WO2024017258A1 - Egfr small molecule inhibitor, pharmaceutical composition containing same, and use thereof - Google Patents

Egfr small molecule inhibitor, pharmaceutical composition containing same, and use thereof 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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French (fr)
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/en

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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.

Abstract

Disclosed in the present invention are a multi-target small molecule inhibitor, a pharmaceutical composition containing same, and a use thereof. Specifically, the compound of the present invention has a structure as shown in formula (I). Further disclosed in the present invention are a preparation method for the compound and a use thereof as an EGFR inhibitor. The compound can be used for treating related diseases (such as cancer) mediated by EGFR, HER-2, c-MET and the like, and especially has a special effect on diseases (such as cancer) having resistance to early related drugs and caused by one or more gene mutations of EGFR dimutation and triple mutation, HER-2 amplification and exon20 mutation, c-MET amplification, and the like.

Description

EGFR小分子抑制剂、含其的药物组合物及其用途EGFR small molecule inhibitors, pharmaceutical compositions containing them and their uses 技术领域Technical field
本发明涉及药物化学领域，具体地涉及一种EGFR小分子抑制剂、含其的药物组合物及其用途。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.
背景技术Background technique
表皮生长因子受体(epidermal growth factor receptor,EGFR,也称作HER-1或c-erbB-1)是由1186个氨基酸组成的，170kDa的跨膜糖蛋白。EGFR是受体酪氨酸激酶c-erbB家族中的一员，其调控了细胞的增殖、存活、粘连、迁移与分化。EGFR由三部分组成：细胞外受体区域；跨膜区域；细胞内酪氨酸激酶区域。已经确认的可以与EGFR结合的配体有：表皮生长因子(EGF)、转化生长因子ɑ(TGFɑ)、双向调节因子、肝素结合EGF、细胞调节素等。EGFR在多种肿瘤细胞中过度活化或持续活化，比如肺癌、乳腺癌、前列腺癌等。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 ɑ (TGFɑ), 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.
目前，已经上市的EGFR-TKI小分子抑制剂包括一代的易瑞沙、特罗凯、凯美纳，二代的阿法替尼和达克替尼以及三代的奥西替尼，使具有EGFR阳性的非小细胞肺癌患者在EGFR-TKI的治疗中获益。但是，治疗过程中，肿瘤的耐药突变，产生抗性是不可避免的问题。在使用一代和二代EGFR-TKI治疗后，大约有60％的患者会发生T790M的耐药突变，导致一代和二代药物失去治疗作用。作为第三代EGFR-TKI的奥西替尼，对T790M具有非常好的抑制活性，从而给患者带来更好的治疗效果和生存获益。但是，随着第三代EGFR-TKI的广泛使用，由此产生了EGFR C797S或C796S三突变，导致第三代抑制剂没办法共价结合到蛋白激酶上，进而使得这些抑制剂失效。此外，最新研究表明，HER-2扩增、c-MET扩增也与三代EGFR-TKI耐药高度相关。Currently, 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. of patients with non-small cell lung cancer benefit from EGFR-TKI treatment. However, during the treatment process, drug-resistant mutations in tumors and the development of resistance are inevitable problems. After treatment with first- and second-generation EGFR-TKIs, approximately 60% of patients will develop T790M resistance mutation, causing the first- and second-generation drugs to lose their therapeutic effect. As a third-generation EGFR-TKI, osimertinib has very good inhibitory activity against T790M, thus bringing better therapeutic effects and survival benefits to patients. However, with the widespread use of third-generation EGFR-TKIs, 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. In addition, the latest research shows that HER-2 amplification and c-MET amplification are also highly related to third-generation EGFR-TKI resistance.
人表皮生长因子受体2(human epidermal growth factor receptor 2，HER-2)，又叫ERBB2，是一种跨膜酪氨酸激酶受体蛋白。HER-2由胞外配体结合区、单链跨膜区及胞内蛋白酪氨酸激酶区三部分组成。HER-2蛋白主要通过与家族中其他成员，包括HER-1(EGFR)、HER-3和HER-4形成异二聚体而与各自的配体结合。HER-2蛋白常为异二聚体首选伴侣，且活性常强于其他异二聚体。当HER-2与配体结合后，主要通过引起受体二聚化及胞质内酪氨酸激酶区的自身磷酸化，激活酪氨酸激酶的活性。HER-2的变异形式包括过表达、突变及扩增。HER-2过表达的发生率在乳腺癌中比例最高，在胃癌、结肠癌中阳性率依次降低。特别的，在经标准EGFR-TKI如奥西替尼治疗后复发的非小细胞肺癌患者中，有研究表明联用HER-2抑制剂可以抑制奥西替尼耐药患者的肿瘤生长。Human epidermal growth factor receptor 2 (HER-2), also called ERBB2, is a transmembrane tyrosine kinase receptor protein. 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. 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. In particular, in patients with non-small cell lung cancer who relapsed after treatment with standard EGFR-TKIs such as osimertinib, studies have shown that combined use of HER-2 inhibitors can inhibit tumor growth in osimertinib-resistant patients.
间质上皮转化因子(cellular-mesenchymal epithelial transition factor，c-MET)编码合成的蛋白c-MET，是一种可以与肝细胞生长因子(HGF)结合的受体酪氨酸激酶。c-MET通路正常表达时可促进组织的分化与修复，当表达异常或发生14号外显子跳跃突变时则可促进肿瘤细胞的增殖与转移。c-MET通路异常激活存在于诸多实体瘤中，包括脑瘤、乳腺癌、结直肠癌、胃癌、头颈癌、肺癌、肝癌、皮肤癌、前列腺癌及软组织肉瘤等。c-MET通路的异常激活可以通过非HGF依赖性机制发生，主要包括c-MET 14外显子跳跃突变、c-MET扩增、重排和c-MET蛋白过表达等。特别的，在经标准EGFR-TKI如奥西替尼治疗后复发的非小细胞肺癌患者中，检测到7.8％的人发生了c-MET突变，因此抑制c-MET不仅可用于治疗多种原发性肿瘤，还可用于治疗EGFR-TKI耐药的非小细胞肺癌。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). 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. In particular, 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.
因此，开发新一代多靶点抑制剂，同时针对EGFR C797S突变、HER-2扩增和c-MET 扩增等耐药突变，既能用于治疗EGFR突变、HER-2扩增、c-MET扩增等引起的疾病，又能用于治疗上述突变所致EGFR-TKI耐药的非小细胞肺癌，是一件具有重大意义的事情。Therefore, 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.
发明内容Contents of the invention
本发明通过以下技术方案实现上述目的：The present invention achieves the above objects through the following technical solutions:
本发明的第一方面，提供一种式I所示的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，
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,
式中，In the formula,
X选自：NR5、CR5Ra或O；X is selected from: NR 5 , CR 5 Ra or O;
Y选自：不存在、NRa、CRaRb或O；Y is selected from: absent, NRa, CRaRb or O;
L选自：C1-C8亚烷基、C2-C8亚烯基、C2-C8亚炔基、-C1-C10亚烷基-O-、-C1-C10亚烷基-NH-、C1-C10亚杂烷基、-C1-C10亚烷基-C(＝O)-NH-、-C1-C10亚烷基-C(＝O)-NH-C1-C10亚烷基-、-C1-C10亚烷基-NH-C(＝O)-、-C1-C10亚烷基-NH-C(＝O)NH-、-C1-C10亚烷基-NH-C(＝O)NH-C1-C10亚烷基-、-C1-C10亚烷基-OC(＝O)-NH-、-C1-C10亚烷基-OC(＝O)-NH-C1-C10亚烷基-、-C1-C10亚烷基-C(＝O)-、-C1-C10亚烷基-C(＝O)-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)-、-C1-C10亚烷基-S(＝O)-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)2-、-C1-C10亚烷基-S(＝O)2-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)2NH-、-C1-C10亚烷基-NHS(＝O)2-、-C1-C10亚烷基-S(＝O)2NH-C1-C10亚烷基-、C1-C8亚烷基C3-C8亚环烷基、C1-C8亚烷基C3-C8亚环烷基C1-C8亚烷基；其中，上述各基团中的H任选地被1、2、3、4、5、6、7或8个Ra取代；L is selected from: C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, -C1-C10 alkylene-O-, -C1-C10 alkylene-NH-, C1-C10 Heteroalkylene, -C1-C10 alkylene-C(=O)-NH-, -C1-C10 alkylene-C(=O)-NH-C1-C10 alkylene-, -C1-C10 Alkylene-NH-C(=O)-, -C1-C10 Alkylene-NH-C(=O)NH-, -C1-C10 Alkylene-NH-C(=O)NH-C1- C10 alkylene-, -C1-C10 alkylene-OC(=O)-NH-, -C1-C10 alkylene-OC(=O)-NH-C1-C10 alkylene-, -C1- C10 alkylene-C(=O)-, -C1-C10 alkylene-C(=O)-C1-C10 alkylene-, -C1-C10 alkylene-S(=O)-,- C1-C10 alkylene-S(=O)-C1-C10 alkylene-, -C1-C10 alkylene-S(=O) 2 -, -C1-C10 alkylene-S(=O) 2 -C1-C10 alkylene-, -C1-C10 alkylene-S(=O) 2 NH-, -C1-C10 alkylene-NHS(=O) 2 -, -C1-C10 alkylene -S(=O) 2 NH-C1-C10 alkylene-, C1-C8 alkylene C3-C8 cycloalkylene, C1-C8 alkylene C3-C8 cycloalkylene C1-C8 alkylene ; Wherein, H in each of the above groups is optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 Ra;
R1和R2各自独立地选自：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、-OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-或5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代；R 1 and R 2 are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra)SO m Rb, -C (O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, -S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O- or 5-10 membered heteroaryl-O-; wherein, each of the above groups H in the group is optionally replaced by 1, 2 or 3 R;
或者，R1、R2以及与它们连接的原子共同形成C5-C6环烷基、5-6元杂环基、苯基或5-6元杂芳基；其中，上述各基团中的H任选地被1、2或3个Ra取代；Alternatively, 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;
R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R’13各自独立地选自：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、-OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-或5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代；R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R' 13 are each independently selected from: H, D, halogen, cyano , nitro, hydroxyl, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra)SO m Rb, -C(O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, -S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl -O-, 3-12 membered hetero Cyclic group -O-, C6-C10 aryl-O- or 5-10 membered heteroaryl -O-; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R;
R9和R10任选地被选自下组的基团取代：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、 -OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-和5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代；R 9 and R 10 are optionally substituted with a group selected from the group consisting of: H, D, halogen, cyano, nitro, hydroxy, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra )SO m Rb, -C(O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, -S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 Membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O- and 5 -10-membered heteroaryl-O-; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R;
Ra和Rb各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、-NRR'、-C(O)NRR'、-N(R)SOmR'、-C(O)R'、-P(＝O)RR'、-S(O)mNRR'、-NRC(O)R'、-C(O)OR、-OC(O)R、-S(O)mR'、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基或5-10元杂芳基；其中，上述各基团中的H任选地被1、2或3个R”取代；Ra and Rb are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, -NRR', -C(O)NRR', -N(R)SO m R', -C( O)R', -P(=O)RR', -S(O) m NRR', -NRC(O)R', -C(O)OR, -OC(O)R, -S(O) m R', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R”;
R、R'和R”各自独立地选自下组：H、D、卤素、氰基、硝基、羟基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)2、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代C3-C12环烷基、取代或未取代3-12元杂环基、取代或未取代C6-C10芳基、取代或未取代5-10元杂芳基；其中，所述取代是指被选自下组的1、2或3个基团取代：D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基和5-10元杂芳基；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. Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3- C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, the 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 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl;
m独立地选自：1或2；m is independently selected from: 1 or 2;
限定条件：Qualifications:
当X为O时，R3、R4以及与它们连接的原子共同形成5-6元杂环基；其中，上述基团中的H任选地被1、2或3个Ra取代；When X is O, 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;
当X为NR5或CR5Ra时，R3、R4以及与它们连接的原子共同形成环A1，环A1为5-6元杂环基，环A1中的H任选地被1、2或3个Ra取代；R4、R5以及与它们连接的原子共同形成环A2，环A2为C5-C6环烷基或5-6元杂环基，环A2中的H任选地被1、2或3个Ra取代；R5、R6以及与它们连接的原子共同形成环A3，环A3为C5-C6环烷基或5-6元杂环基，环A3中的H任选地被1、2或3个Ra取代；并且环A1、环A2和环A3中，有1个环、2个环或3个环是存在的。 When _ _ _ Or 3 Ra substitutions; R 4 , R 5 and the atoms connected to them together form ring A2, 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.
在另一优选例中，所述化合物如式II所示，
In another preferred embodiment, the compound is represented by formula II,
其中，X、Y、L、R1、R2、R3、R4、R6、R9、R10和R11的定义如上所述。Among them, X, Y, L, R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 and R 11 are as defined above.
在另一优选例中，R1选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H或卤素，更优选H、F、Cl或Br，进一步更优选H。In another preferred example, 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.
在另一优选例中，R1选自：甲基。In another preferred embodiment, R 1 is selected from: methyl.
在另一优选例中，R2选自：H、D、卤素、氰基、硝基、羟基、氨基、-C(O)OH、-C(O)OC1-C3烷基、C1-C6烷基(如甲基或乙基)、卤代C1-C6烷基(如CF3)、C1-C6烷氧基(如甲氧基)、卤代C1-C6烷氧基(如OCF3)、C2-C6烯基(如乙烯基、烯丙基或丙烯基)、C2-C6炔基(如乙炔基或丙炔基)、C3-C6环烷基(如环丙基)、3-6元杂环基、苯基或5-6元杂芳基，优选卤素，更 优选F、Cl或Br，进一步更优选Cl或Br。In another preferred example, 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.
在另一优选例中，R11选自：H、D、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基。In another preferred example, R 11 is selected from: H, D, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkoxy.
在另一优选例中，选自：该基团中的H任选地被1、2或3个Ra取代，Ra的定义如上所述。In another preferred example, Selected from: H in this group is optionally substituted by 1, 2 or 3 Ra, as defined above.
在另一优选例中，式I中，X为O，为该基团中的H任选地被1、2或3个R取代，其中，R6、R7、R12和R的定义如上所述。In another preferred example, in formula I, 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.
在另一优选例中，式I中，X为NR5，为该基团中的H任选地被1、2或3个R取代，其中，R3、R6、R7、R12和R的定义如上所述。In another preferred example, in formula I, 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.
在另一优选例中，式I中，X为CR5Ra，为 该基团中的H任选地被1、2或3个R取代，其中，R3、R4、R6、R7、R12和R的定义如上所述。In another preferred example, in formula I, 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.
在另一优选例中，式II中，X为O，为该基团中的H任选地被1、2或3个R取代，其中，R6和R的定义如上所述。In another preferred example, in formula II, 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.
在另一优选例中，式II中，X为NR5，为该 基团中的H任选地被1、2或3个R取代，其中，R3、R6和R的定义如上所述。In another preferred example, in formula II, 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.
在另一优选例中，式II中，X为CR5Ra，为 该基团中的H任选地被1、2或3个R取代，其中，R3、R4、R6和R的定义如上所述。In another preferred example, in formula II, 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.
在另一优选例中，X选自：NR5、CR5Ra或O，其中，R5和Ra各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选地，X选自：O、CH2或NH。In another preferred example, 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.
在另一优选例中，R2选自：溴、氯、氰基、氢、异烯丙基、异丙基、羧基、三氟甲基、环丙基、乙基、甲氧基羰基、乙烯基、异丙氧基羰基或甲基。In another preferred example, R 2 is selected from: bromine, chlorine, cyano, hydrogen, isoallyl, isopropyl, carboxyl, trifluoromethyl, cyclopropyl, ethyl, methoxycarbonyl, ethylene base, isopropoxycarbonyl or methyl.
在另一优选例中，Y选自：CH2或氧。In another preferred embodiment, Y is selected from: CH 2 or oxygen.
在另一优选例中，R9选自：或H。In another preferred example, R 9 is selected from: or H.
在另一优选例中，R10选自：H、F、 In another preferred example, R 10 is selected from: H, F,
在另一优选例中，R11选自：甲氧基、氢、氯或甲基。In another preferred embodiment, R 11 is selected from: methoxy, hydrogen, chlorine or methyl.
在另一优选例中，L选自： In another preferred example, L is selected from:
在另一优选例中，所述化合物具有式III所示的结构
In another preferred embodiment, the compound has the structure shown in formula III
其中，Z1和Z2各自独立地选自：CH或N；Among them, Z 1 and Z 2 are each independently selected from: CH or N;
Y、L、R1、R2、R10和R11的定义如上所述；Y, L, R 1 , R 2 , R 10 and R 11 are defined as above;
优选地，Y选自：CH2或O；Preferably, Y is selected from: CH 2 or O;
优选地，L选自：-(CH2)3-、-(CH2)4-、-(CH2)5-、 Preferably, L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,
优选地，Z2为N，且Z1为CH；Preferably, Z 2 is N, and Z 1 is CH;
优选地，Y选自：CH2或O；且L选自：-(CH2)3-。Preferably, Y is selected from: CH2 or O; and L is selected from: -( CH2 ) 3- .
在另一优选例中，Y选自：CRaRb，其中，Ra和Rb各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选地，Y选自：CH2。In another preferred example, 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 .
在另一优选例中，L选自：C1-C4亚烷基、-C1-C3亚烷基-O-、-C1-C3亚烷基-NH-、亚甲基、亚乙基、 -NH-CH2-、-NH-CH2-CH2-CH2-、 In another preferred example, 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 -,
在另一优选例中，R6选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基。In another preferred example, 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.
在另一优选例中，R7选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H。In another preferred example, 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.
在另一优选例中，R8选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H。In another preferred example, 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.
在另一优选例中，R9选自： 该基团中的H任选地被1、2或3个R取代，其中，R的定义如上所述。In another preferred example, R 9 is selected from: H in this group is optionally substituted by 1, 2 or 3 R, where R is as defined above.
在另一优选例中，R9选自： In another preferred example, R 9 is selected from:
在另一优选例中，R9选自： In another preferred example, R 9 is selected from:
在另一优选例中，R10选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基、5-6元杂芳基、C3-C6环烷基-O-、3-6元杂环基-O-、苯基-O-、5-6元杂芳基-O-、C3-C6环烷基C3-C6亚环烷基-O-、C3-C6环烷基3-6元亚杂环基-O-，优选H、 In another preferred example, 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,
在另一优选例中，R10选自：-Lm1-Lm2-Lm3-Lm4、(C1-C6烷基)HNC1-C6亚烷基-O-、(C1-C6烷基)HNC1-C6亚烷基-N(C1-C6烷基)-、其中，Lm1、Lm2和Lm3各自独立地选自：键、-O-、C1-C6亚烷基、C3-C6亚环烷基、3-6元亚杂环基、7-10元亚双环杂环基、5-6元亚杂芳基或亚苯基；Lm4选自：C1-C6烷基、C3-C6环烷基、 3-6元杂环基、7-10元双环杂环基、5-6元杂芳基或苯基；优选地，R10选自： In another preferred example, 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 10 is selected from:
在另一优选例中，R11选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选C1-C6烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。In another preferred example, 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.
在另一优选例中，R11选自： 该基团中的H任选地被1、2或3个R取代，其中，R的定义如上所述。In another preferred example, R 11 is selected from: H in this group is optionally substituted by 1, 2 or 3 R, where R is as defined above.
在另一优选例中，R12选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选C1-C6烷基，例如甲基。In another preferred example, 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.
在另一优选例中，R12为甲基、乙基或丙基。In another preferred embodiment, R 12 is methyl, ethyl or propyl.
在另一优选例中，R13各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H。In another preferred example, 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.
在另一优选例中，R’13各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H。In another preferred example, 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.
在另一优选例中，所述化合物具有式IV所示的结构
In another preferred embodiment, the compound has the structure shown in formula IV
其中，Z1和Z2各自独立地选自：CH或N；Among them, Z 1 and Z 2 are each independently selected from: CH or N;
Y选自：CH2或O； Y is selected from: CH 2 or O;
L选自：-(CH2)3-、-(CH2)4-、 L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -,
R11为H或甲基；R 11 is H or methyl;
R2选自：H、D、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C6烯基或卤代C2-C6烯基；优选地，R2选自：H、卤素、氰基、C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C3烯基或卤代C2-C3烯基；更优选地，R2为溴、氢、氰基、异烯丙基、异丙基、三氟甲基、环丙基、氯、乙基、乙烯基、甲基、碘或氟。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.
在另一优选例中，所述化合物具有式V所示的结构
In another preferred example, the compound has the structure represented by formula V
其中，R11为H或甲基；R2选自：H、D、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C6烯基或卤代C2-C6烯基；优选地，R2选自：H、卤素、氰基、C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C3烯基或卤代C2-C3烯基；更优选地，R2为溴、氢、氰基、异烯丙基、异丙基、三氟甲基、环丙基、氯、乙基、乙烯基、甲基、碘或氟。Among them, 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.
在另一优选例中，所述化合物选自：








In another preferred embodiment, the compound is selected from:








