquid chromatography, the mobile phase is acetonitrile (A) and water (B) and 0.01%
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • MS mass range 150-750amu; positive ion electrospray ionization.
  • Example 1 3 5 -bromo-5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl )-11-oxa-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocycloundecane
  • Step 7 Preparation of N-(5-bromo-2-chloropyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indole-7-amine
  • Step 8 Synthesis of 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
  • N-(5-bromo-2-chloropyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indole-7-amine (450 mg) was added to dichloromethane (10 mL) , under nitrogen protection, add boron tribromide dichloromethane solution (3.12mL) at 0°C, and stir the reaction solution at 0-30°C for 5 hours. TLC shows that the raw material reaction is complete. The reaction solution is concentrated to remove the solvent, and is purified by preparative TLC.
  • Step 11 Preparation of 5-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol
  • Step 12 tert-butyl (5-(5-hydroxypentyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of urethane
  • reaction solution was concentrated to remove the tetrahydrofuran solvent, and the residue was purified by preparative TLC to obtain a brown oily substance tert-butyl (5-(5-hydroxypentyl)-2-methoxy-4-(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)phenyl)carbamate (350 mg, yield 56%).
  • Step 13 5-((tert-butylcarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentyl
  • Step 14 tert-butyl(5-(7-(5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-yl)oxy)pentyl)- 2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamate
  • Step 15 4-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentyl)oxy)-N -(5-Bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine trifluoroacetate
  • Step 16 3 5 -bromo-5 6 -methoxy-5 4- (4-(4-methylpiperazin-1-yl)piperidine-1-1 1- (methylsulfonyl)-11- Oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 2 5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-11-oxo Hetero-2,4-diaza-3(4,2)-thiophene[3,2-d]pyrimidine-1(7,4)-indoline-5(1,3)-benzocyclo11 alkyl
  • Example 3 3 5 -chloro-5 6 -methoxy-5 4- (4-(4-methylpiperazin-1-yl)piperidine-1-1 1- (methylsulfonyl)-11 -oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 4 3 5 -bromo-5 6 -methoxy-5 4 -(9-methyl-3,9-diazaro[5.5]undecan-3-yl)-1 1 -(methyl Sulfonyl)-1 1 -oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 5 N 1 -(3 5 -bromo-5 6 -methoxy-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo-1(7,4)-indole
  • Example 6 (S)-(1-(3 5 -bromo-5 6 -methoxy-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo-1(7, 4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecan-54-yl)piperidin-3-yl)methanol
  • Example 7 N 1 -(5 6 -methoxy-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo-3(4,2)-thiophene [3,2- d]pyrimidine-1(7,4)-indoline-5(1,3)-phenylcyclodecane-54yl)-N 1 , N 2 , N 2 -trimethylmethane-1,2-di amine
  • Example 8 3 5 -bromo-5 6 -methoxy-5 4 -(5-(1-methyl-1h-pyrazol-4-yl)pyrimidin-2-yl)-1 1 -(methyl Sulfonyl)-1 1 -oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 9 3 5 -bromo-5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl )-12-oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclododecane
  • 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene 500mg
  • 5-hexyn-1-ol 393mg
  • N,N-diisopropylethylamine 1290mg
  • triphenylphosphine 105mg
  • dichloroditriphenylphosphine palladium 140mg
  • copper iodide 76mg
  • Step 3 Preparation of 6-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)hexan-1-ol
  • Step 5 6-(5-((tert-butoxycarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene Preparation of hexyl-4-methylbenzenesulfonate
  • reaction solution was concentrated to remove methylene chloride and purified by preparative TLC to obtain a light yellow liquid 6-(5-((tert-butoxycarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperidine) Azin-1-yl)piperidin-1-yl)phenyl)hexyl-4-methylbenzenesulfonate (450 mg, yield 86%).
