TWI726968B - Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 - Google Patents
Egfr酪胺酸激酶之臨床重要突變體之選擇性抑制劑 Download PDFInfo
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- TWI726968B TWI726968B TW106100545A TW106100545A TWI726968B TW I726968 B TWI726968 B TW I726968B TW 106100545 A TW106100545 A TW 106100545A TW 106100545 A TW106100545 A TW 106100545A TW I726968 B TWI726968 B TW I726968B
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Classifications
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D403/02—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
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- C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
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- C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
- C08F20/52—Amides or imides
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Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117185B (zh) | 2015-08-31 | 2017-11-07 | 广州必贝特医药技术有限公司 | 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用 |
| JP2019501222A (ja) | 2016-01-07 | 2019-01-17 | シーエス ファーマテック リミテッド | Egfrチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
| EP3464275B1 (en) | 2016-05-26 | 2024-05-08 | Recurium IP Holdings, LLC | Egfr inhibitor compounds |
| EP3492462B1 (en) * | 2016-07-26 | 2023-08-30 | Shenzhen TargetRx, Inc. | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
| IL292977A (en) | 2016-09-09 | 2022-07-01 | Incyte Corp | Pyrazolopyridine derivatives as modulators of hpk1 and their use in cancer therapy |
| WO2018049214A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer |
| KR102388312B1 (ko) * | 2017-06-13 | 2022-04-19 | 베이징 아다메이들 바이오테크놀로지 리미티드 라이어빌리티 컴퍼니 | 아미노피리미딘 화합물, 이의 제조방법 및 용도 |
| EP3648753A4 (en) * | 2017-07-05 | 2021-03-17 | CS Pharmatech Limited | SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF EGFR TYROSINE KINASE |
| EP3659307A4 (en) * | 2017-07-28 | 2021-09-22 | Yale University | ANTI-CANCER PRODUCTS AND METHOD FOR MANUFACTURING AND USING THEREOF |
| PT3658547T (pt) * | 2017-07-28 | 2023-10-20 | Yuhan Corp | Processo de preparação de n -(5 -(4 -(4 -formil -3- fenil- 1h -pirazol- 1 -il)pirimidin -2- ilamino) -4 -metoxi 2- morfolinofenil) acrilamida |
| WO2019042187A1 (zh) * | 2017-08-30 | 2019-03-07 | 深圳市塔吉瑞生物医药有限公司 | 一种氨基嘧啶类化合物及包含该化合物的组合物及其用途 |
| CN109503573A (zh) * | 2017-09-14 | 2019-03-22 | 昆明圣加南生物科技有限公司 | 2-取代苯胺基嘧啶衍生物及其用途 |
| CN107827875B (zh) * | 2017-09-25 | 2021-07-09 | 文韬创新药物研究(北京)有限责任公司 | 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用 |
| US20210101881A1 (en) * | 2018-02-12 | 2021-04-08 | Ancureall Pharmaceutical (Shanghai) Co., Ltd. | Pyrimidine compound, preparation method thereof and medical use thereof |
| LT3755703T (lt) | 2018-02-20 | 2022-10-10 | Incyte Corporation | N-(fenil)-2-(fenil)pirimidin-4-karboksamido dariniai ir susiję junginiai, kaip hpk1 inhibitoriai, skirti vėžio gydymui |
| WO2019164949A1 (en) * | 2018-02-20 | 2019-08-29 | Dana-Farber Cancer Institute, Inc. | Pharmaceutical combinations of egfr inhibitors and methods of use thereof |