本发明第二方面，提供一种药物组合物，其包含如第一方面所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物；和药学上可接受的载体。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.
在另一优选例中，提供一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物进行混合，从而形成药物组合物。In another preferred embodiment, a method for preparing a pharmaceutical composition is provided, 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.
在另一优选例中，所述药物组合物还包含其他治疗剂。其他治疗剂可以是EGFR单抗或MEK抑制剂。In another preferred embodiment, the pharmaceutical composition also contains other therapeutic agents. Other therapeutic agents may be EGFR monoclonal antibodies or MEK inhibitors.
其中，所述EGFR单抗选自下组：西妥昔单抗、帕尼单抗、耐昔妥珠单抗、尼妥珠单抗，或其组合。Wherein, the EGFR monoclonal antibody is selected from the following group: cetuximab, panitumumab, nexituzumab, nimotuzumab, or a combination thereof.
其中，所述MEK抑制剂选自下组：司美替尼、曲美替尼、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)，或其组合。Wherein, the MEK inhibitor is selected from the following group: selumetinib, trametinib, PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), or a combination thereof.
本发明第三方面，提供一种如第一方面所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如第二方面所述的药物组合物在制备抑制EGFR激酶的药物或EGFR介导的疾病的药物中的用途。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.
在另一优选例中，所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如第二方面所述的药物组合物在制备EGFR介导的疾病的药物中的用途。In another preferred embodiment, 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.
在另一优选例中，所述EGFR为突变型EGFR，优选为L858R、T790M、C797S、Del19、L792H、G873R、G874D、D855N，或其组合；更优选为L858R、T790M、C797S、Del19，或其组合；进一步更优选为L858R/T790M二突变、T790M/C797S二突变、L858R/T790M/C797S三突变或Del19/T790M/C797S三突变。In another preferred example, 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.
在另一优选例中，所述抑制EGFR激酶的药物为用于治疗癌症的药物，优选地，所述癌症选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤，或其组合。 In another preferred example, the drug that inhibits EGFR kinase is a drug used to treat 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, 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.
在另一优选例中，所述药物用于治疗的肺癌选自下组：In another preferred embodiment, the lung cancer for which the drug is used to treat is selected from the following group:
i)由EGFR L858R突变引起的肺癌；i) Lung cancer caused by EGFR L858R mutation;
ii)由EGFR Del19突变引起的肺癌；ii) Lung cancer caused by EGFR Del19 mutation;
iii)由EGFR C797S突变引起的肺癌；iii) Lung cancer caused by EGFR C797S mutation;
iv)由EGFR T790M突变引起的肺癌；iv) Lung cancer caused by EGFR T790M mutation;
v)由EGFR L858R/T790M突变引起的肺癌；v) Lung cancer caused by EGFR L858R/T790M mutation;
vi)由EGFR T790M/C797S突变引起的肺癌；vi) Lung cancer caused by EGFR T790M/C797S mutation;
vii)由EGFR L858R/T790M/C797S突变引起的肺癌；vii) Lung cancer caused by EGFR L858R/T790M/C797S mutation;
viii)由EGFR Del19/T790M/C797S突变引起的肺癌。viii) Lung cancer caused by EGFR Del19/T790M/C797S mutation.
本发明第四方面，提供一种如第一方面所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如第二方面所述的药物组合物在制备抑制EGFR突变、HER-2扩增和c-MET扩增中的一种或多种突变介导的疾病的药物中的用途。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 Use of the pharmaceutical composition described in the aspect in the preparation of a medicament for inhibiting diseases mediated by one or more of EGFR mutations, HER-2 amplification and c-MET amplification.
在另一优选例中，所述EGFR突变为L858R、T790M、C797S、Del19、L792H、G873R、G874D、D855N、20外显子突变，或其组合；优选为L858R、T790M、C797S、Del19、D770_N771insSVD、A763_Y764insFQEA、V769_D770insASV、H773_V774insNPH，或其组合；更优选为L858R/T790M二突变、T790M/C797S二突变、Del19/C797S二突变、L858R/C797S二突变、L858R/T790M/C797S三突变或Del19/T790M/C797S三突变。In another preferred example, 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.
在另一优选例中，所述HER-2扩增为其基因拷贝数异常所导致的蛋白表达异常。In another preferred embodiment, the HER-2 amplification results in abnormal protein expression due to abnormal gene copy number.
在另一优选例中，所述c-MET扩增为其基因拷贝数异常所导致的蛋白表达异常。In another preferred embodiment, the amplification of c-MET results in abnormal protein expression due to abnormal copy number of its gene.
在另一优选例中，所述药物为用于治疗癌症的药物；优选地，所述癌症选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤，或其组合；In another preferred embodiment, 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 ;
或者，所述药物用于治疗的肿瘤选自下组：Alternatively, the tumor for which the drug is used to treat is selected from the group consisting of:
i)由EGFR L858R突变引起的肿瘤，所述肿瘤优选为肺癌；i) Tumors caused by EGFR L858R mutation, preferably lung cancer;
ii)由EGFR Del19突变引起的肿瘤，所述肿瘤优选为肺癌；ii) Tumors caused by EGFR Del19 mutations, preferably lung cancer;
iii)由EGFR C797S突变引起的肿瘤，所述肿瘤优选为肺癌；iii) Tumors caused by EGFR C797S mutation, preferably lung cancer;
iv)由EGFR T790M突变引起的肿瘤，所述肿瘤优选为肺癌；iv) Tumors caused by EGFR T790M mutation, preferably lung cancer;
v)由EGFR L858R/T790M突变引起的肿瘤，所述肿瘤优选为肺癌；v) Tumors caused by EGFR L858R/T790M mutation, preferably lung cancer;
vi)由EGFR T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；vi) Tumors caused by EGFR T790M/C797S mutations, preferably lung cancer;
vii)由EGFR L858R/T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；vii) Tumors caused by EGFR L858R/T790M/C797S mutations, preferably lung cancer;
viii)由EGFR Del19/T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；viii) Tumors caused by EGFR Del19/T790M/C797S mutations, the tumors are preferably lung cancer;
ix)由HER-2扩增引起的肿瘤，所述肿瘤优选为肺癌；ix) Tumors caused by HER-2 amplification, preferably lung cancer;
x)由c-MET扩增引起的肿瘤，所述肿瘤优选为肺癌。x) Tumors caused by c-MET amplification, preferably lung cancer.
第五方面，本发明提供一种治疗癌症的方法，它包括步骤：给需要治疗的对象施用有效量的如第一方面所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如第二方面所述的药物组合物。In a fifth aspect, 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.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.
具体实施方式 Detailed ways
本发明人通过广泛而深入的研究，首次发现一种新的大环多靶点抑制剂，其可以用于治疗EGFR突变、HER-2扩增、c-MET扩增等基因突变介导的相关疾病(如癌症)，尤其是针对由于EGFR二突变与三突变、HER-2扩增和exon20突变、c-MET扩增等中的一种或多种基因突变所导致的对早期相关药物的耐药性的疾病(如癌症)有特别效果。在此基础上完成了本发明。Through extensive and in-depth research, the inventor discovered for the first time 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), especially resistance to early-stage related drugs caused by one or more gene mutations in EGFR double and triple mutations, HER-2 amplification and exon20 mutation, c-MET amplification, etc. Drug-induced diseases (such as cancer) have special effects. On this basis, the present invention was completed.
本文中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。Unless otherwise specified, the terms used herein have their ordinary meanings known to those skilled in the art.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。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.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, 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. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and between (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, 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."
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个(例如1、2、3、4、5、6、7或8个)碳原子的直链或支链的烷基，优选C1-C6烷基或C1-C4烷基，烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, 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.
如本文所用，术语“烯基”包括直链或支链的烯基。例如C2-C8烯基指具有2-8个(例如2、3、4、5、6、7或8个)碳原子的直链或支链的烯基，优选C2-C6烯基或C2-C4烯基，烯基的实例包括但不限于乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. For example, 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, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.
如本文所用，术语“炔基”包括直链或支链的炔基。例如C2-C8炔基指具有2-8个(例如2、3、4、5、6、7或8个)碳原子的直链或支链的炔基，优选C2-C6炔基或C2-C4炔基，炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、或类似基团。As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, 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.
如本文所用，术语“环烷基”是指包含特定数目的C原子的环状烷基，如“C3-C12环烷基”指具有3-12个(例如3、4、5、6、7、8、9、10、11或12个)碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。所述环烷基也可以稠合于芳基、杂芳基、杂环基环上，其中与母体结构连接在一起的环为环烷基，如等。环烷基优选C3-C8环烷基，更优选C3-C6环烷基。环烷基的实例包括本文中，环烷基意在包含取代环烷基。As used herein, the term "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. Herein, cycloalkyl groups are intended to include substituted cycloalkyl groups.
如本文所用，术语“C1-C10烷氧基”是指具有1-10个碳原子(例如1、2、3、4、5、6、7、8、9或10个)的直链或支链的烷氧基，其具有式C1-C10烷基-O-结构，优选地为C1-C6烷基-O-，例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基或叔丁氧基等。As used herein, the term "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.
如本文所用，“杂环(烷)基(heterocyclyl)”是指具有选自下组N、S和O的杂原子的饱和或部分饱和的环状基团，“3-12元杂环基”是指具有3-12个(例如3、4、5、6、7、8、9、10、11或12个)原子的且其中1-3个(例如1、2或3个)原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。3-12元杂环基优选3-8元杂环基，更优选3-6元或6-8元杂环基。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。所述 杂环基可以稠合于杂芳基、芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，如等。As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from the group consisting of N, S and O, "3-12 membered 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.
如本文所用，“芳基”是指环上不含杂原子的芳香族环基，“C6-C12芳基”是指在环上不含杂原子的具有6至12个(例如6、7、8、9、10、11或12个)碳原子的芳香族环基，所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。如苯基(即六元芳基)、萘基等，其中六元芳基还意在包含六元芳基并5-6元环烷基(如)和六元芳基并5-6元杂环基(如等)。C6-C12芳基优选C6-C10芳基。芳基可以是任选取代的或未取代的。As used herein, "aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring, and "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. Such as phenyl (i.e. six-membered aryl), naphthyl, etc., where the six-membered aryl is also intended to include six-membered aryl and 5-6-membered cycloalkyl (such as ) and six-membered aryl and 5-6-membered heterocyclyl (such as wait). C6-C12 aryl group is preferably C6-C10 aryl group. Aryl groups may be optionally substituted or unsubstituted.
如本文所用，“杂芳基”指具有1-3个(例如1、2或3个)原子为选自下组N、S和O的杂原子的环状芳香基，“5-12元杂芳基”指具有5-12个(例如5、6、7、8、9、10、11或12个)原子的且其中1-3个(例如1、2或3个)原子为选自下组N、S和O的杂原子的环状芳香基团，优选5-10元杂芳基，更优选5-6元杂芳基。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、酰胺基、磺酰胺基、甲酰基、甲酰胺基、羧基和羧酸酯基等。As used herein, "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. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The 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. When substituted, 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.
如本文所用，“C1-C10杂烷基”是指C1-C10烷基链中的C原子(非端位C原子)被O、S、NH等杂原子取代的基团，优选C1-C6杂烷基，C1-C10杂烷基的实例包括但不限于：-CH2-O-CH2CH3、-CH2-O-(CH2)2CH3、-CH2CH2-O-CH2CH3、-CH2-O-CH2CH2CH3、-CH2-S-CH2CH3、-CH2-S-(CH2)2CH3、-CH2CH2-S-CH2CH3、-CH2-S-CH2CH2CH3、-CH2-NH-CH2CH3、-CH2-NH-(CH2)2CH3、-CH2CH2-NH-CH2CH3、-CH2-NH-CH2CH2CH3等。As used herein, "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. Examples of 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 2 CH 3 , etc.
当各基团脱掉一个H原子时，其为相应基团的亚基，且其为二价基团，例如烷基脱掉一个H原子后为亚烷基(例如：亚甲基、亚乙基、亚丙基、亚异丙基(如)、亚丁基(如)、亚戊基(如)、亚己基(如)、亚庚基(如)等)；环烷基对应亚环烷基(如：等)；杂环基对应亚杂环基(如： )，烷氧基对应亚烷氧基(如：-CH2O-、-CH2CH2O-、-OCH2CH2CH2-)，杂烷 基对应亚杂烷基(如：-CH2-O-CH2CH2-、-CH2-O-(CH2)2CH2-、-CH2CH2-O-CH2CH2-、-CH2-O-CH2CH2CH2-、-CH2-S-CH2CH2-、-CH2-S-(CH2)2CH2-、-CH2CH2-S-CH2CH2-、-CH2-S-CH2CH2CH2-、-CH2-NH-CH2CH2-、-CH2-NH-(CH2)2CH2-、-CH2CH2-NH-CH2CH2-、-CH2-NH-CH2CH2CH2-)等。When each group removes an H atom, it is a subunit of the corresponding group, and it is a divalent group. For example, 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 CH 2 -O-CH 2 CH 2 -, -CH 2 -O-CH 2 CH 2 CH 2 -, -CH 2 -S-CH 2 CH 2 -, -CH 2 -S-(CH 2 ) 2 CH 2 -, -CH 2 CH 2 -S-CH 2 CH 2 -, -CH 2 -S-CH 2 CH 2 CH 2 -, -CH 2 -NH-CH 2 CH 2 -, -CH 2 -NH-(CH 2 ) 2 CH 2 -, -CH 2 CH 2 -NH-CH 2 CH 2 -, -CH 2 -NH-CH 2 CH 2 CH 2 -), etc.
如本文所用，“卤素”指F、Cl、Br和I。更佳地，卤素选自F、Cl和Br。As used herein, "halogen" refers to F, Cl, Br and I. More preferably, the halogen is selected from F, Cl and Br.
本文中，“氨基”是指-NH2。As used herein, "amino" refers to -NH2 .
本文中，“羧基”是指-COOH。As used herein, "carboxy" refers to -COOH.
本文中，“C1-C6烷基氨基”是指C1-C6烷基NH2。As used herein, "C1-C6 alkylamino" refers to C1-C6 alkyl NH2 .
本文中，“C3-C12环烷基C1-C6烷基”是指-C3-C12环烷基C1-C6烷基或C3-C12环烷基C1-C6烷基-；此外，“3-12元杂环基C1-C6烷基”、“C6-C10芳基C1-C6烷基”、“5-10元杂芳基C1-C6烷基”具有类似含义。As used herein, "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.
本文中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个被取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。As used herein, the term "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. Unless otherwise specified, 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.
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-12元杂环基、C3-C12环烷基、5-10元杂芳基、C6-C10芳基。Unless otherwise specified as "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.
本文中“任选地”指的是随后描述的事件或状况可能但不是必须出现的，并且该描述包括所述事件或状况发生的情况，以及所述事件或状况不发生的情况。As used herein, "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances where the stated event or condition occurs and instances where the stated event or condition does not occur.
本文中，术语“多个”独立指2、3、4、5或大于5的正整数。As used herein, the term "plurality" independently refers to 2, 3, 4, 5, or a positive integer greater than 5.
除非特别说明，本发明所描述的结构式意在包括所有立体异构体(如顺反异构体、对映异构、非对映异构和几何异构体(或构象异构体))：含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise specified, 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.
如本文所用，术语“溶剂化物”是指式I所示的化合物与溶剂分子配位形成特定比例的配合物。As used herein, the term "solvate" refers to a compound of Formula I coordinated with solvent molecules to form a complex in a specific ratio.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。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.
活性成分active ingredients
如本文所用，“本发明的化合物”指式I所示的化合物，并且还包括式I所示化合物的立体异构体、药学上可接受的盐、前药或溶剂化物。As used herein, "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.
本发明的化合物可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。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. In the preparation of the compounds of the present invention, 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.
制备/分离个别光学异构体(也即，对映体及非对映体)的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral  Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/separation of individual optical isomers (i.e., enantiomers and diastereomers) include chiral synthesis from suitable optically pure precursors, or resolution of foreign matter using, for example, chiral high-performance liquid chromatography. Racemates (or racemates of salts or derivatives), for example, see Gerald Gübitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup ,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。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.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the invention are included within the scope, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both cis (Z) and ant (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。Definitions of specific functional groups and chemical terms are detailed below. For the purposes of this invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry as well as specific functional groups and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。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. In addition, asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers may contain the isomers in various ratios. For example, 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.
本发明还包括同位素标记的化合物(也即，同位素衍生物)，等同于原始化合物在此公开。不过实际上对一个或多个的原子被与其原子量或质量序数不同的原子取代通常会出现。本发明的同位素衍生物中的同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明的化合物的同位素衍生物都在本发明的保护范围之内。本文中，3H标记的化合物和14C标记的化合物，在药物和底物的组织分布实验中是有用的。氚(即3H)和碳-14(即14C)标记的化合物的制备和检测比较容易，是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用披露在示例中的方案可以制备。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. Examples of 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. Here, 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. In addition, 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.
本文中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。As used herein, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本 专业已知的方法制备。"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. , trifluoroacetate, propionate, caproate, caprylate, decanoate, undecenoate, glycolate, gluconate, lactate, sebacate, adipate Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be Prepared by methods known to the profession.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"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, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If one wants to design 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. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, 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.
如本文所述，本发明的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”是指用指定结构取代基，代替氢自由基。当特定结构中的多个位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。本文中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope. Generally, the term "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. The term "substitution" as used herein 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. Herein, heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, 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. The term "stable" as used herein 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.
“前药”是指在体外无活性或者活性较小，在体内经过酶或者非酶的转化释放出活性药物而发挥药效的一类化合物。"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.
式I所示化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为式I所示化合物及其药学可接受的盐的前药，也包含在本发明的保护范围之内。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.
化合物的制备方法Preparation methods of compounds
以下方案中描述了制备式I所示化合物的方法。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。Methods for preparing compounds of formula I are described in the following schemes. In some cases, the order of steps in performing a reaction scheme can be changed to facilitate the reaction or avoid undesired side reaction products. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃-150℃，优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。Generally, in the preparation process, 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.
优选地，本发明的化合物的制备包括步骤：
Preferably, the preparation of the compounds of the invention includes the steps:
式中，G为卤素、OMs、OTs等；In the formula, G is halogen, OMs, OTs, etc.;
R1、R2、R3、R4、R6、R9、R10、R11、X、Y和L的定义如上所述；R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 , R 11 , X, Y and L are defined as above;
S1)在合适的反应条件下(如但不限于偶联反应，取代反应等)，化合物(II-1)与化合物(II-2)反应，得到化合物(II-3)；S1) Under appropriate reaction conditions (such as but not limited to coupling reaction, substitution reaction, etc.), compound (II-1) reacts with compound (II-2) to obtain compound (II-3);
S2)在合适的条件下(如但不限于取代反应等)，化合物(II-3)与化合物(II-4)反应，得到化合物(II-5)；S2) Under appropriate conditions (such as but not limited to substitution reaction, etc.), compound (II-3) reacts with compound (II-4) to obtain compound (II-5);
S3)在合适的条件下(如但不限于酸性条件下)，化合物(II-5)与脱去Boc保护基，得到化合物(II-6)；S3) Under appropriate conditions (such as but not limited to acidic conditions), remove the Boc protecting group from compound (II-5) to obtain compound (II-6);
S4)在合适的条件下(如但不限于偶联反应、取代反应等)，化合物(II-6)合环得到化合物(II)；S4) Under appropriate conditions (such as but not limited to coupling reaction, substitution reaction, etc.), compound (II-6) is ring-closed to obtain compound (II);
以上各反应步骤中，反应溶剂、反应温度、反应时间、催化剂等可以根据具体的反应物进行选择。In each of the above reaction steps, the reaction solvent, reaction temperature, reaction time, catalyst, etc. can be selected according to the specific reactants.
原料和中间体从商业来源购买，或由已知步骤制备，或使用本领域熟知的方法制备。Starting materials and intermediates are purchased from commercial sources or prepared by known procedures or using methods well known in the art.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明的化合物具有优异的EGFR、HER-2、c-MET激酶的抑制活性，因此本发明的化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)EGFR突变、HER-2扩增、c-MET扩增等介导的相关疾病(例如非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤或其组合等)。Since the compound of the present invention has excellent inhibitory activity on EGFR, HER-2, and c-MET kinase, 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. Related diseases mediated by mutations, HER-2 amplification, c-MET amplification, etc. (such as 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.).
本发明的药物组合物包含安全有效量范围内的本发明的化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明的化合物/剂，更佳地，含有10-200mg本发明的化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。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. Typically, 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. Preferably, the "dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是药物组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳 化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"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.
本发明的化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。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).
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，本发明的化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, 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) adsorbents, such as kaolin; and (i) lubricants, such as talc , calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种药物组合物中本发明的化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，本发明的化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。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.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了本发明的化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the compounds of the invention, 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.
除了这些惰性稀释剂外，药物组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the pharmaceutical compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了本发明的化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。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.
用于肠胃外注射的药物组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Pharmaceutical 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.
本发明的化合物可以单独给药，或者与其他药学上可接受的化合物(例如EGFR抑制剂)联合给药。The compounds of the invention can be administered alone or in combination with other pharmaceutically acceptable compounds (eg, EGFR inhibitors).
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如EGFR抑制剂)。该其他药学上可接受的化合物(例如EGFR抑制剂)中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗EGFR激酶的活性或表达量相关的疾病。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.
使用药物组合物时，是将安全有效量的本发明的化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1-2000mg，优选20-500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, 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. For a person weighing 60 kg, The daily dosage is usually 1-2000 mg, preferably 20-500 mg. Of course, 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.
本发明的主要优点在于：The main advantages of the present invention are:
1.本发明的化合物结构新颖且具有优异的EGFR、HER-2、c-MET激酶抑制作用；1. The compound of the present invention has a novel structure and has excellent inhibitory effects on EGFR, HER-2, and c-MET kinases;
2.本发明的化合物可以作为EGFR激酶抑制剂，尤其是作为突变型EGFR(特别是 二突变或三突变，如L858R/T790M、T790M/C797S、L858R/T790M/C797S、Del19/T790M/C797S等)的抑制剂；2. 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.);
3.本发明的化合物可以作为HER-2激酶抑制剂；3. The compounds of the present invention can be used as HER-2 kinase inhibitors;
4.本发明的化合物可以作为c-MET激酶抑制剂；4. The compound of the present invention can be used as a c-MET kinase inhibitor;
5.本发明的化合物可以同时作为上述EGFR突变和HER-2扩增、c-MET扩增的抑制剂，用于治疗同时出现多种基因突变所致疾病。5. 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.
本发明的化合物的合成方法示于下面的方案、方法和实施例。起始原料是市售的或可以根据本领域或本文所描述的已知方法制备。本发明的化合物可通过以下所示的具体实施例来说明。然而，这些具体实施例不应被解释为是本发明的唯一种类。这些实施例进一步详细说明本发明的化合物的制备。本领域的技术人员将容易理解，条件和过程的已知变化可用于制备这些化合物。Methods for the synthesis of compounds of the present invention are shown in the Schemes, Methods and Examples below. Starting materials are commercially available or can be prepared according to known methods in the art or described herein. The compounds of the present invention are illustrated by the specific examples shown below. However, these specific embodiments should not be construed as being the only categories of the invention. These examples further illustrate the preparation of the compounds of the invention. Those skilled in the art will readily appreciate that known variations of conditions and procedures can be used to prepare these compounds.
实施例Example
本文中，所有的温度均为℃，除非另有说明。Herein, all temperatures are in °C unless otherwise stated.
本文中，v％指的是体积百分比。As used herein, v% refers to volume percentage.
本文中，除非另有说明，否则，百分比具有本领域技术人员公知的含义，例如对于纯度，收率而言的百分比为质量百分比；将固体溶解制成溶液时，其百分比为质量百分比；将液体溶解制成溶液时，其百分比为体积百分比；对于气体而言的百分比，为体积百分比，例如5％CO2中5％为体积百分比。In this article, unless otherwise stated, 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.
本文中，除非另有说明，否则，份数比具有本领域技术人员公知的含义，例如，两种固体的份数比为质量份数比，两种液体或两种气体的份数比为体积份数比。In this article, unless otherwise stated, the fraction ratio has the meaning known to those skilled in the art. For example, the fraction ratio of two solids is the mass fraction ratio, and the fraction ratio of two liquids or two gases is the volume fraction ratio. portion ratio.
本文中，PTLC或TLC(薄层色谱)的制备是在20×20cm的板(500微米厚的硅胶)上进行；硅胶层析法用Biotage快速色谱系统。In this article, PTLC or TLC (thin layer chromatography) preparations were performed on 20 × 20 cm plates (500 μm thick silica gel); silica gel chromatography was performed using a Biotage flash chromatography system.
本文中，1H NMR(氢谱)采用Bruker AscendTM400光谱仪，400MHz，298°K，并且将残余质子在氘化试剂中的化学位移(ppm)给出参考：CHCl3的δ(化学位移)为7.26ppm，CH3OH或CH3OD的δ为3.30ppm，DMSO-d6的δ为32.50ppm。In this article, 1 H NMR (hydrogen spectrum) uses a Bruker AscendTM400 spectrometer, 400MHz, 298°K, and the chemical shift (ppm) of the residual proton in the deuterated reagent is given as a reference: the δ (chemical shift) of CHCl 3 is 7.26 ppm, the δ of CH 3 OH or CH 3 OD is 3.30 ppm, and the δ of DMSO-d6 is 32.50 ppm.
本文中，LCMS(液相色谱质谱联用)测试中，液相色谱采用安捷伦科技1200系列或6120四极谱仪；对于液相色谱，流动相为乙腈(A)和水(B)和0.01％甲酸，洗脱剂梯度：6.0分钟5-95％A，5.0分钟60-95％A，5.0分钟80-100％A和10分钟85-100％A，采用SBC1850毫米×4.6毫米×2.7微米的毛细管柱；质谱(MS)通过电喷雾离子质谱法(ESI)进行测定。In this article, in the LCMS (liquid chromatography mass spectrometry) test, 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 μm capillary Column; mass spectrometry (MS) was determined by electrospray ion mass spectrometry (ESI).
本文中，高效液相色谱(HPLC)-质谱(MS)分析条件：In this article, high performance liquid chromatography (HPLC)-mass spectrometry (MS) analysis conditions:
LC1柱：SB-C18 50mm×4.6mm×2.7μm；LC1 column: SB-C18 50mm×4.6mm×2.7μm;
温度：50℃；Temperature: 50℃;
洗脱液：5:95至95:5的乙腈/水(上述比值为体积比)+0.01％甲酸，6分钟；Eluent: 5:95 to 95:5 acetonitrile/water (the above ratio is volume ratio) + 0.01% formic acid, 6 minutes;
流量：1.5mL/min，注射5μL；Flow: 1.5mL/min, inject 5μL;
检测：PDA检测器，200-600nm；Detection: PDA detector, 200-600nm;
MS：质量范围150-750amu；正离子电喷雾电离。MS: mass range 150-750amu; positive ion electrospray ionization.
LC2柱：SB-C18 50mm×4.6mm×2.7μm；LC2 column: SB-C18 50mm×4.6mm×2.7μm;
温度：50℃；Temperature: 50℃;
洗脱液：5:95至95:5的乙腈/水(上述比值为体积比)+0.05％TFA(三氟乙酸)梯度，超 过3.00分钟；Eluent: acetonitrile/water from 5:95 to 95:5 (the above ratio is by volume) + 0.05% TFA (trifluoroacetic acid) gradient, ultra After 3.00 minutes;
流量：1.5mL/min，注射5μL；Flow: 1.5mL/min, inject 5μL;
检测：PDA检测器，200-600nm；Detection: PDA detector, 200-600nm;
MS：质量范围150-750amu；正离子电喷雾电离。MS: mass range 150-750amu; positive ion electrospray ionization.
LC3柱：SB-C18 50mm×4.6mm×2.7μm；LC3 column: SB-C18 50mm×4.6mm×2.7μm;
温度：50℃；Temperature: 50℃;
洗脱液：10:90至98:2的乙腈/水(上述比值为体积比)+0.05％TFA梯度，超过3.75分钟；Eluent: acetonitrile/water from 10:90 to 98:2 (the above ratio is a volume ratio) + 0.05% TFA gradient over 3.75 minutes;
流速：1.0mL/min，注射10μL；Flow rate: 1.0mL/min, inject 10μL;
检测：PDA检测器，200-600nm；Detection: PDA detector, 200-600nm;
MS：质量范围150-750amu；正离子电喷雾电离。MS: mass range 150-750amu; positive ion electrospray ionization.
本文中，各缩写所代表的意思如下所示：In this article, the meanings of each abbreviation are as follows:
AcOH＝乙酸；Alk为烷基；AR为芳基；Boc＝叔丁氧羰基；CH2Cl2＝二氯甲烷；DBU＝1,8-二氮杂双环[5.4.0]十一-7-烯；DCM＝二氯甲烷；DEAD＝偶氮二甲酸二乙酯；DMF＝N，N-二甲基甲酰胺；DMSO＝二甲基亚砜；EA＝乙酸乙酯；Et＝乙基；EtOAc＝乙酸乙酯；EtOH＝乙醇；HOAc＝乙酸；LiOH＝氢氧化锂；Me＝甲基；MeCN＝乙腈；MeOH＝甲醇；MgSO4＝硫酸镁；NaCl＝氯化钠；NaOH＝氢氧化钠；Na2SO4＝硫酸钠；PE＝石油醚；Ph＝苯基；PG＝保护基；TFA＝三氟乙酸；THF＝四氢呋喃；Ts＝对甲苯磺酰基；AcOH=acetic acid; Alk is alkyl; AR is aryl; Boc=tert-butoxycarbonyl; CH 2 Cl 2 =dichloromethane; DBU=1,8-diazabicyclo[5.4.0]undec-7- Alkene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DMF = N, N-dimethylformamide; DMSO = dimethyl sulfoxide; EA = ethyl acetate; Et = ethyl; EtOAc =ethyl acetate; EtOH = ethanol; HOAc = acetic acid; LiOH = lithium hydroxide; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MgSO 4 = magnesium sulfate; NaCl = sodium chloride; NaOH = sodium hydroxide; Na 2 SO 4 = sodium sulfate; PE = petroleum ether; Ph = phenyl; PG = protecting group; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Ts = p-toluenesulfonyl group;
rt＝室温；h＝小时；min＝分钟；bs＝宽峰；s＝单峰；d＝双峰；dd＝双二重峰；t＝三重峰；m＝多重。rt = room temperature; h = hours; min = minutes; bs = broad peak; s = singlet; d = doublet; dd = doublet; t = triplet; m = multiplet.
本申请实施例化合物所用其他中间体可采用商品化试剂、文献报道或本领域常规方法制得的试剂为原料。Other intermediates used for the compounds in the examples of this application can be made from commercial reagents, literature reports or reagents prepared by conventional methods in the field.
实施例1：35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-11-氧杂-2,4-重氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十一烷