  • Step 6 (5-(6-((7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-yl)oxy) Preparation of tert-butyl hexyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamate
  • Step 7 4-((6-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)hexyl)oxy Preparation of methyl)-N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine trifluoroacetate
  • Step 8 3 5 -bromo-5 6 -methoxy-5 4- (4-(4-methylpiperazin-1-yl)piperidine-1-1 1- (methylsulfonyl)-11- Preparation of oxa-2,4-diaza a-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 10 3 5 -bromo- 5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy-1 1 -(methylsulfonyl)- 1 1 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • reaction solution was washed with deionized water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain a brown oily substance 5-(3-(5-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-yl)oxy-5-nitrobenzene)pentan-4-butan-1-ol (270 mg, yield 58%).
  • Step 4 tert-Butyl(3-(5-hydroxypentyl)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)aminomethyl acid ester
  • Step 5 5-(3-(tert-butylcarbonyl)amino)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)pentyl 4-methylbenzenesulfonate
  • Step 6 tert-Butyl (3-(5-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-yloxy)pentyl) -5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenylcarbamate
  • Step 7 4-(5-(3-amino-5-(5-(1-methyl-1h-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)pentyloxy)- N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine
  • reaction solution was concentrated to remove the solvent, and purified by a reversed phase column to obtain a brown oily substance 4-(5-(3-amino-5-(5-(1- Methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)pentyloxy)-N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methyl Sulfo)indole-7-amine trifluoroacetate (159 mg, crude).
  • Step 8 3 5 -bromo- 5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy-1 1 -(methylsulfonyl)-1 1 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 11 5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy)-1 1 -(methylsulfonyl)-1 1 -oxy -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-3 5 -carbonitrile
  • Example 12 3 5 -bromo-5 5 -((1-cyclopropylpiperidin-4-yl)oxy)-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-di Nitrogen-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 13 3 5 -bromo-1 1 -(methylsulfonyl)-5 5 -(3-morpholine-propoxy)-1 1 -oxo-2,4-diaza-1(7, 4)-indole-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 14 3-(3 5 -bromo- 1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo-1(7,4)-indoline-3(4,2 )-pyrimidine-5(1,3)-phenylcyclodecane- 5 5 -yl)oxy-N,N-dimethylpropane-1-amine
  • Example 15 3 5 -bromo-5 5 -((4-methylpiperazin-1-yl)methyl)-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo -1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 18 3 5 -bromo- 1 1 -(methylsulfonyl)-5 5 -((1-(pyrimidin-5-yl)piperidin-4-yl)oxy)-1 1 -oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 19 5 5 -((2-oxo-7-azaspiro[3.5]nonan-7-yl)methyl)-3 5 -bromo-1 1 -(methylsulfonyl)-1 1 -oxo -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 20 3 5 -bromo-1 1 -(methylsulfonyl)-5 5 -((2-(trifluoromethyl)-5,6-dihydroimidazole[1,2-a]pyrazine- 7(8H)-yl)methyl)-1 1 -oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)- phenylcyclodecane
  • Example 21 3 5 -bromo-5 5- (2-(1-methylpiperidin-4-yl)ethyl)-1 1 -(methylsulfonyl)-1 1 -oxo-2,4- Diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 16 2-(3 5 -bromo-1 6 -methoxy-1 4 -(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-6-oxo-2 ,4-Diazepam-3(2,4)-pyrimidine-1(1,3), 5(1,4)-diphenylcyclodecane-5 2yl )-1,2-thiazine 1,1 - Dioxide
  • Step 3 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide
  • reaction solution was concentrated to remove the solvent, and the residue was purified by column chromatography to obtain a yellow oily substance 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-methoxyphenyl)-1, 2-thiazine 1,1-dioxide (847 mg, yield: 95%).
