KR101782668B1 - 인산화 효소 억제제와 이를 이용한 종양을 치료하는 방법. - Google Patents
인산화 효소 억제제와 이를 이용한 종양을 치료하는 방법. Download PDFInfo
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- KR101782668B1 KR101782668B1 KR1020127029064A KR20127029064A KR101782668B1 KR 101782668 B1 KR101782668 B1 KR 101782668B1 KR 1020127029064 A KR1020127029064 A KR 1020127029064A KR 20127029064 A KR20127029064 A KR 20127029064A KR 101782668 B1 KR101782668 B1 KR 101782668B1
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- tumor
- title compound
- alkyl
- cyclopropane
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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| CA2927612C (en) * | 2013-10-18 | 2022-08-30 | University Health Network | Treatment for pancreatic cancer |
| CN104130175A (zh) * | 2014-06-13 | 2014-11-05 | 天津科技大学 | 不同位置取代吲哚酮类衍生物及其应用 |
| US11608334B2 (en) | 2017-02-08 | 2023-03-21 | The National Institutes of Pharmaceutical R&D Co., Ltd. | Pyrrolo-aromatic heterocyclic compound, preparation method therefor, and medical use thereof |
| CN108947961B (zh) * | 2017-05-18 | 2021-06-04 | 四川大学 | 吲唑类衍生物及其制备方法和用途 |
| CA3074876A1 (en) * | 2017-09-08 | 2019-03-14 | University Health Network | Combination therapies for inhibition of polo-like kinase 4 |
| WO2020097398A1 (en) | 2018-11-07 | 2020-05-14 | Dana-Farber Cancer Institute, Inc. | Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof |
| BR112021021106A2 (pt) | 2019-04-24 | 2021-12-14 | Univ Health Network | Forma cristalina s4 do inibidor plk4 fumarato (ir,2s)-(e)-2-(3-(4-((cis-2,6-dimetilmorfolino)metil)estiril)-1h-imidazol-6-il)-5'-metoxiespiro[ciclopropano-1,3'-indolin]-2'ona |
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| CN112250614B (zh) * | 2020-10-20 | 2022-02-01 | 苏州大学 | 3-螺三元环吲哚酮衍生物的合成方法 |
| WO2022140527A1 (en) | 2020-12-23 | 2022-06-30 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| TW202300485A (zh) * | 2021-03-02 | 2023-01-01 | 大陸商上海齊魯製藥研究中心有限公司 | Plk4抑制劑及其用途 |
| US20240270722A1 (en) | 2021-05-11 | 2024-08-15 | Oric Pharmaceuticals, Inc. | Polo like kinase 4 inhibitors |
| CN115677682B (zh) * | 2021-07-30 | 2023-07-18 | 上海齐鲁制药研究中心有限公司 | 螺环类plk4抑制剂及其用途 |
| TW202325289A (zh) | 2021-11-09 | 2023-07-01 | 美商雅捷可斯治療公司 | Jak2抑制劑之形式及組合物 |
| TW202334139A (zh) | 2021-11-09 | 2023-09-01 | 美商雅捷可斯治療公司 | 作為jak2抑制劑之6-雜芳氧基苯并咪唑及氮雜苯并咪唑 |
| WO2024006379A1 (en) * | 2022-06-30 | 2024-01-04 | Axonis Therapeutics, Inc. | Methods and compounds for inhibiting mkk7 enzymes |
| WO2024209363A1 (en) | 2023-04-06 | 2024-10-10 | Pfizer Inc. | Substituted indazole propionic acid derivative compounds and uses thereof as ampk activators |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009079767A1 (en) | 2007-12-21 | 2009-07-02 | University Health Network | Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer |
| WO2009124692A1 (en) | 2008-04-11 | 2009-10-15 | Almirall, S.A. | New substituted spiro[cycloalkyl-1,3'-indol]-2'(1'h)-one derivatives and their use as p38 mitogen-activated kinase inhibitors. |
| WO2009132774A1 (en) | 2008-04-28 | 2009-11-05 | Almirall, S. A. | New substituted indolin-2-one derivatives and their use as p39 mitogen-activated kinase inhibitors |