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

步骤1：5-甲氧基-2,3二氢-1H吲哚的制备
Step 1: Preparation of 5-methoxy-2,3dihydro-1H indole
将4-甲氧基吲哚(5.0g)加入到冰醋酸(30mL)中，降温至0℃，在该温度下缓慢加入NaBH3CN(6.4g)搅拌5min，然后升至室温下搅拌2小时，TLC显示原料反应完毕。反应液加水淬灭，浓缩除去冰醋酸，冰浴下用5M的NaOH溶液调pH至7～8，用DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩除去DCM，得到油状物5-甲氧基-2,3二氢-1H吲哚(5.2g,粗品)，该粗品直接用于下一步。1H NMR(400MHz,CDCl3)δ7.05(t,J＝8.0Hz,1H),6.42(d,J＝8.0Hz,1H),6.37(d,J＝8.0Hz,1H),5.73(s,1H),3.85(s,3H),3.62(t,J＝8.4Hz,2H),3.03(t,J＝8.4Hz,2H). Add 4-methoxyindole (5.0g) to glacial acetic acid (30mL), cool to 0°C, slowly add NaBH 3 CN (6.4g) at this temperature and stir for 5 min, then raise to room temperature and stir for 2 hours. , TLC showed that the raw material reaction was completed. The reaction solution was quenched with water, concentrated to remove glacial acetic acid, adjusted to pH 7-8 with 5M NaOH solution in an ice bath, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove DCM to obtain an oily substance 5- Methoxy-2,3 dihydro-1H indole (5.2g, crude product), this crude product was used directly in the next step. 1 H NMR (400MHz, CDCl 3 ) δ7.05 (t, J = 8.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 5.73 (s ,1H),3.85(s,3H),3.62(t,J＝8.4Hz,2H),3.03(t,J＝8.4Hz,2H).
步骤2：1-(4-甲氧基-2,3-二氢-1H-吲哚-1-基)乙-1-酮的制备
Step 2: Preparation of 1-(4-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one
将5-甲氧基-2,3二氢-1H吲哚(5.2g)加入到DCM(20mL)中，降温至0℃，在该温度下加入乙酰氯(4.1g)以及三乙胺(10.56g)，然后升至室温搅拌1h，TLC监测反应完毕。冰浴下，反应液加水淬灭，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩除去DCM，残余物经层析柱纯化得到油状物1-(4-甲氧基-2,3-二氢-1H-吲哚-1-基)乙-1-酮(5.5g,收率:83％)。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.0Hz,1H),7.20(t,J＝8.2Hz,1H),6.61(d,J＝8.4Hz,1H),4.09(t,J＝8.4Hz,2H),3.86(s,3H),3.14(t,J＝8.6Hz,2H),2.24(s,3H).Add 5-methoxy-2,3 dihydro-1H indole (5.2g) to DCM (20mL), cool to 0°C, and add acetyl chloride (4.1g) and triethylamine (10.56 g), then raised to room temperature and stirred for 1 h, TLC monitored the reaction to completion. Under an ice bath, the reaction solution was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove DCM, and the residue was purified by a chromatography column to obtain an oily substance 1-(4-methoxy-2,3 -Dihydro-1H-indol-1-yl)ethan-1-one (5.5 g, yield: 83%). 1 H NMR (400MHz, CDCl 3 ) δ7.86 (d, J = 8.0Hz, 1H), 7.20 (t, J = 8.2Hz, 1H), 6.61 (d, J = 8.4Hz, 1H), 4.09 (t ,J＝8.4Hz,2H),3.86(s,3H),3.14(t,J＝8.6Hz,2H),2.24(s,3H).
步骤3：1-(4-甲氧基-7-硝基-2,3-二氢-1H-吲哚-1-基)乙-1-酮的制备
Step 3: Preparation of 1-(4-methoxy-7-nitro-2,3-dihydro-1H-indol-1-yl)ethan-1-one
将1-(4-甲氧基-2,3-二氢-1H-吲哚-1-基)乙-1-酮(5.5g)加入TFA(40mL)中降温至-15℃，缓慢加入硝酸钾(2.91g)，在该温度下搅拌2h，TLC显示原料反应完毕。浓缩除去TFA，冰水浴下用5M的NaOH溶液调pH至7～8，EA萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩除去EA，残余物经层析柱纯化得到黄色固体1-(4-甲氧基-7-硝基-2,3-二氢-1H-吲哚-1-基)乙-1-酮(2.0g，收率:29％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝9.2Hz,1H),6.66(d,J＝9.2Hz,1H),4.26(t,J＝8.2Hz,2H),3.93(s,3H),3.11(t,J＝8.2Hz,2H),2.27(s,3H).Add 1-(4-methoxy-2,3-dihydro-1H-indol-1-yl)ethan-1-one (5.5g) to TFA (40mL), cool to -15°C, and slowly add nitric acid Potassium (2.91g), stirred at this temperature for 2h, TLC showed that the raw material reaction was completed. Concentrate to remove TFA, adjust the pH to 7-8 with 5M NaOH solution in an ice-water bath, extract with EA, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate to remove EA, and the residue is purified by chromatography column to obtain a yellow solid 1-( 4-Methoxy-7-nitro-2,3-dihydro-1H-indol-1-yl)ethan-1-one (2.0 g, yield: 29%). 1 H NMR (400MHz, CDCl 3 ) δ7.78 (d, J = 9.2 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 4.26 (t, J = 8.2 Hz, 2H), 3.93 (s ,3H),3.11(t,J=8.2Hz,2H),2.27(s,3H).
步骤4：4-甲氧基-7-硝基-2,3-二氢-1H-吲哚的制备
Step 4: Preparation of 4-methoxy-7-nitro-2,3-dihydro-1H-indole
将1-(4-甲氧基-7-硝基-2,3-二氢-1H-吲哚-1-基)乙-1-酮(2.0g)溶于MeOH(50mL)中，加入CH3ONa(2.29g)，然后升温至90℃搅拌8h，TLC显示反应完毕。在0℃下，反应液加水淬灭，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩除去DCM，残余物经柱层析纯化得到黄色固体4-甲氧基-7-硝基-2,3-二氢-1H-吲哚(1.5g,收率94％),1H NMR(400MHz,CDCl3)δ7.87(d,J＝9.2Hz,1H),6.28(d,J＝9.2Hz,1H),5.32(s,1H),3.91(s,3H),3.88(t,J＝8.8Hz，2H),3.08(t,J＝8.6Hz,2H).Dissolve 1-(4-methoxy-7-nitro-2,3-dihydro-1H-indol-1-yl)ethan-1-one (2.0g) in MeOH (50mL), add CH 3 ONa (2.29g), then the temperature was raised to 90°C and stirred for 8 hours. TLC showed that the reaction was completed. At 0°C, the reaction solution was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to remove DCM, and the residue was purified by column chromatography to obtain a yellow solid 4-methoxy-7-nitro- 2,3-Dihydro-1H-indole (1.5g, yield 94%), 1 H NMR (400MHz, CDCl 3 ) δ7.87 (d, J＝9.2Hz, 1H), 6.28 (d, J＝ 9.2Hz,1H),5.32(s,1H),3.91(s,3H),3.88(t,J＝8.8Hz,2H),3.08(t,J＝8.6Hz,2H).
步骤5：4-甲氧基-1-(甲基磺酰基)-7-硝基-2,3-二氢-1H-吲哚的制备
Step 5: Preparation of 4-methoxy-1-(methylsulfonyl)-7-nitro-2,3-dihydro-1H-indole
将4-甲氧基-7-硝基-2,3-二氢-1H-吲哚(1.5g)溶于干燥的DMF(15mL)中，降温至0℃，在该温度下加入NaH(含量60％)(618.40mg)搅拌10min，然后0℃下缓慢加入MsCl(1.33g)，升至室温下搅拌1小时，TLC显示原料反应完毕。在0℃下，反应液加水淬灭，EA萃取，有机相用饱和NH4Cl溶液洗三遍，无水硫酸钠干燥，浓缩除去EA，残余物经柱层析纯化得到黄色固体4-甲氧基-1-(甲基磺酰基)-7-硝基-2,3-二氢-1H-吲哚(1.5g,收率:71％),1H NMR(400MHz,CDCl3)δ7.93(d,J＝9.2Hz,1H),6.71(d,J＝9.2Hz, 1H),4.28(t,J＝7.8Hz,2H),3.95(s,3H),3.28(s,3H),3.09(t,J＝7.6Hz,2H).Dissolve 4-methoxy-7-nitro-2,3-dihydro-1H-indole (1.5g) in dry DMF (15mL), cool to 0°C, and add NaH (content 60%) (618.40 mg) was stirred for 10 min, then MsCl (1.33g) was slowly added at 0°C, and the mixture was raised to room temperature and stirred for 1 hour. TLC showed that the raw material reaction was completed. At 0°C, the reaction solution was quenched with water, extracted with EA, the organic phase was washed three times with saturated NH 4 Cl solution, dried over anhydrous sodium sulfate, concentrated to remove EA, and the residue was purified by column chromatography to obtain 4-methoxy as a yellow solid. Base-1-(methylsulfonyl)-7-nitro-2,3-dihydro-1H-indole (1.5g, yield: 71%), 1 H NMR (400MHz, CDCl 3 ) δ7.93 (d,J＝9.2Hz,1H),6.71(d,J＝9.2Hz, 1H), 4.28 (t, J = 7.8Hz, 2H), 3.95 (s, 3H), 3.28 (s, 3H), 3.09 (t, J = 7.6Hz, 2H).
步骤6：4-甲氧基-1-(甲基磺酰基)-2,3-二氢-1H-吲哚-7-胺的制备
Step 6: Preparation of 4-methoxy-1-(methylsulfonyl)-2,3-dihydro-1H-indole-7-amine
将4-甲氧基-1-(甲基磺酰基)-7-硝基-2,3-二氢-1H-吲哚(1.5g)溶于MeOH(50mL)中，加入20％Pd/C(300mg)，置换成H2气氛，然后室温下反应4h，LCMS显示反应完毕。混合物通过硅藻土过滤，并用甲醇洗涤，滤液真空浓缩，得到油状物4-甲氧基-1-(甲基磺酰基)-2,3-二氢-1H-吲哚-7-胺(1.35g,粗品),该粗品直接用于下一步。LCMS(ESI)m/z:243.1[M+H]+ Dissolve 4-methoxy-1-(methylsulfonyl)-7-nitro-2,3-dihydro-1H-indole (1.5g) in MeOH (50mL), and add 20% Pd/C (300mg), replaced with H2 atmosphere, and then reacted at room temperature for 4h, LCMS showed that the reaction was completed. The mixture was filtered through celite and washed with methanol, and the filtrate was concentrated in vacuo to give an oil, 4-methoxy-1-(methylsulfonyl)-2,3-dihydro-1H-indole-7-amine (1.35 g, crude product), this crude product was directly used in the next step. LCMS(ESI)m/z:243.1[M+H] +
步骤7：N-(5-溴-2-氯嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚-7-胺的制备
Step 7: Preparation of N-(5-bromo-2-chloropyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indole-7-amine
将4-甲氧基-1-(甲基磺酰基)吲哚-7-胺(300mg)，5-溴-2,4-二氯嘧啶(280mg)，碳酸钾(808mg)加到N,N-二甲基甲酰胺(5mL)中，30℃反应16小时，TLC显示原料反应完毕。反应液浓缩去除溶剂，经制备TLC纯化得到淡黄色固体N-(5-溴-2-氯嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚-7-胺(450mg,收率：84％)。LCMS(ESI)m/z:432.98[M+H]+,1H NMR(400MHz,CDCl3)δ8.31(m,2H),8.03(s,1H),7.24(d,J＝8.8Hz,1H),4.05(t,J＝8.4Hz,2H),3.97(s,3H),3.30(t,J＝8.4Hz,2H),2.93(s,3H).Add 4-methoxy-1-(methylsulfonyl)indole-7-amine (300mg), 5-bromo-2,4-dichloropyrimidine (280mg), potassium carbonate (808mg) to N, N - Dimethylformamide (5 mL), react at 30°C for 16 hours, TLC shows that the reaction of the raw materials is complete. The reaction solution was concentrated to remove the solvent, and purified by preparative TLC to obtain a light yellow solid N-(5-bromo-2-chloropyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indole-7- Amine (450 mg, yield: 84%). LCMS (ESI) m/z: 432.98 [M+H] + , 1 H NMR (400MHz, CDCl 3 ) δ8.31 (m, 2H), 8.03 (s, 1H), 7.24 (d, J = 8.8Hz, 1H), 4.05 (t, J = 8.4Hz, 2H), 3.97 (s, 3H), 3.30 (t, J = 8.4Hz, 2H), 2.93 (s, 3H).
步骤8：合成7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的制备
Step 8: Synthesis of 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
将N-(5-溴-2-氯嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚-7-胺(450mg)加到二氯甲烷(10mL)中，在氮气保护下，0℃加入三溴化硼二氯甲烷溶液(3.12mL)，反应液在0～30℃下搅拌5小时，TLC显示原料反应完毕，反应液浓缩去除溶剂，经制备TLC纯化得到7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(310mg,收率:71％)。LCMS(ESI)m/z:419.97[M+H]+；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. 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol (310 mg, yield: 71%) was obtained. LCMS(ESI)m/z:419.97[M+H] + ;
1H NMR H NMR(400MHz,CDCl3)δ9.08(s,1H),8.28(s,1H),7.70(d,J＝8.8Hz,1H),6.78(d,J＝8.8Hz,1H),4.17(dd,J＝14.4,7.2Hz,2H),3.09(t,J＝7.5Hz,2H),3.00～2.85(m,3H). 1 H NMR H NMR (400MHz, CDCl 3 ) δ9.08 (s, 1H), 8.28 (s, 1H), 7.70 (d, J = 8.8Hz, 1H), 6.78 (d, J = 8.8Hz, 1H) ,4.17(dd,J＝14.4,7.2Hz,2H),3.09(t,J＝7.5Hz,2H),3.00～2.85(m,3H).
步骤9：5-(2-氟-4-甲氧基-5-硝基苯)戊-4-辛-1-醇的制备
Step 9: Preparation of 5-(2-fluoro-4-methoxy-5-nitrobenzene)pentan-4-oct-1-ol
氮气保护下，将1-溴-2-氟-4-甲氧基-5-硝基苯(1.5g)、4-戊炔-1-醇(0.51g)、N,N-二异丙基乙胺(3.88g)、三苯基膦(315mg)、二氯二三苯基膦钯(421mg)和碘化亚铜(229mg)加到N,N-二甲基甲酰胺(20mL)中，在氮气保护下，80℃反应7小时，TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, combine 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.5g), 4-pentyn-1-ol (0.51g), N,N-diisopropyl Ethylamine (3.88g), triphenylphosphine (315mg), dichloroditriphenylphosphine palladium (421mg) and copper iodide (229mg) were added to N,N-dimethylformamide (20mL). Under nitrogen protection, the reaction was carried out at 80°C for 7 hours. TLC showed that the reaction of the raw materials was completed. The next step was taken without purification.
步骤10：5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇的制备
Step 10: 5-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-octane-1 -Preparation of alcohol
将1-甲基-4-(哌啶-4-基)哌嗪(3.3g)，碳酸钾(2.5g)加入到第一步反应液中，在80℃下搅拌16h，LCMS监测反应完毕。然后反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，反应液浓缩除去有机溶剂，残余物经层析柱纯化得到黄色油状物5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇(1.6g,收率:64％)。LCMS:(ESI)m/z:417.54[M+H]+.Add 1-methyl-4-(piperidin-4-yl)piperazine (3.3g) and potassium carbonate (2.5g) to the reaction solution in the first step, stir at 80°C for 16h, and monitor the reaction with LCMS to complete. Then the reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, the reaction solution was concentrated to remove the organic solvent, and the residue was purified by chromatography column to obtain a yellow oily substance 5-(4-methoxy -2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-octan-1-ol (1.6g, yield: 64% ). LCMS:(ESI)m/z:417.54[M+H] + .
步骤11：5-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇的制备
Step 11: Preparation of 5-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol
将5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇(1.6g)加入到甲醇(30mL)中，加入干钯/碳(0.2g)，LCMS显示原料反应完毕。过滤钯/碳，浓缩去除甲醇溶剂，得到棕色油状物5-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇(1.5g，粗品)，该粗品直接用于下一步。LCMS(ESI)m/z:391.32[M+H]+；1H NMR(400MHz,DMSO)δ6.60(s,1H),6.44(s,1H),4.34(m,3H),3.77～3.67(m,3H),3.39(m,3H),2.86(m,4H),2.70～2.57(m,4H),2.48～2.37(m,4H),1.83(m,2H),1.65～1.39(m,6H),1.31(m,2H),1.28～1.14(m,2H).5-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-oct-1-ol (1.6g) was added to methanol (30mL), dry palladium/carbon (0.2g) was added, and LCMS showed that the reaction of the raw materials was complete. Filter the palladium/carbon and concentrate to remove the methanol solvent to obtain a brown oily substance 5-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)pentan-1-ol (1.5g, crude product), which was used directly in the next step. LCMS (ESI) m/z: 391.32[M+H] + ; 1 H NMR (400MHz, DMSO) δ6.60 (s, 1H), 6.44 (s, 1H), 4.34 (m, 3H), 3.77～3.67 (m,3H),3.39(m,3H),2.86(m,4H),2.70～2.57(m,4H),2.48～2.37(m,4H),1.83(m,2H),1.65～1.39(m ,6H),1.31(m,2H),1.28～1.14(m,2H).
步骤12：叔丁基(5-(5-羟戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯的制备
Step 12: tert-butyl (5-(5-hydroxypentyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of urethane
5-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇(500mg)和二碳酸二叔丁酯(838mg)加入四氢呋喃(10mL)中，然后升温至70℃搅拌16h，LCMS显示反应完毕。反应液浓缩除去四氢呋喃溶剂，残余物经制备TLC纯化得到棕色油状物叔丁基(5-(5-羟戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯(350mg,收率56％)。LCMS(ESI)m/z:491.27[M+H]+；1H NMR(400MHz,CDCl3)δ7.79(s,1H),6.88(s,1H),6.65(s,1H),3.84～3.79(m,3H),3.64(td,J＝6.6,3.7Hz,2H),3.48～3.44(m,4H),3.04(m,2H),2.64(m,4H),2.62～2.56(m,4H),2.31(m,5H),1.95(m,2H),1.66～1.59(m,5H),1.52(s,9H),1.39(m,2H).5-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol (500 mg) and di Di-tert-butyl carbonate (838 mg) was added to tetrahydrofuran (10 mL), then the temperature was raised to 70°C and stirred for 16 hours. LCMS showed that the reaction was complete. The 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%). LCMS (ESI) m/z: 491.27 [M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ7.79 (s, 1H), 6.88 (s, 1H), 6.65 (s, 1H), 3.84～ 3.79(m,3H),3.64(td,J＝6.6,3.7Hz,2H),3.48～3.44(m,4H),3.04(m,2H),2.64(m,4H),2.62～2.56(m, 4H),2.31(m,5H),1.95(m,2H),1.66～1.59(m,5H),1.52(s,9H),1.39(m,2H).
步骤13：5-((叔丁基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基4-甲基苯磺酸脂的制备
Step 13: 5-((tert-butylcarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentyl Preparation of 4-methylbenzenesulfonate ester
将叔丁基(5-(5-羟戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯(350mg)溶于二氯甲烷(5mL)，加入三乙胺(359mg)、对甲苯磺酰氯(675mg)和4-二甲氨基吡啶(9mg)，在30℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去二氯甲烷，经制备TLC纯化，得到淡黄色液体5-((叔丁基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基4-甲基苯磺酸脂(380mg,收率83％)。LCMS(ESI)m/z:645.37[M+H]+。Tert-butyl(5-(5-hydroxypentyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)aminomethyl Acid ester (350mg) was dissolved in dichloromethane (5mL), triethylamine (359mg), p-toluenesulfonyl chloride (675mg) and 4-dimethylaminopyridine (9mg) were added, stirred at 30°C for 16h, LCMS showed reaction complete. The reaction solution was concentrated to remove dichloromethane and purified by preparative TLC to obtain a light yellow liquid 5-((tert-butylcarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazine-1- (yl)piperidin-1-yl)phenyl)pentyl 4-methylbenzenesulfonate (380 mg, yield 83%). LCMS(ESI)m/z:645.37[M+H] + .
步骤14：叔丁基(5-(7-(5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基)氧)戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯
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
将5-((叔丁基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基4-甲基苯磺酸脂(380mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(247mg)和碳酸铯(385mg)加入到N,N-二甲基甲酰胺(5mL)中，80℃下搅拌16h，LCMS显示反应完毕。反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到棕色油状物叔丁基(5-(7-(5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基)氧)戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯(370mg,收率64％)。LCMS(ESI)m/z:891.42[M+H]+。5-((tert-butylcarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentyl 4- Toluene sulfonate (380 mg), 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (247 mg), and cesium carbonate (385mg) was added to N,N-dimethylformamide (5mL) and stirred at 80°C for 16h. LCMS showed that the reaction was complete. The reaction solution was washed with deionized water, extracted with dichloromethane/isopropanol, 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 tert-butyl (5-(7-(5- Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-yl)oxy)pentyl)-2-methoxy-4-(4-(4-methyl Piperazin-1-yl)piperidin-1-yl)phenyl)carbamate (370 mg, yield 64%). LCMS(ESI)m/z:891.42[M+H] + .
步骤15：4-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基)氧)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐
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
将叔丁基(5-(7-(5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基)氧)戊基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸酯(370mg)溶于二氯甲烷(5mL)中，然后加入三氟醋酸(5mL)，30℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂得到棕色油状物4-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基)氧)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐(300mg粗品)。LCMS(ESI)m/z:791.31[M+H]+。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 (370 mg) was dissolved in dichloromethane (5 mL) and added Trifluoroacetic acid (5mL), stirred at 30°C for 16h, LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the solvent to obtain a brown oily substance 4-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentyl (300 mg crude product). LCMS(ESI)m/z:791.31[M+H] + .
步骤16：35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
4-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基)氧)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐(300mg)加入乙二醇甲醚(100mL)中，加入甲磺酸(95mg)，90℃下搅拌16h，LCMS监测反应完毕。反应液浓缩除去有机溶剂， 残余物经反相柱纯化得黄色固体35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(11.7mg,收率4％)。LCMS(ESI)m/z:755.30[M+H]+。1H NMR(400MHz,DMSO)δ9.10～8.97(m,1H),8.30(t,J＝5.7Hz,1H),7.96(d,J＝10.3Hz,1H),7.54(d,J＝10.2Hz,1H),7.34(dd,J＝21.0,8.3Hz,1H),7.11(dd,J＝17.9,8.7Hz,1H),6.91–6.78(m,1H),4.42–4.22(m,3H),4.05(dd,J＝17.9,10.3Hz,4H),3.91–3.83(m,6H),3.05(d,J＝7.7Hz,4H),2.93(s,2H),2.78(d,J＝26.0Hz,4H),2.73–2.63(m,2H),2.23(s,1H),2.02(dd,J＝18.2,12.7Hz,4H),1.72(dd,J＝53.8,26.1Hz,6H),1.38(t,J＝31.5Hz,4H).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 (300 mg) was added to ethylene glycol methyl ether (100 mL), and methanesulfonic acid was added (95mg), stirred at 90°C for 16h, and LCMS monitored the reaction to completion. The reaction solution is concentrated to remove the organic solvent. The residue was purified by a reverse-phase column to obtain a yellow solid 3 5 -bromo-5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperidine-1-1 1 -(methane) Sulfonyl)-11-oxa-2,4-diazaa-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodeca alkane (11.7 mg, yield 4%). LCMS (ESI) m/z: 755.30 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.10～8.97 (m, 1H), 8.30 (t, J＝5.7Hz,1H),7.96(d,J＝10.3Hz,1H),7.54(d,J＝10.2Hz,1H),7.34(dd,J＝21.0,8.3Hz,1H),7.11(dd, J＝17.9,8.7Hz,1H),6.91–6.78(m,1H),4.42–4.22(m,3H),4.05(dd,J＝17.9,10.3Hz,4H),3.91–3.83(m,6H) ,3.05(d,J＝7.7Hz,4H),2.93(s,2H),2.78(d,J＝26.0Hz,4H),2.73–2.63(m,2H),2.23(s,1H),2.02( dd,J＝18.2,12.7Hz,4H),1.72(dd,J＝53.8,26.1Hz,6H),1.38(t,J＝31.5Hz,4H).
根据实施例1中化合物相同的方法制备以下化合物：The following compounds were prepared according to the same method as the compounds in Example 1:
实施例2：56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-11-氧杂-2,4-二氮杂-3(4,2)-噻吩[3,2-d]嘧啶-1(7,4)-吲哚啉-5(1,3)-苯并环十一烷
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
浅黄色固体，3.51mg；LCMS:m/z＝733.40[M+H]+.1H NMR(400MHz,DMSO)δ8.34(m,1H),7.45(s,1H),7.37(m,1H),7.08(m,1H),7.01(m,1H),6.82(m,1H),4.48～4.22(m,2H),4.10～3.90(m,2H),3.90～2.40(m,14H),2.40～2.20(m,2H),2.20～1.80(m,7H),1.80～1.10(m,14H).Light yellow solid, 3.51 mg; LCMS: m/z=733.40[M+H] + . 1 H NMR (400MHz, DMSO) δ8.34 (m, 1H), 7.45 (s, 1H), 7.37 (m, 1H) ),7.08(m,1H),7.01(m,1H),6.82(m,1H),4.48～4.22(m,2H),4.10～3.90(m,2H),3.90～2.40(m,14H), 2.40～2.20(m,2H),2.20～1.80(m,7H),1.80～1.10(m,14H).
实施例3：35-氯-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
浅黄色固体，2.04mg；LCMS:m/z＝711.30[M+H]+.1H NMR(400MHz,DMSO)δ8.35～8.25(m,1H),7.60～7.50(m,1H),7.40～7.30(m,1H),7.20～7.00(m,1H),6.80～6.70(m,1H),4.45～4.25(m,2H),4.20～4.00(m,8H),3.25～2.60(m,13H),2.30～2.03(m,5H),2.00～1.90(m,4H),1.90～1.10(m,12H)Light yellow solid, 2.04mg; LCMS: m/z＝711.30[M+H] + . 1 H NMR (400MHz, DMSO) δ8.35～8.25(m,1H),7.60～7.50(m,1H),7.40 ~7.30(m,1H),7.20~7.00(m,1H),6.80~6.70(m,1H),4.45~4.25(m,2H),4.20~4.00(m,8H),3.25~2.60(m, 13H),2.30～2.03(m,5H),2.00～1.90(m,4H),1.90～1.10(m,12H)
实施例4：35-溴-56-甲氧基-54-(9-甲基-3,9-二氮杂罗[5.5]十一烷-3-基)-11-(甲基磺酰基)-11-氧-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，5.02mg；LCMS:m/z＝741.40[M+H]+.1H NMR(400MHz,DMSO)δ9.33(s,1H),9.25(s,1H),8.36(s,1H),8.34～8.26(m,1H),7.47(s,1H),7.35(d,J＝8.9Hz,1H),7.11(d,J＝9.0Hz,1H),6.93(s,1H),4.37(s,2H),3.77(s,3H),3.27(d,J＝8.7Hz,2H),3.04～2.96(m,7H),2.79(m,7H),2.09(m,2H),1.93(s,2H),1.73(s,4H),1.49(m,4H),1.36(m,4H).Off-white solid, 5.02mg; LCMS: m/z＝741.40[M+H] + . 1 H NMR (400MHz, DMSO) δ9.33 (s, 1H), 9.25 (s, 1H), 8.36 (s, 1H) ),8.34～8.26(m,1H),7.47(s,1H),7.35(d,J＝8.9Hz,1H),7.11(d,J＝9.0Hz,1H),6.93(s,1H),4.37 (s,2H),3.77(s,3H),3.27(d,J＝8.7Hz,2H),3.04～2.96(m,7H),2.79(m,7H),2.09(m,2H),1.93( s,2H),1.73(s,4H),1.49(m,4H),1.36(m,4H).
实施例5：N1-(35-溴-56-甲氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-54基)-N1,N2,N2-三甲基甲烷-1,2-二胺
Example 5: N 1 -(3 5 -bromo-5 6 -methoxy-1 1 -(methylsulfonyl)-1 1 -oxo-2,4-diazo-1(7,4)-indole Doline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane-54yl)-N1,N2,N2-trimethylmethane-1,2-diamine
淡黄色固体，2.10mg；LCMS:m/z＝674.40[M+H]+ Light yellow solid, 2.10mg; LCMS: m/z=674.40[M+H] +
实施例6：(S)-(1-(35-溴-56-甲氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-54-基)哌啶-3-基)甲醇
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
白色固体，0.62mg；LCMS:m/z＝687.90[M+H]+.White solid, 0.62 mg; LCMS: m/z=687.90[M+H] + .
实施例7：N1-(56-甲氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-3(4,2)-噻吩[3,2-d]嘧啶-1(7,4)-吲哚啉-5(1,3)-苯环十烷-54基)-N1,N2,N2-三甲基甲烷-1,2-二胺
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
白色固体，2.43mg；LCMS:m/z＝652.30[M+H]+ White solid, 2.43mg; LCMS: m/z=652.30[M+H] +
实施例8:35-溴-56-甲氧基-54-(5-(1-甲基-1h-吡唑-4-基)嘧啶-2-基)-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，3.03mg；LCMS(ESI)m/z:732.50[M+H]+。1H NMR(400MHz,DMSO&D2O)δ9.06(s,2H),8.33(s,1H),8.29(s,1H),8.07(s,1H),7.72(s,1H),7.48(s,1H),7.42(d,J＝9.0Hz,1H),7.13(d,J＝9.2Hz,1H),4.33(s,2H),4.07(d,J＝6.6Hz,2H),3.89(d,J＝2.0Hz,3H),3.01(s,4H),2.05～1.95(m,3H),1.66(s,2H),1.45(s,2H),1.26(s,3H).Off-white solid, 3.03 mg; LCMS (ESI) m/z: 732.50[M+H] + . 1 H NMR(400MHz,DMSO&D2O)δ9.06(s,2H),8.33(s,1H),8.29(s,1H),8.07(s,1H),7.72(s,1H),7.48(s,1H ),7.42(d,J＝9.0Hz,1H),7.13(d,J＝9.2Hz,1H),4.33(s,2H),4.07(d,J＝6.6Hz,2H),3.89(d,J =2.0Hz,3H),3.01(s,4H),2.05～1.95(m,3H),1.66(s,2H),1.45(s,2H),1.26(s,3H).
实施例9：35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-12-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十二碳烷
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
步骤1：6-(2-氟-4-甲氧基-5-硝基苯基)己-5-烯-1-醇的制备
Step 1: Preparation of 6-(2-fluoro-4-methoxy-5-nitrophenyl)hex-5-en-1-ol
氮气保护下将1-溴-2-氟-4-甲氧基-5-硝基苯(500mg)、5-己炔-1-醇(393mg)、N,N-二异丙基乙胺(1290mg)、三苯基膦(105mg)、二氯二三苯基膦钯(140mg)和碘化亚铜(76mg)加到N,N-二甲基甲酰胺(5mL)中，在氮气保护下，80℃反应7小时，TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (500mg), 5-hexyn-1-ol (393mg), N,N-diisopropylethylamine ( 1290mg), triphenylphosphine (105mg), dichloroditriphenylphosphine palladium (140mg) and copper iodide (76mg) were added to N,N-dimethylformamide (5mL) under nitrogen protection. , reacted at 80°C for 7 hours, TLC showed that the reaction of the raw materials was completed, and the next step was taken without purification.
步骤2：6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)己基-5-炔-1-醇的制备
Step 2: 6-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)hexyl-5-yne- Preparation of 1-alcohol
将1-甲基-4-(哌啶-4-基)哌嗪(440mg)和碳酸钾(552mg)加入到第一步反应液中，在80℃下搅拌1h，LCMS监测反应完毕。然后反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经层析柱纯化得到黄色油状物6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)己基-5-炔-1-醇(540mg,收率:63％)。LCMS:(ESI)m/z:431.4[M+H]+。1-Methyl-4-(piperidin-4-yl)piperazine (440 mg) and potassium carbonate (552 mg) were added to the reaction solution in the first step, stirred at 80°C for 1 hour, and LCMS monitored the reaction to completion. Then the reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by chromatography column to obtain a yellow oily substance 6-(4-methoxy-2 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)hexyl-5-yn-1-ol (540 mg, yield: 63%). LCMS:(ESI)m/z:431.4[M+H] + .
步骤3：6-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)己-1-醇的制备
Step 3: Preparation of 6-(5-amino-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)hexan-1-ol
将6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)己基-5-炔-1-醇(540mg)加入到甲醇(10mL)中，加入干钯/碳(100mg)，置换成氢气气氛，室温下搅拌16h，LCMS显示原料反应完毕。过滤钯/碳，浓缩除去甲醇，得到棕色油状物6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯基)己基-5-炔-1-醇(400mg，粗品)，该粗品直接用于下一步。LCMS(ESI)m/z:405.4[M+H]+。6-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)hexyl-5-yne-1- Alcohol (540 mg) was added to methanol (10 mL), dry palladium/carbon (100 mg) was added, replaced with hydrogen atmosphere, and stirred at room temperature for 16 hours. LCMS showed that the raw material reaction was completed. Filter palladium/carbon and concentrate to remove methanol to obtain brown oil 6-(4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrogen phenyl)hexyl-5-yn-1-ol (400 mg, crude product), which was used directly in the next step. LCMS(ESI)m/z:405.4[M+H] + .
步骤4：(5-(6-羟基己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯的制备
Step 4: (tert-butyl 5-(6-hydroxyhexyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamate Preparation of esters
(5-(6-羟基己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯(400mg)和二碳酸二叔丁酯(647mg)加入四氢呋喃(10mL)中，然后升温至70℃搅拌16h，LCMS显示反应完毕。反应液浓缩除去四氢呋喃，残余物经制备TLC纯化得到棕色油状物(5-(6-羟基己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯(400mg,收率63％)。LCMS(ESI)m/z:505.5[M+H]+。(5-(6-Hydroxyhexyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamic acid tert-butyl ester (400 mg ) and di-tert-butyl dicarbonate (647 mg) were added to tetrahydrofuran (10 mL), then the temperature was raised to 70°C and stirred for 16 hours. LCMS showed that the reaction was completed. The reaction solution was concentrated to remove tetrahydrofuran, and the residue was purified by preparative TLC to obtain a brown oily substance (5-(6-hydroxyhexyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperazine) Diphenyl)phenyl)carbamic acid tert-butyl ester (400 mg, yield 63%). LCMS(ESI)m/z:505.5[M+H] + .
步骤5：6-(5-((叔丁氧基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)己基-4-甲基苯磺酸脂的制备
Step 5: 6-(5-((tert-butoxycarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene Preparation of hexyl-4-methylbenzenesulfonate
将(5-(6-羟基己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯(400mg)溶于二氯甲烷(5mL)，加入三乙胺(400mg)、对甲苯磺酰氯(453mg)和4-二甲氨基吡啶(10mg)，在30℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去二氯甲烷，经制备TLC纯化，得到淡黄色液体6-(5-((叔丁氧基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)己基-4-甲基苯磺酸脂(450mg,收率86％)。LCMS(ESI)m/z:659.5[M+H]+。(5-(6-Hydroxyhexyl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamic acid tert-butyl ester ( 400mg) was dissolved in dichloromethane (5mL), added triethylamine (400mg), p-toluenesulfonyl chloride (453mg) and 4-dimethylaminopyridine (10mg), stirred at 30°C for 16h, LCMS showed that the reaction was complete. The 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%). LCMS(ESI)m/z:659.5[M+H] + .
步骤6：(5-(6-((7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚啉-4-基)氧基)己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯的制备
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
将6-(5-((叔丁氧基羰基)氨基)-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)己基-4-甲基苯磺酸脂(450mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(315mg)和碳酸铯(445mg)加入到N,N-二甲基甲酰胺(5mL)中，80℃下搅拌1h，LCMS显示反应完毕。反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩有机溶液，残余物经制备TLC纯化得到棕色油状物(5-(6-((7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚啉-4-基)氧基)己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯(470mg,收率76％)。LCMS(ESI)m/z:907.4[M+H]+。6-(5-((tert-butoxycarbonyl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Hexyl-4-methylbenzenesulfonate (450mg), 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (315mg ) and cesium carbonate (445 mg) were added to N,N-dimethylformamide (5 mL), and stirred at 80°C for 1 h. LCMS showed that the reaction was complete. The reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, and the organic solution was concentrated. The residue was purified by preparative TLC to obtain a brown oil (5-(6-((7-((5 -Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-yl)oxy)hexyl)-2-methoxy-4-(4-(4 -Methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamic acid tert-butyl ester (470 mg, yield 76%). LCMS(ESI)m/z:907.4[M+H] + .
步骤7：4-((6-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)己基)氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐的制备
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
将(5-(6-((7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚啉-4-基)氧基)己基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯(470mg)溶于二氯甲烷(5mL)中，然后加入三氟醋酸(5mL)，30℃下搅拌2h，LCMS显示反应完毕。反应液浓缩除去溶剂，得到棕色油状物4-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基)氧)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐(400mg粗品)。LCMS(ESI)m/z:807.3[M+H]+。(5-(6-((7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-yl)oxy)hexyl) -2-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)carbamic acid tert-butyl ester (470 mg) was dissolved in dichloromethane (5 mL) , then add trifluoroacetic acid (5 mL), stir at 30°C for 2 h, and LCMS shows that the reaction is complete. The reaction solution was concentrated to remove the solvent to obtain a brown oily substance 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 (400 mg crude). LCMS(ESI)m/z:807.3[M+H] + .
步骤8：35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷的制备
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
4-(5-氨基-4-甲氧基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊基)氧)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺三氟醋酸盐(20mg)加入乙二醇二甲醚(20mL)中，加入甲磺酸(9.4mg)，90℃下搅拌16h，LCMS监测反应完毕。反应液浓缩除去有机溶剂，残余物经反相柱纯化得白色固体35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(6mg,收率 32％)。LCMS(ESI)m/z:771.40[M+H]+。1H NMR(400MHz,DMSO)δ9.05(s,1H),8.31(s,1H),8.24(s,1H),7.39(s,1H),7.34(d,J＝8.9Hz,1H),6.96(d,J＝9.0Hz,1H),6.81(s,1H),4.37–4.27(m,4H),4.03–4.00(m,4H),3.84(s,3H),3.18–3.07(m,2H),3.05–2.92(m,8H),2.84(s,3H),2.71(t,J＝11.7Hz,2H),2.18–2.06(m,4H),1.75–1.60(m,4H),1.48(s,4H),1.26(d,J＝15.9Hz,4H).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 (20 mg) was added to ethylene glycol dimethyl ether (20 mL), and methanesulfonate was added Acid (9.4mg), stirred at 90°C for 16h, LCMS monitored that the reaction was complete. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by a reverse-phase column to obtain a white solid 3 5 -bromo-5 6 -methoxy-5 4 -(4-(4-methylpiperazin-1-yl)piperidine- 1-1 1- (methylsulfonyl)-11-oxa-2,4-diazaa-1(7,4)-indoline-3(4,2)-pyrimidine-5(1 ,3)-phenylcyclodecane (6mg, yield 32%). LCMS(ESI)m/z:771.40[M+H] + . 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.9Hz, 1H), 6.96(d,J＝9.0Hz,1H),6.81(s,1H),4.37–4.27(m,4H),4.03–4.00(m,4H),3.84(s,3H),3.18–3.07(m, 2H),3.05–2.92(m,8H),2.84(s,3H),2.71(t,J＝11.7Hz,2H),2.18–2.06(m,4H),1.75–1.60(m,4H),1.48 (s,4H),1.26(d,J＝15.9Hz,4H).