  • Step 4 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-hydroxyphenyl)-1,2-thiazine 1,1-dioxide
  • Step 5 2-(2-(5-(5-hydroxypentyl)-2-methoxy-4-(1,4-dioxaoxo[4.5]dec-8-yl)phenyl)amino) Pyrimidin-4-yl)amino)-5-hydroxyphenyl)-1,2-thiazine 1,1-dioxide
  • Step 6 1-(4-(5-bromo-4-((2-(1,1-dioxy-1,2-thiazin-2-yl)-4-hydroxyphenyl)aminopyrimidine-2) -(yl)amino)-2-(5-bromopentyl)-5-methoxy)piperidin-4-one
  • Step 7 1-(3 5 -bromo-5 2 -(1,1-dioxy-1,2-thiazin-2-yl)-1 6 -methoxy-6-oxo-2,4- Diazo-3(2,4)-pyrimidin-1(1,3),5(1,4)-diphenylcyclodecan-14-yl)piperidin-4-one
  • the reaction solution was concentrated to remove the solvent, and purified by reverse phase column to obtain a brown oily substance 1-(3 5 -bromo-5 2 -(1,1-dioxy-1,2-thiazin-2-yl)-1 6 - Methoxy-6-oxo-2,4-diazo-3(2,4)-pyrimidine-1(1,3),5(1,4)-diphenylcyclodecan-14-yl)piperidine -4-one (100 mg, yield: 56%).
  • Step 8 2-(3 5 -bromo-1 6 -methoxy-1 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-6-oxa-2 ,4-diaza-3(2,4)-pyrimidine-1(1,3),5(1,4)-dibenzocyclodecane-5 2 -yl)-1,2-thiazine 1,1-dioxide
  • Example 17 5 2- (1,1-dioxy-1,2-thiazin-2-yl)-1 6 -methoxy-1 4- (4-(4-methylpiperazine-1- (yl)piperidin-1-yl)-6-oxo-2,4-diazo-3(2,4)-pyrimidine-1(1,3),5(1,4)-diphenylcyclodecane- 3 5 -Carbonitrile
  • Example 22 3 5 -bromo-5 4- (4-(4-methylpiperazin-1-yl)piperidine-1-1 1- (methylsulfonyl)-1 1 -oxa-2 ,4-diaza a-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 3 Preparation of 5-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol
  • Step 4 7-((5-bromo-2-(3-(5-hydroxypentyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)pyrimidin-4-yl)amino)-1-methylsulfonylindol-4-ol
  • reaction solution was purified by reverse-phase column and freeze-dried to obtain a white solid 7-((5-bromo-2-(3-(5-hydroxypentyl)-4-(4-(4-methylpiperazine)- 1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylsulfonylindol-4-ol (420 mg, yield 51%).
  • Step 5 3 5 -bromo-5 4- (4-(4-methylpiperazin-1-yl)piperidine-1-1 1- (methylsulfonyl)-11-oxa-2,4 -Diazepine a-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 23 3 5 -bromo-5 6 -chloro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)- 1 1 -Oxygen -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 24 3 5 -bromo- 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10-oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 3 Preparation of 4-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
  • Step 4 7-(5-bromo-2-(3-(4-hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Aminopyrimidin-4-ylamino)-1-(methylsulfonyl)indole-4-ol
  • reaction solution is concentrated to remove the solvent, and purified by column chromatography to obtain a light yellow solid 7-(5-bromo-2-(3-(4-hydroxybutyl)-4-(4- (4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)aminopyrimidin-4-ylamino)-1-(methylsulfonyl)indole-4-ol (3.2g, collected rate 91%).
  • Step 5 3 5 -bromo-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10-oxo-2, 4-Diazepam-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Diisopropyl azodicarboxylate (4.44g) was dropped into a solution of triphenylphosphine (5.76g) in tetrahydrofuran (100mL) under ice bath, and the mixture was stirred under ice bath for 5 minutes, and then 7-(5-bromo -2-(3-(4-hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)aminopyrimidin-4-ylamino)- A solution of 1-(methylsulfonyl)indol-4-ol (3.2g) in tetrahydrofuran (50mL) was dropped into the mixture in an ice bath, and stirred at 0-20°C for 1 hour.
