TW202302594A - 心臟肌節抑制劑 - Google Patents
心臟肌節抑制劑 Download PDFInfo
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- TW202302594A TW202302594A TW111107659A TW111107659A TW202302594A TW 202302594 A TW202302594 A TW 202302594A TW 111107659 A TW111107659 A TW 111107659A TW 111107659 A TW111107659 A TW 111107659A TW 202302594 A TW202302594 A TW 202302594A
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| RU2318818C1 (ru) | 2006-04-12 | 2008-03-10 | Общество С Ограниченной Ответственностью "Исследовательский Институт Химического Разнообразия" | Азагетероциклы, комбинаторная библиотека, фокусированная библиотека, фармацевтическая композиция и способ получения (варианты) |
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| US8592426B2 (en) | 2011-01-24 | 2013-11-26 | Hoffmann—La Roche Inc. | Aryl-benzocycloalkyl amide derivatives |
| US8759380B2 (en) | 2011-04-22 | 2014-06-24 | Cytokinetics, Inc. | Certain heterocycles, compositions thereof, and methods for their use |
| EA024204B1 (ru) | 2012-01-20 | 2016-08-31 | Актелион Фармасьютиклз Лтд. | Производные гетероциклических амидов в качестве антагонистов p2xрецептора |
| SMT202000071T1 (it) | 2013-06-21 | 2020-03-13 | Myokardia Inc | Composti di pirimidinadione contro le condizioni cardiache |
| US9199945B2 (en) | 2013-06-21 | 2015-12-01 | MyoKardia, Inc. | Cycloalkyl-substituted pyrimidinedione compounds |
| US9663516B2 (en) | 2014-12-18 | 2017-05-30 | MyoKardia, Inc. | Bicyclic-pyrimidinedione compounds |
| CN104539229A (zh) | 2014-12-26 | 2015-04-22 | 金海新源电气江苏有限公司 | 一种太阳能光伏支架 |
| IL295547A (en) | 2015-01-22 | 2022-10-01 | Myokardia Inc | Piperidine-4-methylsulfonyl-modified urea compounds for the treatment of dilated cardiomyopathy (dcm) |
| BR112018012390B1 (pt) | 2015-12-17 | 2023-03-14 | Syngenta Participations Ag | Derivados de oxadiazol microbiocidas |
| EP3390398A1 (en) | 2015-12-18 | 2018-10-24 | Syngenta Participations AG | Microbiocidal oxadiazole derivatives |
| EP3448519A4 (en) | 2016-04-29 | 2020-01-22 | Board Of Regents, The University Of Texas System | SIGMA RECEPTOR BINDING |
| US11066396B2 (en) | 2016-06-23 | 2021-07-20 | Merck Sharp & Dohme Corp. | 3-aryl- heteroaryl substituted 5-trifluoromethyl oxadiazoles as histonedeacetylase 6 (HDAC6) inhibitors |
| EP3519416B1 (en) | 2016-09-27 | 2021-03-31 | Merck Sharp & Dohme Corp. | Chromane, isochromane and dihydroisobenzofuran derivatives as mglur2-negative allosteric modulators, compositions, and their use |
| WO2018089433A1 (en) | 2016-11-08 | 2018-05-17 | Navitor Pharmaceuticals, Inc. | PHENYL mTORC INHIBITORS AND USES THEREOF |
| WO2018156883A1 (en) | 2017-02-23 | 2018-08-30 | Board Of Regents, The University Of Texas System | Methods of treatment for cancer, sterol homeostasis, and neurological diseases |
| FI3661514T3 (fi) | 2017-08-04 | 2025-12-12 | Myokardia Inc | Mavakamteeni käytettäväksi hypertrofisen kardiomyopatian hoidossa |
| BR112020014428A2 (pt) | 2018-01-19 | 2020-12-01 | Cytokinetics, Inc. | composto, composição farmacêutica, e, métodos para o tratamento de uma doença cardíaca em um indivíduo, para o tratamento de uma doença ou condição que está associada com cavidade ventricular esquerda pequena e obliteração da cavidade, contração hiperdinâmica do ventrículo esquerdo, isquemia do miocárdio ou fibrose cardíaca, para o tratamento de uma doença ou condição selecionada dentre distrofias musculares e doenças de armazenamento do glicogênio e para inibição do sarcômero cardíaco |