实施例10:35-溴-55-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：2-(3-溴-5-硝基苯氧基)-5-(1-甲基-1H-吡唑-4-基)嘧啶
Step 1: 2-(3-bromo-5-nitrophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine
将3-溴-5-硝基苯酚(300mg),2-氯-5-(1-甲基-1H-吡唑-4-基)嘧啶(269mg)和碳酸铯(906mg)加入到N,N-二甲基甲酰胺(5mL)中，升温至100℃，在该温度下搅拌5min，然后升至室温下搅拌5小时，TLC显示原料反应完毕。混合物中加水，过滤，固体用水洗涤，干燥得到固体产物2-(3-溴-5-硝基苯氧基)-5-(1-甲基-1H-吡唑-4-基)嘧啶(460mg,收率：88％)。1H NMR(400MHz,CDCl3)δ8.68(s,2H),8.29(d,J＝1.7Hz,1H),8.10(t,J＝2.0Hz,1H),7.77(m,2H),7.69(s,1H),4.01(s,3H).3-Bromo-5-nitrophenol (300 mg), 2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine (269 mg) and cesium carbonate (906 mg) were added to N,N - dimethylformamide (5 mL), raise the temperature to 100°C, stir at this temperature for 5 min, then raise to room temperature and stir for 5 hours. TLC shows that the reaction of the raw materials is complete. Water was added to the mixture, filtered, and the solid was washed with water and dried to obtain the solid product 2-(3-bromo-5-nitrophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine (460 mg , Yield: 88%). 1 H NMR (400MHz, CDCl 3 ) δ8.68 (s, 2H), 8.29 (d, J = 1.7Hz, 1H), 8.10 (t, J = 2.0Hz, 1H), 7.77 (m, 2H), 7.69 (s,1H),4.01(s,3H).
步骤2：5-(3-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-5-硝基苯)戊-4-丁-1-醇
Step 2: 5-(3-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy-5-nitrobenzene)pentan-4-butan-1-ol
将2-(3-溴-5-硝基苯氧基)-5-(1-甲基-1H-吡唑-4-基)(460mg)、4-戊炔-1-醇(207mg)、N,N-二异丙基乙胺(793mg)、三苯基膦(66mg)、二氯二三苯基膦钯(84mg)和碘化亚铜(48mg)加到N,N-二甲基甲酰胺(5mL)中，在氮气保护下，80℃反应6小时，TLC显示原料反应完毕。反应液用去离子水洗涤，二氯甲烷萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到棕色油状物5-(3-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-5-硝基苯)戊-4-丁-1-醇(270mg,收率58％)。2-(3-bromo-5-nitrophenoxy)-5-(1-methyl-1H-pyrazol-4-yl) (460 mg), 4-pentyn-1-ol (207 mg), N,N-diisopropylethylamine (793mg), triphenylphosphine (66mg), dichloroditriphenylphosphine palladium (84mg) and copper iodide (48mg) were added to N,N-dimethyl In formamide (5 mL), the reaction was carried out at 80°C for 6 hours under nitrogen protection. TLC showed that the reaction of the raw materials was completed. The 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%).
步骤3：5-(3-氨基-5-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基)苯戊醇
Step 3: 5-(3-amino-5-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy)phenylpentanol
将5-(3-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-5-硝基苯)戊-4-丁-1-醇(270mg)，二氧化铂(20mg)加入甲醇(10mL)中，氢气氛围下，20℃搅拌5h，LCMS监测反应完毕。反应液过滤，浓缩除去溶剂，得到黄色油状物5-(3-氨基-5-(5-(1-甲基-1h-吡唑-4-基)嘧啶-2-基)氧基)苯戊醇(190mg)。1H NMR(400MHz,CDCl3)δ8.63(s,2H),7.72(s,1H),7.64(s,1H),6.47～6.38(m,2H),6.38～6.27(m,1H),3.98(s,3H),3.63(m,2H),2.55(m,2H),1.65～1.57(m,4H),1.47～1.39(m,2H).5-(3-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy-5-nitrobenzene)pentan-4-butan-1-ol (270 mg ), platinum dioxide (20 mg) was added to methanol (10 mL), stirred at 20°C for 5 hours under a hydrogen atmosphere, and LCMS monitored that the reaction was completed. The reaction solution was filtered, concentrated to remove the solvent, and a yellow oily substance 5-(3-amino-5-(5-(1-methyl-1h-pyrazol-4-yl)pyrimidin-2-yl)oxy)phenylpentane was obtained. Alcohol (190mg). 1 H NMR (400MHz, CDCl 3 ) δ8.63(s,2H),7.72(s,1H),7.64(s,1H),6.47～6.38(m,2H),6.38～6.27(m,1H), 3.98(s,3H),3.63(m,2H),2.55(m,2H),1.65～1.57(m,4H),1.47～1.39(m,2H).
步骤4：叔丁基(3-(5-羟基戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧苯基)氨基甲酸酯
Step 4: tert-Butyl(3-(5-hydroxypentyl)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)aminomethyl acid ester
将5-(3-氨基-5-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基)苯戊醇(190mg)和二碳酸二叔丁酯(353mg)加入四氢呋喃(5mL)中，然后升温至70℃搅拌16h，LCMS显示反应完毕。反应液浓缩除去四氢呋喃，残余物经制备TLC纯化得到棕色油状物叔丁基(3-(5-羟基戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧苯基)氨基甲酸酯(150mg,收率：61％)。LCMS(ESI)m/z:454.22[M+H]+。5-(3-Amino-5-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxy)phenylpentanol (190 mg) and di-tert-butyl dicarbonate (353mg) was added to tetrahydrofuran (5mL), then the temperature was raised to 70°C and stirred for 16h. LCMS showed that the reaction was completed. The reaction solution was concentrated to remove tetrahydrofuran, and the residue was purified by preparative TLC to obtain brown oily substance tert-butyl (3-(5-hydroxypentyl)-5-((5-(1-methyl-1H-pyrazol-4-yl) )pyrimidin-2-yl)oxyphenyl)carbamate (150 mg, yield: 61%). LCMS (ESI) m/z: 454.22 [M+H] + .
步骤5：5-(3-(叔丁基羰基)氨基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基苯基)戊基4-甲基苯磺酸脂
Step 5: 5-(3-(tert-butylcarbonyl)amino)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)pentyl 4-methylbenzenesulfonate
将叔丁基(3-(5-羟基戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧苯基)氨基甲酸酯(150mg)溶于二氯甲烷(5mL)，加入三乙胺(167mg)、对甲苯磺酰氯(126mg)和4-二甲氨基吡啶(4mg)，在20℃下搅拌3.5h，LCMS显示反应完毕。反应液浓缩除去二氯甲烷，经制备TLC纯化，得到淡黄色液体5-(3-(叔丁基羰基)氨基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基苯基)戊基4-甲基苯磺酸脂(200mg,收率99％)。LCMS(ESI)m/z:608.25[M+H]+。tert-Butyl(3-(5-hydroxypentyl)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)carbamate (150mg) was dissolved in dichloromethane (5mL), added triethylamine (167mg), p-toluenesulfonyl chloride (126mg) and 4-dimethylaminopyridine (4mg), stirred at 20°C for 3.5h, LCMS showed that the reaction was complete The reaction solution was concentrated to remove dichloromethane and purified by preparative TLC to obtain a light yellow liquid 5-(3-(tert-butylcarbonyl)amino)-5-((5-(1-methyl-1H-pyrazole-4) -yl)pyrimidin-2-yl)oxyphenyl)pentyl 4-methylbenzenesulfonate (200 mg, yield 99%). LCMS (ESI) m/z: 608.25 [M+H] + .
步骤6：叔丁基(3-(5-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基氧基)戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)苯基氨基甲酸酯
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
将5-(3-(叔丁基羰基)氨基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基苯基)戊基4-甲基苯磺酸脂(200mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(138mg)和碳酸铯(215mg)加入到N,N-二甲基甲酰胺(5mL)中，80℃下搅拌16h，LCMS显示反应完毕。反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到棕色油状物叔丁基(3-(5-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基氧基)戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)苯基氨基甲酸酯(300mg,crude)。LCMS(ESI)m/z:855.19[M+H]+。5-(3-(tert-butylcarbonyl)amino)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)oxyphenyl)pentyl 4 -Toluene sulfonate (200 mg), 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (138 mg) and carbonic acid Cesium (215 mg) was added to N,N-dimethylformamide (5 mL), and stirred at 80°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, 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 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 (300 mg, crude). LCMS (ESI) m/z: 855.19 [M+H] + .
步骤7：4-(5-(3-氨基-5-(5-(1-甲基-1h-吡唑-4-基)嘧啶-2-基氧基)苯基)戊基氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺基)吲哚-7-胺
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
将叔丁基(3-(5-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-基氧基)戊基)-5-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)苯基氨基甲酸酯(300mg)溶于二氯甲烷(5mL)中，然后加入三氟醋酸(5mL)，20℃下搅拌7h，LCMS显示反应完毕。反应液浓缩除去溶剂，经反相柱纯化得到棕色油状物4-(5-(3-氨基-5-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)苯基)戊基氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺基)吲哚-7-胺三氟醋酸盐(159mg，粗品)。LCMS(ESI)m/z:755.19[M+H]+。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 (300 mg) was dissolved in dichloromethane (5 mL), then Tris Fluoroacetic acid (5mL), stirred at 20°C for 7h, LCMS showed that the reaction was complete. The 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). LCMS (ESI) m/z: 755.19 [M+H] + .
步骤8：35-溴-55-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
4-(5-(3-氨基-5-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)苯基)戊基氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺基)吲哚-7-胺三氟醋酸盐(50mg)加入乙二醇甲醚(25mL)中，加入甲磺酸(19mg)，90℃下搅拌16h，LCMS监测反应完毕。反应液浓缩去有机溶剂，残余物经反相柱纯化得黄色固体35-溴-55-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(10mg,收率：21％)。LCMS(ESI)m/z:718.20[M+H]+。1H NMR(400MHz,DMSO)δ9.44(s,1H),8.85(s,2H),8.71(s,1H),8.23(s,2H),7.95(s,1H),7.45(d,J＝8.9Hz,1H),7.18～7.06(m,1H),6.72(s, 1H),6.51(s,1H),4.36(t,J＝5.4Hz,2H),4.08(d,J＝7.5Hz,2H),3.88(s,3H),3.10～2.99(m,5H),2.09(M,2H),1.74(M,2H),1.43(s,4H).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 trifluoroacetate (50 mg) was added to ethylene glycol methyl ether (25 mL), and methanesulfonate was added acid (19 mg), stirred at 90°C for 16 hours, and LCMS monitored the reaction to completion. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by a reversed-phase column to obtain a yellow solid 3 5 -bromo-5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl) Oxy-1 1 -(methylsulfonyl)-1 1 -oxy-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3 )-Benzenecyclodecane (10 mg, yield: 21%). LCMS (ESI) m/z: 718.20 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.44 (s, 1H), 8.85 (s,2H),8.71(s,1H),8.23(s,2H),7.95(s,1H),7.45(d,J＝8.9Hz,1H),7.18～7.06(m,1H),6.72( s, 1H),6.51(s,1H),4.36(t,J＝5.4Hz,2H),4.08(d,J＝7.5Hz,2H),3.88(s,3H),3.10～2.99(m,5H), 2.09(M,2H),1.74(M,2H),1.43(s,4H).
根据实施例10中化合物相同的方法制备以下化合物：The following compounds were prepared according to the same method as the compounds in Example 10:
实施例11：55-((5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氧基)-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-35-碳腈
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
白色固体，2.64mg；LCMS(ESI)m/z:665.40[M+H]+ White solid, 2.64mg; LCMS(ESI)m/z:665.40[M+H] +
实施例12：35-溴-55-((1-环丙基哌啶-4-基)氧基)-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.38mg；LCMS(ESI)m/z:638.40[M+H]+.1H NMR(400MHz,DMSO)δ9.27(d,J＝8.8Hz,1H),8.65(s,1H),8.21(s,1H),7.40(d,J＝9.0Hz,1H),7.29(s,1H),7.09(d,J＝9.1Hz,1H),6.55(d,J＝17.5Hz,1H),6.36(d,J＝15.3Hz,1H),4.34(s,1H),4.07(s,2H),3.58(s,2H),3.25(d,J＝3.3Hz,4H),2.27(s,1H),2.09～1.94(m,5H),1.72(s,4H),1.43(s,4H),0.93(s,2H),0.85(m,3H).Off-white solid, 2.38mg; LCMS (ESI) m/z: 638.40[M+H] + . 1 H NMR (400MHz, DMSO) δ9.27 (d, J = 8.8Hz, 1H), 8.65 (s, 1H) ),8.21(s,1H),7.40(d,J＝9.0Hz,1H),7.29(s,1H),7.09(d,J＝9.1Hz,1H),6.55(d,J＝17.5Hz,1H ),6.36(d,J＝15.3Hz,1H),4.34(s,1H),4.07(s,2H),3.58(s,2H),3.25(d,J＝3.3Hz,4H),2.27(s ,1H),2.09～1.94(m,5H),1.72(s,4H),1.43(s,4H),0.93(s,2H),0.85(m,3H).
实施例13:35-溴-11-(甲基磺酰基)-55-(3-吗啉-丙氧基)-11-氧-2,4-二氮杂-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并环癸烷
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
类白色固体，2.04mg；LCMS(ESI)m/z:687.60[M+H]+。Off-white solid, 2.04 mg; LCMS (ESI) m/z: 687.60[M+H] + .
实施例14:3-(35-溴-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-55-基)氧基-N,N-二甲基丙烷-1-胺
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
类白色固体，2.01mg；LCMS(ESI)m/z:645.40[M+H]+。Off-white solid, 2.01 mg; LCMS (ESI) m/z: 645.40[M+H] + .
实施例15:35-溴-55-((4-甲基哌嗪-1-基)甲基)-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.12mg；LCMS(ESI)m/z:656.40[M+H]+.1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.12(s,1H),7.70(s,1H),7.62！7.52(m,2H),7.21(s,1H),6.90(d,J＝9.0Hz,1H),6.68(s,1H),6.63(s,1H),4.35(t,J＝5.9Hz,2H),4.19(t,J＝7.5Hz,2H),3.55(s,2H),3.11(m,2H),2.94(s,3H),2.83(m,2H),2.67(m,2H),1.69(m,8H),1.50(m,2H),1.30(m,5H).Off-white solid, 2.12mg; LCMS (ESI) m/z: 656.40[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.62 (s, 1H), 8.12 (s, 1H), 7.70 ( s,1H),7.62!7.52(m,2H),7.21(s,1H),6.90(d,J＝9.0Hz,1H),6.68(s,1H),6.63(s,1H),4.35(t ,J＝5.9Hz,2H),4.19(t,J＝7.5Hz,2H),3.55(s,2H),3.11(m,2H),2.94(s,3H),2.83(m,2H),2.67 (m,2H),1.69(m,8H),1.50(m,2H),1.30(m,5H).
实施例18:35-溴-11-(甲基磺酰基)-55-((1-(嘧啶-5-基)哌啶-4-基)氧基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.62mg；LCMS(ESI)m/z:721.60[M+H]+。Off-white solid, 2.62 mg; LCMS (ESI) m/z: 721.60[M+H] + .
实施例19:55-((2-氧-7-氮杂螺[3.5]壬-7-基)甲基)-35-溴-11-(甲基磺酰基)-11-氧-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，17.14mg；LCMS(ESI)m/z:683.50[M+H]+。Off-white solid, 17.14 mg; LCMS (ESI) m/z: 683.50[M+H] + .
实施例20:35-溴-11-(甲基磺酰基)-55-((2-(三氟甲基)-5,6-二氢咪唑[1,2-a]吡嗪-7(8H)-基)甲基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.34mg；LCMS(ESI)m/z:747.50[M+H]+.1H NMR(400MHz,DMSO)δ9.49(s,1H),8.74(s,1H),8.24(s,1H),7.82(s,1H),7.63(s,1H),7.40(d,J＝8.9Hz,1H),7.10(d,J＝9.1Hz,1H),6.95(s,1H),6.77(s,1H),4.35(t,J＝5.6Hz,2H),4.14(s,3H),4.06(d,J＝7.4Hz,2H),3.06～2.87(m,5H),2.15～1.95(m,3H),1.73(s,2H),1.45(s,4H),1.24(s,4H).Off-white solid, 2.34mg; LCMS(ESI)m/z:747.50[M+H] + . 1 H NMR(400MHz, DMSO)δ9.49(s,1H),8.74(s,1H),8.24(s ,1H),7.82(s,1H),7.63(s,1H),7.40(d,J＝8.9Hz,1H),7.10(d,J＝9.1Hz,1H),6.95(s,1H),6.77 (s,1H),4.35(t,J＝5.6Hz,2H),4.14(s,3H),4.06(d,J＝7.4Hz,2H),3.06～2.87(m,5H),2.15～1.95( m,3H),1.73(s,2H),1.45(s,4H),1.24(s,4H).
实施例21:35-溴-55-(2-(1-甲基哌啶-4-基)乙基)-11-(甲基磺酰基)-11-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.59mg；LCMS(ESI)m/z:669.50[M+H]+.1H NMR(400MHz,DMSO)δ9.20(s,1H),8.60(s,1H),8.19(s,1H),7.46(s,1H),7.41(d,J＝9.0Hz,1H),7.08(d,J＝9.0Hz,1H),6.72(s,1H),6.52(s,1H),4.33(t,J＝5.7Hz,2H),4.07(t,J＝7.5Hz,2H),3.10-3.00(m,6H),2.94(s,3H),2.48-2.41(m,3H),2.33(s,3H),2.03(m,3H),1.69-1.73(m,4H),1.42(m,7H).Off-white solid, 2.59mg; LCMS(ESI)m/z:669.50[M+H] + . 1 H NMR(400MHz, DMSO)δ9.20(s,1H),8.60(s,1H),8.19(s ,1H),7.46(s,1H),7.41(d,J＝9.0Hz,1H),7.08(d,J＝9.0Hz,1H),6.72(s,1H),6.52(s,1H),4.33 (t,J＝5.7Hz,2H),4.07(t,J＝7.5Hz,2H),3.10-3.00(m,6H),2.94(s,3H),2.48-2.41(m,3H),2.33( s,3H),2.03(m,3H),1.69-1.73(m,4H),1.42(m,7H).
实施例16：2-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-6-氧-2,4-二氮-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯环十烷-52基)-1,2-噻嗪烷1,1-二氧化物
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
步骤1：2-(5-甲氧基-2-硝基苯)-1,2-噻嗪烷1,1-二氧化物
Step 1: 2-(5-methoxy-2-nitrobenzene)-1,2-thiazine 1,1-dioxide
将2-氟-4-甲氧基-1-硝基苯(1g),1,2-噻嗪烷1,1-二氧化物(790mg)和碳酸铯(3.78g)加入到N,N-二甲基甲酰胺(10mL)中，升温至80℃，搅拌5小时，TLC显示原料反应完毕。混合物中加水，过滤，固体用水洗涤，干燥得到固体产物2-(5-甲氧基-2-硝基苯)-1,2-噻嗪烷1,1-二氧化物(1.8g,粗品)。2-Fluoro-4-methoxy-1-nitrobenzene (1g), 1,2-thiazine 1,1-dioxide (790mg) and cesium carbonate (3.78g) were added to N,N- Dimethylformamide (10 mL) was heated to 80°C and stirred for 5 hours. TLC showed that the reaction of the raw materials was completed. Water was added to the mixture, filtered, the solid was washed with water, and dried to obtain the solid product 2-(5-methoxy-2-nitrobenzene)-1,2-thiazine 1,1-dioxide (1.8g, crude product) .
步骤2：2-(2-氨基-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物
Step 2: 2-(2-Amino-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide
将2-(5-甲氧基-2-硝基苯)-1,2-噻嗪烷1,1-二氧化物(1.8g,粗品)和干钯碳(200mg)加到甲醇(30mL)中，在氢气氛围下，20℃反应6小时，LCMS显示原料反应完毕。过滤催化剂，浓缩除去有机溶剂，得到棕色油状物2-(2-氨基-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物(1.58g)。1H NMR(400MHz,DMSO)δ6.71(m,3H),4.73(s,2H),3.64(s,3H),3.55！3.38(m,2H),3.26(d,J＝12.9Hz,2H),2.24-2.03(m,2H),1.97-1.73(m,2H).2-(5-Methoxy-2-nitrobenzene)-1,2-thiazine 1,1-dioxide (1.8 g, crude) and dry palladium on carbon (200 mg) were added to methanol (30 mL) In the hydrogen atmosphere, the reaction was carried out at 20°C for 6 hours, and LCMS showed that the reaction of the raw materials was completed. The catalyst was filtered, and the organic solvent was concentrated to remove the organic solvent to obtain 2-(2-amino-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide (1.58g) as a brown oil. 1H NMR (400MHz, DMSO) δ6.71 (m, 3H), 4.73 (s, 2H), 3.64 (s, 3H), 3.55! 3.38 (m, 2H), 3.26 (d, J = 12.9Hz, 2H) ,2.24-2.03(m,2H),1.97-1.73(m,2H).
步骤3：2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物
Step 3: 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide
将2-(2-氨基-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物(500mg)、5-溴-2,4-二氯嘧啶(441mg)和N,N-二异丙基乙胺(774mg)加入异丙醇(10mL)中，80℃下搅拌6h，LCMS监测反应完毕。反应液浓缩除去溶剂，残余物经柱层析纯化得到黄色油状物2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物(847mg,收率:95％)。2-(2-Amino-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide (500 mg), 5-bromo-2,4-dichloropyrimidine (441 mg) and N,N-diisopropylethylamine (774 mg) was added to isopropyl alcohol (10 mL), stirred at 80°C for 6 hours, and LCMS monitored the reaction to completion. The 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%).
步骤4：2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物
Step 4: 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-hydroxyphenyl)-1,2-thiazine 1,1-dioxide
将2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物(847mg)加入二氯甲烷(15mL)中，在氮气保护下，0℃加入三溴化硼二氯甲烷溶液(3.12mL)，反应在0～30℃下搅拌5小时，TLC显示原料反应完毕。反应液浓缩除去溶剂，柱层析纯化得到2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物(636mg,收率：77％)。LCMS(ESI)m/z:432.97[M+H]+。2-(2-(5-Bromo-2-chloropyrimidin-4-yl)amino)-5-methoxyphenyl)-1,2-thiazine 1,1-dioxide (847 mg) was added To dichloromethane (15 mL), under nitrogen protection, add boron tribromide dichloromethane solution (3.12 mL) at 0°C, and stir the reaction at 0-30°C for 5 hours. TLC shows that the raw material reaction is complete. The reaction solution was concentrated to remove the solvent, and purified by column chromatography to obtain 2-(2-(5-bromo-2-chloropyrimidin-4-yl)amino)-5-hydroxyphenyl)-1,2-thiazane 1,1 - Dioxide (636 mg, yield: 77%). LCMS(ESI)m/z:432.97[M+H] + .
步骤5：2-(2-(5-(5-羟戊基)-2-甲氧基-4-(1,4-二氧杂氧[4.5]癸-8-基)苯基)氨基)嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物
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
将2-(2-(5-溴-2-氯嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物(200mg),5-(5-氨基-4-甲氧基-2-(1,4-二氧杂氧-8-氮杂螺[4.5]癸-8-基)苯基)戊-1-醇(161mg)和三氟醋酸(42mg)溶于叔丁醇(5mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，经制备TLC纯化，得到淡黄色液体2-(2-(5-(5-羟戊基)-2-甲氧基-4-(1,4-二氧杂氧[4.5]癸-8-基)苯基)氨基)嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物(300mg,收率87％)。LCMS(ESI)m/z:747.21[M+H]+。2-(2-(5-Bromo-2-chloropyrimidin-4-yl)amino)-5-hydroxyphenyl)-1,2-thiazine 1,1-dioxide (200 mg), 5- (5-Amino-4-methoxy-2-(1,4-dioxaox-8-azaspiro[4.5]dec-8-yl)phenyl)pentan-1-ol (161 mg) and tris Fluoroacetic acid (42 mg) was dissolved in tert-butanol (5 mL) and stirred at 90°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the solvent and purified by preparative TLC to obtain a light yellow liquid 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 (300 mg, yield 87%) . LCMS(ESI)m/z:747.21[M+H] + .
步骤6：1-(4-(5-溴-4-((2-(1,1-二氧基-1,2-噻嗪-2-基)-4-羟基苯基)氨基嘧啶-2-基)氨基)-2-(5-溴戊基)-5-甲氧基)哌啶-4-酮
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
将2-(2-(5-(5-羟戊基)-2-甲氧基-4-(1,4-二氧杂氧[4.5]癸-8-基)苯基)氨基)嘧啶-4-基)氨基)-5-羟基苯基)-1,2-噻嗪烷1,1-二氧化物(300mg)加入到二氯甲烷(20mL)中，三溴化磷(327mg)缓慢滴加到反应液中，反应液20℃下搅拌16h，LCMS显示反应完毕。反应液滴入碳酸氢钠饱和水溶液中，二氯甲烷/异丙醇(10/1)萃取，浓缩有机相，得到粗品1-(4-(5-溴-4-((2-(1,1-二氧基-1,2-噻嗪-2-基)-4-羟基苯基)氨基嘧啶-2-基)氨基)-2-(5-溴戊基)-5-甲氧基)哌啶-4-酮(200mg,粗品)。2-(2-(5-(5-hydroxypentyl)-2-methoxy-4-(1,4-dioxaoxo[4.5]dec-8-yl)phenyl)amino)pyrimidine- 4-yl)amino)-5-hydroxyphenyl)-1,2-thiazine 1,1-dioxide (300mg) was added to dichloromethane (20mL), and phosphorus tribromide (327mg) was slowly dropped Add to the reaction solution, stir the reaction solution at 20°C for 16 hours, and LCMS shows that the reaction is complete. The reaction solution was dropped into a saturated aqueous solution of sodium bicarbonate, extracted with dichloromethane/isopropanol (10/1), and the organic phase was concentrated to obtain crude product 1-(4-(5-bromo-4-((2-(1, 1-Dioxy-1,2-thiazin-2-yl)-4-hydroxyphenyl)aminopyrimidin-2-yl)amino)-2-(5-bromopentyl)-5-methoxy) Piperidin-4-one (200 mg, crude product).
步骤7：1-(35-溴-52-(1,1-二氧基-1,2-噻嗪-2-基)-16-甲氧基-6-氧-2,4-二氮-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯环十烷-14-基)哌啶-4-酮
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
将1-(4-(5-溴-4-((2-(1,1-二氧基-1,2-噻嗪-2-基)-4-羟基苯基)氨基嘧啶-2-基)氨基)-2-(5-溴戊基)-5-甲氧基)哌啶-4-酮(200mg,粗品)、碳酸钾(108mg)和碘化钾(4.3mg)加入到于N,N-二甲基甲酰胺(40mL)中，反应在60℃下搅拌5h，LCMS显示反应完毕。反应液浓缩除去溶剂，经反相柱纯化得到棕色油状物1-(35-溴-52-(1,1-二氧基-1,2-噻嗪-2-基)-16-甲氧基-6-氧-2,4-二氮-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯环十烷-14-基)哌啶-4-酮(100mg，收率：56％)。LCMS(ESI)m/z:685.17[M+H]+。1-(4-(5-bromo-4-((2-(1,1-dioxy-1,2-thiazin-2-yl)-4-hydroxyphenyl)aminopyrimidin-2-yl )Amino)-2-(5-bromopentyl)-5-methoxy)piperidin-4-one (200mg, crude product), potassium carbonate (108mg) and potassium iodide (4.3mg) were added to N,N- In dimethylformamide (40 mL), the reaction was stirred at 60°C for 5 h, and LCMS showed that the reaction was complete. 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%). LCMS(ESI)m/z:685.17[M+H] + .
步骤8：2-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-6-氧杂-2,4-二氮杂-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯并环癸烷-52-基)-1,2-噻嗪烷1,1-二氧化物
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
41-(35-溴-52-(1,1-二氧基-1,2-噻嗪-2-基)-16-甲氧基-6-氧-2,4-二氮-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯环十烷-14-基)哌啶-4-酮(100mg)，N-甲基哌嗪(75mg)和醋酸(40mg)加入甲醇(10mL)中，混合物20℃下搅拌1小时后，加入氰基硼氢化钠(47.3mg)，20℃下搅拌16h，LCMS监测反应完毕。反应液浓缩除去有机溶，残余物经反相柱纯化得黄色固体 2-(35-溴-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-6-氧杂-2,4-二氮杂-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯并环癸烷-52-基)-1,2-噻嗪烷1,1-二氧化物(24mg,收率：21％)。LCMS(ESI)m/z:769.80[M+H]+。41-(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)piperidin-4-one (100mg), N-methylpiperazine ( 75 mg) and acetic acid (40 mg) were added to methanol (10 mL). After the mixture was stirred at 20°C for 1 hour, sodium cyanoborohydride (47.3 mg) was added and stirred at 20°C for 16 hours. LCMS monitored the reaction to completion. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by a reversed-phase column to obtain a yellow solid. 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 (24 mg, yield: 21%). LCMS(ESI)m/z:769.80[M+H] + .
根据实施例16中化合物相同的方法制备以下化合物：The following compounds were prepared according to the same method as the compounds in Example 16:
实施例17:52-(1,1-二氧化-1,2-噻嗪-2-基)-16-甲氧基-14-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-6-氧-2,4-二氮-3(2,4)-嘧啶-1(1,3)，5(1,4)-二苯环十烷-35-碳腈
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
类白色固体，4.43mg；LCMS(ESI)m/z:717.00[M+H]+。1H NMR(400MHz,DMSO)δ9.11(s,1H),8.46(s,1H),7.92(s,1H),7.36(s,1H),7.25(d,J＝8.8Hz,1H),7.07(m,1H),6.99(t,J＝7.0Hz,1H),6.74(s,1H),4.33(s,2H),3.81(s,3H),3.74-3.54(m,6H),3.41(s,6H),3.12(m,5H),2.91(m,2H),2.71(m,5H),2.11-1.94(m,5H),1.70(m,3H),1.55(m,4H).Off-white solid, 4.43 mg; LCMS (ESI) m/z: 717.00[M+H] + . 1 H NMR (400MHz, DMSO) δ9.11 (s, 1H), 8.46 (s, 1H), 7.92 (s, 1H), 7.36 (s, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.07(m,1H),6.99(t,J＝7.0Hz,1H),6.74(s,1H),4.33(s,2H),3.81(s,3H),3.74-3.54(m,6H),3.41 (s,6H),3.12(m,5H),2.91(m,2H),2.71(m,5H),2.11-1.94(m,5H),1.70(m,3H),1.55(m,4H).
实施例22:35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：5-(2-氟-5-硝基苯)戊-4-辛-1-醇的制备
Step 1: Preparation of 5-(2-fluoro-5-nitrobenzene)pentan-4-oct-1-ol
氮气保护下，将3-溴-4-氟硝基苯(500mg)、4-戊炔-1-醇(383mg)、N,N-二异丙基乙胺(884mg)、三苯基膦(120mg)、二氯二三苯基膦钯(160mg)和碘化亚铜(87mg)加到N,N-二甲基甲酰胺(10mL)中，在氮气保护下，80℃反应7h，TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, 3-bromo-4-fluoronitrobenzene (500mg), 4-pentyn-1-ol (383mg), N,N-diisopropylethylamine (884mg), triphenylphosphine ( 120 mg), dichloroditriphenylphosphine palladium (160 mg) and copper iodide (87 mg) were added to N,N-dimethylformamide (10 mL), and reacted at 80°C for 7 hours under nitrogen protection. TLC showed After the raw material reaction is completed, the next step is taken without purification.
步骤2：5-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇的制备
Step 2: Preparation of 5-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-oct-1-ol
将1-甲基-4-(哌啶-4-基)哌嗪(501mg)，碳酸钾(630mg)加入到第一步反应液中，在80℃下搅拌16h，LCMS监测反应完毕。然后反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩有机相溶液，残余物经层析柱纯化得到黄色油状物5-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇(450mg,收率:51％)。LCMS: (ESI)m/z:387.23[M+H]+.1-Methyl-4-(piperidin-4-yl)piperazine (501 mg) and potassium carbonate (630 mg) were added to the reaction solution in the first step, stirred at 80°C for 16 hours, and LCMS monitored the reaction to completion. Then the reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, the organic phase solution was concentrated, and the residue was purified by chromatography column to obtain a yellow oily substance 5-(2-(4-(4 -Methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-oct-1-ol (450 mg, yield: 51%). LCMS: (ESI)m/z:387.23[M+H] + .
步骤3：5-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇的制备
Step 3: Preparation of 5-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol
将5-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯)戊-4-辛-1-醇(450mg)加入到甲醇(15mL)中，加入二氧化铂(45mg)，LCMS显示原料反应完毕。过滤二氧化铂，浓缩除去甲醇，得到棕色油状物5-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇(400mg，粗品)，该粗品直接用于下一步。LCMS(ESI)m/z:361.29[M+H]+.5-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzene)pentan-4-oct-1-ol (450 mg) was added to methanol (15 mL), add platinum dioxide (45 mg), and LCMS shows that the reaction of the raw materials is complete. Filter the platinum dioxide and concentrate to remove the methanol to obtain a brown oily substance 5-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1 - Alcohol (400 mg, crude), which was used directly in the next step. LCMS(ESI)m/z:361.29[M+H] + .
步骤4：7-((5-溴-2-(3-(5-羟基戊基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-甲基磺酰基吲哚-4-醇的制备
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
将5-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)戊-1-醇(400mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(300mg)和三氟乙酸(380mg)加入到叔丁醇(10mL)中，90℃下搅拌16h，LCMS显示反应完毕。反应液经反相柱纯化，冻干，得到白色固状物7-((5-溴-2-(3-(5-羟基戊基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-甲基磺酰基吲哚-4-醇(420mg,收率51％)。LCMS(ESI)m/z:743.26[M+H]+.5-(5-Amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pentan-1-ol (400 mg), 7-((5- Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (300 mg) and trifluoroacetic acid (380 mg) were added to tert-butanol (10 mL), 90°C Stir for 16 hours, and LCMS shows that the reaction is complete. The 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%). LCMS(ESI)m/z:743.26[M+H] + .
步骤5：35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
将三苯基膦(740mg)与无水四氢呋喃(5ml)先行溶解在三口瓶中，氮气保护下，搅拌5min，将偶氮二甲酸二异丙酯(572mg)与无水四氢呋喃(5mL)充分溶解后用注射器在冰浴条件下缓慢滴加进三口瓶中，搅拌5分钟，再将7-((5-溴-2-(3-(5-羟基戊基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-甲基磺酰基吲哚-4-醇(420mg)与无水四氢呋喃(5mL)充分溶解后用注射器在冰浴条件下缓慢滴加进三口瓶中，撤掉冰浴，室温下搅拌3h，LCMS显示反应完毕。反应液浓缩除去有机溶剂，残余物经反相纯化，冻干后得白色固体35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-11-(甲基磺酰基)-11-氧杂a-2,4-二氮杂a-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(120mg，收率30％)。LCMS(ESI)m/z:725.25[M+H]+.Dissolve triphenylphosphine (740mg) and anhydrous tetrahydrofuran (5ml) in a three-necked flask, stir for 5 minutes under nitrogen protection, and fully dissolve diisopropyl azodicarboxylate (572mg) and anhydrous tetrahydrofuran (5mL). Then use a syringe to slowly drop into the three-necked flask under ice bath conditions, stir for 5 minutes, and then add 7-((5-bromo-2-(3-(5-hydroxypentyl)-4-(4-(4) -Methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylsulfonylindol-4-ol (420 mg) and anhydrous tetrahydrofuran (5 mL) was fully dissolved and slowly dripped into the three-necked flask using a syringe under ice bath conditions. Remove the ice bath and stir at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by reverse phase and freeze-dried to obtain a white solid 3 5 -bromo-5 4 -(4-(4-methylpiperazin-1-yl)piperidine-1-1 1 -(methylsulfonyl)-11-oxa-2,4-diazaa-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)- Benzenecyclodecane (120 mg, yield 30%). LCMS (ESI) m/z: 725.25[M+H] + .
根据实施例22相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 22:
实施例23:35-溴-56-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-11-氧 -2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷
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
类白色固体，4.14mg；LCMS(ESI)m/z:759.40[M+H]+。Off-white solid, 4.14 mg; LCMS (ESI) m/z: 759.40[M+H] + .
实施例24:35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：4-(2-氟-5-硝基苯基)3-正-1-醇的制备
Step 1: Preparation of 4-(2-fluoro-5-nitrophenyl)3-n-1-ol
氮气保护下将2-溴-1-氟-4-硝基苯(10.0g)、3-丁炔-1-醇(0.51g)、N,N-二异丙基乙胺(29.0g)、三苯基膦(2.36g)、二氯二三苯基膦钯(3.16g)和碘化亚铜(1.71g)加到N,N-二甲基甲酰胺(100mL)中，在氮气保护下，80℃反应7小时，TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, 2-bromo-1-fluoro-4-nitrobenzene (10.0g), 3-butyn-1-ol (0.51g), N,N-diisopropylethylamine (29.0g), Triphenylphosphine (2.36g), dichloroditriphenylphosphine palladium (3.16g) and copper iodide (1.71g) were added to N,N-dimethylformamide (100mL) under nitrogen protection. , reacted at 80°C for 7 hours, TLC showed that the reaction of the raw materials was completed, and the next step was taken without purification.
步骤2：4-(2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁炔-1-醇的制备
Step 2: Preparation of 4-(2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butyn-1-ol
将1-甲基-4-(哌啶-4-基)哌嗪(8.24g)，碳酸钾(12.4g)加入到第一步反应液中，在80℃下搅拌16h，LCMS监测反应完毕。然后反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机相溶剂，残余物经层析柱纯化得到黄色油状物4-(2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁炔-1-醇(9g,收率:53％)。LCMS:(ESI)m/z:373.30[M+H]+.1-Methyl-4-(piperidin-4-yl)piperazine (8.24g) and potassium carbonate (12.4g) were added to the reaction solution in the first step, stirred at 80°C for 16h, and LCMS monitored the reaction to completion. Then the reaction solution was washed with deionized water, extracted with dichloromethane/isopropanol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by a chromatography column to obtain a yellow oil 4-(2-(4-( 4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butyn-1-ol (9g, yield: 53%). LCMS: (ESI)m /z:373.30[M+H] + .
步骤3：4-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇的制备
Step 3: Preparation of 4-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
将4-(2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁炔-1-醇(9.0g)加入到甲醇(100mL)中，加入二氧化铂(1.1g)，氢气氛围下搅拌16小时，LCMS显示原料反应完 毕。过滤二氧化铂，浓缩除去甲醇，得到棕色油状物4-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(8.0g，收率：96％)。LCMS(ESI)m/z:347.40[M+H]+；1H NMR(400MHz,CDCl3)δ6.87～6.82(m,1H),6.64(d,J＝2.9Hz,1H),6.61-6.53(m,1H),5.71-5.64(m,1H),3.70(m,2H),3.19(d,J＝12.0Hz,2H),2.71-2.62(m,4H),2.62-2.43(m,10H),2.35-2.28(m,5H),1.91(d,J＝12.4Hz,2H),1.71-1.67(m,2H).4-(2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butyn-1-ol (9.0 g) was added To methanol (100 mL), add platinum dioxide (1.1g) and stir for 16 hours under a hydrogen atmosphere. LCMS shows that the raw material reaction is complete. complete. Filter the platinum dioxide and concentrate to remove the methanol to obtain a brown oily substance 4-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (8.0 g, yield: 96%). LCMS (ESI) m/z: 347.40 [M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ6.87～6.82 (m, 1H), 6.64 (d, J ＝2.9Hz,1H),6.61-6.53(m,1H),5.71-5.64(m,1H),3.70(m,2H),3.19(d,J＝12.0Hz,2H),2.71-2.62(m, 4H),2.62-2.43(m,10H),2.35-2.28(m,5H),1.91(d,J＝12.4Hz,2H),1.71-1.67(m,2H).
步骤4：7-(5-溴-2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基嘧啶-4-基氨基)-1-(甲基磺酰基)吲哚-4-醇
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