  • Example 25 3 5 -bromo-5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-1 1 -(methylsulfonyl )-10-Oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 27 3 5 -bromo-5 6 -chloro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)- 10-Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 28 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10-oxo-2,4-diazo -1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-3 5 -carbonitrile
  • Example 29 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methylsulfonyl)-3 5- (prop-1-ene-2 -yl)-10-oxo-2,4-diaza-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 30 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10-oxo-2,4-diazo -3(4,2)-thiophene[3,2-d]pyrimidine-1(7,4)-indoline-5(1,3)-phenylcyclodecane
  • Example 31 3 5 -isopropyl-5 4- (4-(4-methylpiperazin-1-yl)piperazin-1-yl)-1 1 -(methylsulfonyl)-10-oxo -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 32 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10-oxo-2,4-diazo -1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-3 5 -carboxylic acid
  • Example 33 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-3 5- (trifluoromethyl)- 10-Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 34 3 5 -cyclopropyl-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10-oxo -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 35 3 5 -Chloro- 5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10-oxo-2 ,4-diazo -1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 36 3 5 -ethyl-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10-oxo- 2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 37 Methyl 5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-10-oxo-2,4- Diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-3 5 -carboxylate
  • Example 38 5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-3 5 -vinyl-10-oxy- 2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 39 Isopropyl 5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10-oxo-2,4 -Diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-3 5 -carboxylate
  • Example 40 3 6 -methyl-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-10-oxo- 2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 54 3 5 ,3 6 -methyl-5 4 -(4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-10 -Oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 55 5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-3 6 ,3 7 -dihydro-3 5Hydro -10-oxo-2,4-diaza-3(4,2)-cyclopentadiene[d]pyrimidine-1(7,4)-indoline-5(1,3)-benzo cyclodecane
  • Example 56 3 5 -bromo-5 4- (4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1 1 -(methylsulfonyl)-10-oxa- 2,4-diaza-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 57 3 5 -methyl-5 4- (4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1 1 -(methylsulfonyl)-10-oxa -2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 58 3 5 -bromo-1 1 -(methylsulfonyl)-5 4 -morpholinyl-10-oxa-2,4-diaza-1(7,4)-indole-3 (4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 59 3 5 -iodo-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-10-oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 60 3 5 -fluoro-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-10-oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 41 3 5 -methyl-54-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10-oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 2 Preparation of 7-((2-chloro-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
  • Step 3 7-(2-(3-(4-hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidine-1-phenyl)amino)-5-methyl pyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol
  • Step 4 3 5 -methyl-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methylsulfonyl)-10-oxo-2, 4-Dinitrogen -1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 42 3 5 -bromo-5 5 -fluoro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)- 10-Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 2 4-(3-fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol preparation
  • Step 3 Preparation of 4-(5-amino-3-fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
  • Step 4 7-(5-bromo-2-(3-fluoro-5-(4-hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)aminopyrimidin-4-yl)amino-1-(methylsulfonyl)indol-4-ol
  • reaction solution is concentrated to remove the solvent, and purified by column chromatography to obtain a light yellow solid (5-bromo-2-(5-(4-hydroxybutyl)-2-methyl-4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4- Alcohol (100 mg, yield 24%).
  • Step 5 3 5 -bromo- 5 5 -fluoro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 64 3 5 -bromo- 5 5 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl) -10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 43 3 5 -bromo-5 6 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl) -10-Oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 3 Preparation of 4-(5-amino-4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
  • Step 4 (5-bromo-2-(5-(4-hydroxybutyl)-2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol
  • reaction solution was concentrated to remove the solvent and purified by column chromatography to obtain a light yellow solid (5-bromo-2-(5-(4-hydroxybutyl)-2-methyl- 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4 -Alcohol (30 mg, yield 7.2%).