Family Cites Families (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3310891A1 (de) | 1983-03-25 | 1984-09-27 | Boehringer Mannheim Gmbh, 6800 Mannheim | Neue indolinon-(2)-derivate, verfahren zu ihrer herstellung, diese verbindungen enthaltende arzneimittel und zwischenprodukte |
| US5182397A (en) * | 1990-05-31 | 1993-01-26 | American Cyanamid Company | Aryloxyspiroalkylindolinone herbicides |
| GB9507298D0 (en) | 1995-04-07 | 1995-05-31 | Pharmacia Spa | Substituted indolylmethylene-oxindale analogues as tyrosine kinase inhibitors |
| US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| ATE308520T1 (de) | 1996-08-23 | 2005-11-15 | Sugen Inc | Kombinatorische bibliotheken von indolinone und verwandte produkte und verfahren zur behandlung von krankheiten |
| GB9716557D0 (en) | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
| US6133305A (en) * | 1997-09-26 | 2000-10-17 | Sugen, Inc. | 3-(substituted)-2-indolinones compounds and use thereof as inhibitors of protein kinase activity |
| CA2383623A1 (en) | 1998-08-04 | 2000-02-17 | Sugen, Inc. | 3-methylidenyl-2-indolinone modulators of protein kinase |
| EP1165513A1 (en) | 1999-03-24 | 2002-01-02 | Sugen, Inc. | Indolinone compounds as kinase inhibitors |
| YU54202A (sh) * | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije |
| EP1294688A2 (en) | 2000-06-02 | 2003-03-26 | Sugen, Inc. | Indolinone derivatives as protein kinase/phosphatase inhibitors |
| US6897231B2 (en) | 2000-07-31 | 2005-05-24 | Signal Pharmaceuticals, Inc. | Indazole derivatives as JNK inhibitors and compositions and methods related thereto |
| IL164209A0 (en) | 2002-05-31 | 2005-12-18 | Eisai Co Ltd | Pyrazole derivatives and pharmaceutical compositions containing the same |
| US7148249B2 (en) | 2002-09-12 | 2006-12-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments |
| US7205328B2 (en) | 2002-10-21 | 2007-04-17 | Irm Llc | Oxindoles with anti-HIV activity |
| WO2005058309A1 (en) | 2003-12-16 | 2005-06-30 | Leo Pharma A/S | Novel therapeutic use of indolinone derivatives |
| US20050211590A1 (en) | 2004-03-26 | 2005-09-29 | Mcclure George K | Protective cover for medical devices |
| DE102005005395A1 (de) | 2005-02-03 | 2006-08-10 | Schering Aktiengesellschaft | Thiazolidinone, deren Herstellung und Verwendung als Arzneimittel |
| US7309787B2 (en) * | 2005-07-13 | 2007-12-18 | Allergan, Inc. | Kinase inhibitors |
| WO2007058626A1 (en) * | 2005-11-16 | 2007-05-24 | S*Bio Pte Ltd | Indazole compounds |
| US20070135509A1 (en) | 2005-12-09 | 2007-06-14 | Blackburn Thomas P | Indolone compounds useful to treat cognitive impairment |
| FR2896503B1 (fr) | 2006-01-23 | 2012-07-13 | Aventis Pharma Sa | Nouveaux derives soufres d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases |
| WO2007109026A2 (en) | 2006-03-15 | 2007-09-27 | The Trustees Of Columbia University In The City Of New York | Pten compositions and methods for detecting breast cancer |
| GB0606234D0 (en) | 2006-03-29 | 2006-05-10 | Pliva Istrazivanje I Razvoj D | Pharmaceutically acceptable salts and polymorphic forms |
