WO2018157737A1 - Inhibiteur de kinase multi-cibles - Google Patents

Inhibiteur de kinase multi-cibles Download PDF

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WO2018157737A1
WO2018157737A1 PCT/CN2018/076447 CN2018076447W WO2018157737A1 WO 2018157737 A1 WO2018157737 A1 WO 2018157737A1 CN 2018076447 W CN2018076447 W CN 2018076447W WO 2018157737 A1 WO2018157737 A1 WO 2018157737A1
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fluorophenyl
compound
formula
structural formula
cyclopropane
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PCT/CN2018/076447
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Chinese (zh)
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金锋
冯贻东
王彦青
佘琴
靳如意
唐田
冯汉林
于琳
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深圳海王医药科技研究院有限公司
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Publication of WO2018157737A1 publication Critical patent/WO2018157737A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention belongs to the field of medicine and relates to a novel multi-target protein kinase inhibitor.
  • Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins. The most important life activities in cells are related to the phosphorylation of proteins. By mediating cell signal transduction, phosphorylation of proteins regulates cell fate, for example. Cell proliferation, differentiation and apoptosis. Some human fatal diseases, such as tumors, are significantly associated with abnormal protein kinase activity. Therefore, protein kinases have become a hot drug target, and kinase inhibitor drugs have become the most important component of tumor-targeted therapy.
  • kinase inhibitors have been widely used in tumor targeting therapy, inflammation therapy, etc.
  • drug resistance has become one of the key issues facing the current clinical research.
  • the data show that activation of the bypass compensatory signaling pathway is one of the important reasons for kinase inhibitor resistance.
  • the development of multi-target kinase inhibitors that can act on multiple signaling pathways simultaneously can not only effectively cope with the biological characteristics of tumor multi-molecular abnormalities, but also alleviate drug resistance problems to some extent.
  • the human genome encodes 518 protein kinases.
  • the protein kinases of eukaryotic cells can be divided into five categories, namely serine/threonine protein kinase, tyrosine protein kinase, group/ Lai/arginine protein kinase, cysteine protein kinase and aspartate/glutamate protein kinase.
  • Most protein kinases have a more conserved catalytic binding domain, and these catalytic domains are sequence-dependent, thus structurally ensuring the feasibility of multi-target kinase inhibitor design.
  • multi-targeted drugs may be the only effective drug treatment.
  • liver cancer is a type of cancer with great heterogeneity. It is not sensitive to most chemotherapy drugs.
  • a number of targeted drugs, including Brivanib, Suntinib, and Linifanib, have failed in clinical trials of liver cancer, and only a drug of sorafenib has been approved by the FDA.
  • Sorafenib is a multi-target kinase inhibitor, the main targets include c-Raf, VEGFR2, c-kit, p38 ⁇ , etc.
  • the multi-target synergistic mechanism of this drug may be an important reason for its effectiveness in advanced liver cancer. Recently, a number of ongoing Alzheimer's disease drugs have experienced major setbacks in clinical phase III, suggesting that the single target assumed in the early stage may not be an effective therapeutic target.
  • VEGFR the epidermal growth factor receptor
  • c-Met a hepatocyte growth factor receptor
  • Raf kinase is involved in the Ras-Raf-Mek-ERK signal transduction cascade, which regulates cell cycle, differentiation, proliferation and apoptosis.
  • c-Kit is a stem cell growth factor receptor that plays an important role in hematopoietic cell function.
  • Chinese patent application CN105541798A discloses an N 1 -(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N 2 -substituted heterocyclic ring-N having antitumor activity 3 -Phenylmalonamide quinoline multi-target kinase inhibitor and preparation method thereof.
  • the compound has strong inhibitory activity against tumor cell line human thyroid carcinoma SW579, human liver cancer HepG2, human lung adenocarcinoma A549, human intestinal cancer HCT116 and human gastric cancer MKN45. Most of the target compounds have been confirmed by in vitro cell experiments for two kinases. KDR and MET showed strong inhibitory activity.
  • Chinese patent application CN103214489A discloses a N-(6-substituted-3,4,6,7-tetrahydro-2H-pyrimido[1,6-c]quinazolin-2-alkenyl) substituted aniline