| BR112020018094A2 (pt) | 2018-03-08 | 2020-12-22 | Incyte Corporation | Compostos de aminopirazina diol como inibidores de pi3k-¿ |
| US10710994B2 (en) | 2018-03-19 | 2020-07-14 | Genentech, Inc. | Oxadiazole transient receptor potential channel inhibitors |
| EP3814342B1 (en) | 2018-06-26 | 2022-07-27 | Cytokinetics, Inc. | Cardiac sarcomere inhibitors |
| JP7610985B2 (ja) | 2018-06-26 | 2025-01-09 | サイトキネティックス， インコーポレイテッド | 心臓サルコメア阻害剤 |
| KR20210054510A (ko) | 2018-08-31 | 2021-05-13 | 제논 파마슈티칼스 인크. | 헤테로아릴-치환된 술폰아미드 화합물 및 치료제로서의 그의 용도 |
| JP7447089B2 (ja) | 2018-08-31 | 2024-03-11 | サイトキネティックス， インコーポレイテッド | 心筋サルコメア阻害剤 |
| SG11202104218SA (en) | 2018-10-29 | 2021-05-28 | Myokardia Inc | Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compounds |
| HRP20240200T1 (hr) | 2019-07-17 | 2024-04-26 | Cytokinetics, Inc. | Oralne formulacije inhibitora kardijskih sarkomera |
| EP3999180B1 (en) | 2019-07-17 | 2024-05-08 | Cytokinetics, Inc. | Polymorphs of (r)-n-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1h-inden-1-yl)-1-methyl-1h-pyrazole-4-carboxamide |
| CN114945372A (zh) | 2019-11-10 | 2022-08-26 | 迈奥卡迪亚公司 | 用肌球蛋白调节剂的治疗方法 |
| CA3190060A1 (en) | 2020-08-28 | 2022-03-03 | MyoKardia, Inc. | Methods of treatment with myosin modulator |
| CN114456163B (zh) | 2020-11-09 | 2023-08-11 | 江苏恒瑞医药股份有限公司 | 四氢吡啶并嘧啶二酮类衍生物、其制备方法及其在医药上的应用 |
| CN114516843B (zh) | 2020-11-19 | 2024-10-22 | 江苏恒瑞医药股份有限公司 | 嘧啶二酮类衍生物、其制备方法及其在医药上的应用 |
| US20240010639A1 (en) | 2020-11-20 | 2024-01-11 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | Triazine dione derivative, preparation method therefor and application thereof in medicine |
| CN114539257B (zh) | 2020-11-24 | 2023-08-11 | 江苏恒瑞医药股份有限公司 | 嘧啶二酮类螺环衍生物、其制备方法及其在医药上的应用 |
| TW202227402A (zh) | 2020-11-24 | 2022-07-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | 嘧啶二酮類衍生物、其製備方法及其在醫藥上的應用 |
| CN114539229B (zh) | 2020-11-24 | 2024-10-22 | 江苏恒瑞医药股份有限公司 | 嘧啶二酮类衍生物、其制备方法及其在医药上的应用 |
| AR125588A1 (es) | 2021-03-04 | 2023-08-02 | Lilly Co Eli | Compuestos inhibidores de fgfr3 |
| MX2023010125A (es) | 2021-03-04 | 2023-09-11 | Cytokinetics Inc | Inhibidores del sarcomero cardiaco. |
| KR20250119513A (ko) | 2022-09-02 | 2025-08-07 | 싸이토키네틱스, 인코포레이티드 | 5-(3,4-디플루오로벤질)-8-((1r,4r)-4-메틸시클로헥실)-6,9-디옥소-2,5,8-트리아자스피로[3.5]노난-2-카르브알데히드의결정질 형태 |
-
2022
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| US11919909B2 (en) | 2024-03-05 |
| CN117083275A (zh) | 2023-11-17 |
| CL2024001620A1 (es) | 2024-11-04 |
| US20220306642A1 (en) | 2022-09-29 |
| AR125026A1 (es) | 2023-05-31 |
| IL305628A (en) | 2023-11-01 |
| US20240309011A1 (en) | 2024-09-19 |
| MX2023010125A (es) | 2023-09-11 |
| JP7850737B2 (ja) | 2026-04-23 |
| CL2023002616A1 (es) | 2024-02-02 |
| KR20240015622A (ko) | 2024-02-05 |
| CA3209557A1 (en) | 2022-09-09 |
| AU2022229390A1 (en) | 2023-09-21 |
| JP2024508526A (ja) | 2024-02-27 |
| WO2022187501A1 (en) | 2022-09-09 |
| US12286437B2 (en) | 2025-04-29 |
| BR112023017461A2 (pt) | 2023-09-26 |
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