  • Step 5 3 5 -bromo-5 6 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)- 10-Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 44 3 5 -chloro-5 6 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl) -10-Oxo-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 45 3 5 ,5 6 -dimethyl-54-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 1 7-((2-(5-(4-hydroxybutyl)-2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene (yl)amino)-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol
  • Step 2 3 5 ,5 6 -dimethyl-54-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-10- Oxygen-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 61 3 5 ,5 6 -dimethyl-5 4 -(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1 1 -(methylsulfonyl)- 10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 62 3 5 -bromo-5 6 -methyl-(4-(1-methylpiperidin-4-acyl)piperazine-1-acyl)-1 1 -(methylsulfonyl)-10- Oxygen-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 63 3 5 -fluoro-5 6 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl) -10-oxa-2,4-diaza-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-benzocyclodecane
  • Example 46 3 5 -bromo-5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)-1 1 -(methylsulfonyl )-10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzoic acid cyclodecane
  • Step 2 4-(3-Amino-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)phenyl)butan-1-ol preparation
  • Step 3 7-((5-bromo-2-((3-(4-hydroxybutyl))-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazine-2) Preparation of -yl)oxy)phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
  • Step 4 3 5 -bromo-5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)-1 1 -(methylsulfonyl)
  • Example 47 3 5 -bromo-5 5 -(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)-1 1 -(methylsulfonyl)-10 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 48 3 5 -bromo-5 5- (4-(4-methylpiperazin-1-yl)phenoxy)-1 1 -(methylsulfonyl)-10-oxo-2,4- Diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 49 3 5 -bromo- 5 5- (5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy-1 1 -(methylsulfonyl)-10 -Oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Example 50 3 5 -bromo-5 6 -chloro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)- 10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzonaphthocyclodecane-7-ene
  • Step 1 Preparation of 4-(allyloxy)-N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine
  • Step 5 N 2 -(5-allyl-2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(4 Preparation of -(allyloxy)-1-(methylsulfonyl)indol-7-yl)-5-bromopyrimidine-2,4-diamine
  • Step 6 3 5 -bromo-5 6 -chloro-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-10 -oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzonaphthocyclodecane-7-ene preparation
  • Example 51 3 5 -bromo-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-10-oxo-2 ,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-7-ene
  • Example 52 3 5 -bromo-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonyl)-6-10-di Preparation of oxy-2,4-diaza-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-benzonacyclodecane
  • Step 4 7-((5-bromo-2-((3-(3-hydroxypropoxy)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) Phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol
  • Step 5 3 5 -bromo-5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1- (methylsulfonyl)-6-10-dioxo -2,4-Diazepam-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-benzonacyclodecane
  • PPh 3 (140 mg) was added to THF (10 mL). Under nitrogen protection, DIAD (108 mg) was dissolved in THF (1 mL). Add dropwise to the above solution under ice bath, stir for 5 minutes, and then slowly add 7-((5 -Bromo-2-((3-(3-hydroxypropoxy)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine-4 -Amino)-1-(methylsulfonyl)indole-4-ol (78.0 mg) was dissolved in THF (1 mL). After stirring at room temperature for 2 h, LCMS confirmed that the reaction was complete.
  • Example 53 3 5 -bromo-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-7,10-di Preparation of oxopyrimidine-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Step 3 Preparation of 2-((5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzyl)oxy)ethane-1-ol
  • Step 4 7-((5-bromo-2-((3-((2-hydroxyethoxy)methyl)-4-(4-(4-methylpiperazin-1-yl)piperidine- Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
  • Step 5 3 5 -bromo-5 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-7,10-dioxo pyrimidine
  • 4- (4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1- (methylsulfonyl)-7,10-dioxo pyrimidine Preparation of pyrimidine-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
  • Triphenylphosphine 45 mg was added to a three-necked flask, and under nitrogen protection, diisopropyl azodicarboxylate (34 mg) was added. After stirring at room temperature for 5 minutes, 7-((5-bromo-2-( (3-((2-hydroxyethoxy)methyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl The tetrahydrofuran solution of )amino)-1-(methylsulfonyl)indole-4-ol was slowly dropped into the three-necked flask and stirred at room temperature for 2 hours.