| EP3755338A4 (en) * | 2018-02-20 | 2021-11-03 | Dana-Farber Cancer Institute, Inc. | PHARMACEUTICAL COMBINATIONS OF EGFR INHIBITORS AND THEIR METHODS OF USE |
| US12448374B2 (en) | 2018-06-07 | 2025-10-21 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 |
| CN112543757A (zh) | 2018-06-15 | 2021-03-23 | 卡迪拉保健有限公司 | 对结核菌具有抗菌活性的缩合氮杂杂芳基化合物 |
| CN110790749B (zh) * | 2018-08-03 | 2023-07-14 | 北京普祺医药科技股份有限公司 | 一种含氮杂环化合物、药物组合物以及其用途 |
| US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
| CN110857292A (zh) * | 2018-08-22 | 2020-03-03 | 上海艾力斯医药科技有限公司 | 一种egfr激酶抑制剂及其制备方法和应用 |
| EP3897670A4 (en) | 2018-12-19 | 2022-09-07 | Disarm Therapeutics, Inc. | MRSA1 INHIBITORS IN COMBINATION WITH NEUROPROTECTIVE AGENTS |
| CN113227073B (zh) * | 2019-01-05 | 2022-09-16 | 山东轩竹医药科技有限公司 | Egfr酪氨酸激酶的选择性抑制剂的盐及其晶型 |
| CN111410651B (zh) * | 2019-01-05 | 2021-06-04 | 山东轩竹医药科技有限公司 | 酪氨酸激酶抑制剂的盐及其晶型 |
| US12157730B2 (en) | 2019-03-19 | 2024-12-03 | Voronoi Inc. | Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component |
| PL3943491T3 (pl) | 2019-03-19 | 2025-11-17 | Voronoi Inc. | Pochodna heteroarylowa, sposób jej wytwarzania i kompozycja farmaceutyczna zawierająca ją jako skuteczny składnik |
| CN111825658B (zh) * | 2019-04-18 | 2024-11-08 | 华东理工大学 | Egfr三突变抑制剂及其应用 |
| CN112174961A (zh) * | 2019-07-04 | 2021-01-05 | 微境生物医药科技(上海)有限公司 | 一类抑制egfr激酶的化合物及其制备方法和用途 |
| KR102470980B1 (ko) * | 2019-07-26 | 2022-11-25 | 차이나 리소시즈 파마수티컬 홀딩스 컴퍼니 리미티드 | Egfr 및 erbb2에 작용하는 피리미딘계 화합물 |
| EP4010338A1 (en) | 2019-08-06 | 2022-06-15 | Incyte Corporation | Solid forms of an hpk1 inhibitor |
| TW202128670A (zh) * | 2019-11-26 | 2021-08-01 | 大陸商上海翰森生物醫藥科技有限公司 | 含氮多環類衍生物抑制劑、其製備方法和應用 |
| CN113045475A (zh) * | 2019-12-27 | 2021-06-29 | 上海泓博智源医药股份有限公司 | 一种5-溴-7-甲基吲哚的制备方法 |
| CN113493419A (zh) * | 2020-03-18 | 2021-10-12 | 南京药石科技股份有限公司 | Egfr酪氨酸激酶抑制剂及其用途 |
| WO2021243596A1 (en) * | 2020-06-03 | 2021-12-09 | InventisBio Co., Ltd. | Aminopyrimidine compounds, preparation methods and uses thereof |
| TW202214600A (zh) * | 2020-09-24 | 2022-04-16 | 大陸商廣州費米子科技有限責任公司 | 嘧啶基衍生物、其製備方法及其用途 |
| WO2022081478A1 (en) * | 2020-10-12 | 2022-04-21 | Dana-Farber Cancer Institute, Inc. | Covalent egfr inhibitors and methods of use thereof |
| JP2023550591A (ja) * | 2020-11-02 | 2023-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | EGFR阻害薬としての置換1H-ピラゾロ[4,3-c]及び誘導体 |
| CN114539269B (zh) * | 2020-11-19 | 2023-04-28 | 上海医药工业研究院有限公司 | 一种含氮大环化合物、其制备方法及其应用 |
| WO2022115753A1 (en) * | 2020-11-30 | 2022-06-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Merged scaffold taf1 inhibitors |
| CA3196068A1 (en) * | 2020-12-02 | 2022-06-09 | Abbisko Therapeutics Co., Ltd | 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine derivative, preparation method therefor, and application thereof |
| EP4359400B1 (en) * | 2021-06-23 | 2025-07-02 | Blueprint Medicines Corporation | Salt and crystal form of an azetidinyl substituted isoquinline acting as epidermal growth factor receptor inhibitor for the treatment of cancer |
| TW202317542A (zh) * | 2021-06-23 | 2023-05-01 | 美商纜圖藥品公司 | 製備egfr抑制劑的方法 |
| CN115701429B (zh) * | 2021-08-02 | 2024-03-12 | 上海和誉生物医药科技有限公司 | 4-(1h-吲哚-1-基)嘧啶-2-氨基衍生物及其制备方法和应用 |
