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WO2011063602A1 - Utilisation de 2, 4-thiazolidinediones 5-substituées dans la préparation de médicaments pour modulation du récepteur du facteur de croissance 1 analogue à l'insuline - Google Patents

Utilisation de 2, 4-thiazolidinediones 5-substituées dans la préparation de médicaments pour modulation du récepteur du facteur de croissance 1 analogue à l'insuline Download PDF

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Publication number
WO2011063602A1
WO2011063602A1 PCT/CN2010/001839 CN2010001839W WO2011063602A1 WO 2011063602 A1 WO2011063602 A1 WO 2011063602A1 CN 2010001839 W CN2010001839 W CN 2010001839W WO 2011063602 A1 WO2011063602 A1 WO 2011063602A1
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WO
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Prior art keywords
group
acid
substituted
alkoxy
growth factor
Prior art date
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PCT/CN2010/001839
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English (en)
Chinese (zh)
Inventor
蒋华良
丁健
李洪林
谢华
刘晓峰
童林江
徐玉芳
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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Publication of WO2011063602A1 publication Critical patent/WO2011063602A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics.
  • the present invention relates to the use of a 5-substituted-2,4-thiazolidinedione compound for the preparation of a medicament for the treatment of a cancer-related disease, which has a strong cell which inhibits the insulin-like growth factor 1 receptor protein. Endo-tyrosine kinase activity, with potential for the treatment of tumor or cancer diseases.
  • BACKGROUND OF THE INVENTION Cancer is a major ailment that seriously endangers human health. There are 9 million people with cancer every year in the world, and 6 million people die of cancer. The annual number of cancers in China is about 1.2 million. The number of people who die of cancer every year is more than 900,000, and the number of patients to be treated exceeds 1.5 million. Overcoming cancer difficulties is a major task for medical workers.
  • the drugs that have been studied and applied for a long time are targets for the use of cancer cells as drugs. Therefore, cytotoxic drugs have always been the main drugs for treating cancer, but the problem of side effects of such anticancer drugs has not been solved.
  • the search for anticancer drugs has gradually entered the stage of targeting specific proteins.
  • protein tyrosine kinases plays an important role in tumorigenesis, and it is known that more than half of proto-oncogenes express proteins with PTK activity.
  • the role of protein tyrosine kinases is to transfer the phosphate group of ATP to a specific tyrosine residue of a functional protein that regulates cell growth, proliferation and differentiation.
  • the insulin-like growth factor (IGF) system plays an important role in the formation and development of tumors.
  • the IGF system includes insulin-like growth factor, insulin-like growth factor receptor, insulin-like growth factor binding protein and its hydrolase.
  • IGF1R insulin-like growth factor type I receptor
  • IGF1R is the most important, and this receptor mediates the main physiological functions of IGF.
  • IGF1R is a tyrosine kinase transmembrane protein that binds to its ligand and promotes cell proliferation and inhibits apoptosis.
  • IGF1R is up-regulated in many malignant tumors (such as breast cancer, hepatocellular carcinoma, colorectal cancer, etc.), and is closely related to malignant transformation, infiltration, and metastasis of tumor cells.
  • IGF1R contains a 706 amino acid alpha subunit and a 626 amino acid beta subunit.
  • the ⁇ and ⁇ subunits form an ⁇ - ⁇ half receptor through a disulfide bond, and the two ⁇ - ⁇ half receptors are further linked by a disulfide bond to form a mature ⁇ - ⁇ - ⁇ - ⁇ tetramer.
  • the alpha subunit is located extracellularly and has a cysteine-rich region that specifically binds to IGF1, while the beta subunit is distributed across the membrane, with extracellular regions, transmembrane regions, and tyrosine kinase-containing activities. Intracellular region.
