CA2869954C - Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof in medical conditions related to modulation of bruton's tyrosine kinase activity - Google Patents
Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof in medical conditions related to modulation of bruton's tyrosine kinase activity Download PDFInfo
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- CA2869954C CA2869954C CA2869954A CA2869954A CA2869954C CA 2869954 C CA2869954 C CA 2869954C CA 2869954 A CA2869954 A CA 2869954A CA 2869954 A CA2869954 A CA 2869954A CA 2869954 C CA2869954 C CA 2869954C
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- Prior art keywords
- dihydro
- pyrrolo
- benzoxazepin
- hydroxymethyl
- crarb
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- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title abstract description 9
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Classifications
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Landscapes
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- Chemical & Material Sciences (AREA)
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Hematology (AREA)
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- Cardiology (AREA)
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- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1573/CHE/2012 | 2012-04-20 | ||
| IN1573CH2012 IN2012CH01573A (Direct) | 2012-04-20 | 2013-04-18 | |
| PCT/IN2013/000259 WO2013157022A1 (en) | 2012-04-20 | 2013-04-18 | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2869954A1 CA2869954A1 (en) | 2013-10-24 |
| CA2869954C true CA2869954C (en) | 2023-01-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2869954A Active CA2869954C (en) | 2012-04-20 | 2013-04-18 | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof in medical conditions related to modulation of bruton's tyrosine kinase activity |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US9233983B2 (Direct) |
| EP (1) | EP2838898B1 (Direct) |
| JP (1) | JP6182593B2 (Direct) |
| CN (1) | CN104662018B (Direct) |
| AU (1) | AU2013250726B2 (Direct) |
| CA (1) | CA2869954C (Direct) |
| IL (1) | IL235146A (Direct) |
| IN (1) | IN2012CH01573A (Direct) |
| WO (1) | WO2013157022A1 (Direct) |
| ZA (1) | ZA201407341B (Direct) |
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| EP2571361A4 (en) | 2010-05-19 | 2013-11-13 | Univ North Carolina | PYRAZOLOPYRIMIDINE COMPOUNDS FOR CANCER TREATMENT |
| ES2650630T3 (es) | 2011-10-03 | 2018-01-19 | The University Of North Carolina At Chapel Hill | Compuestos de pirrolopirimidina para el tratamiento del cáncer |
| RU2014145121A (ru) | 2012-05-22 | 2016-07-10 | Зэ Юниверсити Оф Норд Каролина Эт Чапел Хилл | Пиримидиновые соединения для лечения злокачественной опухоли |
| AP2015008203A0 (en) | 2012-08-10 | 2015-01-31 | Boehringer Ingelheim Int | Heteroaromatic compounds as bruton's tyrosine kinase (BTK) inhibitors |
| EP2909211A4 (en) | 2012-10-17 | 2016-06-22 | Univ North Carolina | PYRAZOLOPYRIMIDINE COMPOUNDS FOR CANCER TREATMENT |
| WO2014085225A1 (en) | 2012-11-27 | 2014-06-05 | The University Of North Carolina At Chapel Hill | Pyrimidine compounds for the treatment of cancer |
