TWI501956B - 用於抑制ｃｈｋ１之化合物 - Google Patents
用於抑制ｃｈｋ１之化合物 Download PDFInfo
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- TWI501956B TWI501956B TW100139492A TW100139492A TWI501956B TW I501956 B TWI501956 B TW I501956B TW 100139492 A TW100139492 A TW 100139492A TW 100139492 A TW100139492 A TW 100139492A TW I501956 B TWI501956 B TW I501956B
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- Prior art keywords
- cancer
- pharmaceutically acceptable
- compound
- acceptable salt
- methyl
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| HRP20220351T1 (hr) | 2016-02-04 | 2022-05-13 | Pharmaengine, Inc. | 3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene |
| EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
| CN112457306A (zh) | 2019-09-06 | 2021-03-09 | 上海瑛派药业有限公司 | 3,5-二取代吡唑化合物作为激酶抑制剂及其应用 |
| AU2021389190A1 (en) | 2020-11-30 | 2023-06-29 | Sumitomo Pharma Co., Ltd. | 5-heteroaryl-1h-pyrazol-3-amine derivative |
| US11564920B2 (en) | 2020-11-30 | 2023-01-31 | Sumitomo Pharma Co., Ltd. | 5-heteroaryl-1H-pyrazol-3-amine derivative |
| US11932648B2 (en) | 2021-06-28 | 2024-03-19 | Blueprint Medicines Corporation | CDK2 inhibitors |
| US20250129049A1 (en) * | 2021-12-24 | 2025-04-24 | Sumitomo Pharma Co., Ltd. | 1h-pyrazole-3-amine derivative having bicyclic backbone |
| US20250352541A1 (en) * | 2022-05-27 | 2025-11-20 | Sumitomo Pharma Co., Ltd. | Therapeutic for cancer refractory to immune checkpoint inhibitor |
| TW202442234A (zh) * | 2023-04-14 | 2024-11-01 | 美商纜圖藥品公司 | Ｃｄｋ２抑制劑 |
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| MXPA06000933A (es) * | 2003-07-25 | 2006-03-30 | Pfizer | Compuestos de aminopirazol y uso como inhibidores de chk1. |
| BRPI0418351A (pt) * | 2004-01-05 | 2007-05-08 | Astrazeneca Ab | composto ou um sal farmaceuticamente aceitável do mesmo, métodos de limitar a proliferação celular em um humano ou animal, de tratamento de um humano ou animal sofrendo de cáncer, de tratamento de profilaxia de cáncer, de tratamento de um humano ou animal sofrendo de uma doença neoplásica, de tratamento de um humano ou animal sofrendo de uma doença prolifetativa de tratamento de cáncer, para o tratamento de infecções associadas com cáncer, para o tratamento profilático de infecções associadas com cáncer, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, método de inibir a chk1 quinase, e, processo para a preparação de um composto ou um sal farmaceuticamente aceitável do mesmo |
| EA011671B1 (ru) | 2004-06-04 | 2009-04-28 | Арена Фармасьютикалз, Инк. | Замещенные производные арила и гетероарила в качестве модуляторов метаболизма и для профилактики и лечения связанных с ним расстройств |
| CN101218229A (zh) * | 2005-05-05 | 2008-07-09 | 阿斯利康(瑞典)有限公司 | 吡唑基-氨基取代的嘧啶及其在癌症治疗中的应用 |
| AU2006258101A1 (en) * | 2005-06-09 | 2006-12-21 | Merck Sharp & Dohme Corp. | Inhibitors of checkpoint kinases |
| PA8850801A1 (es) * | 2008-12-17 | 2010-07-27 | Lilly Co Eli | Compuestos útiles para inhibir chk1 |
-
2011
- 2011-10-27 JO JOP/2011/0323A patent/JO3145B1/ar active
- 2011-10-27 AR ARP110103973A patent/AR083575A1/es active IP Right Grant
- 2011-10-28 TW TW100139492A patent/TWI501956B/zh active
- 2011-11-01 EA EA201390499A patent/EA022096B1/ru not_active IP Right Cessation
- 2011-11-01 WO PCT/US2011/058692 patent/WO2012064548A1/en not_active Ceased
- 2011-11-01 AU AU2011326230A patent/AU2011326230B2/en active Active
- 2011-11-01 SI SI201130467T patent/SI2638033T1/sl unknown
- 2011-11-01 US US13/877,923 patent/US9067920B2/en active Active
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- 2011-11-01 ME MEP-2015-69A patent/ME02119B/me unknown
- 2011-11-01 HR HRP20150530TT patent/HRP20150530T1/hr unknown
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008117050A1 (en) * | 2007-03-27 | 2008-10-02 | Astrazeneca Ab | Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer |
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| Publication number | Publication date |
|---|---|
| AU2011326230A1 (en) | 2013-05-09 |
| EP2638033A1 (en) | 2013-09-18 |
| JP5792316B2 (ja) | 2015-10-07 |
| EA201390499A1 (ru) | 2013-08-30 |
| CA2816944C (en) | 2015-12-22 |
| KR101533166B1 (ko) | 2015-07-01 |
| BR112013010009B1 (pt) | 2021-10-19 |
| CN103180311A (zh) | 2013-06-26 |
| DK2638033T3 (en) | 2015-04-27 |
| BR112013010009A2 (pt) | 2020-09-29 |
| PT2638033E (pt) | 2015-06-01 |
| JO3145B1 (ar) | 2017-09-20 |
| EP2638033B1 (en) | 2015-04-08 |
| CA2816944A1 (en) | 2012-05-18 |
| AR083575A1 (es) | 2013-03-06 |
| CN103180311B (zh) | 2014-08-20 |
| JP2013541586A (ja) | 2013-11-14 |
| ME02119B (me) | 2015-10-20 |
| US20130190262A1 (en) | 2013-07-25 |
| HRP20150530T1 (hr) | 2015-06-19 |
| US9067920B2 (en) | 2015-06-30 |
| WO2012064548A1 (en) | 2012-05-18 |
| EA022096B1 (ru) | 2015-10-30 |
| RS54012B1 (sr) | 2015-10-30 |
| PL2638033T3 (pl) | 2015-09-30 |
| ES2541414T3 (es) | 2015-07-20 |
| KR20130099146A (ko) | 2013-09-05 |
| SI2638033T1 (sl) | 2015-05-29 |
| AU2011326230B2 (en) | 2015-02-19 |
| TW201305138A (zh) | 2013-02-01 |
| MX2013005181A (es) | 2013-10-17 |
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