将4-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(1.7g),7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚林-4-醇(2.0g)和三氟醋酸(1.64g)溶于叔丁醇(50mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，柱层析纯化，得到淡黄色固体7-(5-溴-2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基嘧啶-4-基氨基)-1-(甲基磺酰基)吲哚-4-醇(3.2g,收率91％)。LCMS(ESI)m/z:729.84[M+H]+。4-(5-Amino-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (1.7g), 7-((5-bromo-2 -Chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-ol (2.0g) and trifluoroacetic acid (1.64g) were dissolved in tert-butanol (50mL) at 90 Stir for 16 hours at ℃, and LCMS shows that the reaction is complete. The 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%). LCMS (ESI) m/z: 729.84[M+H] + .
步骤5：35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
将偶氮二甲酸二异丙酯(4.44g)冰浴下滴入三苯基膦(5.76g)的四氢呋喃(100mL)的溶液中，混合物冰浴下搅拌5分钟，之后7-(5-溴-2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基嘧啶-4-基氨基)-1-(甲基磺酰基)吲哚-4-醇(3.2g)的四氢呋喃(50mL)溶液冰浴下滴入混合物中，在0～20℃下搅拌1h，LCMS显示反应完毕。反应液浓缩除去溶剂，重结晶，得到白色固体35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(1.0g,收率32％)。LCMS(ESI)m/z:711.70[M+H]+.1H NMR(400MHz,DMSO)δ9.18(s,1H),8.45(s,1H),8.15(s,1H),7.49(d,J＝2.2Hz,1H),7.45(d,J＝9.0Hz,1H),7.34(d,J＝8.8Hz,1H),6.94(d,J＝8.6Hz,1H),6.87(m,1H),4.81(t,J＝12.0Hz,1H),4.20(m,2H),3.90(m,1H),3.27-3.13(m,1H),3.02(s,3H),2.94-2.80(m,2H),2.75(m,1H),2.66-2.53(m,4H),2.46(s,4H),2.39-2.16(m,5H),2.15(s,3H),2.00(s,1H),1.80(s,2H),1.66(m,1H),1.55-1.37(m,3H),1.06(m,1H).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. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the solvent and recrystallized to obtain a white solid 3 5 -bromo-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 -(methylsulfonate) Acyl)-10-oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane (1.0g, collected rate 32%). LCMS(ESI)m/z:711.70[M+H] + . 1 H NMR(400MHz, DMSO)δ9.18(s,1H),8.45(s,1H),8.15(s,1H),7.49(d ,J＝2.2Hz,1H),7.45(d,J＝9.0Hz,1H),7.34(d,J＝8.8Hz,1H),6.94(d,J＝8.6Hz,1H),6.87(m,1H ),4.81(t,J＝12.0Hz,1H),4.20(m,2H),3.90(m,1H),3.27-3.13(m,1H),3.02(s,3H),2.94-2.80(m, 2H),2.75(m,1H),2.66-2.53(m,4H),2.46(s,4H),2.39-2.16(m,5H),2.15(s,3H),2.00(s,1H),1.80 (s,2H),1.66(m,1H),1.55-1.37(m,3H),1.06(m,1H).
根据实施例24相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 24:
实施例25:35-溴-56-甲氧基-54-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，1.37mg；LCMS:m/z＝741.40[M+H]+.Off-white solid, 1.37mg; LCMS: m/z=741.40[M+H] + .
实施例26:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
Example 26:5 4- (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methylsulfonyl)-10-oxo-2,4-diazo- 1(7,4)-Indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane
类白色固体，1.90mg；LCMS(ESI)m/z:633.70[M+H]+。Off-white solid, 1.90 mg; LCMS (ESI) m/z: 633.70[M+H] + .
实施例27:35-溴-56-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.30mg；LCMS(ESI)m/z:745.60[M+H]+。Off-white solid, 2.30 mg; LCMS (ESI) m/z: 745.60[M+H] + .
实施例28:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-35-碳腈
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
类白色固体，4.67mg；LCMS(ESI)m/z:658.70[M+H]+。 Off-white solid, 4.67 mg; LCMS (ESI) m/z: 658.70[M+H] + .
实施例29:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-35-(丙-1-烯-2-基)-10-氧-2,4-二氮-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，2.04mg；LCMS(ESI)m/z:673.70[M+H]+。Off-white solid, 2.04 mg; LCMS (ESI) m/z: 673.70[M+H] + .
实施例30:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-3(4,2)-噻吩[3,2-d]嘧啶-1(7,4)-吲哚啉-5(1,3)-苯环十烷
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
黄色固体，4.93mg；LCMS(ESI)m/z:689.60[M+H]+。Yellow solid, 4.93 mg; LCMS (ESI) m/z: 689.60[M+H] + .
实施例31:35-异丙基-54-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
白色固体，3.81mg；LCMS(ESI)m/z:675.80[M+H]+。White solid, 3.81 mg; LCMS (ESI) m/z: 675.80[M+H] + .
实施例32:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-35-羧酸
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
白色固体，2.55mg；LCMS(ESI)m/z:677.70[M+H]+。White solid, 2.55 mg; LCMS (ESI) m/z: 677.70[M+H] + .
实施例33:54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-35-(三氟甲基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
淡黄色固体，4.01mg；LCMS(ESI)m/z:701.70[M+H]+.1H NMR(400MHz,DMSO)δ9.60(s,1H),8.49(s,1H),8.32(s,1H),7.47(t,J＝5.6Hz,2H),7.37(d,J＝8.9Hz,1H),6.94(m,2H),4.79(d,J＝11.7Hz,1H),4.28-4.16(m,2H),3.95-3.75(m,2H),3.71-3.58(m,1H),3.25-3.15(m,1H),3.01(s,3H),2.87-2.89(m,2H),2.76-2.78(m,1H),2.61-2.62(m,4H),2.45-2.32(m,4H),2.27-2.11(m,4H),1.94-1.96(m,2H),1.88-1.74(m,3H),1.67-1.69(m,2H),1.47-1.49(m,3H).Light yellow solid, 4.01 mg; LCMS (ESI) m/z: 701.70 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.60 (s, 1H), 8.49 (s, 1H), 8.32 (s ,1H),7.47(t,J＝5.6Hz,2H),7.37(d,J＝8.9Hz,1H),6.94(m,2H),4.79(d,J＝11.7Hz,1H),4.28-4.16 (m,2H),3.95-3.75(m,2H),3.71-3.58(m,1H),3.25-3.15(m,1H),3.01(s,3H),2.87-2.89(m,2H),2.76 -2.78(m,1H),2.61-2.62(m,4H),2.45-2.32(m,4H),2.27-2.11(m,4H),1.94-1.96(m,2H),1.88-1.74(m, 3H),1.67-1.69(m,2H),1.47-1.49(m,3H).
实施例34:35-环丙基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
淡黄色固体，2.84mg；LCMS(ESI)m/z:673.70[M+H]+.1H NMR(400MHz,DMSO)δ10.35(s,1H),9.63(s,1H),7.86(s,1H),7.60-7.30(m,3H),7.08(d,J＝8.6Hz,1H),6.86(d,J＝6.3Hz,1H),4.82(t,J＝11.6Hz,1H),4.30-4.08(m,3H),4.03-3.93(m,2H),3.36-3.27(m,3H),3.21-3.11(m,3H),3.07-2.83(m,8H),2.80(s,2H),2.72-2.57(m,3H),2.34(s,2H),2.02(s,3H),1.55-1.51(m,5H),0.91-0.89(m,3H),0.71-0.69(m,2H).Light yellow solid, 2.84 mg; LCMS (ESI) m/z: 673.70 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.35 (s, 1H), 9.63 (s, 1H), 7.86 (s ,1H),7.60-7.30(m,3H),7.08(d,J＝8.6Hz,1H),6.86(d,J＝6.3Hz,1H),4.82(t,J＝11.6Hz,1H),4.30 -4.08(m,3H),4.03-3.93(m,2H),3.36-3.27(m,3H),3.21-3.11(m,3H),3.07-2.83(m,8H),2.80(s,2H) ,2.72-2.57(m,3H),2.34(s,2H),2.02(s,3H),1.55-1.51(m,5H),0.91-0.89(m,3H),0.71-0.69(m,2H) .
实施例35:35-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮 -1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，4.30mg；LCMS(ESI)m/z:667.70[M+H]+.1H NMR(400MHz,DMSO)δ9.18(s,1H),8.53(s,1H),8.09(s,1H),7.53(d,J＝2.4Hz,1H),7.46(d,J＝9.0Hz,1H),7.36(d,J＝8.8Hz,1H),6.94(d,J＝8.6Hz,1H),6.87(m,1H),4.81(t,J＝12.1Hz,1H),4.20(t,J＝13.6Hz,2H),3.92-3.90(m,2H),3.27-3.13(m,4H),3.01(s,3H),2.89-2.87(m,3H),2.78-2.76(m,2H),2.63-2.61(m,5H),2.39-2.37(m,4H),2.02-2.00(m,2H),1.84(s,2H),1.72-1.60(m,2H),1.55-1.37(m,4H).Off-white solid, 4.30mg; LCMS(ESI)m/z:667.70[M+H] + . 1 H NMR(400MHz, DMSO)δ9.18(s,1H),8.53(s,1H),8.09(s ,1H),7.53(d,J＝2.4Hz,1H),7.46(d,J＝9.0Hz,1H),7.36(d,J＝8.8Hz,1H),6.94(d,J＝8.6Hz,1H ),6.87(m,1H),4.81(t,J＝12.1Hz,1H),4.20(t,J＝13.6Hz,2H),3.92-3.90(m,2H),3.27-3.13(m,4H) ,3.01(s,3H),2.89-2.87(m,3H),2.78-2.76(m,2H),2.63-2.61(m,5H),2.39-2.37(m,4H),2.02-2.00(m, 2H),1.84(s,2H),1.72-1.60(m,2H),1.55-1.37(m,4H).
实施例36:35-乙基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷
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
类白色固体，3.58mg；LCMS(ESI)m/z:661.90[M+H]+.1H NMR(400MHz,DMSO)δ8.81(s,1H),8.12(s,1H),7.84(s,1H),7.59(d,J＝2.4Hz,1H),7.44(d,J＝9.0Hz,1H),7.34(d,J＝8.8Hz,1H),6.91(d,J＝8.6Hz,1H),6.83(m,1H),4.80(t,J＝12.0Hz,1H),4.20-4.17(m,2H),3.92-3.90(m,1H),3.27-3.13(m,1H),3.01(s,3H),2.93-2.81(m,2H),2.77-2.75(m,1H),2.69-2.52(m,5H),2.42-2.40(m,5H),2.21(s,3H),1.99-1.97(m,1H),1.84-1.80(m,2H),1.66(t,J＝13.4Hz,1H),1.56-1.32(m,3H),1.20(t,J＝7.5Hz,3H),1.09-1.07(m,1H).Off-white solid, 3.58mg; LCMS(ESI)m/z:661.90[M+H] + . 1 H NMR(400MHz, DMSO)δ8.81(s,1H),8.12(s,1H),7.84(s ,1H),7.59(d,J＝2.4Hz,1H),7.44(d,J＝9.0Hz,1H),7.34(d,J＝8.8Hz,1H),6.91(d,J＝8.6Hz,1H ),6.83(m,1H),4.80(t,J＝12.0Hz,1H),4.20-4.17(m,2H),3.92-3.90(m,1H),3.27-3.13(m,1H),3.01( s,3H),2.93-2.81(m,2H),2.77-2.75(m,1H),2.69-2.52(m,5H),2.42-2.40(m,5H),2.21(s,3H),1.99- 1.97(m,1H),1.84-1.80(m,2H),1.66(t,J＝13.4Hz,1H),1.56-1.32(m,3H),1.20(t,J＝7.5Hz,3H),1.09 -1.07(m,1H).
实施例37:甲基54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷-35-羧酸酯
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
类白色固体，4.47mg；LCMS(ESI)m/z:691.80[M+H]+.1H NMR(400MHz,DMSO)δ9.98(s,1H),9.65(s,1H),8.63(s,1H),7.48(s,1H),7.41(d,J＝9.2Hz,1H),7.30(d,J＝8.9Hz,1H),6.95(m,2H),4.85-4.73(m,1H),4.19(d,J＝12.4Hz,2H),3.82(s,3H), 3.22-3.11(m,1H),2.99(s,3H),2.92-2.81(m,2H),2.76(s,1H),2.70-2.53(m,4H),2.36(d,J＝17.9Hz,4H),2.16(s,3H),2.00(d,J＝7.9Hz,2H),1.81(s,2H),1.68(s,1H),1.55-1.31(m,4H),1.24(s,3H),1.13(s,2H),0.86(s,1H).Off-white solid, 4.47 mg; LCMS (ESI) m/z: 691.80 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.98 (s, 1H), 9.65 (s, 1H), 8.63 (s ,1H),7.48(s,1H),7.41(d,J＝9.2Hz,1H),7.30(d,J＝8.9Hz,1H),6.95(m,2H),4.85-4.73(m,1H) ,4.19(d,J＝12.4Hz,2H),3.82(s,3H), 3.22-3.11(m,1H),2.99(s,3H),2.92-2.81(m,2H),2.76(s,1H),2.70-2.53(m,4H),2.36(d,J＝17.9Hz, 4H),2.16(s,3H),2.00(d,J＝7.9Hz,2H),1.81(s,2H),1.68(s,1H),1.55-1.31(m,4H),1.24(s,3H ),1.13(s,2H),0.86(s,1H).
实施例38:54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-35-乙烯基-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷
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
类白色固体，3.88mg；LCMS(ESI)m/z:659.90[M+H]+.1H NMR(400MHz,DMSO)δ9.10(s,1H),8.31(s,1H),8.19(s,1H),7.56(d,J＝2.4Hz,1H),7.43(d,J＝9.0Hz,1H),7.32(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H),6.87(m,1H),6.63(m,1H),5.66(m,1H),5.26–5.18(m,1H),4.78(t,J＝11.9Hz,1H),4.18(m,2H),3.93-3.84(m,1H),3.25-3.11(m,2H),3.03-2.95(m,3H),2.94–2.79(m,3H),2.77(d,J＝11.2Hz,1H),2.67–2.55(m,4H),2.45(s,4H),2.24(s,3H),2.00(d,J＝8.6Hz,2H),1.82(s,2H),1.74–1.58(m,2H),1.45(d,J＝19.5Hz,4H),1.25(d,J＝2.9Hz,1H).Off-white solid, 3.88mg; LCMS(ESI)m/z:659.90[M+H] + . 1 H NMR(400MHz, DMSO)δ9.10(s,1H),8.31(s,1H),8.19(s ,1H),7.56(d,J＝2.4Hz,1H),7.43(d,J＝9.0Hz,1H),7.32(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H ),6.87(m,1H),6.63(m,1H),5.66(m,1H),5.26–5.18(m,1H),4.78(t,J＝11.9Hz,1H),4.18(m,2H) ,3.93-3.84(m,1H),3.25-3.11(m,2H),3.03-2.95(m,3H),2.94–2.79(m,3H),2.77(d,J＝11.2Hz,1H),2.67 –2.55(m,4H),2.45(s,4H),2.24(s,3H),2.00(d,J＝8.6Hz,2H),1.82(s,2H),1.74–1.58(m,2H), 1.45(d,J＝19.5Hz,4H), 1.25(d,J＝2.9Hz,1H).
实施例39:异丙基54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷-35-羧酸酯
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
类白色固体，1.30mg；LCMS(ESI)m/z:719.90[M+H]+。Off-white solid, 1.30 mg; LCMS (ESI) m/z: 719.90[M+H] + .
实施例40:36-甲基-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷
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
类白色固体，4.26mg；LCMS(ESI)m/z:647.90[M+H]+。Off-white solid, 4.26 mg; LCMS (ESI) m/z: 647.90[M+H] + .
实施例54:35,36-甲基-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，2.80mg；LCMS(ESI)m/z:661.60[M+H]+。Off-white solid, 2.80 mg; LCMS (ESI) m/z: 661.60[M+H] + .
实施例55:54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-36,37-二氢-35氢-10-氧-2,4-二氮-3(4,2)-环戊二烯[d]嘧啶-1(7,4)-吲哚啉-5(1,3)-苯并环十碳烷
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
类白色固体，4.30mg；LCMS(ESI)m/z:673.70[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.93(s,1H),7.65(d,J＝2.0Hz,1H),7.43(d,J＝9.2Hz,1H),7.31(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,1H),6.82-6.80(m,J＝8.6,1H),4.82-4.76(m,1H),4.22-4.15(m,2H),3.90(m,1H),3.47-3.40(m,2H),3.21-3.17(m,2H),3.02(s,2H),3.00(s,3H),2.91-2.84(m,4H),2.70-2.64(m,7.7Hz,8H),2.59-2.56(m,4H),2.44(s,2H),2.34(s,1H),2.09-2.01(m,3H),1.85(s,2H),1.65-11.62(m,2H),1.50(s,2H).Off-white solid, 4.30mg; LCMS(ESI)m/z:673.70[M+H]+; 1H NMR(400MHz, DMSO-d6)δ8.86(s,1H),7.93(s,1H),7.65( d,J＝2.0Hz,1H),7.43(d,J＝9.2Hz,1H),7.31(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,1H),6.82-6.80( m,J＝8.6,1H),4.82-4.76(m,1H),4.22-4.15(m,2H),3.90(m,1H),3.47-3.40(m,2H),3.21-3.17(m,2H ),3.02(s,2H),3.00(s,3H),2.91-2.84(m,4H),2.70-2.64(m,7.7Hz,8H),2.59-2.56(m,4H),2.44(s, 2H),2.34(s,1H),2.09-2.01(m,3H),1.85(s,2H),1.65-11.62(m,2H),1.50(s,2H).
实施例56:35-溴-54-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，9.8mg；纯度98.8％；LCMS(ESI)m/z:711.50[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.46(s,1H),8.16(s,1H),7.50(m,1H),7.46(m,1H),7.35(m,1H),6.97(m,1H),6.91-6.86(m,1H),4.25-4.15(m,2H),3.95-3.86(m,2H),3.02(s,3H),2.92-2.83(m,4H),2.74-2.68(m,2H),2.60-2.55(m,4H),2.22(s,3H),1.77(m,2H),1.68-1.57(m,2H),1.50-1.38(m,4H),1.27-1.23(m,2H).Off-white solid, 9.8 mg; purity 98.8%; LCMS (ESI) m/z: 711.50 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.20(s,1H),8.46(s,1H),8.16(s,1H),7.50(m,1H),7.46(m,1H),7.35(m ,1H),6.97(m,1H),6.91-6.86(m,1H),4.25-4.15(m,2H),3.95-3.86(m,2H),3.02(s,3H),2.92-2.83(m ,4H),2.74-2.68(m,2H),2.60-2.55(m,4H),2.22(s,3H),1.77(m,2H),1.68-1.57(m,2H),1.50-1.38(m ,4H),1.27-1.23(m,2H).
实施例57:35-甲基-54-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，3.4mg；纯度90.1％；LCMS(ESI)m/z:647.70[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.03(s,1H),7.83(s,1H),7.60(m,1H),7.43(m,1H),7.32(m,1H),6.93(m,1H),6.86-6.82(m,1H),4.84-4.73(m,2H),4.22-4.14(m,2H),3.94-3.84(m,2H),3.01(s,3H),2.89-2.81(m,4H),2.74-2.69(m,4H),2.68-2.61(m,4H),2.58-2.54(m, 4H),2.19(s,3H),2.02(s,3H),1.76(m,3H),1.47-1.41(m,4H).Off-white solid, 3.4 mg; purity 90.1%; LCMS (ESI) m/z: 647.70 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.03(s,1H),7.83(s,1H),7.60(m,1H),7.43(m,1H),7.32(m ,1H),6.93(m,1H),6.86-6.82(m,1H),4.84-4.73(m,2H),4.22-4.14(m,2H),3.94-3.84(m,2H),3.01(s ,3H),2.89-2.81(m,4H),2.74-2.69(m,4H),2.68-2.61(m,4H),2.58-2.54(m, 4H),2.19(s,3H),2.02(s,3H),1.76(m,3H),1.47-1.41(m,4H).
实施例58:35-溴-11-(甲基磺酰基)-54-吗啉基-10-氧杂-2,4-二氮杂-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，18.9mg；纯度98.2％；LCMS(ESI)m/z:615.40[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.46(s,1H),8.16(s,1H),7.50(m，1H),7.46(d,J＝8.0Hz，1H),7.35(d,J＝8.0Hz，1H),7.00(d,J＝8.0Hz，1H),6.91-6.86(m,1H),4.84-4.78(m,1H),4.25-4.15(m,2H),3.75-3.65(m,1H),3.30-3.05(m,1H),3.02(s,3H),2.92-2.83(m,1H),2.74-2.68(m,4H),2.60-2.45(m,6H),2.02(m,1H),1.77-1.65(m,1H),1.50-1.37(m,1H),1.50-1.38(m,1H).Off-white solid, 18.9 mg; purity 98.2%; LCMS (ESI) m/z: 615.40[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.50 (m, 1H), 7.46 (d, J = 8.0Hz, 1H ),7.35(d,J＝8.0Hz,1H),7.00(d,J＝8.0Hz,1H),6.91-6.86(m,1H),4.84-4.78(m,1H),4.25-4.15(m, 2H),3.75-3.65(m,1H),3.30-3.05(m,1H),3.02(s,3H),2.92-2.83(m,1H),2.74-2.68(m,4H),2.60-2.45( m,6H),2.02(m,1H),1.77-1.65(m,1H),1.50-1.37(m,1H),1.50-1.38(m,1H).
实施例59:35-碘-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，0.53mg；LCMS(ESI)m/z:759.60[M+H]+。Off-white solid, 0.53 mg; LCMS (ESI) m/z: 759.60[M+H] + .
实施例60:35-氟-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，25.76mg；LCMS(ESI)m/z:651.40[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.43(s,1H),8.04(d,J＝3.2Hz,1H),7.54(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),7.34(d,J＝8.8Hz,1H),6.92(d,J＝8.8Hz,1H),6.85-6.82(m,1H),4.82-4.76(m,1H),4.20-4.17(m,2H),3.97-3.89(m,1H),3.19-3.15(m,2H),2.99(s,3H),2.92-2.83(m,5H),2.59-2.57(m,4H),2.43-2.39(m,4H),2.21(s,3H),2.00(s,2H),1.80(s,2H),1.66(s,2H),1.50-1.34(m,4H). Off-white solid, 25.76 mg; LCMS (ESI) m/z: 651.40 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.43 (s, 1H), 8.04 (d,J＝3.2Hz,1H),7.54(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),7.34(d,J＝8.8Hz,1H),6.92(d ,J＝8.8Hz,1H),6.85-6.82(m,1H),4.82-4.76(m,1H),4.20-4.17(m,2H),3.97-3.89(m,1H),3.19-3.15(m ,2H),2.99(s,3H),2.92-2.83(m,5H),2.59-2.57(m,4H),2.43-2.39(m,4H),2.21(s,3H),2.00(s,2H ),1.80(s,2H),1.66(s,2H),1.50-1.34(m,4H).
实施例41:35-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：N-(2-氯-5-甲基嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚林-7-胺的制备
Step 1: Preparation of N-(2-chloro-5-methylpyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indolin-7-amine
2,4-二氯-5-甲基嘧啶(495mg)、4-甲氧基-1-(甲磺酰基)吲哚林-7-胺(500mg)、N,N-二异丙基乙胺(529mg)加到异丙醇(10mL)中，在氮气保护下，90℃反应16小时，TLC显示原料反应完毕。反应液浓缩除去溶剂，柱层析纯化得到黄色固体N-(2-氯-5-甲基嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚林-7-胺(530mg,收率:71％)。LCMS(ESI)m/z:369.07[M+H]+。2,4-Dichloro-5-methylpyrimidine (495mg), 4-methoxy-1-(methanesulfonyl)indolin-7-amine (500mg), N,N-diisopropylethylamine (529 mg) was added to isopropyl alcohol (10 mL), and the reaction was carried out at 90°C for 16 hours under nitrogen protection. TLC showed that the reaction of the raw materials was completed. The reaction solution was concentrated to remove the solvent, and purified by column chromatography to obtain yellow solid N-(2-chloro-5-methylpyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indoleline-7 -Amine (530 mg, yield: 71%). LCMS(ESI)m/z:369.07[M+H] + .
步骤2：7-((2-氯-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的制备
Step 2: Preparation of 7-((2-chloro-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol
将N-(2-氯-5-甲基嘧啶-4-基)-4-甲氧基-1-(甲基磺酰基)吲哚林-7-胺(530mg)加入二氯甲烷(10mL)中，在氮气保护下，0℃加入三溴化硼二氯甲烷溶液(4.32mL)，反应在0～30℃下搅拌5小时，TLC显示原料反应完毕。反应液浓缩除去溶剂，柱层析纯化得到7-((2-氯-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(200mg,收率：39％)。LCMS(ESI)m/z:355.60[M+H]+。Add N-(2-chloro-5-methylpyrimidin-4-yl)-4-methoxy-1-(methylsulfonyl)indolin-7-amine (530 mg) to dichloromethane (10 mL) , under nitrogen protection, add boron tribromide dichloromethane solution (4.32 mL) at 0°C, and stir the reaction at 0-30°C for 5 hours. TLC shows that the reaction of the raw materials is complete. The reaction solution was concentrated to remove the solvent, and purified by column chromatography to obtain 7-((2-chloro-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (200 mg, collected rate: 39%). LCMS(ESI)m/z:355.60[M+H] + .
步骤3：7-(2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇
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
将4-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(204mg)、7-((2-氯-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(200mg)和三氟醋酸(319mg)溶于叔丁醇(10mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，柱层析纯化，得到淡黄色固体7-(2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(160mg,收率43％)。LCMS(ESI)m/z:665.40[M+H]+。4-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (204 mg), 7-((2-chloro-5- Methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (200 mg) and trifluoroacetic acid (319 mg) were dissolved in tert-butanol (10 mL) and stirred at 90°C 16h, LCMS showed that the reaction was completed. The reaction solution was concentrated to remove the solvent and purified by column chromatography to obtain a light yellow solid 7-(2-(3-(4-hydroxybutyl)-4-(4-(4-methylpiperazine) -1-yl)piperidin-1-phenyl)amino)-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (160 mg, yield 43% ). LCMS(ESI)m/z:665.40[M+H] + .
步骤4：35-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮 -1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
冰浴下，将偶氮二甲酸二异丙酯(243mg)滴入三苯基膦(316mg)的四氢呋喃(50mL)的溶液中，混合物在冰浴下搅拌5分钟，之后7-(2-(3-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(160mg)的四氢呋喃(10mL)溶液冰浴下滴入混合物中，在0～20℃下搅拌1h，LCMS显示反应完毕。反应液浓缩除去溶剂，经制备TLC纯化，得到白色固体35-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(22.18mg,收率14％)。LCMS(ESI)m/z:647.90[M+H]+.1H NMR(400MHz,CDCl3)δ8.23(s,1H),7.73(s,1H),7.67(s,1H),7.49(d,J＝8.8Hz,1H),7.23(d,J＝8.9Hz,1H),6.99(t,J＝12.2Hz,1H),6.68(d,J＝8.3Hz,1H),4.77(t,J＝12.0Hz,1H),4.29(m,2H),4.10-3.90(m,1H),3.25-3.14(m,1H),3.02-3.00(m,2H),2.95-2.74(m,8H),2.72-2.56(m,4H),2.49(s,3H),2.16(s,3H),1.92-1.90(m,6H),1.75-1.70(m,5H).Under an ice bath, diisopropyl azodicarboxylate (243 mg) was dropped into a solution of triphenylphosphine (316 mg) in tetrahydrofuran (50 mL). The mixture was stirred under an ice bath for 5 minutes, and then 7-(2-( 3-(4-hydroxybutyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-phenyl)amino)-5-methylpyrimidin-4-yl)amino) A solution of -1-(methylsulfonyl)indole-4-ol (160 mg) in tetrahydrofuran (10 mL) was dropped into the mixture under ice bath, and stirred at 0-20°C for 1 hour. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the solvent and purified by preparative TLC to obtain a white solid 3 5 -methyl-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methane) Sulfonyl)-10-oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane (22.18mg , yield 14%). LCMS(ESI)m/z:647.90[M+H] + . 1 H NMR(400MHz, CDCl 3 )δ8.23(s,1H),7.73(s,1H),7.67(s,1H),7.49( d,J＝8.8Hz,1H),7.23(d,J＝8.9Hz,1H),6.99(t,J＝12.2Hz,1H),6.68(d,J＝8.3Hz,1H),4.77(t, J＝12.0Hz,1H),4.29(m,2H),4.10-3.90(m,1H),3.25-3.14(m,1H),3.02-3.00(m,2H),2.95-2.74(m,8H) ,2.72-2.56(m,4H),2.49(s,3H),2.16(s,3H),1.92-1.90(m,6H),1.75-1.70(m,5H).
实施例42:35-溴-55-氟-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：4-(2,3-二氟-5-硝基苯)丁-3-N-1醇的制备
Step 1: Preparation of 4-(2,3-difluoro-5-nitrobenzene)butan-3-N-1-ol
氮气保护下将1-溴-2,3-二氟-5-硝基苯(900mg)、3-丁炔-1-醇(397mg)、N,N-二异丙基乙胺(2.44g)、四三苯基膦钯(439mg)和碘化亚铜(144mg)加到N,N-二甲基甲酰胺(10mL)中，在氮气保护下，80℃反应7小时。TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, combine 1-bromo-2,3-difluoro-5-nitrobenzene (900mg), 3-butyn-1-ol (397mg), and N,N-diisopropylethylamine (2.44g). , tetrakis triphenylphosphine palladium (439 mg) and copper iodide (144 mg) were added to N,N-dimethylformamide (10 mL), and reacted at 80°C for 7 hours under nitrogen protection. TLC showed that the raw material reaction was completed, and the next step was taken without purification.
步骤2：4-(3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇的制备
Step 2: 4-(3-fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol preparation
将1-甲基-4-(哌啶-4-基)哌嗪(1.04g)和碳酸钾(1.04g)加入到第一步反应液中，在80℃下搅拌16h，LCMS监测反应完毕。然后反应液用去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机相溶剂，残余物经层析柱纯化得到黄色油状物4-(3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇(900mg,粗品)。LCMS:(ESI)m/z:391.20[M+H]+.1-Methyl-4-(piperidin-4-yl)piperazine (1.04g) and potassium carbonate (1.04g) were added to the reaction solution in the first step, stirred at 80°C for 16h, and LCMS monitored the reaction to completion. Then the reaction solution was washed with deionized water, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by a chromatography column to obtain a yellow oily substance 4-(3-fluoro-2- (4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol (900 mg, crude product). LCMS: (ESI)m/ z:391.20[M+H] + .
步骤3：4-(5-氨基-3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇的制备
Step 3: Preparation of 4-(5-amino-3-fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
将4-(3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇(900mg)加入到甲醇(20mL)中，加入二氧化铂(30mg)，氢气氛围下搅拌16小时，LCMS显示原料反应完毕。过滤二氧化铂，浓缩除去甲醇，得到棕色油状物4-(5-氨基-3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(700mg，收率：84％)。LCMS(ESI)m/z:365.30[M+H]+。4-(3-Fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol (900 mg) Add to methanol (20 mL), add platinum dioxide (30 mg), and stir for 16 hours under a hydrogen atmosphere. LCMS shows that the raw material reaction is complete. Filter the platinum dioxide and concentrate to remove the methanol to obtain a brown oily substance 4-(5-amino-3). -Fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (700 mg, yield: 84%). LCMS (ESI) m/z: 365.30 [M+H] + .
步骤4：7-(5-溴-2-(3-氟-5-(4-羟基丁基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基嘧啶-4-基)氨基-1-(甲基磺酰基)吲哚-4-醇
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
将4-(5-氨基-3-氟-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(200mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚林-4-醇(230mg)和三氟醋酸(264mg)溶于叔丁醇(10mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，柱层析纯化，得到淡黄色固体(5-溴-2-(5-(4-羟丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰)吲哚-4-醇(100mg,收率24％)。LCMS(ESI)m/z:747.70[M+H]+。4-(5-Amino-3-fluoro-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (200 mg), 7-((5- Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-ol (230 mg) and trifluoroacetic acid (264 mg) were dissolved in tert-butanol (10 mL). Stir for 16 hours at 90°C, and LCMS shows that the reaction is complete. The 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%). LCMS(ESI)m/z:747.70[M+H] + .
步骤5：35-溴-55-氟-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
将(5-溴-2-(5-(4-羟丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰)吲哚-4-醇(100mg)，氰基亚甲基三正丁基膦(157mg)加入到甲苯(20mL)中，反应液在氮气保护下130℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，重结晶，得到白色固体35-溴-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(25mg,收率：27％)。LCMS(ESI)m/z:729.50[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.45(s,1H),8.18(s,1H),7.45(d,J＝9.0Hz,1H),7.33(m,2H),6.71(m,1H),4.80(t,J＝12.1Hz,1H),4.21(t,J＝10.7Hz,2H),3.90-3.88(m,1H),3.25-3.12(m,2H),3.01(s,3H),2.98-2.54(m,10H),2.50-2.31(m,5H),2.28(s,3H),2.00(s,1H),1.72-1.70(m,3H),1.36-1.38(m,3H).(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-ol (100 mg), cyanomethylene tri-n-butylphosphine (157 mg) were added to toluene (20 mL) , the reaction solution was stirred at 130°C for 16 hours under nitrogen protection, and LCMS showed that the reaction was completed. The reaction solution was concentrated to remove the solvent and recrystallized to obtain a white solid 35-bromo-56-methyl-54-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methyl) Sulfonyl)-10-oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane (25mg, Yield: 27%). LCMS(ESI)m/z:729.50[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.45(s,1H),8.18(s,1H),7.45 (d,J＝9.0Hz,1H),7.33(m,2H),6.71(m,1H),4.80(t,J＝12.1Hz,1H),4.21(t,J＝10.7Hz,2H),3.90 -3.88(m,1H),3.25-3.12(m,2H),3.01(s,3H),2.98-2.54(m,10H),2.50-2.31(m,5H),2.28(s,3H),2.00 (s,1H),1.72-1.70(m,3H),1.36-1.38(m,3H).
根据实施例42相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 42:
实施例64:35-溴-55-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，3.97mg；LCMS(ESI)m/z:727.60[M+H]+。Off-white solid, 3.97 mg; LCMS (ESI) m/z: 727.60[M+H] + .
实施例43:35-溴-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：4-(2-氟-5-硝基苯基)3-正-1-醇的制备
Step 1: Preparation of 4-(2-fluoro-5-nitrophenyl)3-n-1-ol
氮气保护下将1-溴-2-氟-4-甲基-5-硝基苯(2.0g)、3-丁炔-1-醇(1.2g)、N,N-二异丙基乙胺(5.5g)、四三苯基膦钯(993mg)和碘化亚铜(323mg)加到N,N-二甲基甲酰胺(20mL)中，在氮气保护下，80℃反应7小时，TLC显示原料反应完毕，未做纯化直接下一步。Under nitrogen protection, combine 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (2.0g), 3-butyn-1-ol (1.2g), and N,N-diisopropylethylamine. (5.5g), tetrakistriphenylphosphine palladium (993mg) and copper iodide (323mg) were added to N,N-dimethylformamide (20mL), and reacted at 80°C for 7 hours under nitrogen protection, TLC It shows that the raw material reaction is completed, and the next step is taken without purification.
步骤2：4-(4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇的制备
Step 2: 4-(4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol Preparation
将1-甲基-4-(哌啶-4-基)哌嗪(1.57g)，碳酸钾(2.37g)加入到第一步反应液中，在80℃下搅拌16h，LCMS监测反应完毕。然后去离子水洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机相溶剂，残余物经层析柱纯化得到黄色油状物4-(4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇(3.7g,crude)。LCMS:(ESI)m/z:387.30[M+H]+.Add 1-methyl-4-(piperidin-4-yl)piperazine (1.57g) and potassium carbonate (2.37g) to the reaction solution in the first step, stir at 80°C for 16h, and monitor the reaction with LCMS to complete. Then wash with deionized water, extract with dichloromethane/isopropyl alcohol, dry with anhydrous sodium sulfate, concentrate to remove the organic phase solvent, and the residue is purified by chromatography column to obtain a yellow oily substance 4-(4-methyl-2-(4 -(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol (3.7g, crude). LCMS: (ESI) m/z :387.30[M+H]+.
步骤3：4-(5-氨基-4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇的制备
Step 3: Preparation of 4-(5-amino-4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol
将4-(4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)-5-硝基苯丁-3-丁-1-醇(3.7g)加入到甲醇(50mL)中，加入二氧化铂(0.3g)，氢气氛围下搅拌16小时，LCMS显示原料反应完毕。过滤二氧化铂，浓缩除去甲醇，得到棕色油状物4-(5-氨基-4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(2.9g，收率：85％)。LCMS(ESI)m/z:361.30[M+H]+；1H NMR(400MHz,CDCl3)δ6.82(s,1H),6.54(s,1H),3.75-3.65(m,2H),3.52-3.50(m,6H),3.02(d,J＝12.0Hz,2H),2.98-2.78(m,6H),2.68-2.66(m,2H),2.62-2.56(m,2H),2.46(s,3H),2.02-2.00(m,2H),1.84-1.80(m,2H),1.71-1.58(m,4H).4-(4-Methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)-5-nitrophenyl-3-butan-1-ol (3.7 g) into methanol (50 mL), add platinum dioxide (0.3g), and stir for 16 hours under a hydrogen atmosphere. LCMS shows that the raw material reaction is complete. Filter the platinum dioxide and concentrate to remove the methanol to obtain brown oil 4-(5- Amino-4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (2.9 g, Yield: 85%). LCMS (ESI) m/z:361.30[M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ6.82 (s, 1H), 6.54 (s, 1H), 3.75-3.65 (m, 2H), 3.52-3.50 ( m,6H),3.02(d,J＝12.0Hz,2H),2.98-2.78(m,6H),2.68-2.66(m,2H),2.62-2.56(m,2H),2.46(s,3H) ,2.02-2.00(m,2H),1.84-1.80(m,2H),1.71-1.58(m,4H).
步骤4：(5-溴-2-(5-(4-羟丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰)吲哚-4-醇
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
将4-(5-氨基-4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(200mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚林-4-醇(232mg)和三氟醋酸(319mg)溶于叔丁醇(5mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，柱层析纯化，得到淡黄色固体(5-溴-2-(5-(4-羟丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰)吲哚-4-醇(30mg,收率7.2％)。LCMS(ESI)m/z:743.70[M+H]+。4-(5-Amino-4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (200 mg), 7-((5 -Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indolin-4-ol (232 mg) and trifluoroacetic acid (319 mg) were dissolved in tert-butanol (5 mL), After stirring at 90°C for 16 hours, LCMS showed that the reaction was complete. The 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%). LCMS(ESI)m/z:743.70[M+H] + .
步骤5：35-溴-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
将(5-溴-2-(5-(4-羟丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰)吲哚-4-醇(30mg)和氰基亚甲基三正丁基膦(48mg)加入到甲苯(5mL)中，反应液在氮气保护下130℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，重结晶，得到白色固体35-溴-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(3.01mg,收率：10％)。LCMS(ESI)m/z:725.60[M+H]+.1H NMR(400MHz,DMSO)δ8.44(s,1H),8.16(s,1H),7.78(s,1H),7.47～7.29(m,3H),6.85(s,1H),4.77(s,1H),4.18(s,2H),3.87(d,J＝9.9Hz,1H),3.19(s,2H),3.01(s,3H),2.88(s,2H),2.68～2.70(m,3H),2.26～2.27(m,6H),2.17(s,3H),1.92～1.94(m,2H),1.82(s,2H),1.66～1.21(m,9H).(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-ol (30 mg) and cyanomethylenetri-n-butylphosphine (48 mg) were added to toluene (5 mL) , the reaction solution was stirred at 130°C for 16 hours under nitrogen protection, and LCMS showed that the reaction was completed. The reaction solution was concentrated to remove the solvent and recrystallized to obtain a white solid 35-bromo-56-methyl-54-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-11-(methyl) Sulfonyl)-10-oxo-2,4-diazo-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-phenylcyclodecane (3.01 mg , Yield: 10%). LCMS(ESI)m/z:725.60[M+H] + . 1 H NMR(400MHz, DMSO)δ8.44(s,1H),8.16(s,1H),7.78(s,1H),7.47～7.29 (m,3H),6.85(s,1H),4.77(s,1H),4.18(s,2H),3.87(d,J＝9.9Hz,1H),3.19(s,2H),3.01(s, 3H),2.88(s,2H),2.68～2.70(m,3H),2.26～2.27(m,6H),2.17(s,3H),1.92～1.94(m,2H),1.82(s,2H) ,1.66～1.21(m,9H).
根据实施例43相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 43:
实施例44:35-氯-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
淡黄色固体，1.5mg；LCMS(ESI)m/z:681.60[M+H]+。Light yellow solid, 1.5 mg; LCMS (ESI) m/z: 681.60[M+H] + .