  • An antitumor compound that has broad-spectrum inhibitory activity against a variety of tumor-associated kinases, but some of which have significant cytotoxic effects.
  • a first object of the invention is to provide a novel multi-target protein kinase inhibitor
  • a second object of the present invention is to provide a pharmaceutical composition of a multi-target protein kinase inhibitor
  • a third object of the present invention is to provide a novel multi-target protein kinase inhibitor for use in the preparation of a medicament for treating a disease caused by abnormal protein kinase activity.
  • a multi-target protein kinase inhibitor having moderate selectivity ie, capable of acting on a plurality of target protein kinases while maintaining certain specificity
  • the multi-target protein kinase inhibitor designed and synthesized for this purpose is a compound of formula (I):
  • R 1 is H, or is in the ortho, meta or para-halogen atom, non-cyclic alkyl, C3-C6 substituted or non-substituted heterocyclic, C3-C7 cycloalkyl;
  • R 2 is H, or a halogen atom or an acyclic alkyl group in the ortho or meta or para position of the linker;
  • M 1 is O or NH in the linker alignment or meta position
  • M 2 is one selected from the group consisting of formula (II), (III) and (IV):
  • R 3 is a spiro ring, or an unsubstituted or substituted C3-C6 heterocyclic ring;
  • X 1 is CH or N;
  • Y 1 is CH or N;
  • Z 1 is CH, S, NH, or O;
  • Z 2 is N, CH or NH;
  • Linker is selected from one of formula (VI) and formula (VII):
  • R 1 is H, or a halogen atom at a different substitution position, an alkyl group, a C3-C6 unsubstituted or substituted heterocyclic ring, a C3-C7 cycloalkane;
  • R 2 is H, or is at a different substitution position.
  • R 3 is selected from one of the following structures:
  • R 5 is one selected from the following structures:
  • R 6 is one selected from the following structures:
  • n is a positive integer of 1 to 5; and in the formula (IX), X 4 to X 8 are independently selected from CH 2 , NH, O or S.
  • acyclic alkyl group is selected from one of the following functional groups:
  • C3-C6 heterocyclic ring described in R 3 , R 4 , R 5 and R 6 is selected from one of the following functional groups:
  • the multi-target protein kinase inhibitor provided by the present invention is selected from the following compounds:
  • salts of the above compounds also have the same effect, and the specific salt forms include, but are not limited to, maleate, hydrochloride, sulfate, phosphate, malate, tosylate , mesylate, acetate, tartrate, trifluoroacetate, and the like.
  • a pharmaceutical composition is prepared by using the compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable drug delivery system containing the compound as an active ingredient .
  • the inhibitory activity of a compound against a plurality of protein kinases is investigated, and the compound of the present invention has excellent inhibitory activity against protein kinases in comparison with the effects of existing commercial preparations;
  • the compounds of the invention are directed against a receptor tyrosine protein kinase, a non-receptor tyrosine protein kinase, and a serine/threonine protein kinase.
  • the protein kinase inhibition test indicates that the compound of the present invention has sufficient commercialization level of inhibition ability; inhibition tests of various cells indicate that the compound of the present invention has excellent selection specificity and can effectively prevent toxic side effects, which is complicated The treatment of heterogeneous diseases and the overcoming of drug resistance have great prospects.
  • the reagent materials of the present invention are all commercially available.
  • Compound 8c (6.40 g, 21.80 mmol, purity 90%) was obtained.
  • compound 7D-1 (300.00 mg, 796.31 umol, 1.00 eq) was added, dissolved in 10 mL isopropanol, and compound 1-30 (171.08 mg, 1.19 mmol, 1.50 eq), DIEA (205.83) was added. The mixture was reacted at 85 ° C for 16 hours, and LC-MS monitoring showed that the starting material was completely reacted and the desired product was formed. After completion of the reaction, the solution was evaporated to give a crude material which was purified to afford compound 30 (85.00 mg, 170.52.
  • compound 7D-1 (300.00 mg, 796.31 umol, 1.00 eq) was added, dissolved in 10 mL isopropanol, and then compound 1-31 (187.84 mg, 1.19 mmol, 1.50 eq) was added, DIEA (205.83 mg, 1.59 mmol, 2.00 eq), the mixture was heated to 85 ° C for 16 hr. After completion of the reaction, the mixture was evaporated to give 650 mg of crude material. After preparative chromatography, compound 31 (115.00 mg, 219.58.