| WO2023011505A1 (zh) * | 2021-08-06 | 2023-02-09 | 上海和誉生物医药科技有限公司 | 嘧啶或吡啶衍生物及其制备方法和在药学上的应用 |
| CN115703760B (zh) * | 2021-08-11 | 2024-05-31 | 山东大学 | 2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用 |
| CN116283914A (zh) * | 2021-12-01 | 2023-06-23 | 上海艾力斯医药科技股份有限公司 | 一类嘧啶类化合物、其制备方法及应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
Family Cites Families (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
| KR0166088B1 (ko) | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
| GB9518953D0 (en) | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
| WO2000035298A1 (en) | 1996-11-27 | 2000-06-22 | Wm. Wrigley Jr. Company | Chewing gum containing medicament active agents |
| CA2280515A1 (en) | 1997-03-11 | 1998-09-17 | E.I. Du Pont De Nemours And Company | Heteroaryl azole herbicides |
| GB9711643D0 (en) | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
| GB9905075D0 (en) | 1999-03-06 | 1999-04-28 | Zeneca Ltd | Chemical compounds |
| US6897208B2 (en) * | 2001-10-26 | 2005-05-24 | Aventis Pharmaceuticals Inc. | Benzimidazoles |
| US7582631B2 (en) * | 2004-01-14 | 2009-09-01 | Amgen Inc. | Substituted heterocyclic compounds and methods of use |
| ATE502920T1 (de) | 2007-12-14 | 2011-04-15 | Pulmagen Therapeutics Asthma Ltd | Indole und ihre therapeutische verwendung |
| TWI458721B (zh) | 2008-06-27 | 2014-11-01 | Celgene Avilomics Res Inc | 雜芳基化合物及其用途 |
| WO2010142934A1 (en) | 2009-06-12 | 2010-12-16 | Pulmagen Therapeutics (Asthma) Limited | Indole derivatives as ligands of crth2 receptors |
| ES2654177T3 (es) | 2011-07-27 | 2018-02-12 | Astrazeneca Ab | Derivados de 2-(2,4,5-anilino sustituido)pirimidina como moduladores de EGFR útiles para tratar el cáncer |
| EP2763976B1 (en) * | 2011-10-05 | 2016-05-18 | Merck Sharp & Dohme Corp. | 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors |
| NZ703162A (en) | 2012-07-03 | 2017-05-26 | 3-V Biosciences Inc | Heterocyclic modulators of lipid synthesis |
| CN104513253A (zh) * | 2013-10-01 | 2015-04-15 | 南京波尔泰药业科技有限公司 | 用于治疗增殖性疾病的大环化合物 |
| CN104761544B (zh) | 2014-01-03 | 2019-03-15 | 北京轩义医药科技有限公司 | Egfr酪氨酸激酶的临床重要突变体的选择性抑制剂 |
| US20170166598A1 (en) | 2014-05-13 | 2017-06-15 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| CN111892579B (zh) * | 2014-06-12 | 2023-07-25 | 上海艾力斯医药科技股份有限公司 | 一类激酶抑制剂 |
| CN105315259B (zh) | 2014-07-29 | 2018-03-09 | 上海艾力斯医药科技有限公司 | 吡啶胺基嘧啶衍生物、其制备方法及应用 |
| CN113121575A (zh) | 2014-08-25 | 2021-07-16 | 四川海思科制药有限公司 | 一种(取代的苯基)(取代的嘧啶)胺基衍生物及其制备方法和药物用途 |
| CN105461695B (zh) | 2014-09-29 | 2018-03-27 | 齐鲁制药有限公司 | 嘧啶或三嗪衍生物及其制备方法和用途 |
| SI3205650T1 (sl) * | 2014-10-11 | 2021-10-29 | Shanghai Hansoh Biomedical Co Ltd | Zaviralec EGFR-ja in priprava ter uporaba le-tega |
| HRP20250213T1 (hr) | 2014-10-13 | 2025-04-25 | Yuhan Corporation | Spojevi i pripravci za modulaciju aktivnosti egfr mutantne kinaze |
| KR102387699B1 (ko) | 2014-12-23 | 2022-04-18 | 미츠비시 하이텍 페이퍼 유럽 게엠베하 | 오프셋 인쇄용 감열 기록 재료 |
| WO2016105525A2 (en) | 2014-12-23 | 2016-06-30 | Dana-Farber Cancer Institute, Inc. | Novel pyrimidines as egfr inhibitors and methods of treating disorders |
| CN104788427B (zh) | 2015-02-05 | 2017-05-31 | 上海泓博智源医药股份有限公司 | 3‑(2‑嘧啶氨基)苯基丙烯酰胺类化合物及其应用 |