实施例45:35,56-二甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
步骤1：7-((2-(5-(4-羟基丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇
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
将4-(5-氨基-4-甲基-2-(4-(4-甲基哌嗪-1-基)哌嗪-1-基)苯基丁醇(200mg),7-((2-氯-5- 甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(230mg)和三氟醋酸(319mg)溶于叔丁醇(10mL)中，在90℃下搅拌16h，LCMS显示反应完毕。反应液浓缩除去溶剂，TLC纯化，得到淡黄色固体7-((2-(5-(4-羟基丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(100mg,收率24％)。LCMS(ESI)m/z:679.40[M+H]+。4-(5-Amino-4-methyl-2-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenylbutanol (200 mg), 7-((2 -Chlorine-5- Methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (230 mg) and trifluoroacetic acid (319 mg) were dissolved in tert-butanol (10 mL) and stirred at 90°C 16h, LCMS showed that the reaction was completed. The reaction solution was concentrated to remove the solvent and purified by TLC to obtain a light yellow solid 7-((2-(5-(4-hydroxybutyl)-2-methyl-4-(4-(4-methylpiperazine-1- (yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (100 mg, yield 24%) . LCMS(ESI)m/z:679.40[M+H] + .
步骤2：35,56-二甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
冰浴下，将偶氮二甲酸二异丙酯(75mg)滴入三苯基膦(194mg)的四氢呋喃(15mL)的溶液中，混合物冰浴下搅拌5分钟，之后7-((2-(5-(4-羟基丁基)-2-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(100mg)的四氢呋喃(5mL)溶液冰浴下滴入混合物中，在0～20℃下搅拌1h，LCMS显示反应完毕。反应液浓缩除去溶剂，经制备TLC纯化，得到白色固体35-氯-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷(4.01mg,收率8％)。LCMS(ESI)m/z:661.80[M+H]+。Under ice bath, diisopropyl azodicarboxylate (75 mg) was dropped into a solution of triphenylphosphine (194 mg) in tetrahydrofuran (15 mL), and the mixture was stirred under ice bath for 5 minutes, and then 7-((2-( 5-(4-hydroxybutyl)-2-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidine A solution of -4-yl)amino)-1-(methylsulfonyl)indol-4-ol (100 mg) in tetrahydrofuran (5 mL) was dropped into the mixture in an ice bath, and stirred at 0 to 20°C for 1 hour. LCMS showed The reaction is complete. The reaction solution was concentrated to remove the solvent and purified by preparative TLC to obtain a white solid 3 5 -chloro-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)-benzene Cyclodecane (4.01 mg, yield 8%). LCMS(ESI)m/z:661.80[M+H] + .
根据实施例45相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 45:
实施例61:35,56-二甲基-54-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，18.4mg；纯度95.2％；LCMS(ESI)m/z:661.70[M+H]+。1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.82(s,1H),7.76(s,1H),7.50(d,J＝8.9Hz,1H),7.21(d,J＝9.0Hz,1H),6.92(s,1H),6.70(s,1H),4.76(t,J＝12.0Hz,1H),4.34-4.22(m,2H),4.02-3.93(m,1H),3.24-3.14(m,1H),3.07(s,2H),3.03-2.92(m,2H),2.92-2.86(m,2H),2.86(s,3H),2.84-2.78(m,2H),2.73-2.62(m,4H),2.58(m,2H),2.41(s,3H),2.24(s,3H),2.14(s,3H),2.11-2.03(m,2H),1.96-1.90(m,2H),1.85-1.69(m,4H),1.32-1.23(m,2H).Off-white solid, 18.4 mg; purity 95.2%; LCMS (ESI) m/z: 661.70 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.98 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.50 (d, J＝8.9Hz, 1H), 7.21 (d, J＝ 9.0Hz,1H),6.92(s,1H),6.70(s,1H),4.76(t,J＝12.0Hz,1H),4.34-4.22(m,2H),4.02-3.93(m,1H), 3.24-3.14(m,1H),3.07(s,2H),3.03-2.92(m,2H),2.92-2.86(m,2H),2.86(s,3H),2.84-2.78(m,2H), 2.73-2.62(m,4H),2.58(m,2H),2.41(s,3H),2.24(s,3H),2.14(s,3H),2.11-2.03(m,2H),1.96-1.90( m,2H),1.85-1.69(m,4H),1.32-1.23(m,2H).
实施例62:35-溴-56-甲基-(4-(1-甲基哌啶-4-酰基)哌嗪-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，9.83mg；LCMS(ESI)m/z:725.50[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.16(s,1H),7.79(s,1H),7.42-7.33(m,3H),6.88(s,1H),4.76-4.74(m,1H),4.21-4.17(m,2H),3.90-3.86(m,1H),3.19-3.17(m,2H),3.00(s,3H),2.88(s,2H),2.79(s,2H),2.63-2.56(m,4H),2.44-2.38(m,2H),2.25(s,3H),2.17(s,4H),2.19-1.99(s,4H),1.76(s,2H),1.57(s,2H),1.45(d,J＝8.8Hz,2H),1.24(s,2H).Off-white solid, 9.83mg; LCMS(ESI)m/z:725.50[M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ8.44(s,1H),8.16(s,1H),7.79 (s,1H),7.42-7.33(m,3H),6.88(s,1H),4.76-4.74(m,1H),4.21-4.17(m,2H),3.90-3.86(m,1H),3.19 -3.17(m,2H),3.00(s,3H),2.88(s,2H),2.79(s,2H),2.63-2.56(m,4H),2.44-2.38(m,2H),2.25(s ,3H),2.17(s,4H),2.19-1.99(s,4H),1.76(s,2H),1.57(s,2H),1.45(d,J＝8.8Hz,2H),1.24(s, 2H).
实施例63:35-氟-56-甲基-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并环十碳烷
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
类白色固体，1.53mg；纯度95.0％；LCMS(ESI)m/z:665.50[M+H]+。Off-white solid, 1.53 mg; purity 95.0%; LCMS (ESI) m/z: 665.50[M+H] + .
实施例46:35-溴-55-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯甲酸环十烷
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
步骤1：4-(3-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-5-硝基苯基)丁-3-炔-1-醇的制备
Step 1: 4-(3-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)-5-nitrophenyl)but-3-yne Preparation of -1-alcohol
氮气保护下，将2-(3-溴-5-硝基苯氧基)-5-(1-甲基-1H-吡唑-4-基)吡嗪(1.1g)、3-丁炔-1-醇(250mg)、N,N-二异丙基乙胺(1.94g)、三苯基膦(157mg)、二氯二三苯基膦钯(210mg)和碘化亚铜(114mg)加到N,N-二甲基甲酰胺(10mL)中，在氮气保护下，80℃反应4小时，TLC显示原料反应完毕。反应液浓缩除去有机溶剂，残余物经层析柱纯化得到黄色油状物4-(3-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-5-硝基苯基)丁-3-炔-1-醇(780mg,收率71％).LCMS(ESI)m/z:366.3[M+H]+。Under nitrogen protection, 2-(3-bromo-5-nitrophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrazine (1.1g), 3-butyne- 1-alcohol (250mg), N,N-diisopropylethylamine (1.94g), triphenylphosphine (157mg), dichloroditriphenylphosphine palladium (210mg) and copper iodide (114mg) were added into N,N-dimethylformamide (10 mL), and reacted at 80°C for 4 hours under nitrogen protection. TLC showed that the reaction of the raw materials was completed. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by chromatography column to obtain 4-(3-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxygen) as a yellow oil (780 mg, yield 71%). LCMS (ESI) m/z: 366.3 [M+H] + .
步骤2：4-(3-氨基-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)丁-1-醇的制备
Step 2: 4-(3-Amino-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)phenyl)butan-1-ol preparation
将4-(3-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-5-硝基苯基)丁-3-炔-1-醇(780mg)加入到甲醇(10mL)中，加入二氧化铂(48mg)，置换成氢气气氛，室温下搅拌2h，LCMS显示原料反应完毕。过滤二氧化铂，浓缩除去甲醇，残余物经制备TLC纯化得到棕色油状物4-(3-氨基-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)丁-1-醇(160mg,收率22％)。LCMS(ESI)m/z:340.4[M+H]+。4-(3-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)-5-nitrophenyl)but-3-yne-1 -Alcohol (780 mg) was added to methanol (10 mL), platinum dioxide (48 mg) was added, replaced with hydrogen atmosphere, and stirred at room temperature for 2 hours. LCMS showed that the raw material reaction was completed. The platinum dioxide was filtered and concentrated to remove methanol. The residue was purified by preparative TLC to obtain a brown oily substance 4-(3-amino-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazine- 2-yl)oxy)phenyl)butan-1-ol (160 mg, yield 22%). LCMS(ESI)m/z:340.4[M+H] + .
步骤3：7-((5-溴-2-((3-(4-羟基丁基)-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的制备
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
将4-(3-氨基-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)丁-1-醇(160mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(198mg)和三氟乙酸(269mg)加入到叔丁醇(10mL)中，90℃下搅拌16h，LCMS显示反应完毕。反应液用饱和碳酸氢钠水溶液洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到淡粉色固体7-((5-溴-2-((3-(4-羟基丁基)-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(300mg,收率88％)。LCMS(ESI)m/z:722.4[M+H]+。4-(3-Amino-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)phenyl)butan-1-ol (160 mg) , 7-((5-bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (198 mg) and trifluoroacetic acid (269 mg) were added to tert-butanol (10 mL), stirred at 90°C for 16 h, LCMS showed that the reaction was complete. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain a pale pink solid 7-((5-bromo-2- ((3-(4-hydroxybutyl)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)phenyl)amino)pyrimidine- 4-yl)amino)-1-(methylsulfonyl)indol-4-ol (300 mg, yield 88%). LCMS(ESI)m/z:722.4[M+H] + .
步骤4：35-溴-55-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯甲酸环十烷的制备
Step 4: 3 5 -bromo-5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)-1 1 -(methylsulfonyl) Preparation of -10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3)-benzoic acid cyclodecane
将三苯基膦(90mg)加入到三口瓶中，氮气保护下加入偶氮二甲酸二异丙酯(70mg),室温下搅拌5分钟后，将7-((5-溴-2-((3-(4-羟基丁基)-5-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的四氢呋喃溶液缓慢滴加入三口瓶中，室温下搅拌2h，LCMS显示反应完毕。反应液浓缩除去有机溶剂，残余物经制备TLC纯化得到白色粉末35-溴-55-((5-(1-甲基-1H-吡唑-4-基)吡嗪-2-基)氧基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯甲酸环十烷(30mg,收率62％)。LCMS(ESI)m/z:706.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.53(d,J＝1.2Hz,1H),8.47(s,1H),8.38(d,J＝1.2Hz,1H),8.29(s,1H),8.19(s,1H),8.05–7.95(m,1H),7.46-7.34(m,3H),6.72(s,1H),6.49(s,1H),4.79(t,J＝11.8Hz,1H),4.29–4.14(m,2H),4.02-3.83(m,4H),3.27-3.19(m,1H),3.03(s,3H),2.89(m,1H),2.81–2.70(m,1H),2.16-2.05(m,1H),1.98-1.86(m,1H),1.67(t,J＝13.2Hz,1H),1.53-1.39(m,1H),1.29-1.23(m,1H)。Add triphenylphosphine (90mg) into a three-necked flask, add diisopropyl azodicarboxylate (70mg) under nitrogen protection, stir at room temperature for 5 minutes, add 7-((5-bromo-2-(( 3-(4-hydroxybutyl)-5-((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)oxy)phenyl)amino)pyrimidine-4- The tetrahydrofuran solution of (methyl)amino)-1-(methylsulfonyl)indole-4-ol was slowly added dropwise into the three-necked flask, and stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain white powder 3 5 -bromo-5 5 -((5-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl) Oxygen)-1 1 -(methylsulfonyl)-10-oxa-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1 ,3)-Cyclodecabenzoate (30 mg, yield 62%). LCMS(ESI)m/z:706.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.53 (d, J = 1.2Hz, 1H), 8.47 (s, 1H), 8.38 (d, J = 1.2Hz, 1H), 8.29(s,1H),8.19(s,1H),8.05–7.95(m,1H),7.46-7.34(m,3H),6.72(s,1H),6.49(s,1H),4.79(t, J＝11.8Hz,1H),4.29–4.14(m,2H),4.02-3.83(m,4H),3.27-3.19(m,1H),3.03(s,3H),2.89(m,1H),2.81 –2.70(m,1H),2.16-2.05(m,1H),1.98-1.86(m,1H),1.67(t,J＝13.2Hz,1H),1.53-1.39(m,1H),1.29-1.23 (m,1H).
根据实施例46相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 46:
实施例47:35-溴-55-(5-(1-甲基-1H-吡唑-4-基)嘧啶-2-基氧基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，4.35mg；LCMS(ESI)m/z:704.50[M+H]+。Off-white solid, 4.35 mg; LCMS (ESI) m/z: 704.50[M+H] + .
实施例48:35-溴-55-(4-(4-甲基哌嗪-1-基)苯氧基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
类白色固体，7.20mg；LCMS(ESI)m/z:720.50[M+H]+。Off-white solid, 7.20 mg; LCMS (ESI) m/z: 720.50[M+H] + .
实施例49:35-溴-55-(5-(1-甲基-1H-吡唑-4-基)吡啶-2-基)氧基-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷
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
黄色固体，2.00mg；LCMS(ESI)m/z:703.40[M+H]+。Yellow solid, 2.00 mg; LCMS (ESI) m/z: 703.40[M+H] + .
实施例50:35-溴-56-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并萘环十烷-7-烯
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
步骤1：4-(烯丙氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺的制备
Step 1: Preparation of 4-(allyloxy)-N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine
将7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(100mg)和3-溴丙烯(29mg)碳酸钾(66mg)溶于N,N-二甲基甲酰胺(5mL)中，室温下反应20h，LCMS显示原料反应完毕。反应液浓缩除去有机溶剂，残余物经制备TLC纯化得到淡黄色固体4-(烯丙氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺(80mg,收率73％)。LCMS(ESI)m/z:461.3[M+H]+。7-((5-Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indol-4-ol (100 mg) and 3-bromopropene (29 mg) potassium carbonate (66 mg ) was dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature for 20 h. LCMS showed that the reaction of the raw materials was completed. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain a light yellow solid 4-(allyloxy)-N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl) ) indole-7-amine (80 mg, yield 73%). LCMS(ESI)m/z:461.3[M+H] + .
步骤2：1-(1-(2-溴-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪的制备
Step 2: Preparation of 1-(1-(2-bromo-5-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine
将1-溴-4-氯-2-氟-5-硝基苯(1g)、1-甲基-4-(4-哌啶基)哌嗪(756mg)和碳酸钾(1.08g)溶于乙腈(20mL)中，室温下反应24h，LCMS显示原料反应完毕。反应液过滤掉碳酸钾后，滤液浓缩得到黄色固体1-(1-(2-溴-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(1.4g,收率85％)。LCMS(ESI)m/z:419.3[M+H]+。Dissolve 1-bromo-4-chloro-2-fluoro-5-nitrobenzene (1g), 1-methyl-4-(4-piperidyl)piperazine (756mg) and potassium carbonate (1.08g) in In acetonitrile (20 mL), the reaction was carried out at room temperature for 24 hours. LCMS showed that the reaction of the raw materials was completed. After the reaction solution was filtered off potassium carbonate, the filtrate was concentrated to obtain a yellow solid 1-(1-(2-bromo-5-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1.4 g, yield 85%). LCMS(ESI)m/z:419.3[M+H] + .
步骤3：1-(1-(2-烯丙基-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪的制备
Step 3: Preparation of 1-(1-(2-allyl-5-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine
将1-(1-(2-溴-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(1400mg)、烯丙基硼酸频哪醇酯(563mg)、四三苯基膦钯(387mg)和氟化铯(1018mg)溶于1,4-二氧六环(15mL)和水(5mL)的混合溶剂中，氮气保护下，升温至80℃反应20h，LCMS显示原料反应完毕。反应液浓缩除去有机溶剂，残余物经层析柱纯化得到黄色油状物1-(1-(2-烯丙基-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(800mg，收率63％)。LCMS(ESI)m/z:379.3[M+H]+。1-(1-(2-Bromo-5-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (1400mg), allylboronic acid pinacol ester (563mg ), tetrakis triphenylphosphine palladium (387 mg) and cesium fluoride (1018 mg) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (5 mL). Under nitrogen protection, the temperature was raised to 80°C for reaction. 20h, LCMS showed that the raw material reaction was completed. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by chromatography column to obtain 1-(1-(2-allyl-5-chloro-4-nitrophenyl)piperidin-4-yl)-4 as a yellow oil. - Methylpiperazine (800 mg, yield 63%). LCMS(ESI)m/z:379.3[M+H] + .
步骤4：5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺的制备
Step 4: Preparation of 5-allyl-2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline
将1-(1-(2-烯丙基-5-氯-4-硝基苯基)哌啶-4-基)-4-甲基哌嗪(800mg)、铁粉(590mg)、氯化铵(1118mg)溶于乙醇(20mL)和水(5mL)的混合溶剂中，70℃下反应16h，LCMS显示原料反应完毕。反应液过滤掉铁粉后，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经层析柱纯化得到黄色油状物5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(500mg,收率：68％)。LCMS(ESI)m/z:349.3[M+H]+。1-(1-(2-allyl-5-chloro-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (800mg), iron powder (590mg), chlorinated Ammonium (1118 mg) was dissolved in a mixed solvent of ethanol (20 mL) and water (5 mL), and the reaction was carried out at 70°C for 16 hours. LCMS showed that the reaction of the raw materials was completed. The reaction solution was filtered to remove iron powder, extracted with dichloromethane/isopropanol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by a chromatography column to obtain 5-allyl-2-chloro-4 as a yellow oil. -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (500 mg, yield: 68%). LCMS(ESI)m/z:349.3[M+H] + .
步骤5：N2-(5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(4-(烯丙氧基)-1-(甲基磺酰基)吲哚-7-基)-5-溴嘧啶-2,4-二胺的制备
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
将5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯胺(60mg)、4-(烯丙氧基)-N-(5-溴-2-氯嘧啶-4-基)-1-(甲基磺酰基)吲哚-7-胺(80mg)和甲磺酸(167mg)加入到叔丁醇(5mL)中，90℃下搅拌16h，LCMS显示反应完毕。反应液用饱和碳酸氢钠水溶液洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到黄色固体N2-(5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(4-(烯丙氧基)-1-(甲基磺酰基)吲哚-7-基)-5-溴嘧啶-2,4-二胺(60mg,收率：45％)。LCMS(ESI)m/z:774.3[M+H]+。5-allyl-2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (60 mg), 4-(allyloxy)-N -(5-Bromo-2-chloropyrimidin-4-yl)-1-(methylsulfonyl)indole-7-amine (80 mg) and methanesulfonic acid (167 mg) were added to tert-butanol (5 mL). After stirring at 90°C for 16 hours, LCMS showed that the reaction was complete. The reaction solution was washed with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane/isopropyl alcohol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain yellow solid N 2 -(5-allyl-2 -Chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(4-(allyloxy)-1-(methylsulfonate) Acyl)indol-7-yl)-5-bromopyrimidine-2,4-diamine (60 mg, yield: 45%). LCMS(ESI)m/z:774.3[M+H] + .
步骤6：35-溴-56-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并萘环十烷-7-烯的制备
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
将N2-(5-烯丙基-2-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(4-(烯丙氧基)-1-(甲基磺酰基)吲哚-7-基)-5-溴嘧啶-2,4-二胺、Grubbs II代催化剂(11mg)溶于二氯甲烷(10mL)中，置换成氮气气氛后，升温至40℃下反应2h，LCMS显示反应完毕。反应液浓缩除去有机溶剂，残余物经制备TLC纯化得到35-溴-56-氯-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-10-氧杂-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯并萘环十烷-7-烯(2.67mg,收率5％)。LCMS(ESI)m/z:743.60[M+H]+。N 2 -(5-allyl-2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(4-( Allyloxy)-1-(methylsulfonyl)indol-7-yl)-5-bromopyrimidine-2,4-diamine, Grubbs II catalyst (11 mg) was dissolved in dichloromethane (10 mL) , after replacing with nitrogen atmosphere, the temperature was raised to 40°C and the reaction was carried out for 2 hours. LCMS showed that the reaction was completed. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain 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)- Benzonaphthylcyclodecane-7-ene (2.67 mg, yield 5%). LCMS(ESI)m/z:743.60[M+H] + .
根据实施例50相同的方法制备了以下化合物：The following compounds were prepared according to the same method as Example 50:
实施例51:35-溴-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-10-氧-2,4-二氮-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十烷-7-烯
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
类白色固体，1.78mg；LCMS(ESI)m/z:709.60[M+H]+。Off-white solid, 1.78 mg; LCMS (ESI) m/z: 709.60[M+H] + .
实施例52:35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-6-10-二氧-2,4-二氮-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并那环十烷的制备
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
步骤1：3-(2-氟-5-硝基苯氧基)丙-1-醇
Step 1: 3-(2-fluoro-5-nitrophenoxy)propan-1-ol
2-氟-5-硝基苯酚(400mg)和3-溴丙-1-醇(422mg)加入DMF(10mL)中，室温条件下加入K2CO3(704mg)，80℃搅拌3h，LCMS确认反应完全。反应体系加入乙酸乙酯和去离 子水，萃取，收集有机层，无水硫酸钠干燥，浓缩除去有机溶剂，得到残余物粗品黄色油状物3-(2-氟-5-硝基苯氧基)丙-1-醇(530mg，收率96.6％)。MS(ESI)m/z:216.20[M+H]+。2-Fluoro-5-nitrophenol (400mg) and 3-bromopropan-1-ol (422mg) were added to DMF (10mL), K 2 CO 3 (704mg) was added at room temperature, stirred at 80°C for 3h, and confirmed by LCMS Complete response. Add ethyl acetate to the reaction system and remove water, extracted, collected the organic layer, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and obtained the crude yellow oily residue 3-(2-fluoro-5-nitrophenoxy)propan-1-ol (530 mg, Yield 96.6%). MS(ESI)m/z:216.20[M+H] + .
步骤2：3-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯氧基)丙-1-醇
Step 2: 3-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenoxy)propan-1-ol
3-(2-氟-5-硝基苯氧基)丙-1-醇(530mg)和1-甲基-4-(哌啶-4-基)哌嗪(541mg)加入乙腈(10mL)中，室温条件下加入K2CO3(680mg)，80℃搅拌16h，LCMS确认反应完全后。反应液浓缩除去乙腈，残余物加入乙酸乙酯和去离子水，萃取，收集有机层，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经柱层析纯化，得到黄色油状物3-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯氧基)丙-1-醇(452mg，收率48.6％)。MS(ESI)m/z:379.40[M+H]+。3-(2-Fluoro-5-nitrophenoxy)propan-1-ol (530 mg) and 1-methyl-4-(piperidin-4-yl)piperazine (541 mg) were added to acetonitrile (10 mL) , add K 2 CO 3 (680 mg) at room temperature, stir at 80°C for 16 hours, and confirm the reaction is complete by LCMS. The reaction solution was concentrated to remove acetonitrile, and ethyl acetate and deionized water were added to the residue for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by column chromatography to obtain yellow oil 3-(2 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenoxy)propan-1-ol (452 mg, yield 48.6%). MS(ESI)m/z:379.40[M+H] + .
步骤3：3-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯氧基)丙-1-醇
Step 3: 3-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenoxy)propan-1-ol
3-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苯氧基)丙-1-醇(100mg)溶于入MeOH(10mL)中，加入Pd/C(10mg,Wt＝10％)，氢气氛围下，室温搅拌过夜，LCMS确认反应完全。反应液过滤除去Pd/C，滤液浓缩后得到粗品3-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯氧基)丙-1-醇(99mg)，不用纯化直接用于下一步。MS(ESI)m/z:349.40[M+H]+。3-(2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenoxy)propan-1-ol (100 mg) was dissolved in MeOH (10 mL ), add Pd/C (10 mg, Wt=10%), stir at room temperature overnight under hydrogen atmosphere, and confirm the reaction is complete by LCMS. The reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to obtain crude product 3-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenoxy)propan- 1-Alcohol (99 mg) was used in the next step without purification. MS(ESI)m/z:349.40[M+H] + .
步骤4：7-((5-溴-2-((3-(3-羟基丙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇
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
3-(5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯氧基)丙-1-醇(99mg)和7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(119mg)加入叔丁醇(5mL)中，室温下加入TFA(97.1mg)，90℃条件下搅拌16h，LCMS确认反应完全。反应液浓缩除去叔丁醇，残余物经反相柱纯化，浓缩除去乙腈，残余物加入EA和去离子水，萃取，收集有机层，无水硫酸钠干燥，浓缩除去乙酸乙酯，得到白色固体7-((5-溴-2-((3-(3-羟基丙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(78.0mg，收率37.6％)。MS(ESI)m/z:731.40[M+H]+。 3-(5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenoxy)propan-1-ol (99 mg) and 7-((5- Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (119 mg) was added to tert-butanol (5 mL), and TFA (97.1 mg) was added at room temperature, 90 Stir for 16 hours at ℃, and LCMS confirms that the reaction is complete. The reaction solution was concentrated to remove tert-butanol, and the residue was purified by a reverse-phase column. Concentrate to remove acetonitrile. Add EA and deionized water to the residue for extraction. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain a white solid. 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 (78.0 mg, yield 37.6%). MS(ESI)m/z:731.40[M+H] + .
步骤5：35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-6-10-二氧-2,4-二氮-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并那环十烷
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
PPh3(140mg)加入THF(10mL)中，氮气保护下，DIAD(108mg)溶于THF(1mL)中，冰浴下滴加至上述溶液，搅拌5分钟，再缓慢滴加7-((5-溴-2-((3-(3-羟基丙氧基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(78.0mg)溶于THF(1mL)的溶液，室温下搅拌2h后，LCMS确认反应完全。反应液浓缩除去THF，残余物经柱层析纯化得到白色固体35-溴-54-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-11-(甲基磺酰基)-6-10-二氧-2,4-二氮-1(7,4)-吲哚-3(4,2)-嘧啶-5(1,3)-苯并那环十烷(58.0mg，收率76.8％)。MS(ESI)m/z:713.40[M+H]+。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. The reaction solution was concentrated to remove THF, and the residue was purified by column chromatography to obtain a white solid 3 5 -bromo-5 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 - (Methylsulfonyl)-6-10-dioxo-2,4-diaza-1(7,4)-indole-3(4,2)-pyrimidine-5(1,3)-benzona Cyclodecane (58.0 mg, yield 76.8%). MS(ESI)m/z:713.40[M+H] + .
实施例53:35-溴-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-7,10-二氧嘧啶-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷的制备
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
步骤1：2-(2-氟-5-硝基苄基)氧基)乙烷-1-醇的制备
Step 1: Preparation of 2-(2-fluoro-5-nitrobenzyl)oxy)ethane-1-ol
将氢化钠(41mg)加入乙二醇(10mL)中，室温下搅拌0.5h，加入2-溴甲基-1-氟-4-硝基苯(200mg)，室温下搅拌48h，LCMS显示反应完毕。反应液用去离子水洗涤，乙酸乙酯萃取，无水硫酸钠干燥，浓缩除去有机相溶剂，得到黄色油状物2-(2-氟-5-硝基苄基)氧基)乙烷-1-醇(300mg，粗品)。LCMS(ESI)m/z:216.4[M+H]+。Add sodium hydride (41mg) to ethylene glycol (10mL), stir at room temperature for 0.5h, add 2-bromomethyl-1-fluoro-4-nitrobenzene (200mg), stir at room temperature for 48h, LCMS shows that the reaction is complete . The reaction solution was washed with deionized water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to remove the organic solvent to obtain a yellow oily substance 2-(2-fluoro-5-nitrobenzyl)oxy)ethane-1. -Alcohol (300 mg, crude). LCMS(ESI)m/z:216.4[M+H] + .
步骤2：2-((2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苄基)氧基)乙烷-1-醇的制备
Step 2: Preparation of 2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzyl)oxy)ethane-1-ol
将2-(2-氟-5-硝基苄基)氧基)乙烷-1-醇(300mg)、1-甲基-4-(4-哌啶基)哌嗪(280mg)、碳酸钾(384mg)溶于乙腈(10mL)中，80℃下搅拌20h，LCMS显示反应完毕。反应液浓缩除去有机溶剂，残余物经制备TLC纯化得到黄色油状物2-((2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苄基)氧基)乙烷-1-醇(100mg，收率：19％)。LCMS(ESI)m/z:379.3[M+H]+。Combine 2-(2-fluoro-5-nitrobenzyl)oxy)ethane-1-ol (300 mg), 1-methyl-4-(4-piperidyl)piperazine (280 mg), and potassium carbonate (384mg) was dissolved in acetonitrile (10mL) and stirred at 80°C for 20h. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain 2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitro) as a yellow oil. Benzyl)oxy)ethane-1-ol (100 mg, yield: 19%). LCMS(ESI)m/z:379.3[M+H] + .
步骤3：2-((5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苄基)氧基)乙烷-1-醇的制备
Step 3: Preparation of 2-((5-amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzyl)oxy)ethane-1-ol
将2-((2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-5-硝基苄基)氧基)乙烷-1-醇(100mg)、锌粉(85mg)、氯化铵(140mg)溶于乙醇(8mL)和水(8mL)的混合溶剂中，室温下反应2h，LCMS显示原料反应完毕。过滤掉锌粉后浓缩除去溶剂，残余物经制备TLC纯化得到黄色油状物2-((5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苄基)氧基)乙烷-1-醇(60mg,收率：65％)。LCMS(ESI)m/z:349.3[M+H]+。2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrobenzyl)oxy)ethane-1-ol (100 mg), Zinc powder (85 mg) and ammonium chloride (140 mg) were dissolved in a mixed solvent of ethanol (8 mL) and water (8 mL). The reaction was carried out at room temperature for 2 hours. LCMS showed that the reaction of the raw materials was completed. The zinc powder was filtered off and the solvent was concentrated to remove. The residue was purified by preparative TLC to obtain 2-((5-amino-2-(4-(4-methylpiperazin-1-yl))piperidin-1-yl) as a yellow oil. )benzyl)oxy)ethane-1-ol (60 mg, yield: 65%). LCMS(ESI)m/z:349.3[M+H] + .
步骤4：7-((5-溴-2-((3-((2-羟基乙氧基)甲基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的制备
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
将2-((5-氨基-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苄基)氧基)乙烷-1-醇(60mg)、7-((5-溴-2-氯嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(72mg)和甲磺酸(50mg)加入到叔丁醇(5mL)中，90℃下搅拌16h，LCMS显示反应完毕。反应液用饱和碳酸氢钠水溶液洗涤，二氯甲烷/异丙醇萃取，无水硫酸钠干燥，浓缩除去有机溶剂，残余物经制备TLC纯化得到黄色固体7-((5-溴-2-((3-((2-羟基乙氧基)甲基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇(50mg,收率：40％)。LCMS(ESI)m/z:733.3[M+H]+。2-((5-Amino-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzyl)oxy)ethan-1-ol (60 mg), 7 -((5-Bromo-2-chloropyrimidin-4-yl)amino)-1-(methylsulfonyl)indole-4-ol (72 mg) and methanesulfonic acid (50 mg) were added to tert-butanol (5 mL ), stirred at 90°C for 16h, LCMS showed that the reaction was completed. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane/isopropanol, dried over anhydrous sodium sulfate, concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain a yellow solid 7-((5-bromo-2-( (3-((2-hydroxyethoxy)methyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl )Amino)-1-(methylsulfonyl)indole-4-ol (50 mg, yield: 40%). LCMS(ESI)m/z:733.3[M+H] + .
步骤5：35-溴-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-7,10-二氧嘧 啶-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷的制备
Step 5: 3 5 -bromo-5 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
将三苯基膦(45mg)加入到三口瓶中，氮气保护下，加入偶氮二甲酸二异丙酯(34mg)，室温下搅拌5分钟后，将7-((5-溴-2-((3-((2-羟基乙氧基)甲基)-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)-1-(甲基磺酰基)吲哚-4-醇的四氢呋喃溶液缓慢滴加入三口瓶中，室温下搅拌2h，LCMS显示反应完毕。反应液浓缩除去有机溶剂，残余物经制备TLC纯化得到类白色粉末35-溴-54-(4-(4-甲基哌嗪-1-酰基)哌啶-1-酰基)-11-(甲基磺酰基)-7,10-二氧嘧啶-2,4-二氮杂-1(7,4)-吲哚啉-3(4,2)-嘧啶-5(1,3)-苯环十碳烷(15mg，收率62％)。LCMS(ESI)m/z:713.6[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.52(s,1H),8.16(s,1H),7.66(d,J＝2.6Hz,1H),7.36-7.29(m,2H),7.00(m,1H),6.90(d,J＝8.7Hz,1H),4.94-4.84(m,1H),4.44(d,J＝8.1Hz,1H),4.28-4.18(m,1H),4.09(d,J＝13.7Hz,1H),3.97-3.89(m,2H),3.89-3.81(m,2H),3.28-3.15(m,3H),3.09-3.03(m,1H),3.01(s,3H),2.97-2.89(m,1H),2.63-2.54(m,4H),2.50-2.39(m,6H),2.24(s,3H),1.90-1.79(m,2H),1.62-1.47(m,2H).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. LCMS showed that the reaction was complete. The reaction solution was concentrated to remove the organic solvent, and the residue was purified by preparative TLC to obtain an off-white powder 3 5 -bromo-5 4 -(4-(4-methylpiperazine-1-acyl)piperidine-1-acyl)-1 1 -(methylsulfonyl)-7,10-dioxopyrimidine-2,4-diaza-1(7,4)-indoline-3(4,2)-pyrimidine-5(1,3) - Benzenecyclodecane (15 mg, yield 62%). LCMS(ESI)m/z:713.6[M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 8.52 (s, 1H), 8.16 (s, 1H), 7.66 (d, J = 2.6Hz, 1H), 7.36-7.29 (m, 2H),7.00(m,1H),6.90(d,J＝8.7Hz,1H),4.94-4.84(m,1H),4.44(d,J＝8.1Hz,1H),4.28-4.18(m,1H ),4.09(d,J＝13.7Hz,1H),3.97-3.89(m,2H),3.89-3.81(m,2H),3.28-3.15(m,3H),3.09-3.03(m,1H), 3.01(s,3H),2.97-2.89(m,1H),2.63-2.54(m,4H),2.50-2.39(m,6H),2.24(s,3H),1.90-1.79(m,2H), 1.62-1.47(m,2H).
效果例1：EGFR激酶活性抑制评价Effect example 1: Evaluation of EGFR kinase activity inhibition
实验方法：experimental method:
将化合物(10μM，1μM，100nM，10nM，1nM，0.1nM，0.01nM)和含纯化的EGFR-WT、EGFR-L858R/T790M、EGFR-Del19/T790M/C797S或EGFR-L858R/T790M/C797S的孵育缓冲液加入384反应板(ProxiPlate-384Plus，PerkinElmer)中，室温孵育半小时后，加入底物缓冲液启动反应，室温孵育一个小时后，加入XL665和抗体继续孵育一个小时，最终用Envision检测荧光信号665nm和620nm的比值。同时设不加酶的空白对照组、以DMSO替代化合物的溶剂对照组、以及阳性对照组(AZD-9291、BI-4020)。反应终体积为10μL，具体反应体系为2v％DMSO，0.04ng/μL EGFR，1μM TK-s，0.002(EGFR-WT)～1mM ATP(EGFR-L858R/T790M、EGFR-Del19/T790M/C797S、EGFR-L858R/T790M/C797S)，5mM MgCl2，1mM DTT，1×kinase buffer(激酶缓冲液)。Compounds (10 μM, 1 μM, 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. Finally, Envision was used to detect the fluorescence signal. The ratio of 665nm and 620nm. At the same time, a blank control group without enzyme, a solvent control group with DMSO replacing the compound, and a positive control group (AZD-9291, BI-4020) were set up. The final volume of the reaction is 10 μL. The specific reaction system is 2v% DMSO, 0.04ng/μL EGFR, 1 μM 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.
其中，XL665，TK-s底物、抗体和各种缓冲液均来自HTRF KinEASE STK Discovery kit(Cisbio,62ST0PEB)。Among them, XL665, TK-s substrate, antibodies and various buffers are from HTRF KinEASE STK Discovery kit (Cisbio, 62ST0PEB).
经测试，本发明的化合物对EGFR-WT、EGFR-L858R/T790M、EGFR-L858R/T790M/C797S、EGFR-Del19/T790M/C797S的IC50值分别均为0.1nM-10000nM。具体实验结果如表1所示。After testing, the IC50 values of the compounds of the present invention for EGFR-WT, EGFR-L858R/T790M, EGFR-L858R/T790M/C797S, and EGFR-Del19/T790M/C797S were all 0.1nM-10000nM respectively. The specific experimental results are shown in Table 1.
实验结果表明：本发明的化合物对突变型EGFR具有优异的抑制活性，尤其是二突变和三突变，可以克服对早期相关药物的耐药性，有望进一步开发成为用于制备调节EGFR(L858R/T790M、L858R/T790M/C797S、Del19/T790M/C797S等)激酶活性或治疗EGFR(L858R/T790M、L858R/T790M/C797S、Del19/T790M/C797S等)相关疾病方面的药物。 Experimental results show that 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.
测试数据分为以下几种：A:IC50<50nM；B:50nM≤IC50<100nM；C:100nM≤IC50<1000nM；D:1000nM≤IC50<10000nM；E:IC50≥10000nM；ND:not detected。The 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.
表1