  • compound 1-3 (300.00 mg, 619.08 umol, 1.00 eq) was added, 15 mL of THF was dissolved, and the compound triethylamine (375.87 mg, 3.71 mmol, 514.89 uL, 6.00 eq) was added at 0 ° C.
  • the reaction was stirred for 0.5 hours, then compound 6A (0.3M, 5.17 mL of THF, 2.50 eq) was slowly added, and the mixture was stirred at 20 ° C for 17 hours, and LC-MS monitoring showed that the starting material was completely and the product was formed.
  • the experimental method is as follows:
  • 1X kinase buffer 50mM HEPES, pH 7.5, 0.0015% Brij-35, 2mM DTT;
  • Stop solution 100 mM HEPES, pH 7.5, 0.015% Brij-35.
  • a 50-fold compound was prepared: the final concentration of the compound was 2 ⁇ M, and the concentration was 50-fold, that is, 100 ⁇ M.
  • 100 ⁇ L of 50-fold compound was added to the second well of a 96-well plate, and the other wells were added to 60 ⁇ L of 100% DMSO.
  • 30 ⁇ L of the compound was taken from the second well and added to the third well, and 10 dilutions were sequentially performed, and a total of 10 concentrations were diluted.
  • Formulate 2.5 times the enzyme solution Add the kinase to the 1X kinase buffer to form a 2.5-fold enzyme solution.
  • a 2.5-fold substrate solution was prepared: FAM-labeled polypeptide and ATP were added to 1X kinase buffer to form a 2.5-fold substrate solution.
  • the enzyme solution was added to the 384-well plate: 5 ⁇ L of 10% DMSO-dissolved 5-fold compound was present in the 384-well reaction plate. 10 ⁇ L of the 2.5-fold enzyme solution was added to the 384-well reaction plate, and the mixture was incubated at room temperature for 10 minutes. The substrate solution was added to the 384-well plate, and 10 ⁇ L of a 2.5-fold substrate solution was added to the 384-well reaction plate.
  • the conversion rate data was replicated from Caliper; the conversion rate was converted to inhibition rate data, where max is the conversion of the DMSO control and min is the conversion of the enzyme-free control.
  • * refers to the inhibition rate at 100 nM concentration
  • ND means not tested; NA means inhibition rate ⁇ 10% at 100 nM.
  • Example 2 According to the results of the protein kinase inhibitory activity in Example 2, the selection effect was superior to or similar to that of the control products Sorafenib and Cabozantinib, that is, the selection compounds td32-4, td32-5, td32-6, t-3, 51, 29 were used. Inhibition of cell proliferation activity test.
  • Hs746T (ATCC, Cat. No. HTB-135, Lot. No. 5006453)
  • HepG2 (ATCC, Cat. No. HB-8065, Lot. No. 7579337)
  • F-12K medium (Invitrogen, Cat. No. 21127-022, Lot. No. 1759876)
  • MEM medium (Invitrogen, Cat. No. 11095-098, Lot. No. 1798295)
  • IMDM medium (Invitrogen, Cat. No. 12440-061, Lot. No. 1806052)
  • DMEM medium (Invitrogen, Cat. No. 12430-062, Lot. No. 1810223)
  • Adherent cells aspirate the medium, wash it with trypsin, discard the waste, and add 3 ml of fresh trypsin to the culture flask for digestion. When the cells are loose to leave the bottle wall, add 8 ml of complete medium to stop trypsin digestion and mix gently. The cell suspension was pipetted into a centrifuge tube and centrifuged at 800-1000 rpm for 3-5 minutes. Suspension of cells: Aspirate the cell suspension and transfer to a centrifuge tube and centrifuge at 800-1000 rpm for 3-5 minutes.
  • a solution of 20 mM or 10 mM was prepared in DMSO.
  • test compound was diluted to 2 mM in DMSO, added to the compound plate, and subjected to a 3-fold gradient dilution with DMSO.
  • Inhibition rate (%) (1-(RLU compound-RLU blank) / (RLU DMSO-RLU blank)) ⁇ 100%.
  • the compounds t-3, td32-4, td32-5 and td32-6 which can significantly inhibit the activity of c-met protein kinase, have very strong cells. Proliferation inhibitory activity, while most of the cell lines amplified by non-c-met gene have moderate inhibitory activity, while compound 51 selectively inhibits HepG2 and A673 cell lines. The compound showed very good cell selective inhibition.
  • IV intravenous
  • PO oral
  • LC/MS/MS LC/MS/MS was used to determine the concentration of each substance in the plasma of rats after administration of the test substance and calculate relevant parameters.
  • Intravenous 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.
  • Oral before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.
  • Liquid Chromatograph Shiadzu LC
  • LC-20AD solution transfer pump
  • DGU-20A3 online degassing instrument
  • SIL-20AHT autosampler
  • CBM-20A controller
  • CTO-20A column Thermostat
  • Mass spectrometer (API 4000, Applied Biosystems, USA), electrospray ionization source (ESI), tandem quadrupole mass analyzer.
  • the data processing system is Analyst Software (Applied Biosystems, Inc., software version number 1.5.1).