| AU2014231567A1 (en) * | 2013-03-14 | 2015-10-01 | Abbvie Inc. | Pyrrolo[2,3-b]pyridine CDK9 kinase inhibitors |
| CN104211703B (zh) * | 2013-05-30 | 2018-04-03 | 南京勇山生物科技有限公司 | 一类作为布鲁顿激酶抑制剂的稠杂环化合物 |
| US9512084B2 (en) | 2013-11-29 | 2016-12-06 | Novartis Ag | Amino pyrimidine derivatives |
| AU2015244179A1 (en) | 2014-04-11 | 2016-11-03 | The University Of North Carolina At Chapel Hill | Mertk-specific pyrrolopyrimidine compounds |
| CN105294571B (zh) | 2014-07-03 | 2019-04-23 | 浙江九洲药业股份有限公司 | 一种依鲁替尼中间体及其制备方法和用途 |
| EP3177611B1 (en) | 2014-08-04 | 2021-10-06 | Nuevolution A/S | Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases |
| WO2016057500A1 (en) | 2014-10-06 | 2016-04-14 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
| WO2016061190A1 (en) | 2014-10-14 | 2016-04-21 | The Board Of Trustees Of The Leland Stanford Junior University | Method for treating neurodegenerative diseases |
| RS60629B1 (sr) * | 2014-10-24 | 2020-09-30 | Bristol Myers Squibb Co | Jedinjenja indol karboksamida korisna kao inhibitori kinaze |
| EP3042903B1 (en) * | 2015-01-06 | 2019-08-14 | Impetis Biosciences Ltd. | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| EA201890086A1 (ru) | 2015-06-18 | 2018-06-29 | Сефалон, Инк. | 1,4-замещенные производные пиперидина |
| EP3310773B1 (en) | 2015-06-18 | 2020-12-02 | 89Bio Ltd. | Substituted 4-benzyl and 4-benzoyl piperidine derivatives |
| GB201517217D0 (en) * | 2015-09-29 | 2015-11-11 | Astex Therapeutics Ltd And Cancer Res Technology Ltd | Pharmaceutical compounds |
| GB201517216D0 (en) * | 2015-09-29 | 2015-11-11 | Cancer Res Technology Ltd And Astex Therapeutics Ltd | Pharmaceutical compounds |
| US10653669B2 (en) | 2015-12-15 | 2020-05-19 | The Board Of Trustees Of The Leland Stanford Junior University | Method for preventing and/or treating aging-associated cognitive impairment and neuroinflammation |
| US10570118B2 (en) | 2016-01-13 | 2020-02-25 | Boehringer Ingelheim International Gmbh | Isoquinolones as BTK inhibitors |
| US10709708B2 (en) | 2016-03-17 | 2020-07-14 | The University Of North Carolina At Chapel Hill | Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor |
| PT3442977T (pt) | 2016-04-15 | 2023-10-04 | Blueprint Medicines Corp | Inibidores do recetor de activina de tipo quinase |
| CA2969295A1 (en) | 2016-06-06 | 2017-12-06 | Pfizer Inc. | Substituted carbonucleoside derivatives, and use thereof as a prmt5 inhibitor |
| US10266528B2 (en) * | 2016-08-16 | 2019-04-23 | Merck Patent Gmbh | 2-oxo-imidazopyridines as reversible BTK inhibitors and uses thereof |
| WO2018097234A1 (ja) | 2016-11-25 | 2018-05-31 | カルナバイオサイエンス株式会社 | 新規オキソイソキノリン誘導体 |
| CN106883235B (zh) * | 2016-12-29 | 2019-04-30 | 天津国际生物医药联合研究院 | 恶二唑类化合物的制备和应用 |
| JP7164203B2 (ja) * | 2017-02-08 | 2022-11-01 | 中国医▲薬▼研究▲開▼▲発▼中心有限公司 | ピロロ芳香族複素環化合物及びその製造方法並びに医薬用途 |
| CN108794480A (zh) * | 2017-04-28 | 2018-11-13 | 天津药物研究院有限公司 | 吡咯并嘧啶类化合物、其制备方法和用途 |
| JP7278273B2 (ja) | 2017-10-18 | 2023-05-19 | ブループリント メディシンズ コーポレイション | アクチビン受容体様キナーゼの阻害剤としての置換ピロロピリジン |
| CN111712498B (zh) * | 2017-12-13 | 2023-09-29 | 鲁平有限公司 | 作为prmt5抑制剂的取代的二环杂环化合物 |
| CN109293638B (zh) * | 2018-03-27 | 2020-08-14 | 大连理工大学 | 一种增强型的靶向识别受体酪氨酸激酶的荧光传感器及细胞膜荧光成像的应用 |