Table 1

效果例2：EGFR突变细胞的增殖抑制活性评价Effect example 2: Evaluation of proliferation inhibitory activity of EGFR mutant cells
实验方法：experimental method:
Ba/F3(EGFR-Del19/T790M/C797S)和Ba/F3(EGFR-L858R/T790M/C797S)分别为过表达EGFR-Del19/T790M/C797S和EGFR-L858R/T790M/C797S的工程细胞株，均通过逆病毒载体感染并经抗性筛选所构建。Ba/F3(EGFR-Del19/T790M/C797S)和Ba/F3(EGFR-L858R/T790M/C797S)均培养于RPMI-1640+10v％FBS中。试验时，分别接种2000cell/孔的细胞于96孔板，随后加入10000,2000,400,80,16,3.2,0.64,0.128nM的化合物，以0.2v％DMSO作为对照，于37℃培养箱中培养72h。随后每孔加入20μL CellTiter 96 AQueous One Solution Cell Proliferation Assay试剂，37℃孵育1-2h后，于酶标仪检测490nm和690nm吸光值，计算OD490nm-OD690nm，最后将各化合物处理孔吸光值(OD490nm-OD690nm)相对0.2v％DMSO对照孔的吸光值(OD490nm-OD690nm)的百分比作为细胞相对活力。根据化合物不同浓度下的细胞相对活力百分数，以四参数回归模型(four  parameter logistic model)计算化合物的IC50。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. During the test, 2000 cells/well were seeded into 96-well plates, and then 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128nM compounds were added, with 0.2v% DMSO as a control, and incubated at 37°C Culture for 72h. Then add 20 μL CellTiter 96 AQueous One Solution Cell Proliferation Assay reagent to each well, incubate at 37°C for 1-2 hours, detect the absorbance values at 490nm and 690nm on a microplate reader, calculate OD 490nm - OD 690nm , and finally calculate the absorbance value of each compound-treated well ( The percentage of OD 490nm - OD 690nm ) relative to the absorbance value (OD 490nm - OD 690nm ) of the 0.2v% DMSO control well was used as the relative cell viability. According to the relative cell viability percentage at different concentrations of the compound, a four-parameter regression model (four parameter logistic model) to calculate the IC50 of the compound.
经测试，本发明的化合物对Ba/F3(EGFR-Del19/T790M/C797S)和Ba/F3(EGFR-L858R/T790M/C797S)的IC50值分别均为0.1nM-10000nM。具体实验结果如表2所示。After testing, 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.
实验结果表明：本发明的化合物对过表达三突变EGFR的Ba/F3(EGFR-Del19/T790M/C797S)和Ba/F3(EGFR-L858R/T790M/C797S)工程细胞株均具有优异的细胞增殖抑制活性，有望开发成用于针对上述EGFR突变相关疾病方面的药物。Experimental results show that the compounds of the present invention have excellent cell proliferation inhibition on both Ba/F3 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) engineering cell lines that overexpress triple mutant EGFR. activity, it is expected to be developed into drugs for the above-mentioned EGFR mutation-related diseases.
测试数据分为以下几种：A:IC50<25nM；B:25nM≤IC50<60nM；C:60nM≤IC50<200nM；D:200nM≤IC50<1000nM；E:1000nM≤IC50<10000；ND:not detected。The 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.
表2