  • Effect example 1 Evaluation of EGFR kinase activity inhibition
  • Compounds (10 ⁇ M, 1 ⁇ M, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM) were incubated with purified EGFR-WT, EGFR-L858R/T790M, EGFR-Del19/T790M/C797S or EGFR-L858R/T790M/C797S.
  • the buffer was added to the 384 reaction plate (ProxiPlate-384Plus, PerkinElmer). After incubating at room temperature for half an hour, the substrate buffer was added to start the reaction. After incubating at room temperature for one hour, XL665 and antibody were added and incubated for another hour.
  • the specific reaction system is 2v% DMSO, 0.04ng/ ⁇ L EGFR, 1 ⁇ M TK-s, 0.002 (EGFR-WT) ⁇ 1mM ATP (EGFR-L858R/T790M, EGFR-Del19/T790M/C797S, EGFR -L858R/T790M/C797S), 5mM MgCl 2 , 1mM DTT, 1 ⁇ kinase buffer.
  • XL665, TK-s substrate, antibodies and various buffers are from HTRF KinEASE STK Discovery kit (Cisbio, 62ST0PEB).
  • the compound of the present invention has excellent inhibitory activity against mutant EGFR, especially double mutations and triple mutations. It can overcome the resistance to early related drugs and is expected to be further developed into a compound for the preparation of EGFR modulators (L858R/T790M , L858R/T790M/C797S, Del19/T790M/C797S, etc.) kinase activity or drugs for the treatment of EGFR (L858R/T790M, L858R/T790M/C797S, Del19/T790M/C797S, etc.) related diseases.
  • EGFR modulators L858R/T790M , L858R/T790M/C797S, Del19/T790M/C797S, etc.
  • test data is divided into the following categories: A: IC 50 ⁇ 50nM; B: 50nM ⁇ IC 50 ⁇ 100nM; C: 100nM ⁇ IC 50 ⁇ 1000nM; D: 1000nM ⁇ IC 50 ⁇ 10000nM; E: IC 50 ⁇ 10000nM; ND :not detected.
  • Effect example 2 Evaluation of proliferation inhibitory activity of EGFR mutant cells
  • Ba/F3 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) are engineering cell lines overexpressing EGFR-Del19/T790M/C797S and EGFR-L858R/T790M/C797S respectively. Constructed through retroviral vector infection and resistance selection. Both Ba/F3 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) were cultured in RPMI-1640+10v% FBS.
  • the IC50 values of the compounds of the present invention for Ba/F3 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) are 0.1nM-10000nM respectively.
  • the specific experimental results are shown in Table 2.
  • test data is divided into the following categories: A: IC 50 ⁇ 25nM; B: 25nM ⁇ IC 50 ⁇ 60nM; C: 60nM ⁇ IC 50 ⁇ 200nM; D: 200nM ⁇ IC 50 ⁇ 1000nM; E: 1000nM ⁇ IC 50 ⁇ 10000 ;ND:not detected.
  • AZD-9291 The structure of AZD-9291 is as follows:
  • BI-4020 The structure of BI-4020 is as follows:
  • A-29 comes from the patent WO2021216440 compound A29, with the following structure:
  • SK-BR-3 and MDA-MB-468 are breast cancer cells that overexpress HER-2 and are classic model cells for evaluating HER-2 inhibitors.
  • SK-BR-3 was cultured in McCoy's 5A+10v% FBS medium
  • MDA-MB-468 was cultured in DMEM+10v% FBS.
  • 10,000 cells/well of SK-BR-3 and MDA-MB-468 were inoculated respectively.
  • 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128nM compounds were added to the 96-well plate, using 0.2v% DMSO as a control, and cultured in a 37°C incubator for 72h.
  • test data is divided into the following categories: A: IC 50 ⁇ 50nM; B: 50nM ⁇ IC 50 ⁇ 200nM; C: 200nM ⁇ IC 50 ⁇ 1000nM; D: 1000nM ⁇ IC 50 ⁇ 10000nM; E: IC 50 >10000nM; ND :not detected.