  • the target site for tyrosine kinase catalytic subunit and kinase action is located in the cytoplasmic portion of the beta subunit.
  • IGF1R mediates a number of signaling pathways within cells. IGF1R binds to its ligand (insulin growth factor I and insulin growth factor II) and initiates two signal transduction pathways: 1 phosphatidylinositol-3-kinase ( ⁇ 3 ⁇ )-Akt pathway; 2 mitogen-activated protein kinase ( MAPK) pathway.
  • ligand insulin growth factor I and insulin growth factor II
  • MAPK mitogen-activated protein kinase
  • IGFIRa subunit binds to its ligand, causing an allosteric effect between the two ⁇ , ⁇ subunits of the receptor molecule, allowing the tyrosine base at the C-terminus of the ⁇ subunit to rapidly autophosphorylate and activate
  • IGF1R's tyrosine kinase then rapidly signals the various substrates in the cell, causing multiple site phosphorylation of insulin receptor substrate 1 (IRS1), which in turn forms IRS1, GRB2 and ornithine exchange.
  • IRS1 insulin receptor substrate 1
  • IRS1-GRB2-SOS leads to activation of the GTP-binding protein ras, activation of ras into a phosphorylation and activation of MAP kinase/ERK, and ERK transmits signals to the nucleus, Start the mitosis process. Simultaneous phosphorylation of IRS1 activates PIP3 kinase, which initiates a PIP3-mediated pathway that transmits cell growth signals.
  • PIP3 phosphatidyl-3,4,5-triphosphate
  • IGF1R binds to its ligand and promotes mitosis and anti-apoptosis. It is not required for cells to grow under normal conditions, but it must be in the absence of cells or in the growth of tumor transplanters. Indispensable role. Studies have shown (J. Med. Chem., 2009, 52, 4981-5004) that IGF1R is closely associated with transformation, proliferation, metastasis, and radioresistance in many malignancies. This makes IGF1R a very attractive target for targeted tumor therapy.
  • IGF1R small molecule inhibitors of IGF1R have been reported abroad (J. Med. Chem., 2009, 52, 4981-5004), such as benzimidazole pyridines, isoquinolinediones, and pyrrolopimidines.
  • the compound of the parent nucleus has an effect of inhibiting the activity of IGF1R tyrosine kinase.
  • most of these compounds are designed by pharmaceutical chemists based on experience.
  • the substituted-2,4-thiazolidinedione compound has a good activity of inhibiting the catalytic activity of the IGF1R kinase domain.
  • Thiazolidinedione compounds have been widely reported in the literature and patents (rrew in Investigational Drugs, 2003, 4, 406-411 ) has a strong inhibitory effect on peroxisome proliferator receptor gamma (PPARy) activity, and its representative drug rosiglitazone has been marketed for the treatment of type 2 diabetes.
  • PPARy peroxisome proliferator receptor gamma
  • novel 5-substituted-2,4-thiazolidinedione compounds we have discovered have activity for inhibiting the catalysis of the IGF1R kinase domain, and there has been no report on the use of the compounds of the present invention in the preparation of a medicament for cancer-related diseases. This has broadened the field of clinical treatment of such compounds. Disclosure of the Invention An object of the present invention is to provide a novel 5-substituted-2,4-thiazolidinedione compound having a function of inhibiting the insulin-like growth factor 1 receptor (IGF1R) or a pharmaceutically acceptable salt thereof (structural formula) Use as shown in I) in the manufacture of a medicament for cancer-related diseases.
  • IGF1R insulin-like growth factor 1 receptor
  • the compound of the present invention can be used as a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) to block the growth, proliferation and differentiation of tumor cells by blocking its catalytic activity, thereby blocking the life cycle of tumor cells. Therefore, it can be developed into a new anti-tumor drug.
  • IGF1R insulin-like growth factor 1 receptor
  • the present invention provides a 5-substituted-2,4-thiazolidinedione compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
  • X is selected from 0, N or S
  • B is a benzene ring, a 5 or 6 membered aromatic heterocyclic ring
  • the wavy line indicates the Z-type and E-type geometric isomers of the double bond