| WO2008152014A2 (en) | 2007-06-12 | 2008-12-18 | Boehringer Ingelheim International Gmbh | 3-hetrocyclylidene-indolinone derivatives as inhibitors of specific cell cycle kinases |
| EP2564850B1 (en) | 2007-09-25 | 2014-08-13 | Takeda Pharmaceutical Company Limited | Polo-like kinase inhibitors |
| WO2009065232A1 (en) | 2007-11-20 | 2009-05-28 | University Health Network | Cancer diagnostic and therapeutic methods that target plk4/sak |
| JP2009173629A (ja) * | 2007-12-21 | 2009-08-06 | Banyu Pharmaceut Co Ltd | Rsk1阻害作用を有する新規スピロインダン誘導体 |
| EP2262499B1 (en) * | 2008-03-11 | 2016-12-21 | University Health Network | Mk-0557 for use in the treatment of cancer |
| CA2728225A1 (en) | 2008-06-16 | 2010-01-21 | Tigris Pharmaceuticals, Inc. | Methods for determining sensitivity to aminoflavones |
| DE102008040187A1 (de) * | 2008-07-04 | 2010-01-07 | Robert Bosch Gmbh | Sensorelement, Verfahren zu seiner Herstellung sowie Verwendung |
| EP2320907A4 (en) | 2008-08-05 | 2012-09-05 | Merck Sharp & Dohme | THERAPEUTIC COMPOUNDS |
| ES2465971T3 (es) | 2009-04-06 | 2014-06-09 | University Health Network | Inhibidores de quinasa y método para tratar cáncer con los mismos |
| WO2011069298A1 (en) * | 2009-12-11 | 2011-06-16 | F. Hoffmann-La Roche Ag | Novel cyclopropane indolinone derivatives |
| JP5056876B2 (ja) | 2010-03-19 | 2012-10-24 | Jfeスチール株式会社 | 冷間加工性と焼入れ性に優れた熱延鋼板およびその製造方法 |
| NZ602350A (en) | 2010-04-06 | 2014-05-30 | Univ Health Network | Kinase inhibitors and method of treating cancer with same |
| EP2588110B1 (en) | 2010-07-02 | 2018-10-17 | University Health Network | Methods of targeting pten mutant diseases and compositions therefor |
| WO2012048411A1 (en) | 2010-10-13 | 2012-04-19 | University Health Network | Plk-4 inhibitors and method of treating cancer with same |
| KR20130105675A (ko) | 2010-11-25 | 2013-09-25 | 라티오팜 게엠베하 | 아파티닙의 신규 염 및 다형 |
| JP2014511389A (ja) | 2011-02-28 | 2014-05-15 | エピザイム インコーポレイテッド | 置換6,5−縮合二環式ヘテロアリール化合物 |
| GB201109966D0 (en) | 2011-06-10 | 2011-07-27 | Cancer Res Inst Royal | Materials and methods for treating pten mutated or deficient cancer |
| US9580390B2 (en) | 2011-10-12 | 2017-02-28 | University Health Network | Indazole compounds as kinase inhibitors and method of treating cancer with same |
| SI3057965T1 (sl) | 2013-10-18 | 2019-04-30 | University Health Network | Sol in kristalne oblike inhibitorja PLK-4 |
| CA2927612C (en) | 2013-10-18 | 2022-08-30 | University Health Network | Treatment for pancreatic cancer |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009079767A1 (en) | 2007-12-21 | 2009-07-02 | University Health Network | Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer |
| WO2009124692A1 (en) | 2008-04-11 | 2009-10-15 | Almirall, S.A. | New substituted spiro[cycloalkyl-1,3'-indol]-2'(1'h)-one derivatives and their use as p38 mitogen-activated kinase inhibitors. |
| WO2009132774A1 (en) | 2008-04-28 | 2009-11-05 | Almirall, S. A. | New substituted indolin-2-one derivatives and their use as p39 mitogen-activated kinase inhibitors |
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