JP2013533883A - ＰＩ３Ｋδ阻害剤としての含窒素複素環化合物 - Google Patents
ＰＩ３Ｋδ阻害剤としての含窒素複素環化合物 Download PDFInfo
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- JP2013533883A JP2013533883A JP2013518684A JP2013518684A JP2013533883A JP 2013533883 A JP2013533883 A JP 2013533883A JP 2013518684 A JP2013518684 A JP 2013518684A JP 2013518684 A JP2013518684 A JP 2013518684A JP 2013533883 A JP2013533883 A JP 2013533883A
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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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- C—CHEMISTRY; METALLURGY
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
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Landscapes
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- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36000110P | 2010-06-30 | 2010-06-30 | |
| US61/360,001 | 2010-06-30 | ||
| PCT/US2011/042506 WO2012003264A1 (en) | 2010-06-30 | 2011-06-30 | Nitrogen containing heterocyclic compounds as pik3 -delta inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013533883A true JP2013533883A (ja) | 2013-08-29 |
| JP2013533883A5 JP2013533883A5 (https=) | 2014-08-14 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013518684A Withdrawn JP2013533883A (ja) | 2010-06-30 | 2011-06-30 | ＰＩ３Ｋδ阻害剤としての含窒素複素環化合物 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20130079342A1 (https=) |
| EP (1) | EP2588473A1 (https=) |
| JP (1) | JP2013533883A (https=) |
| AU (1) | AU2011271462A1 (https=) |
| CA (1) | CA2803620A1 (https=) |
| MX (1) | MX2012015143A (https=) |
| WO (1) | WO2012003264A1 (https=) |
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| WO2014072937A1 (en) | 2012-11-08 | 2014-05-15 | Rhizen Pharmaceuticals Sa | Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor |
| BR112015011147A8 (pt) * | 2012-11-16 | 2019-10-01 | Merck Sharp & Dohme | composto, composição farmacêutica, e, uso do referido composto |
| BR112015011148A8 (pt) | 2012-11-16 | 2019-10-01 | Merck Sharp & Dohme | composto, composição farmacêutica, e combinação |
| HK1232227A1 (zh) | 2014-07-04 | 2018-01-05 | Lupin Limited | 作为pi3k抑制剂的喹嗪酮衍生物 |
| MA40957A (fr) * | 2014-10-09 | 2017-09-19 | Biomarin Pharm Inc | Inhibiteurs de biosynthèse d'héparane sulfate pour traiter des maladies |
| JP6740354B2 (ja) | 2015-10-05 | 2020-08-12 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | オートファジーの流れ及びホスホリパーゼｄ及びタウを含むタンパク質凝集体のクリアランスの活性化剤ならびにタンパク質症の治療方法 |
| TW201815787A (zh) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201813963A (zh) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201825465A (zh) | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| US12522583B2 (en) | 2018-11-07 | 2026-01-13 | Dana-Farber Cancer Institute, Inc. | Benzimidazole derivatives and aza-benzimidazole derivatives as Janus kinase 2 inhibitors and uses thereof |
| EP3877371A4 (en) | 2018-11-07 | 2022-07-27 | Dana-Farber Cancer Institute, Inc. | IMIDAZOPYRIDINE DERIVATIVES AND AZA-IMIDAZOPYRIDINE DERIVATIVES AS JANUS KINASE 2 INHIBITORS AND USES THEREOF |
| EP3876939A4 (en) | 2018-11-07 | 2022-08-10 | Dana-Farber Cancer Institute, Inc. | Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof |
| US12590298B2 (en) | 2019-10-18 | 2026-03-31 | The Regents Of The University Of California | Ex vivo tumor angiogenesis model |
| KR20220087497A (ko) | 2019-10-18 | 2022-06-24 | 더 리전츠 오브 더 유니버시티 오브 캘리포니아 | 병원성 혈관을 표적화하기 위한 화합물 및 방법 |
| EP4075980B1 (en) | 2019-12-18 | 2025-07-23 | Stinginn LLC | Substituted 1,2, 4-triazoles and methods of use |
| US11618751B1 (en) | 2022-03-25 | 2023-04-04 | Ventus Therapeutics U.S., Inc. | Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives |
| US11897888B1 (en) | 2020-04-30 | 2024-02-13 | Stinginn Llc | Small molecular inhibitors of sting signaling compositions and methods of use |
