CN112457298B - 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 - Google Patents
取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 Download PDFInfo
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- CN112457298B CN112457298B CN202011112986.3A CN202011112986A CN112457298B CN 112457298 B CN112457298 B CN 112457298B CN 202011112986 A CN202011112986 A CN 202011112986A CN 112457298 B CN112457298 B CN 112457298B
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Classifications
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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
- C07D403/02—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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D403/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011112986.3A CN112457298B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
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| US201462090869P | 2014-12-11 | 2014-12-11 | |
| US62/090,869 | 2014-12-11 | ||
| US201562166883P | 2015-05-27 | 2015-05-27 | |
| US62/166,883 | 2015-05-27 | ||
| CN201580067776.8A CN108024993B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
| PCT/US2015/065286 WO2016094821A2 (en) | 2014-12-11 | 2015-12-11 | Substituted 2-anilinopyrimidine derivatives as egfr modulators |
| CN202011112986.3A CN112457298B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
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| CN201580067776.8A Division CN108024993B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
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| CN112457298A CN112457298A (zh) | 2021-03-09 |
| CN112457298B true CN112457298B (zh) | 2024-05-07 |
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| CN202011112986.3A Active CN112457298B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
| CN202011112988.2A Active CN112375067B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
| CN201580067776.8A Active CN108024993B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
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| CN202011112988.2A Active CN112375067B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
| CN201580067776.8A Active CN108024993B (zh) | 2014-12-11 | 2015-12-11 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
Country Status (17)
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Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085489B (zh) * | 2014-11-05 | 2019-03-01 | 益方生物科技（上海）有限公司 | 嘧啶或吡啶类化合物、其制备方法和医药用途 |
| CN112457298B (zh) * | 2014-12-11 | 2024-05-07 | 贝达医药公司 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
| TW201740951A (zh) * | 2016-05-11 | 2017-12-01 | 貝達醫藥公司 | 做為用於治療腦癌的治療劑之2-苯胺嘧啶 |
| CN109311858B (zh) | 2016-05-26 | 2021-12-03 | 里科瑞尔姆Ip控股有限责任公司 | Egfr抑制剂化合物 |
| SG11201810976TA (en) | 2016-06-17 | 2019-01-30 | Beta Pharma Inc | Pharmaceutical salts of n-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide and crystalline forms thereof |
| CN106243044A (zh) * | 2016-06-30 | 2016-12-21 | 浙江大学 | 含卤代丙烯酰胺侧链的嘧啶类衍生物及制备和应用 |
| CN108602802B (zh) | 2016-07-26 | 2020-01-21 | 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氨基嘧啶类化合物 |
| JP7045726B2 (ja) * | 2017-06-16 | 2022-04-01 | ベータ ファーマ，インコーポレイテッド | Ｎ－（２－（２－（ジメチルアミノ）エトキシ）－４－メトキシ－５－（（４－（１－メチル－１ｈ－インドール－３－イル）ピリミジン－２－イル）アミノ）フェニル）アクリルアミドおよびその塩の医薬品製剤 |
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| CN108017633A (zh) * | 2018-01-30 | 2018-05-11 | 天津大学 | N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-2-氟代丙烯酰胺衍生物及应用 |
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| US12336995B2 (en) | 2018-09-10 | 2025-06-24 | Mirati Therapeutics, Inc. | Combination therapies |
| EP4034121A4 (en) | 2019-09-23 | 2023-10-18 | Beta Pharma, Inc. | TREATMENT OF EGFR MUTANT-RELATED CANCERS USING A COMBINATION OF EGFR AND CDK4/6 INHIBITORS |
| US20210161897A1 (en) | 2019-11-12 | 2021-06-03 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
| JP2023510426A (ja) | 2020-01-20 | 2023-03-13 | アストラゼネカ・アクチエボラーグ | 癌を治療するための上皮細胞増殖因子受容体チロシンキナーゼ阻害剤 |
| US20210369709A1 (en) | 2020-05-27 | 2021-12-02 | Astrazeneca Ab | EGFR TKIs FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER |
| EP4370212A1 (en) * | 2021-07-13 | 2024-05-22 | ACEA Therapeutics, Inc. | Heterocyclic compounds and uses thereof |
| WO2023187037A1 (en) | 2022-03-31 | 2023-10-05 | Astrazeneca Ab | Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors in combination with an akt inhibitor for the treatment of cancer |
| WO2023209090A1 (en) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | Bicyclic heteroaromatic compounds and their application in the treatment of cancer |
| US20240116926A1 (en) | 2022-04-28 | 2024-04-11 | Astrazeneca Ab | Heteroaromatic compounds |
| CA3249080A1 (en) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | CONDENSED BICYCLIC HETEROAROMATIC COMPOUNDS AND THEIR USE IN CANCER TREATMENT |
| WO2023209088A1 (en) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | Bicyclic heteroaromatic compounds and their use in the treatment of cancer |
| IL317733A (en) | 2022-06-27 | 2025-02-01 | Astrazeneca Ab | Combinations involving epidermal growth factor receptor tyrosine kinase inhibitors for cancer treatment |
| CA3261476A1 (en) | 2022-07-08 | 2024-01-11 | Astrazeneca Ab | Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Combination with HGF Receptor Inhibitors for the Treatment of Cancer |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413213A (zh) * | 1999-12-24 | 2003-04-23 | 阿文蒂斯药物有限公司 | 氮杂吲哚类化合物 |
| CN1665809A (zh) * | 2001-06-21 | 2005-09-07 | 艾文蒂斯药品有限公司 | 氮杂吲哚 |
| CN101547917A (zh) * | 2006-12-08 | 2009-09-30 | 霍夫曼-拉罗奇有限公司 | 用作jnk调节剂的取代的嘧啶类化合物及它们的应用 |
| WO2010059711A1 (en) * | 2008-11-18 | 2010-05-27 | Wisconsin Alumni Research Foundation | Sigma-1 receptor ligands and methods of use |
| CN103501612A (zh) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | 抑制表皮生长因子受体导致的癌症中细胞增殖的化合物 |
| CN103702990A (zh) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症 |
| 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 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5918693B2 (ja) * | 2009-05-05 | 2016-05-18 | ダナ ファーバー キャンサー インスティテュート インコーポレイテッド | Ｅｇｆｒ阻害剤及び疾患の治療方法 |
| JP6469567B2 (ja) * | 2012-05-05 | 2019-02-13 | アリアド・ファーマシューティカルズ・インコーポレイテッド | Ｅｇｆｒ発動性がんの細胞増殖阻害用化合物 |
| CN104860941B (zh) | 2014-02-25 | 2017-03-22 | 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 |
| AP2017009690A0 (en) * | 2014-06-19 | 2017-01-31 | Ariad Pharma Inc | Heteroaryl compounds for kinase inhibition |
| WO2016029839A1 (zh) | 2014-08-25 | 2016-03-03 | 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 |
| CN112457298B (zh) * | 2014-12-11 | 2024-05-07 | 贝达医药公司 | 取代的2-苯胺基嘧啶衍生物及其作为表皮生长因子受体调节剂 |
-
2015
- 2015-12-11 CN CN202011112986.3A patent/CN112457298B/zh active Active
- 2015-12-11 CN CN202011112988.2A patent/CN112375067B/zh active Active
- 2015-12-11 AU AU2015360360A patent/AU2015360360B2/en active Active
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- 2015-12-11 WO PCT/US2015/065286 patent/WO2016094821A2/en not_active Ceased
- 2015-12-11 CN CN201580067776.8A patent/CN108024993B/zh active Active
- 2015-12-11 US US15/534,838 patent/US10590111B2/en active Active
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- 2017-05-28 IL IL252554A patent/IL252554A0/en active IP Right Grant
- 2017-06-07 PH PH12017501057A patent/PH12017501057A1/en unknown
- 2017-07-11 CO CONC2017/0006962A patent/CO2017006962A2/es unknown
-
2020
- 2020-03-16 US US16/819,539 patent/US11414401B2/en active Active
- 2020-05-25 JP JP2020090467A patent/JP7181558B2/ja active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1413213A (zh) * | 1999-12-24 | 2003-04-23 | 阿文蒂斯药物有限公司 | 氮杂吲哚类化合物 |
| CN1665809A (zh) * | 2001-06-21 | 2005-09-07 | 艾文蒂斯药品有限公司 | 氮杂吲哚 |
| CN101547917A (zh) * | 2006-12-08 | 2009-09-30 | 霍夫曼-拉罗奇有限公司 | 用作jnk调节剂的取代的嘧啶类化合物及它们的应用 |
| WO2010059711A1 (en) * | 2008-11-18 | 2010-05-27 | Wisconsin Alumni Research Foundation | Sigma-1 receptor ligands and methods of use |
| CN103501612A (zh) * | 2011-05-04 | 2014-01-08 | 阿里亚德医药股份有限公司 | 抑制表皮生长因子受体导致的癌症中细胞增殖的化合物 |
| CN103702990A (zh) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症 |
| 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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