| CN108707154A (zh) * | 2018-07-10 | 2018-10-26 | 刘凤娟 | 一种治疗癌症的药物溶剂合物及其制备方法 |
| WO2020033359A1 (en) | 2018-08-06 | 2020-02-13 | The Board Of Trustees Of The Leland Stanford Junior University | 2-arylbenzimidazoles as ppargc1a activators for treating neurodegenerative diseases |
| CN112654618A (zh) * | 2018-09-06 | 2021-04-13 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的新型环脒化合物 |
| CN109369619A (zh) * | 2018-10-04 | 2019-02-22 | 南京先进生物材料与过程装备研究院有限公司 | 酞嗪酮类化合物晶型b及其制备方法 |
| CN109180642A (zh) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | 酞嗪酮类btk抑制剂及其应用 |
| CN109336863A (zh) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | 一种新型酞嗪酮类btk抑制剂、制备及其应用 |
| CN109485636A (zh) * | 2018-10-04 | 2019-03-19 | 南京先进生物材料与过程装备研究院有限公司 | 一种新型btk激酶抑制剂的盐酸盐及其制备方法与用途 |
| CN109293635A (zh) * | 2018-10-04 | 2019-02-01 | 南京先进生物材料与过程装备研究院有限公司 | 一种新型btk激酶抑制剂的p晶型及其制备方法 |
| CN109336864A (zh) * | 2018-10-04 | 2019-02-15 | 南京先进生物材料与过程装备研究院有限公司 | 酞嗪酮类化合物晶型n及其制备方法 |
| CN109180643A (zh) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | 酞嗪酮类化合物晶型a及其制备方法 |
| CN109180644A (zh) * | 2018-10-04 | 2019-01-11 | 南京先进生物材料与过程装备研究院有限公司 | 一种新型btk激酶抑制剂的甲磺酸盐及其制备方法与用途 |
| SI3980417T1 (sl) * | 2019-06-10 | 2024-02-29 | Lupin Limited | Prmt5 inhibitorji |
| CN110305140B (zh) * | 2019-07-30 | 2020-08-04 | 上海勋和医药科技有限公司 | 二氢吡咯并嘧啶类选择性jak2抑制剂 |
| WO2021120890A1 (en) * | 2019-12-20 | 2021-06-24 | Novartis Ag | Pyrazolyl derivatives useful as anti-cancer agents |
| CA3160522A1 (en) | 2019-12-20 | 2021-06-24 | Sanne Schroder Glad | Compounds active towards nuclear receptors |
| CN114728170B (zh) | 2019-12-20 | 2024-03-01 | 纽韦卢森公司 | 对核受体具有活性的化合物 |
| CA3174252A1 (en) | 2020-03-31 | 2021-10-07 | Nuevolution A/S | Compounds active towards nuclear receptors |
| EP4126875A1 (en) | 2020-03-31 | 2023-02-08 | Nuevolution A/S | Compounds active towards nuclear receptors |
| WO2022140246A1 (en) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Methods and compounds for targeted autophagy |
| JP2023140319A (ja) * | 2022-03-22 | 2023-10-04 | アッヴィ・インコーポレイテッド | ブルトン型チロシンキナーゼを分解するためのピリミジン |
| CN116854709A (zh) * | 2022-03-28 | 2023-10-10 | 药雅科技(上海)有限公司 | Bruton′s酪氨酸激酶可逆抑制剂及其应用 |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
| GB0115393D0 (en) | 2001-06-23 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
| CN1523991A (zh) * | 2001-08-10 | 2004-08-25 | ��˹��ŵ�� | 单独的c-Src抑制剂或其与STI571的组合用于治疗白血病的用途 |
| WO2003041649A2 (en) | 2001-11-13 | 2003-05-22 | Merck Frosst Canada & Co. | Cyanoalkylamino derivatives as protease inhibitors |
| US20060183746A1 (en) * | 2003-06-04 | 2006-08-17 | Currie Kevin S | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
| CN101124227A (zh) * | 2004-11-10 | 2008-02-13 | Cgi制药有限公司 | 可用作激酶活性调节剂的咪唑并[1,2-a]吡嗪-8-基胺 |
| ES2337831T3 (es) | 2005-06-24 | 2010-04-29 | Bristol-Myers Squibb Company | Derivados de fenilglicinamida y piridilclicinamida utiles como agentes anticoagulantes. |
| US8071609B2 (en) * | 2005-08-11 | 2011-12-06 | Ariad Pharmaceuticals, Inc. | Unsaturated heterocyclic derivatives |
| JP2009506123A (ja) | 2005-08-29 | 2009-02-12 | バーテックス ファーマシューティカルズ インコーポレイテッド | 非受容体型チロシンキナーゼのｔｅｃファミリーの阻害剤として有用な３，５−二置換ピリド−２−オン |