  • a blank control group without enzyme, a solvent control group with DMSO replacing the compound, and a positive control group (staurosporine) were set up.
  • the final volume of the reaction is 10 ⁇ L.
  • the specific reaction system is 2v% DMSO, 0.04ng/ ⁇ L c-MET, 1 ⁇ M TK-s, 2 ⁇ M ATP, 5mM MgCl 2 , 1mM DTT, and 1 ⁇ kinase buffer.
  • XL665, TK-s substrate, antibodies and various buffers are from HTRF KinEASE STK Discovery kit (Cisbio, 62ST0PEB).
  • test data is divided into the following categories: A: IC 50 ⁇ 50nM; B: 50nM ⁇ IC 50 ⁇ 200nM; C: 200nM ⁇ IC 50 ⁇ 1000nM; D: 1000nM ⁇ IC 50 ⁇ 10000nM; E: IC 50 >10000nM; ND :not detected.

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Abstract

La présente invention concerne un inhibiteur multicible à petites molécules, une composition pharmaceutique le contenant, et son utilisation. Plus particulièrement, le composé selon la présente invention a une structure telle que représentée dans la formule (I). La présente invention concerne en outre un procédé de préparation du composé et son utilisation en tant qu'inhibiteur d'EGFR. Le composé peut être utilisé pour traiter des maladies associées (telles que le cancer) médiées par EGFR, HER-2, c-MET et analogues, et présente en particulier un effet spécial sur des maladies (telles que le cancer) ayant une résistance à des médicaments précoces et provoquée par une ou plusieurs mutations géniques de la dimutation EGFR et de la triple mutation, l'amplification HER-2 et la mutation exon20, l'amplification c-MET, et analogues.
PCT/CN2023/107949 2022-07-19 2023-07-18 Inhibiteur à petites molécules egfr, composition pharmaceutique le contenant et son utilisation WO2024017258A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102143750A (zh) * 2008-09-08 2011-08-03 默克专利有限公司 用作蛋白激酶抑制剂的大环嘧啶
CN102718775A (zh) * 2003-05-27 2012-10-10 詹森药业有限公司 作为抗增殖剂的大环喹唑啉衍生物
WO2020009179A1 (fr) * 2018-07-06 2020-01-09 Shionogi & Co., Ltd. Dérivés hétérocycliques fusionnés ayant une activité inhibitrice sélective de bace1
WO2021163627A1 (fr) * 2020-02-14 2021-08-19 Salk Institute For Biological Studies Inhibiteurs macrocycliques d'ulk1/2
WO2021216440A1 (fr) * 2020-04-20 2021-10-28 Tenova Pharmaceuticals Inc. Nouveaux inhibiteurs de protéines kinases
CN113956272A (zh) * 2020-07-20 2022-01-21 首药控股(北京)有限公司 Dna-pk选择性抑制剂及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102718775A (zh) * 2003-05-27 2012-10-10 詹森药业有限公司 作为抗增殖剂的大环喹唑啉衍生物
CN102143750A (zh) * 2008-09-08 2011-08-03 默克专利有限公司 用作蛋白激酶抑制剂的大环嘧啶
WO2020009179A1 (fr) * 2018-07-06 2020-01-09 Shionogi & Co., Ltd. Dérivés hétérocycliques fusionnés ayant une activité inhibitrice sélective de bace1
WO2021163627A1 (fr) * 2020-02-14 2021-08-19 Salk Institute For Biological Studies Inhibiteurs macrocycliques d'ulk1/2
WO2021216440A1 (fr) * 2020-04-20 2021-10-28 Tenova Pharmaceuticals Inc. Nouveaux inhibiteurs de protéines kinases
CN113956272A (zh) * 2020-07-20 2022-01-21 首药控股(北京)有限公司 Dna-pk选择性抑制剂及其制备方法和用途

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