  • R 0 , , R 2 , R 3 , R 4 and R 5 are the same or different and are each independently selected from the group consisting of: hydrogen, C r C 6 linear or branched saturated or unsaturated hydrocarbon group (optionally containing one) Or a plurality of substituents selected from the group consisting of 3 ⁇ 4, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, alkoxy, decyl and dC 4 acyl groups and chains Containing one or more C r C 4 alkane groups selected from 0 and S), a C 3 -C 7 saturated or unsaturated cycloalkane group, a halogen, a cyano group, a nitro group, a hydroxyl group, Hydroxymethyl, dC 4 alkoxy, dC 4 unsaturated alkoxy, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl,
  • hydrocarbyl refers to an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl group having from 1 to 10 carbon atoms.
  • aromatic Ar as used herein means phenyl, substituted phenyl, naphthyl or biphenyl, wherein the substituent is a linear or branched hydrocarbon group selected from 3 ⁇ 4, CC 6 , cyano, nitrate 1-4 groups of acyl group of amino group, amino group, hydroxyl group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxyl group, alkoxy group, fluorenyl group, d-do thioalkyl group and C r C 4 group.
  • heterocyclyl refers to a single or fused ring structure, which may be aromatic or non-aromatic in nature, and which preferably contains from 3 to 20 ring atoms, more preferably from 5 to 8 ring atoms, of which at least 1 and preferably up to 4 are heteroatoms.
  • heterocyclic group examples include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, Pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl and benzofuranyl.
  • heteroatom as used herein includes oxygen, sulfur and nitrogen.
  • the nitrogen atom may be substituted with a group such as hydrogen or a Crdo alkyl group.
  • aromatic heterocycle refers to those heterocyclic groups which have aromatic character as described above.
  • alkyl when used alone or as a suffix, it has a linear or branched structure. These groups may contain up to 10, preferably up to 6, and more preferably up to 4 carbon atoms.
  • alkenyl and alkynyl have an unsaturated straight or branched chain structure containing from 2 to 10, preferably from 2 to 6 carbon atoms.
  • cyclic moiety such as a cycloalkyl group, a cycloalkenyl group and a cycloalkynyl group are similar in nature and have at least 3 carbon atoms, preferably 3 to 20 carbon atoms, more preferably 3 to 7 carbon atoms.
  • alkoxy refers to an alkyl group attached to an oxygen atom as described above, Alkenyl, alkynyl.
  • thioalkyl refers to an alkyl, alkenyl, alkynyl group attached to a sulfur atom as described above.
  • halogen as used herein includes fluoro, chloro, bromo and iodo.
  • the "pharmaceutically acceptable salt” described in the present specification specifically includes the compound provided by the present invention and formic acid, acetic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, propionic acid, malonic acid, succinic acid, An organic acid such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid or citric acid or a salt formed with an acidic base such as aspartic acid or glutamic acid and then formed with an inorganic base such as sodium, potassium or calcium.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid forms a salt.
  • a preferred embodiment of the invention is that the compound has the formula shown by the formula ( ⁇ ):
  • X is preferably selected as 0, S;
  • Y is selected from 0, S, N; wavy lines represent Z-type and E-type geometric isomers of double bonds;
  • R 6 is selected from an aromatic Ar or a 5-7 membered aromatic heterocyclic ring, wherein the 5-7 membered aromatic heterocyclic ring contains 1-2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be selected from halogens, Halogenated C r C 3 alkyl, C r C 3 alkyl, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC 3 alkoxy and aryl Ar Replaced by one or more of the groups.
  • Another preferred embodiment of the invention is that the compound has the structural formula of formula (III):
  • X is selected from 0, s; the wavy line indicates the Z-type and E-type geometric isomers of the double bond;