Table 2

AZD-9291的结构如下：
The structure of AZD-9291 is as follows:
BI-4020的结构如下：
The structure of BI-4020 is as follows:
A-29来自专利WO2021216440种化合物A29，结构如下：
A-29 comes from the patent WO2021216440 compound A29, with the following structure:
效果例3：肿瘤细胞增殖抑制实验Effect Example 3: Tumor Cell Proliferation Inhibition Experiment
SK-BR-3和MDA-MB-468是HER-2过表达的乳腺癌细胞，为评价HER-2抑制剂的经典模型细胞。SK-BR-3培养于McCoy’s 5A+10v％FBS培养基中，MDA-MB-468培养于DMEM+10v％FBS中。试验时，分别接种10000cell/孔的SK-BR-3和MDA-MB-468 于96孔板，随后加入10000,2000,400,80,16,3.2,0.64,0.128nM的化合物，以0.2v％DMSO作为对照，于37℃培养箱中培养72h。随后每孔加入20μL CellTiter 96AQueous One Solution Cell Proliferation Assay试剂，37℃孵育1-2h后，于酶标仪检测490nm和690nm吸光值，计算OD490nm-OD690nm，最后将各化合物处理孔吸光值(OD490nm-OD690nm)相对0.2v％DMSO对照孔的吸光值(OD490nm-OD690nm)的百分比作为细胞相对活力。根据化合物不同浓度下的细胞相对活力百分数，以四参数回归模型(four parameter logistic model)计算化合物的IC50。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, and MDA-MB-468 was cultured in DMEM+10v% FBS. During the experiment, 10,000 cells/well of SK-BR-3 and MDA-MB-468 were inoculated respectively. Then, 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. Then add 20 μL CellTiter 96AQueous One Solution Cell Proliferation Assay reagent to each well, incubate at 37°C for 1-2 hours, detect the absorbance values at 490nm and 690nm on a microplate reader, calculate OD 490nm - OD 690nm , and finally calculate the absorbance value (OD) of each compound-treated well. The percentage of the absorbance value (OD 490nm - OD 690nm ) relative to the 0.2v % DMSO control well was used as the relative cell viability. Based on the relative cell viability percentage at different concentrations of the compound, the IC50 of the compound was calculated using a four-parameter logistic model.
经测试，本发明的化合物对SK-BR-3和MDA-MB-468的IC50值分别均为0.1nM-10000nM。具体实验结果如表3所示。After testing, the IC50 values of the compounds of the present invention for SK-BR-3 and MDA-MB-468 are 0.1nM-10000nM respectively. The specific experimental results are shown in Table 3.
测试数据分为以下几种：A:IC50<50nM；B:50nM≤IC50<200nM；C:200nM≤IC50<1000nM；D:1000nM≤IC50<10000nM；E:IC50>10000nM；ND:not detected。The 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.
表3
table 3
实验结果表明：本发明的化合物对HER-2阳性乳腺癌细胞SK-BR-3和MDA-MB-468具有优异的增殖抑制活性，有望进一步开发成为用于制备调节HER-2激酶活性或治疗HER-2扩增相关疾病方面的药物。Experimental results show that the compound of the present invention has excellent proliferation inhibitory activity on HER-2 positive breast cancer cells SK-BR-3 and MDA-MB-468, and is expected to be further developed into a preparation for regulating HER-2 kinase activity or treating HER -2 Expansion of drugs for related diseases.
效果例4：c-MET激酶活性抑制评价Effect Example 4: Evaluation of c-MET kinase activity inhibition
实验方法：experimental method:
将化合物(10μM，1μM，100nM，10nM，1nM，0.1nM，0.01nM)和含纯化的c-MET激酶的孵育缓冲液加入384反应板(ProxiPlate-384Plus，PerkinElmer)中，室温孵育半小时后，加入底物缓冲液启动反应，室温孵育一个小时后，加入XL665和抗体继续孵育一 个小时，最终用Envision检测荧光信号665nm和620nm的比值。同时设不加酶的空白对照组、以DMSO替代化合物的溶剂对照组、以及阳性对照组(staurosporine)。反应终体积为10μL，具体反应体系为2v％DMSO，0.04ng/μL c-MET，1μM TK-s，2μM ATP，5mM MgCl2，1mM DTT，1×kinase buffer(激酶缓冲液)。Compounds (10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM) and the incubation buffer containing purified c-MET kinase were added to the 384 reaction plate (ProxiPlate-384Plus, PerkinElmer), and after incubation at room temperature for half an hour, Add substrate buffer to start the reaction. After incubating at room temperature for one hour, add XL665 and antibody and continue incubating for another hour. hours, and finally use Envision to detect the ratio of fluorescence signals at 665nm and 620nm. At the same time, 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 μL. The specific reaction system is 2v% DMSO, 0.04ng/μL c-MET, 1 μM TK-s, 2 μM ATP, 5mM MgCl 2 , 1mM DTT, and 1×kinase buffer.
其中，XL665，TK-s底物、抗体和各种缓冲液均来自HTRF KinEASE STK Discovery kit(Cisbio,62ST0PEB)。Among them, XL665, TK-s substrate, antibodies and various buffers are from HTRF KinEASE STK Discovery kit (Cisbio, 62ST0PEB).
经测试，本发明的化合物对c-MET的IC50值分别均为0.1nM-10000nM。具体实验结果如表4所示。After testing, the IC50 values of the compounds of the present invention for c-MET are respectively 0.1nM-10000nM. The specific experimental results are shown in Table 4.
测试数据分为以下几种：A:IC50<50nM；B:50nM≤IC50<200nM；C:200nM≤IC50<1000nM；D:1000nM≤IC50<10000nM；E:IC50>10000nM；ND:not detected。The 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.
表4
Table 4
实验结果表明：本发明的化合物对c-MET具有优异的抑制活性，有望进一步开发成为用于制备调节c-MET激酶活性或治疗c-MET扩增相关疾病方面的药物。Experimental results show that the compound of the present invention has excellent inhibitory activity against c-MET and is expected to be further developed into a drug for regulating c-MET kinase activity or treating c-MET amplification-related diseases.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (16)

  1. 一种式I所示的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，
    A compound represented by formula I, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate,
    式中，In the formula,
    X选自：NR5、CR5Ra或O；X is selected from: NR 5 , CR 5 Ra or O;
    Y选自：不存在、NRa、CRaRb或O；Y is selected from: absent, NRa, CRaRb or O;
    L选自：C1-C8亚烷基、C2-C8亚烯基、C2-C8亚炔基、-C1-C10亚烷基-O-、-C1-C10亚烷基-NH-、C1-C10亚杂烷基、-C1-C10亚烷基-C(＝O)-NH-、-C1-C10亚烷基-C(＝O)-NH-C1-C10亚烷基-、-C1-C10亚烷基-NH-C(＝O)-、-C1-C10亚烷基-NH-C(＝O)NH-、-C1-C10亚烷基-NH-C(＝O)NH-C1-C10亚烷基-、-C1-C10亚烷基-OC(＝O)-NH-、-C1-C10亚烷基-OC(＝O)-NH-C1-C10亚烷基-、-C1-C10亚烷基-C(＝O)-、-C1-C10亚烷基-C(＝O)-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)-、-C1-C10亚烷基-S(＝O)-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)2-、-C1-C10亚烷基-S(＝O)2-C1-C10亚烷基-、-C1-C10亚烷基-S(＝O)2NH-、-C1-C10亚烷基-NHS(＝O)2-、-C1-C10亚烷基-S(＝O)2NH-C1-C10亚烷基-、C1-C8亚烷基C3-C8亚环烷基、C1-C8亚烷基C3-C8亚环烷基C1-C8亚烷基；其中，上述各基团中的H任选地被1、2、3、4、5、6、7或8个Ra取代；L is selected from: C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, -C1-C10 alkylene-O-, -C1-C10 alkylene-NH-, C1-C10 Heteroalkylene, -C1-C10 alkylene-C(=O)-NH-, -C1-C10 alkylene-C(=O)-NH-C1-C10 alkylene-, -C1-C10 Alkylene-NH-C(=O)-, -C1-C10 Alkylene-NH-C(=O)NH-, -C1-C10 Alkylene-NH-C(=O)NH-C1- C10 alkylene-, -C1-C10 alkylene-OC(=O)-NH-, -C1-C10 alkylene-OC(=O)-NH-C1-C10 alkylene-, -C1- C10 alkylene-C(=O)-, -C1-C10 alkylene-C(=O)-C1-C10 alkylene-, -C1-C10 alkylene-S(=O)-,- C1-C10 alkylene-S(=O)-C1-C10 alkylene-, -C1-C10 alkylene-S(=O) 2 -, -C1-C10 alkylene-S(=O) 2 -C1-C10 alkylene-, -C1-C10 alkylene-S(=O) 2 NH-, -C1-C10 alkylene-NHS(=O) 2 -, -C1-C10 alkylene -S(=O) 2 NH-C1-C10 alkylene-, C1-C8 alkylene C3-C8 cycloalkylene, C1-C8 alkylene C3-C8 cycloalkylene C1-C8 alkylene ; Wherein, H in each of the above groups is optionally replaced by 1, 2, 3, 4, 5, 6, 7 or 8 Ra;
    R1和R2各自独立地选自：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、-OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-或5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代；R 1 and R 2 are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra)SO m Rb, -C (O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, -S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O- or 5-10 membered heteroaryl-O-; wherein, each of the above groups H in the group is optionally replaced by 1, 2 or 3 R;
    或者，R1、R2以及与它们连接的原子共同形成C5-C6环烷基、5-6元杂环基、苯基或5-6元杂芳基；其中，上述各基团中的H任选地被1、2或3个Ra取代；Alternatively, 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;
    R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13和R’13各自独立地选自：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、-OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-或5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代；R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R' 13 are each independently selected from: H, D, halogen, cyano , nitro, hydroxyl, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra)SO m Rb, -C(O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, -S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl -O-, 3-12 membered hetero Cyclic group -O-, C6-C10 aryl-O- or 5-10 membered heteroaryl -O-; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R;
    R9和R10任选地被选自下组的基团取代：H、D、卤素、氰基、硝基、羟基、甲氧基、-NRaRb、-C(O)NRaRb、-N(Ra)SOmRb、-C(O)Ra、-P(＝O)RaRb、-S(O)mNRaRb、-NRaC(O)Rb、-C(O)ORa、-OC(O)Ra、-S(O)mRa、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、C3-C12环烷基-O-、3-12元杂环基-O-、C6-C10芳基-O-和5-10元杂芳基-O-；其中，上述各基团中的H任选地被1、2或3个R取代； R 9 and R 10 are optionally substituted with a group selected from the group consisting of: H, D, halogen, cyano, nitro, hydroxy, methoxy, -NRaRb, -C(O)NRaRb, -N(Ra )SO m Rb, -C(O)Ra, -P(=O)RaRb, -S(O) m NRaRb, -NRaC(O)Rb, -C(O)ORa, -OC(O)Ra, - S(O) m Ra, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 Aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl-O-, 3-12 membered heterocyclyl-O-, C6-C10 aryl-O- and 5-10 membered heteroaryl-O -; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R;
    Ra和Rb各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、-NRR'、-C(O)NRR'、-N(R)SOmR'、-C(O)R'、-P(＝O)RR'、-S(O)mNRR'、-NRC(O)R'、-C(O)OR、-OC(O)R、-S(O)mR'、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基或5-10元杂芳基；其中，上述各基团中的H任选地被1、2或3个R”取代；Ra and Rb are each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, -NRR', -C(O)NRR', -N(R)SO m R', -C( O)R', -P(=O)RR', -S(O) m NRR', -NRC(O)R', -C(O)OR, -OC(O)R, -S(O) m R', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; wherein, H in each of the above groups is optionally substituted by 1, 2 or 3 R”;
    R、R'和R”各自独立地选自下组：H、D、卤素、氰基、硝基、羟基、氨基、-NH(C1-C6烷基)、-N(C1-C6烷基)2、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代的C1-C6烷氧基、取代或未取代C3-C12环烷基、取代或未取代3-12元杂环基、取代或未取代C6-C10芳基、取代或未取代5-10元杂芳基；其中，所述取代是指被选自下组的1、2或3个基团取代：D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基和5-10元杂芳基；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. Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3- C12 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein, the substitution refers to 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 membered heterocyclyl, C6-C10 aryl and 5-10 membered heteroaryl;
    m独立地选自：1或2；m is independently selected from: 1 or 2;
    限定条件：Qualifications:
    当X为O时，R3、R4以及与它们连接的原子共同形成5-6元杂环基；其中，上述基团中的H任选地被1、2或3个Ra取代；When X is O, 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;
    当X为NR5或CR5Ra时，R3、R4以及与它们连接的原子共同形成环A1，环A1为5-6元杂环基，环A1中的H任选地被1、2或3个Ra取代；R4、R5以及与它们连接的原子共同形成环A2，环A2为C5-C6环烷基或5-6元杂环基，环A2中的H任选地被1、2或3个Ra取代；R5、R6以及与它们连接的原子共同形成环A3，环A3为C5-C6环烷基或5-6元杂环基，环A3中的H任选地被1、2或3个Ra取代；并且环A1、环A2和环A3中，有1个环、2个环或3个环是存在的。 When _ _ _ Or 3 Ra substitutions; R 4 , R 5 and the atoms connected to them together form ring A2, 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.
  2. 如权利要求1所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物如式II所示，
    The compound of claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that the compound is represented by formula II,
    其中，X、Y、L、R1、R2、R3、R4、R6、R9、R10和R11的定义如权利要求1所述。Wherein, X, Y, L, R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 and R 11 are as defined in claim 1.
  3. 如权利要求1或2所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，R1选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H或卤素，更优选H、F、Cl或Br，进一步更优选H；The compound according to claim 1 or 2, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that R 1 is 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 H or halogen, more preferably H, F, Cl or Br, further more preferably H;
    或者，R2选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选卤素，更优选F、Cl或Br，进一步更优选Cl或Br；Alternatively, R 2 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl Oxygen, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably halogen, more preferably F, Cl or Br, even more preferably Cl or Br;
    或者，选自：该基团中的H任选地被1、2或3个Ra取代， Ra的定义如权利要求1所述。or, Selected from: H in this group is optionally substituted by 1, 2 or 3 Ra, Ra is defined as in claim 1.
  4. 如权利要求1所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，The compound of claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that,
    X为O，为该基团中的H任选地被1、2或3个R取代，其中，R6、R7、R12和R的定义如权利要求1所述；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 in claim 1;
    或者，X为NR5，为该基团中的H任选地被1、2或3个R取代，其中，R3、R6、R7、R12和R的定义如权利要求1所述；Or, 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 in claim 1;
    或者，X为CR5Ra，为 该基团中的H任选地被1、2或3个R取代，其中，R3、R4、R6、R7、R12和R的定义如权利要求1所述；Alternatively, 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 , R 7 , R 12 and R are as defined in claim 1;
    或者，R12选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选C1-C6烷基，例如甲基；Alternatively, R 12 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl Oxygen, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably C1-C6 alkyl, such as methyl;
    或者，R12为甲基、乙基或丙基；Alternatively, R 12 is methyl, ethyl or propyl;
    或者，R7选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H；Alternatively, R 7 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl Oxygen, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H;
    或者，R8选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H；Alternatively, R 8 is selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl Oxygen, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H;
    或者，R13各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选H；Alternatively, R 13 is each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1 -C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, preferably H;
    或者，R’13各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基 或5-6元杂芳基，优选H。Alternatively, R' 13 is each independently selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl Or 5-6 membered heteroaryl, preferably H.
  5. 如权利要求2所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，X为O，为该基团中的H任选地被1、2或3个R取代，其中，R6和R的定义如权利要求1所述；The compound of claim 2, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that, 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 in claim 1;
    或者，X为NR5，为该基团中的H任选地被1、2或3个R取代，其中，R3、R6和R的定义如权利要求1所述；Or, X is NR 5 , for H in this group is optionally substituted by 1, 2 or 3 R, wherein R 3 , R 6 and R are as defined in claim 1;
    或者，X为CR5Ra，为 该基团中的H任选地被1、2或3个R取代，其中，R3、R4、R6和R的定义如权利要求1所述。Alternatively, 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 in claim 1 .
  6. 如权利要求1-5中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，R2选自：H、D、卤素、氰基、硝基、羟基、氨基、-C(O)OH、-C(O)OC1-C3烷基、C1-C6烷基(如甲基或乙基)、卤代C1-C6烷基(如CF3)、C1-C6烷氧基(如甲氧基)、卤代C1-C6烷氧基(如OCF3)、C2-C6烯基(如乙烯基、烯丙基或丙烯基)、C2-C6炔基(如乙炔基或丙炔基)、C3-C6环烷基(如环丙基)、3-6元杂环基、苯基或5-6元杂芳基；The compound according to any one of claims 1 to 5, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that R 2 is selected From: H, D, halogen, cyano, nitro, hydroxyl, amino, -C(O)OH, -C(O)OC1-C3 alkyl, C1-C6 alkyl (such as methyl or ethyl), Halogenated C1-C6 alkyl (such as CF 3 ), C1-C6 alkoxy (such as methoxy), halogenated C1-C6 alkoxy (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 membered heterocyclyl, phenyl or 5-6 metaheteroaryl;
    或者，R11选自：H、D、卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基。Alternatively, R 11 is selected from: H, D, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy.
  7. 如权利要求1-6中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物具有一个或多个如下特征：The compound according to any one of claims 1 to 6, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that, the compound Have one or more of the following characteristics:
    R2选自：溴、氯、氰基、氢、异烯丙基、异丙基、羧基、三氟甲基、环丙基、乙基、甲氧基羰基、乙烯基、异丙氧基羰基或甲基；R 2 is selected from: bromine, chlorine, cyano, hydrogen, isoallyl, isopropyl, carboxyl, trifluoromethyl, cyclopropyl, ethyl, methoxycarbonyl, vinyl, isopropoxycarbonyl or methyl;
    Y选自：CH2或氧；Y is selected from: CH 2 or oxygen;
    R9选自：或H； R 9 is selected from: or H;
    R10选自：H、F、 R 10 is selected from: H, F,
    R11选自：甲氧基、氢、氯或甲基；R 11 is selected from: methoxy, hydrogen, chlorine or methyl;
    L选自： L is selected from:
  8. 如权利要求1-7中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物具有式III所示的结构
    The compound according to any one of claims 1 to 7, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that, the compound Has the structure shown in formula III
    其中，Z1和Z2各自独立地选自：CH或N；Among them, Z 1 and Z 2 are each independently selected from: CH or N;
    Y、L、R1、R2、R10和R11的定义如权利要求1所述；Y, L, R 1 , R 2 , R 10 and R 11 are as defined in claim 1;
    优选地，Y选自：CH2或O；Preferably, Y is selected from: CH 2 or O;
    优选地，L选自：-(CH2)3-、-(CH2)4-、-(CH2)5-、 Preferably, L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -,
    优选地，Z2为N，且Z1为CH；Preferably, Z 2 is N, and Z 1 is CH;
    优选地，Y选自：CH2或O；且L选自：-(CH2)3-。 Preferably, Y is selected from: CH2 or O; and L is selected from: -( CH2 ) 3- .
  9. 如权利要求1-8中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物具有如下一个或多个特征：The compound according to any one of claims 1 to 8, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that, the compound Have one or more of the following characteristics:
    X选自：NR5、CR5Ra或O，其中，R5和Ra各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选地，X选自：O、CH2或NH；X is selected from: NR 5 , CR 5 Ra or O, where 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, CH 2 or NH;
    Y选自：CRaRb，其中，Ra和Rb各自独立地选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选地，Y选自：CH2；Y is selected from: CRaRb, where 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 is selected from: CH 2 ;
    R6选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基；R 6 is 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;
    R9选自： 该基团中的H任选地被1、2或3个R取代，其中，R的定义如权利要求1所述；R 9 is selected from: H in this group is optionally substituted by 1, 2 or 3 R, wherein R is as defined in claim 1;
    R10选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基、5-6元杂芳基、C3-C6环烷基-O-、3-6元杂环基-O-、苯基-O-、5-6元杂芳基-O-、C3-C6环烷基C3-C6亚环烷基-O-、C3-C6环烷基3-6元亚杂环基-O-，优选H、 R 10 is 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, 5-6 membered heteroaryl, C3-C6 cycloalkyl-O-, 3-6 membered heterocyclyl-O-, phenyl -O-, 5-6 membered heteroaryl-O-, C3-C6 cycloalkyl C3-C6 cycloalkylene-O-, C3-C6 cycloalkyl 3-6 membered heterocyclylene-O-, Preferably H,
    R11选自：H、D、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、苯基或5-6元杂芳基，优选C1-C6烷氧基，例如甲氧基、乙氧基、正丙氧基或异丙氧基。R 11 is 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 C1-C6 alkoxy, such as methoxy, ethoxy, n-propoxy or iso Propoxy.
  10. 如权利要求1-9中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，L选自：C1-C4亚烷基、-C1-C3亚烷基-O-、-C1-C3亚烷基-NH-、亚甲基、亚乙基、 -NH-CH2-、-NH-CH2-CH2-CH2-、 The compound according to any one of claims 1 to 9, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that, 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 -,
  11. 如权利要求1所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物具有式IV所示的结构
    The compound of claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that the compound has formula IV. structure
    其中，Z1和Z2各自独立地选自：CH或N；Among them, Z 1 and Z 2 are each independently selected from: CH or N;
    Y选自：CH2或O；Y is selected from: CH 2 or O;
    L选自：-(CH2)3-、-(CH2)4-、 L is selected from: -(CH 2 ) 3 -, -(CH 2 ) 4 -,
    R11为H或甲基；R 11 is H or methyl;
    R2选自：H、D、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C6烯基或卤代C2-C6烯基；优选地，R2选自：H、卤素、氰基、C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C3烯基或卤代C2-C3烯基；更优选地，R2为溴、氢、氰基、异烯丙基、异丙基、三氟甲基、环丙基、氯、乙基、乙烯基、甲基、碘或氟。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.
  12. 如权利要求1所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物具有式V所示的结构
    The compound of claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that the compound has formula V structure
    其中，R11为H或甲基；R2选自：H、D、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C6烯基或卤代C2-C6烯基；优选地，R2选自：H、卤素、氰基、C1-C3烷基、卤代C1-C3烷基、C3-C6环烷基、卤代C3-C6环烷基、C2-C3烯基或卤代C2-C3烯基；更优选地，R2为溴、氢、氰基、异烯丙基、异丙基、三氟甲基、环丙基、氯、乙基、乙烯基、甲基、碘或氟。Among them, 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.
  13. 如权利要求1所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，其特征在于，所述化合物选自：







    The compound of claim 1, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that the compound is selected from:







  14. 一种药物组合物，其包含如权利要求1-13中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物；和药学上可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1-13, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate ; and a pharmaceutically acceptable carrier.
  15. 一种如权利要求1-13中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如权利要求14所述的药物组合物在制备抑 制EGFR激酶的药物或EGFR介导的疾病的药物中的用途；A compound as claimed in any one of claims 1 to 13, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as claimed in claim 14 The pharmaceutical composition is prepared Use in drugs that inhibit EGFR kinase or drugs for EGFR-mediated diseases;
    特别地，In particular,
    所述EGFR为突变型EGFR，优选为L858R、T790M、C797S、Del19、L792H、G873R、G874D、D855N，或其组合；更优选为L858R、T790M、C797S、Del19，或其组合；进一步更优选为L858R/T790M二突变、T790M/C797S二突变、L858R/T790M/C797S三突变或Del19/T790M/C797S三突变；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; further more preferably, it is L858R. /T790M double mutation, T790M/C797S double mutation, L858R/T790M/C797S triple mutation or Del19/T790M/C797S triple mutation;
    或者，所述抑制EGFR激酶的药物为用于治疗癌症的药物；优选地，所述癌症选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤，或其组合；Alternatively, the drug that inhibits EGFR kinase is a drug used to treat 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 , 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 combinations thereof;
    或者，所述药物用于治疗的肺癌选自下组：Alternatively, the lung cancer for which the drug is used to treat is selected from the group consisting of:
    i)由EGFR L858R突变引起的肺癌；i) Lung cancer caused by EGFR L858R mutation;
    ii)由EGFR Del19突变引起的肺癌；ii) Lung cancer caused by EGFR Del19 mutation;
    iii)由EGFR C797S突变引起的肺癌；iii) Lung cancer caused by EGFR C797S mutation;
    iv)由EGFR T790M突变引起的肺癌；iv) Lung cancer caused by EGFR T790M mutation;
    v)由EGFR L858R/T790M突变引起的肺癌；v) Lung cancer caused by EGFR L858R/T790M mutation;
    vi)由EGFR T790M/C797S突变引起的肺癌；vi) Lung cancer caused by EGFR T790M/C797S mutation;
    vii)由EGFR L858R/T790M/C797S突变引起的肺癌；vii) Lung cancer caused by EGFR L858R/T790M/C797S mutation;
    viii)由EGFR Del19/T790M/C797S突变引起的肺癌。viii) Lung cancer caused by EGFR Del19/T790M/C797S mutation.
  16. 一种如权利要求1-13中任一项所述的化合物、其立体异构体、其光学异构体、其药学上可接受的盐、其前药或其溶剂化物，或如权利要求14所述的药物组合物在制备抑制EGFR突变、HER-2扩增和c-MET扩增中的一种或多种突变介导的疾病的药物中的用途；A compound as claimed in any one of claims 1 to 13, its stereoisomer, its optical isomer, its pharmaceutically acceptable salt, its prodrug or its solvate, or as claimed in claim 14 The use of the pharmaceutical composition in preparing drugs for inhibiting diseases mediated by one or more mutations in EGFR mutation, HER-2 amplification and c-MET amplification;
    特别地，In particular,
    所述EGFR突变为L858R、T790M、C797S、Del19、L792H、G873R、G874D、D855N、20外显子突变，或其组合；优选为L858R、T790M、C797S、Del19、D770_N771insSVD、A763_Y764insFQEA、V769_D770insASV、H773_V774insNPH，或其组合；更优选为L858R/T790M二突变、T790M/C797S二突变、Del19/C797S二突变、L858R/C797S二突变、L858R/T790M/C797S三突变或Del19/T790M/C797S三突变；The EGFR mutation is L858R, T790M, C797S, Del19, L792H, G873R, G874D, D855N, exon 20 mutation, or a combination thereof; preferably L858R, T790M, C797S, Del19, D770_N771insSVD, A763_Y764insFQEA, V769_D77 0insASV, H773_V774insNPH, or The combination 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 Del19/T790M/C797S triple mutation;
    或者，所述HER-2扩增为其基因拷贝数异常所导致的蛋白表达异常；Alternatively, the HER-2 amplification results in abnormal protein expression due to abnormal gene copy number;
    或者，所述c-MET扩增为其基因拷贝数异常所导致的蛋白表达异常；Alternatively, the c-MET amplification results in abnormal protein expression due to abnormal gene copy number;
    或者，所述药物为用于治疗癌症的药物；优选地，所述癌症选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、头颈部肿瘤、结肠癌、直肠癌、胶质瘤，或其组合；Alternatively, the drug is a drug for treating cancer; preferably, the cancer is selected from the group consisting of 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 cancer, colon cancer, rectal cancer, glioma, or combinations thereof;
    或者，所述药物用于治疗的肿瘤选自下组：Alternatively, the tumor for which the drug is used to treat is selected from the group consisting of:
    i)由EGFR L858R突变引起的肿瘤，所述肿瘤优选为肺癌；i) Tumors caused by EGFR L858R mutation, preferably lung cancer;
    ii)由EGFR Del19突变引起的肿瘤，所述肿瘤优选为肺癌；ii) Tumors caused by EGFR Del19 mutations, preferably lung cancer;
    iii)由EGFR C797S突变引起的肿瘤，所述肿瘤优选为肺癌；iii) Tumors caused by EGFR C797S mutation, preferably lung cancer;
    iv)由EGFR T790M突变引起的肿瘤，所述肿瘤优选为肺癌；iv) Tumors caused by EGFR T790M mutation, preferably lung cancer;
    v)由EGFR L858R/T790M突变引起的肿瘤，所述肿瘤优选为肺癌；v) Tumors caused by EGFR L858R/T790M mutation, preferably lung cancer;
    vi)由EGFR T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；vi) Tumors caused by EGFR T790M/C797S mutations, preferably lung cancer;
    vii)由EGFR L858R/T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；vii) Tumors caused by EGFR L858R/T790M/C797S mutations, preferably lung cancer;
    viii)由EGFR Del19/T790M/C797S突变引起的肿瘤，所述肿瘤优选为肺癌；viii) Tumors caused by EGFR Del19/T790M/C797S mutations, the tumors are preferably lung cancer;
    ix)由HER-2扩增引起的肿瘤，所述肿瘤优选为肺癌； ix) Tumors caused by HER-2 amplification, preferably lung cancer;
    x)由c-MET扩增引起的肿瘤，所述肿瘤优选为肺癌。 x) Tumors caused by c-MET amplification, preferably lung cancer.
PCT/CN2023/107949 2022-07-19 2023-07-18 Egfr small molecule inhibitor, pharmaceutical composition containing same, and use thereof WO2024017258A1 (en)

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CN102718775A (en) * 2003-05-27 2012-10-10 詹森药业有限公司 Macrocyclic quinazoline derivatives as antiproliferative agents
WO2020009179A1 (en) * 2018-07-06 2020-01-09 Shionogi & Co., Ltd. Fused heterocyclic derivatives having selective bace1 inhibitory activity
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CN102718775A (en) * 2003-05-27 2012-10-10 詹森药业有限公司 Macrocyclic quinazoline derivatives as antiproliferative agents
CN102143750A (en) * 2008-09-08 2011-08-03 默克专利有限公司 Macrocyclics pyrimidines as aurora kinase inhibitors
WO2020009179A1 (en) * 2018-07-06 2020-01-09 Shionogi & Co., Ltd. Fused heterocyclic derivatives having selective bace1 inhibitory activity
WO2021163627A1 (en) * 2020-02-14 2021-08-19 Salk Institute For Biological Studies Macrocyclic ulk1/2 inhibitors
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