| CN104844580B (zh) | 2015-04-17 | 2017-10-20 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
| JP6457697B2 (ja) | 2015-04-29 | 2019-01-23 | カントン チョンション ファーマシューティカル カンパニー,リミティド | キナーゼ阻害剤としての縮合環式または三環式アリールピリミジン化合物 |
| WO2016183278A1 (en) | 2015-05-13 | 2016-11-17 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| KR102666414B1 (ko) | 2015-07-16 | 2024-05-17 | 치아타이 티안큉 파마수티컬 그룹 주식회사 | 아닐린 피리미딘 유도체 및 그의 용도 |
| CN105001208A (zh) | 2015-08-06 | 2015-10-28 | 南京雷科星生物技术有限公司 | 一种表皮生长因子受体egfr抑制剂及其制备方法与用途 |
| CN106117185B (zh) | 2015-08-31 | 2017-11-07 | 广州必贝特医药技术有限公司 | 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用 |
| CN106749193B (zh) * | 2015-11-23 | 2020-11-20 | 南京圣和药业股份有限公司 | 吲唑取代的表皮生长因子受体抑制剂及其应用 |
| CN106928150B (zh) | 2015-12-31 | 2020-07-31 | 恩瑞生物医药科技(上海)有限公司 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
| JP2019501222A (ja) | 2016-01-07 | 2019-01-17 | シーエス ファーマテック リミテッド | Egfrチロシンキナーゼの臨床的に重要な変異体の選択的阻害薬 |
| CN106279160B (zh) | 2016-03-18 | 2017-09-26 | 海南越康生物医药有限公司 | N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途 |
| WO2017190637A1 (zh) | 2016-05-06 | 2017-11-09 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的稠合嘧啶类化合物 |
| KR20190006991A (ko) | 2016-05-11 | 2019-01-21 | 베타 파마, 인크. | 뇌암의 치료를 위한 치료제로서의 2-아닐리노피리미딘 유도체 |
| EP3492462B1 (en) | 2016-07-26 | 2023-08-30 | Shenzhen TargetRx, Inc. | Amino pyrimidine compound for inhibiting protein tyrosine kinase activity |
| EP3648753A4 (en) | 2017-07-05 | 2021-03-17 | CS Pharmatech Limited | SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF EGFR TYROSINE KINASE |
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2017
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- 2017-01-06 KR KR1020187022731A patent/KR20180105161A/ko not_active Withdrawn
- 2017-01-06 CN CN201780016875.2A patent/CN109328059B/zh active Active
- 2017-01-06 WO PCT/US2017/012466 patent/WO2017120429A1/en not_active Ceased
- 2017-01-06 EP EP17736401.5A patent/EP3399968B8/en not_active Not-in-force
- 2017-01-06 TW TW106100545A patent/TWI726968B/zh not_active IP Right Cessation
- 2017-01-06 US US16/068,559 patent/US10435388B2/en active Active
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015127872A1 (zh) * | 2014-02-25 | 2015-09-03 | 上海海雁医药科技有限公司 | 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物 |
| WO2015195228A1 (en) * | 2014-06-19 | 2015-12-23 | Ariad Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| CN105085489A (zh) * | 2014-11-05 | 2015-11-25 | 上海页岩科技有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
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| KR20180105161A (ko) | 2018-09-27 |
| WO2017120429A1 (en) | 2017-07-13 |
| TW201734013A (zh) | 2017-10-01 |
| EP3399968A4 (en) | 2019-07-24 |
| EP3399968A1 (en) | 2018-11-14 |
| CN109328059B (zh) | 2021-08-17 |
| US10435388B2 (en) | 2019-10-08 |
| JP2021091703A (ja) | 2021-06-17 |
| EP3399968B1 (en) | 2021-10-20 |
| US20190023689A1 (en) | 2019-01-24 |
| CN109328059A (zh) | 2019-02-12 |
| EP3399968B8 (en) | 2021-12-01 |
| JP2019501222A (ja) | 2019-01-17 |
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