  • R 7, R 8, R 9 , R 1 () and R u may be the same or different, are each independently hydrogen, C r C straight or branched chain 6 saturated or unsaturated hydrocarbon, C 3 -C 7 of Saturated or unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC 4 alkoxy, dC 4 unsaturated alkoxy, C r C 6 carboxyalkoxy, dC 6 ester alkoxy, CC 6 carboxyalkyl, dC 6 ester alkyl, 3-7 membered cycloalkyl or heterocyclic, benzyl , benzyloxy, aryl or 5-7 membered aromatic heterocyclic ring, or any two adjacent groups of R 7 -R u may be joined to form a ring, the ring may be optionally substituted and
  • X is selected from 0, S;
  • the wavy line indicates the Z-type and E-type geometric isomers of the double bond;
  • R 12, R 13, R 14 , R 15 and R 16 may be the same or different, are each independently hydrogen, C r C linear or branched, saturated or unsaturated hydrocarbon group 6, C 3 -C 7 saturated or Unsaturated cycloalkane, halogen, cyano, nitro, hydroxy, hydroxymethyl, carboxy, ester, trifluoromethyl, trifluoromethoxy, sulfonyl, decyl, dC 4 alkoxy, dC 4 Saturated alkoxy group, C r C 6 carboxyalkoxy group, dC 6 ester alkoxy group, C r C 6 carboxyalkyl group, dC 6 ester alkyl group.
  • the compounds provided by the present invention were obtained by virtual screening by computer aided drug design methods.
  • the invention comprehensively utilizes structure-based pharmacophore matching and receptor-based molecular docking method to perform virtual screening of SPECS compound database (230,000 chemical molecular structures) of SPECS Chemical Company of the Netherlands, and finally selects the compound provided by the invention. Specific examples 1 to 75.
  • the SPECS database was coarsely screened based on the structure-based pharmacophore matching method.
  • LigandScout was used to generate a pharmacophore model that can characterize the interaction mode between IGF1R and BMI.
  • the model as a question model, the three-dimensional structure in the specs small molecule database was matched by the pharmacophore module in Di SCOve rySt U rdi O 2.0, and finally a total of 3326 molecular structures with matching scores higher than 0.0 were retained.
  • the crystal structure of the complex of IGF1R and its small molecule inhibitor BMI (PDB database No. 20 J9) was used as a receptor, and the 3326 compound structures screened in (1) were docked into the receptor by Glide docking software.
  • the docking mode was Glide. "Extremely accurate mode" (XP mode), of course Then, GlideGscore was used to sort and match each compound docking mode. After careful analysis and analysis of the docking binding mode of each compound with IGF-1R, 75 compounds were finally selected for in vitro test to inhibit IGF-1R activity. All compounds were tested. Both were purchased from SPECS (www.specs.net) in the Netherlands.
  • IGF1R insulin-like growth factor 1 receptor
  • the tyrosine kinase used in the experiment was obtained by expression and purification using an insect baculovirus expression system.
  • Poly(Glu, Tyr) 4: i is a product of Sigma (St Louis, MO, USA); ATP, OPD is Amresco (Solon, Ohio, USA); anti-phosphotyrosine monoclonal antibody PY99 is Santa Cruz The product of the company (Santa Cruz, CA, USA); horseradish peroxidase-labeled goat anti-mouse IgG is a product of Calbiochem (Darmstadt, Germany); the ELISA plate is a product of Corning (New York, USA).
  • the biological activity test method is a tyrosine kinase activity test based on enzyme-linked immunofluorescence analysis.
  • reaction buffer formulation HEPES (pH 7.4) 50 mM, MgCl 2 50 mM, MnCl 2 0.5 mM, Na 3 VO 4 0.2 mM, DTT 1 mM.
  • T_PBS potassium ion-free PBS solution
  • Sample inhibition rate % [1 - (compound OD value - no enzyme control well OD value) / (compound OD value - no enzyme control well OD value)] x l00%
  • Table 1 provides a compound of the invention on half of human IGF1R inhibitory protein Inhibitory concentration IC 50 values
  • IGF1R insulin-like growth factor 1 receptor
  • the 5-substituted-2,4-thiazolidinedione compounds of the present invention have a good effect in inhibiting the activity of the insulin-like growth factor 1 receptor (IGF1R) kinase, and IGF1R plays an important role in the proliferation and differentiation of tumor cells. Promoting action, therefore, the compounds of the invention are useful in the preparation of a medicament for the treatment of neoplastic diseases.
  • IGF1R insulin-like growth factor 1 receptor