| US20070129364A1 (en) | 2005-12-07 | 2007-06-07 | Han-Qing Dong | Pyrrolopyridine kinase inhibiting compounds |
| HRP20150642T1 (hr) | 2006-12-22 | 2015-08-14 | Astex Therapeutics Limited | BICIKLIÄŚKE HETEROCIKLIÄŚKE TVARI KAO INHIBITORI FGFR-a |
| US7989465B2 (en) | 2007-10-19 | 2011-08-02 | Avila Therapeutics, Inc. | 4,6-disubstituted pyrimidines useful as kinase inhibitors |
| MX2010008197A (es) | 2008-02-05 | 2010-08-23 | Hoffmann La Roche | Nuevas piridinonas y piridazinonas. |
| EP2265603B1 (en) | 2008-03-13 | 2014-05-07 | The General Hospital Corporation | Inhibitors of the bmp signaling pathway |
| MX2010013627A (es) | 2008-06-11 | 2010-12-21 | Genentech Inc | Diazacarbazoles y metodos de uso. |
| KR101523451B1 (ko) | 2008-07-02 | 2015-05-27 | 에프. 호프만-라 로슈 아게 | 키나아제 억제제로서의 신규 페닐피라지논 |
| JP2011526931A (ja) | 2008-07-03 | 2011-10-20 | エグゼリクシス， インコーポレイテッド | Ｃｄｋモジュレーター |
| CA2730116A1 (en) | 2008-07-08 | 2010-01-14 | Boehringer Ingelheim International Gmbh | Pyrrolidinyl and piperidinyl compounds useful as nhe-1 inhibitors |
| UY31984A (es) | 2008-07-16 | 2010-02-26 | Boehringer Ingelheim Int | DERIVADOS DE 1-(3,4-difluorobencil)-6-oxo-1,6-dihidropirimidin-5-carboxamidas N-sustituidas y de 2-(3,4-difluorobencil)-3-oxo-2,3-dihidro-1H-pirazol-4-carboxamidas N-sustituidas. |
| ES2461494T3 (es) | 2008-07-18 | 2014-05-20 | F. Hoffmann-La Roche Ag | Nuevas fenilimidazopirazinas |
| WO2010048149A2 (en) | 2008-10-20 | 2010-04-29 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
| WO2010068806A1 (en) * | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Amide derivatives as btk inhibitors in the treatment of allergic, autoimmune and inflammatory disorders as well as cancer |
| WO2010068810A2 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
| WO2010068788A1 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Heterocyclic amides as btk inhibitors |
| EA019041B1 (ru) | 2008-12-19 | 2013-12-30 | Бристол-Маерс Сквибб Компани | Карбазолкарбоксамидные соединения, применимые в качестве ингибиторов киназы |
| US8299077B2 (en) | 2009-03-02 | 2012-10-30 | Roche Palo Alto Llc | Inhibitors of Bruton's tyrosine kinase |
| EP2421854B1 (en) | 2009-04-24 | 2014-07-23 | F.Hoffmann-La Roche Ag | Inhibitors of bruton's tyrosine kinase |
| JP2012529535A (ja) | 2009-06-12 | 2012-11-22 | ブリストル−マイヤーズ スクイブ カンパニー | キナーゼモジュレーターとして有用なニコチンアミド化合物 |
| WO2011019780A1 (en) | 2009-08-11 | 2011-02-17 | Bristol-Myers Squibb Company | Azaindazoles as btk kinase modulators and use thereof |
| ES2891543T3 (es) * | 2009-09-04 | 2022-01-28 | Biogen Ma Inc | Inhibidores de la tirosina quinasa de Bruton |
| US7741330B1 (en) | 2009-10-12 | 2010-06-22 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase |
| KR101906791B1 (ko) | 2010-01-27 | 2018-10-11 | 베링거 인겔하임 인터내셔날 게엠베하 | Ｃｒｔｈ２ 길항제로서의 피라졸 화합물 |
| WO2012136343A1 (en) * | 2011-04-05 | 2012-10-11 | Eth Zurich | Droplet dispensing device and light source comprising such a droplet dispensing device |
| CN103732596B (zh) | 2011-07-08 | 2016-06-01 | 诺华股份有限公司 | 吡咯并嘧啶衍生物 |
| KR20140052032A (ko) | 2011-08-17 | 2014-05-02 | 에프. 호프만-라 로슈 아게 | 브루톤 티로신 키나아제의 억제제 |
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