JP2013531055A - プロテインキナーゼＩＫＫε及び／又はＴＢＫ−１の阻害剤としてのピリミジン化合物、それらの製造方法及びそれらを含む医薬組成物 - Google Patents
プロテインキナーゼＩＫＫε及び／又はＴＢＫ−１の阻害剤としてのピリミジン化合物、それらの製造方法及びそれらを含む医薬組成物 Download PDFInfo
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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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
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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
- C07D403/14—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
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Landscapes
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| GBGB1012105.1A GB201012105D0 (en) | 2010-07-19 | 2010-07-19 | Novel pyrimidine compounds |
| GB1012105.1 | 2010-07-19 | ||
| PCT/GB2011/001075 WO2012010826A1 (en) | 2010-07-19 | 2011-07-18 | Pyrimidine compounds as inhibitors of protein kinases ikk epsilon and/or tbk-1, processes for their preparation, and pharmaceutical compositions containing them |
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| JP2013531055A true JP2013531055A (ja) | 2013-08-01 |
| JP2013531055A5 JP2013531055A5 (enExample) | 2014-09-04 |
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| US (1) | US8962609B2 (enExample) |
| EP (1) | EP2595964B1 (enExample) |
| JP (1) | JP2013531055A (enExample) |
| CN (1) | CN103119025B (enExample) |
| BR (1) | BR112013001341A2 (enExample) |
| CA (1) | CA2805567A1 (enExample) |
| GB (1) | GB201012105D0 (enExample) |
| WO (1) | WO2012010826A1 (enExample) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018504415A (ja) * | 2015-02-05 | 2018-02-15 | エービー サイエンス | 抗腫瘍活性を有する化合物 |
| JP2020508341A (ja) * | 2017-02-23 | 2020-03-19 | ドメイネクス リミテッド | Ｉｋｋｅ、ｔｂｋ１及び／又はｓｉｋ２キナーゼ阻害剤としての５−（ピリミジン−４−イル）−２−（ピロリジン−１−イル）ニコチノニトリル化合物 |
| JP2020537671A (ja) * | 2017-10-17 | 2020-12-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用 |
| JP2022529309A (ja) * | 2019-04-08 | 2022-06-21 | リンク ファーマシューティカルズ シーオー．エルティーディー． | ピラゾリル－アミノ－ピリミジニル誘導体のベンズエーテルとアニリン、およびその組成物と方法 |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2696683A4 (en) * | 2011-04-12 | 2014-08-13 | Alzheimer S Inst Of America Inc | COMPOSITIONS AND THERAPEUTIC APPLICATIONS OF IKK-MEDIATED KINASE EPSILON AND TANK BINDING KINASE-1 HEMMER |
| GB201114051D0 (en) | 2011-08-15 | 2011-09-28 | Domainex Ltd | Compounds and their uses |
| DE102011112978A1 (de) * | 2011-09-09 | 2013-03-14 | Merck Patent Gmbh | Benzonitrilderivate |
| RU2622034C2 (ru) * | 2012-02-09 | 2017-06-09 | Мерк Патент Гмбх | ПРОИЗВОДНЫЕ ФУРО[3,2-В]- И ТИЕНО[3,2-В]ПИРИДИНА В КАЧЕСТВЕ ИНГИБИТОРОВ TBK1 И IKKε |
| GB201303109D0 (en) * | 2013-02-21 | 2013-04-10 | Domainex Ltd | Novel pyrimidine compounds |
| CA2946538A1 (en) | 2014-04-04 | 2015-10-08 | Del Mar Pharmaceuticals | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer |
| TW201613916A (en) | 2014-06-03 | 2016-04-16 | Gilead Sciences Inc | TANK-binding kinase inhibitor compounds |
| JP6499282B2 (ja) | 2014-09-26 | 2019-04-10 | ギリアード サイエンシーズ， インコーポレイテッド | Ｔａｎｋ結合キナーゼ阻害剤化合物として有用なアミノトリアジン誘導体 |
| US9938257B2 (en) | 2015-09-11 | 2018-04-10 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| CU20180059A7 (es) | 2015-12-17 | 2018-10-04 | Gilead Sciences Inc | Compuestos inhibidores de la quinasa de unión a tank |
| EP3390387B1 (en) | 2015-12-18 | 2021-11-17 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| WO2017207534A1 (en) | 2016-06-03 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituted heteroarylbenzimidazole compounds |
| KR20200071756A (ko) | 2017-10-17 | 2020-06-19 | 메르크 파텐트 게엠베하 | 피리미딘 TBK/IKKε 억제제 화합물 및 이의 용도 |
| CN110862380A (zh) | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009032861A1 (en) * | 2007-09-04 | 2009-03-12 | The Scripps Research Institute | Substituted pyrimidinyl-amines as protein kinase inhibitors |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7429599B2 (en) | 2000-12-06 | 2008-09-30 | Signal Pharmaceuticals, Llc | Methods for treating or preventing an inflammatory or metabolic condition or inhibiting JNK |
| US7129242B2 (en) | 2000-12-06 | 2006-10-31 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto |
| US7122544B2 (en) | 2000-12-06 | 2006-10-17 | Signal Pharmaceuticals, Llc | Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto |
| HUP0402352A2 (hu) | 2001-06-19 | 2005-02-28 | Bristol-Myers Squibb Co. | Foszfodiészteráz (PDE) 7 inhibitorként alkalmazható pirimidinszármazékok és ezeket tartalmazó gyógyszerkészítmények |
| EP1648875A1 (en) | 2003-07-30 | 2006-04-26 | Cyclacel Limited | 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors |
| GB0317841D0 (en) * | 2003-07-30 | 2003-09-03 | Cyclacel Ltd | Compound |
| KR20070084067A (ko) | 2004-10-13 | 2007-08-24 | 와이어쓰 | Ｎ-벤젠설포닐 치환 아닐리노-피리미딘 동족체 |
| EA200870217A1 (ru) | 2006-01-30 | 2009-02-27 | Экселиксис, Инк. | 4-арил-2-аминопиримидины или 4-арил-2-аминоалкилпиримидины в качестве модуляторов jak-2 и содержащие их фармацевтические композиции |
| WO2007120593A1 (en) | 2006-04-12 | 2007-10-25 | Wyeth | Anilino-pyrimidine phenyl and benzothiophene analogs |
| MX2009005182A (es) | 2006-11-23 | 2009-05-25 | Novartis Ag | Derivados de 2-hidroxi-1,3-diamino-propano. |
| FR2911139A1 (fr) | 2007-01-05 | 2008-07-11 | Sanofi Aventis Sa | Nouveaux derives de phenyl-(4-phenyl-pyrimidin-2-yl)amines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk |
| KR101737753B1 (ko) | 2007-03-12 | 2017-05-18 | 와이엠 바이오사이언시즈 오스트레일리아 피티와이 엘티디 | 페닐 아미노 피리미딘 화합물 및 이의 용도 |
| WO2008124085A2 (en) | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
| US20090048282A1 (en) | 2007-08-14 | 2009-02-19 | Wyeth | Pyrimidine sulfonamide analogs and their use as agonists of the wnt-beta-catenin cellular messaging system |
| BR112012008677A2 (pt) * | 2009-10-12 | 2018-03-20 | Myrexis Inc | compostos amino-pirimidina como inibidores de tbkl e/ou ikk epsilon |
| EP2696683A4 (en) | 2011-04-12 | 2014-08-13 | Alzheimer S Inst Of America Inc | COMPOSITIONS AND THERAPEUTIC APPLICATIONS OF IKK-MEDIATED KINASE EPSILON AND TANK BINDING KINASE-1 HEMMER |
-
2010
- 2010-07-19 GB GBGB1012105.1A patent/GB201012105D0/en not_active Ceased
-
2011
- 2011-07-18 CA CA2805567A patent/CA2805567A1/en not_active Abandoned
- 2011-07-18 US US13/811,164 patent/US8962609B2/en not_active Expired - Fee Related
- 2011-07-18 JP JP2013520197A patent/JP2013531055A/ja active Pending
- 2011-07-18 EP EP20110738026 patent/EP2595964B1/en not_active Not-in-force
- 2011-07-18 BR BR112013001341A patent/BR112013001341A2/pt not_active IP Right Cessation
- 2011-07-18 CN CN201180045048.9A patent/CN103119025B/zh not_active Expired - Fee Related
- 2011-07-18 WO PCT/GB2011/001075 patent/WO2012010826A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009032861A1 (en) * | 2007-09-04 | 2009-03-12 | The Scripps Research Institute | Substituted pyrimidinyl-amines as protein kinase inhibitors |
| JP2010538076A (ja) * | 2007-09-04 | 2010-12-09 | ザ スクリプス リサーチ インスティチュート | タンパク質キナーゼ阻害剤としての置換されたピリミジニル−アミン |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018504415A (ja) * | 2015-02-05 | 2018-02-15 | エービー サイエンス | 抗腫瘍活性を有する化合物 |
| US10570122B2 (en) | 2015-02-05 | 2020-02-25 | Ab Science | Compounds with anti-tumoral activity |
| JP2020508341A (ja) * | 2017-02-23 | 2020-03-19 | ドメイネクス リミテッド | Ｉｋｋｅ、ｔｂｋ１及び／又はｓｉｋ２キナーゼ阻害剤としての５−（ピリミジン−４−イル）−２−（ピロリジン−１−イル）ニコチノニトリル化合物 |
| JP7136793B2 (ja) | 2017-02-23 | 2022-09-13 | ドメイネクス リミテッド | Ｉｋｋｅ、ｔｂｋ１及び／又はｓｉｋ２キナーゼ阻害剤としての５－（ピリミジン－４－イル）－２－（ピロリジン－１－イル）ニコチノニトリル化合物 |
| JP2020537671A (ja) * | 2017-10-17 | 2020-12-24 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用 |
| JP7266592B2 (ja) | 2017-10-17 | 2023-04-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用 |
| JP2022529309A (ja) * | 2019-04-08 | 2022-06-21 | リンク ファーマシューティカルズ シーオー．エルティーディー． | ピラゾリル－アミノ－ピリミジニル誘導体のベンズエーテルとアニリン、およびその組成物と方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103119025B (zh) | 2015-09-09 |
| EP2595964A1 (en) | 2013-05-29 |
| BR112013001341A2 (pt) | 2016-05-17 |
| CN103119025A (zh) | 2013-05-22 |
| CA2805567A1 (en) | 2012-01-26 |
| GB201012105D0 (en) | 2010-09-01 |
| US20130267491A1 (en) | 2013-10-10 |
| HK1181753A1 (en) | 2013-11-15 |
| WO2012010826A1 (en) | 2012-01-26 |
| US8962609B2 (en) | 2015-02-24 |
| EP2595964B1 (en) | 2015-04-29 |
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