Abstract

La présente invention concerne un inhibiteur de protéine kinase multi-cibles, une composition pharmaceutique de celui-ci, et une utilisation de l'inhibiteur de kinase multi-cibles dans la préparation d'un médicament pour le traitement de maladies induites par une activité de protéine kinase anormale. L'inhibiteur de kinase multi-cibles de la présente invention est représenté par la formule structurale générale (I). L'inhibiteur de kinase multi-cibles de la présente invention possède un effet inhibiteur idéal et une sélectivité spécifique, et présente une large perspective dans le traitement de maladies hétérogènes complexes et de permet de surmonter la résistance aux médicaments.
PCT/CN2018/076447 2017-03-02 2018-02-12 Inhibiteur de kinase multi-cibles WO2018157737A1 (fr)

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CN201710121054.7A CN108530464B (zh) 2017-03-02 2017-03-02 一种多靶点激酶抑制剂
CN201710121054.7 2017-03-02

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Cited By (2)

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CN109384799A (zh) * 2018-11-12 2019-02-26 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
EP4108666A4 (fr) * 2020-02-18 2024-03-13 Shenzhen Neptunus Pharmaceutical Res Institute Co Ltd Inhibiteur de la tyrosine kinase à plusieurs cibles

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WO2021180006A1 (fr) * 2020-03-10 2021-09-16 南京明德新药研发有限公司 Composés de pyridine à substitution vinylique
CN114644642B (zh) * 2022-04-06 2023-05-12 深圳海王医药科技研究院有限公司 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物

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CN101796055A (zh) * 2005-05-20 2010-08-04 梅赛尔基因股份有限公司 Vegf受体和hgf受体信号的抑制剂
WO2009026720A1 (fr) * 2007-08-29 2009-03-05 Methylgene Inc. Procédés et intermédiaires de préparation d'inhibiteurs de kinases hétérocycliques fusionnés
CN105777776A (zh) * 2007-08-29 2016-07-20 梅特希尔基因公司 蛋白酪氨酸激酶活性的抑制剂
CN102256493A (zh) * 2008-10-29 2011-11-23 迪赛孚尔制药有限公司 表现出抗癌活性和抗增殖活性的环丙烷酰胺及其类似物
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* Cited by examiner, † Cited by third party
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CN109384799A (zh) * 2018-11-12 2019-02-26 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
EP4108666A4 (fr) * 2020-02-18 2024-03-13 Shenzhen Neptunus Pharmaceutical Res Institute Co Ltd Inhibiteur de la tyrosine kinase à plusieurs cibles

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