| US11691963B2 (en) | 2020-05-06 | 2023-07-04 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors |
| US12043632B2 (en) | 2020-12-23 | 2024-07-23 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors |
| US11319319B1 (en) | 2021-04-07 | 2022-05-03 | Ventus Therapeutics U.S., Inc. | Compounds for inhibiting NLRP3 and uses thereof |
| US12162881B2 (en) | 2021-11-09 | 2024-12-10 | Ajax Therapeutics, Inc. | Forms and compositions of inhibitors of JAK2 |
| WO2023086319A1 (en) | 2021-11-09 | 2023-05-19 | Ajax Therapeutics, Inc. | 6-he tero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| US12331048B2 (en) | 2022-10-31 | 2025-06-17 | Ventus Therapeutics U.S., Inc. | Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 inhibitors |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| DE3020458C2 (de) | 1980-05-29 | 1986-07-31 | Herzog, Thomas, Prof. Dr., 3500 Kassel | Vorgehängte Fassaden-, Bau- oder Dekorationsplatte |
| US5430153A (en) * | 1991-04-03 | 1995-07-04 | Korea Research Institute Of Chemical Technology | 2-quinolinone derivatives |
| US6043062A (en) | 1995-02-17 | 2000-03-28 | The Regents Of The University Of California | Constitutively active phosphatidylinositol 3-kinase and uses thereof |
| GB9611460D0 (en) | 1996-06-01 | 1996-08-07 | Ludwig Inst Cancer Res | Novel lipid kinase |
| US5858753A (en) | 1996-11-25 | 1999-01-12 | Icos Corporation | Lipid kinase |
| US5822910A (en) | 1997-10-02 | 1998-10-20 | Shewmake; I. W. | Fishing line tensioning device |
| WO2004108704A1 (en) * | 2003-06-05 | 2004-12-16 | Astrazeneca Ab | Pyrimidin-4-yl 3-cyanoquinoline derivatives for use in the treatment of tumours |
| WO2004108703A1 (en) * | 2003-06-05 | 2004-12-16 | Astrazeneca Ab | Pyrazinyl 3-cyanoquinoline derivatives for use in the treatment of tumours |
| TW200529846A (en) * | 2004-02-20 | 2005-09-16 | Wyeth Corp | 3-quinolinecarbonitrile protein kinase inhibitors |
| DK2137186T3 (en) * | 2007-03-23 | 2016-04-18 | Amgen Inc | Heterocyclic compounds and their uses |
| EP2139882B1 (en) * | 2007-03-23 | 2013-12-25 | Amgen Inc. | 3- substituted quinoline or quinoxaline derivatives and their use as phosphatidylinositol 3-kinase (pi3k) inhibitors |
| EP2231641B1 (en) * | 2007-12-21 | 2016-06-01 | UCB Biopharma SPRL | Quinoxaline and quinoline derivatives as kinase inhibitors |
| SG176986A1 (en) * | 2009-06-25 | 2012-02-28 | Amgen Inc | Polycyclic derivatives of pyridine and their use in the treatment of (inter alia) rheumatoid arthritis and similar diseases |
| CN102625799A (zh) * | 2009-06-25 | 2012-08-01 | 安姆根有限公司 | 杂环化合物及其用途 |
| EP2499126B1 (en) * | 2009-11-12 | 2015-01-07 | UCB Pharma, S.A. | Fused bicyclic pyridine and pyrazine derivatives as kinase inhibitors |
| EA026115B1 (ru) * | 2010-12-17 | 2017-03-31 | Ф. Хоффманн-Ля Рош Аг | Замещенные 6,6-конденсированные азотсодержащие гетероциклические соединения и их применение |
-
2011
- 2011-06-30 MX MX2012015143A patent/MX2012015143A/es unknown
- 2011-06-30 CA CA2803620A patent/CA2803620A1/en not_active Abandoned
- 2011-06-30 WO PCT/US2011/042506 patent/WO2012003264A1/en not_active Ceased
- 2011-06-30 EP EP11738520.3A patent/EP2588473A1/en not_active Withdrawn
- 2011-06-30 AU AU2011271462A patent/AU2011271462A1/en not_active Abandoned
- 2011-06-30 JP JP2013518684A patent/JP2013533883A/ja not_active Withdrawn
- 2011-06-30 US US13/701,912 patent/US20130079342A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012003264A1 (en) | 2012-01-05 |
| EP2588473A1 (en) | 2013-05-08 |
| AU2011271462A1 (en) | 2013-01-10 |
| MX2012015143A (es) | 2013-07-03 |
| CA2803620A1 (en) | 2012-01-05 |
| US20130079342A1 (en) | 2013-03-28 |
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