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Abstract

L'invention porte sur l'utilisation de 2, 4-thiazolidinediones 5-substituées de la formule (I) ou de sels de qualité pharmaceutique de celles-ci dans la préparation de médicaments pour la modulation du récepteur du facteur de croissance 1 analogue à l'insuline (IGF1R). Les composés de la présente invention peuvent inhiber l'activité d'IGF1R-kinase et peuvent être utilisés pour traiter le cancer.
PCT/CN2010/001839 2009-11-27 2010-11-16 Utilisation de 2, 4-thiazolidinediones 5-substituées dans la préparation de médicaments pour modulation du récepteur du facteur de croissance 1 analogue à l'insuline Ceased WO2011063602A1 (fr)

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CN200910199632.4 2009-11-27
CN2009101996324A CN102078318A (zh) 2009-11-27 2009-11-27 5-取代-2，4-噻唑烷二酮类化合物在制备igf1r功能调节药物中的应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2583969A4 (fr) * 2010-06-18 2013-10-23 Avixgen Inc Nouveaux dérivés de rhodanine, procédé pour les préparer et composition pharmaceutique pour la prévention ou le traitement du sida contenant les dérivés de rhodanine comme principes actifs
US9255088B2 (en) 2010-08-11 2016-02-09 The Regents Of The University Of California Premature-termination-codons readthrough compounds
US9598395B2 (en) 2012-03-23 2017-03-21 The Regents Of The University Of California Premature-termination-codons readthrough compounds
WO2017119570A1 (fr) * 2016-01-08 2017-07-13 조선대학교 산학협력단 Dérivé de thiazolidinedione et son utilisation
JP2017537940A (ja) * 2014-12-10 2017-12-21 マサチューセッツ インスティテュート オブ テクノロジー 増殖性疾患の処置に有用な融合１，３−アゾール誘導体
KR20180123109A (ko) * 2016-04-04 2018-11-14 연세대학교 산학협력단 Ras를 분해하는 이종원자고리화합물 및 이의 용도
KR20190124666A (ko) * 2018-04-26 2019-11-05 재단법인 의약바이오컨버젼스연구단 mTOR 저해제로서의 신규 화합물 및 이의 용도

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* Cited by examiner, † Cited by third party
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CN102731429A (zh) * 2012-07-18 2012-10-17 西南大学 5-芳亚甲基噻唑烷-2，4-二酮及其合成方法和应用
KR102297501B1 (ko) * 2018-06-08 2021-09-02 재단법인 의약바이오컨버젼스연구단 신규 mTOR 저해제를 포함하는 암 예방 또는 치료용 조성물

Citations (2)

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WO2004028535A1 (fr) * 2002-09-26 2004-04-08 Pintex Pharmaceuticals, Inc. Composes de modulation de pin-1 et leurs procedes d'utilisation
WO2009105621A1 (fr) * 2008-02-22 2009-08-27 The Ohio State University Research Foundation Agents ablatifs du récepteur androgène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004028535A1 (fr) * 2002-09-26 2004-04-08 Pintex Pharmaceuticals, Inc. Composes de modulation de pin-1 et leurs procedes d'utilisation
WO2009105621A1 (fr) * 2008-02-22 2009-08-27 The Ohio State University Research Foundation Agents ablatifs du récepteur androgène

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8759536B2 (en) 2010-06-18 2014-06-24 Avixgen Inc. Rhodanine derivatives, method for preparing same, and pharmaceutical composition for the prevention or treatment of aids containing the rhodanine derivatives as active ingredients
EP2583969A4 (fr) * 2010-06-18 2013-10-23 Avixgen Inc Nouveaux dérivés de rhodanine, procédé pour les préparer et composition pharmaceutique pour la prévention ou le traitement du sida contenant les dérivés de rhodanine comme principes actifs
US9255088B2 (en) 2010-08-11 2016-02-09 The Regents Of The University Of California Premature-termination-codons readthrough compounds
US9598395B2 (en) 2012-03-23 2017-03-21 The Regents Of The University Of California Premature-termination-codons readthrough compounds
JP2017537940A (ja) * 2014-12-10 2017-12-21 マサチューセッツ インスティテュート オブ テクノロジー 増殖性疾患の処置に有用な融合１，３−アゾール誘導体
US10787425B2 (en) 2016-01-08 2020-09-29 Industry-Academic Cooperation Foundation Chosun University Thiazolidinedione derivative and use thereof
WO2017119570A1 (fr) * 2016-01-08 2017-07-13 조선대학교 산학협력단 Dérivé de thiazolidinedione et son utilisation
KR20180123109A (ko) * 2016-04-04 2018-11-14 연세대학교 산학협력단 Ras를 분해하는 이종원자고리화합물 및 이의 용도
KR102304478B1 (ko) * 2016-04-04 2021-09-24 주식회사 바오밥에이바이오 Ras를 분해하는 이종원자고리화합물 및 이의 용도
KR20190124666A (ko) * 2018-04-26 2019-11-05 재단법인 의약바이오컨버젼스연구단 mTOR 저해제로서의 신규 화합물 및 이의 용도
KR102308134B1 (ko) * 2018-04-26 2021-10-01 재단법인 의약바이오컨버젼스연구단 mTOR 저해제로서의 신규 화합물 및 이의 용도
JP2021527629A (ja) * 2018-04-26 2021-10-14 メディシナル バイオコンバージェンス リサーチ センター ｍＴＯＲ阻害剤としての新規化合物及びその用途
US11649231B2 (en) 2018-04-26 2023-05-16 Medicinal Bioconvergence Research Center Compound as mTOR inhibitor and use thereof
JP7491510B2 (ja) 2018-04-26 2024-05-28 メディシナル バイオコンバージェンス リサーチ センター ｍＴＯＲ阻害剤としての新規化合物及びその用途

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