AU2012285931B2 - Novel substituted indole derivatives as gamma secretase modulators - Google Patents
Novel substituted indole derivatives as gamma secretase modulators Download PDFInfo
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- AU2012285931B2 AU2012285931B2 AU2012285931A AU2012285931A AU2012285931B2 AU 2012285931 B2 AU2012285931 B2 AU 2012285931B2 AU 2012285931 A AU2012285931 A AU 2012285931A AU 2012285931 A AU2012285931 A AU 2012285931A AU 2012285931 B2 AU2012285931 B2 AU 2012285931B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
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| EP11174120.3 | 2011-07-15 | ||
| EP11174120 | 2011-07-15 | ||
| PCT/EP2012/063667 WO2013010904A1 (en) | 2011-07-15 | 2012-07-12 | Novel substituted indole derivatives as gamma secretase modulators |
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| AU2012285931A1 AU2012285931A1 (en) | 2014-01-23 |
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| WO2010089292A1 (en) | 2009-02-06 | 2010-08-12 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| WO2010145883A1 (en) | 2009-05-07 | 2010-12-23 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Novel substituted indazole and aza-indazole derivatives as gamma secretase modulators |
| EA021047B1 (ru) | 2009-07-15 | 2015-03-31 | Янссен Фармасьютикалз, Инк. | Замещенные производные триазола и имидазола в качестве модуляторов гамма-секретазы |
| MX2012008260A (es) | 2010-01-15 | 2012-08-17 | Janssen Pharmaceuticals Inc | Novedosos derivados de triazol sustituidos como moduladores de la gamma secretasa. |
| AU2012230348A1 (en) | 2011-03-24 | 2013-08-29 | Cellzome Limited | Novel substituted triazolyl piperazine and triazolyl piperidine derivatives as gamma secretase modulators |
| WO2013010904A1 (en) | 2011-07-15 | 2013-01-24 | Janssen Pharmaceuticals, Inc. | Novel substituted indole derivatives as gamma secretase modulators |
| AU2013261023B2 (en) | 2012-05-16 | 2016-11-24 | Cellzome Limited | Substituted 3, 4 - dihydro - 2H - pyrido [1, 2 -a] pyrazine - 1, 6 - dione derivatives useful for the treatment of (inter alia) Alzheimer's disease |
| EP2738172A1 (en) * | 2012-11-28 | 2014-06-04 | Almirall, S.A. | New bicyclic compounds as crac channel modulators |
| JP6275161B2 (ja) | 2012-12-20 | 2018-02-07 | ヤンセン ファーマシューティカ エヌ．ベー． | γセクレターゼ調節剤としての新規な三環式３，４−ジヒドロ−２Ｈ−ピリド［１，２−ａ］ピラジン−１，６−ジオン誘導体 |
| CA2891755C (en) | 2013-01-17 | 2021-10-26 | Janssen Pharmaceutica Nv | Substituted pyrido-piperazinone derivatives as gamma secretase modulators |
| US10562897B2 (en) | 2014-01-16 | 2020-02-18 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators |
| GB201506660D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
| GB201506658D0 (en) | 2015-04-20 | 2015-06-03 | Cellcentric Ltd | Pharmaceutical compounds |
| CA3031675A1 (en) | 2016-07-30 | 2018-02-08 | Bristol-Myers Squibb Company | Dimethoxyphenyl substituted indole compounds as tlr7, tlr8 or tlr9 inhibitors |
| ES2902504T3 (es) | 2016-09-09 | 2022-03-28 | Bristol Myers Squibb Co | Compuestos de indol sustituidos con piridilo |
| JOP20190060A1 (ar) | 2016-09-26 | 2019-03-26 | Chugai Pharmaceutical Co Ltd | مشتق بيرازولو بيريدين له تأثير مساعد لمستقبل glp-1 |
| WO2019028301A1 (en) | 2017-08-04 | 2019-02-07 | Bristol-Myers Squibb Company | INDOLE COMPOUNDS SUBSTITUTED WITH [1,2,4] TRIAZOLO [4,3-A] PYRIDINYL |
| ES2909401T3 (es) | 2017-08-04 | 2022-05-06 | Bristol Myers Squibb Co | Compuestos de indol sustituidos útiles como inhibidores de TLR7/8/9 |
| AU2018348930A1 (en) * | 2017-10-11 | 2020-03-26 | F. Hoffmann-La Roche Ag | Bicyclic compounds for use as RIP 1 kinase inhibitors |
| EP3710440B1 (en) * | 2017-11-14 | 2023-04-05 | Bristol-Myers Squibb Company | Substituted indole compounds |
| US12030878B2 (en) | 2017-12-15 | 2024-07-09 | Bristol-Myers Squibb Company | Substituted indole ether compounds |
| SI3728252T1 (sl) | 2017-12-18 | 2023-11-30 | Bristol-Myers Squibb Company | 4-azaindolne spojine |
| CN111491930B (zh) | 2017-12-19 | 2023-09-26 | 百时美施贵宝公司 | 可用作tlr抑制剂的经取代的吲哚化合物 |
| AU2018392316B2 (en) | 2017-12-19 | 2022-05-12 | Bristol-Myers Squibb Company | Amide substituted indole compounds useful as TLR inhibitors |
| JP7304352B2 (ja) | 2017-12-19 | 2023-07-06 | ブリストル－マイヤーズ スクイブ カンパニー | ６－アザインドール化合物 |
| AU2018390544A1 (en) | 2017-12-20 | 2020-08-06 | Bristol-Myers Squibb Company | Diazaindole compounds |
| AU2018390610A1 (en) | 2017-12-20 | 2020-08-06 | Bristol-Myers Squibb Company | Amino indole compounds useful as TLR inhibitors |
| US11420958B2 (en) | 2017-12-20 | 2022-08-23 | Bristol-Myers Squibb Company | Aryl and heteroaryl substituted indole compounds |
| HUE064554T2 (hu) * | 2018-09-03 | 2024-03-28 | Hoffmann La Roche | Bicikluszos heteroaril származékok |
| EP3628669A1 (en) * | 2018-09-28 | 2020-04-01 | GenKyoTex Suisse SA | Novel compounds as nadph oxidase inhibitors |
| US12172995B2 (en) | 2018-10-24 | 2024-12-24 | Bristol-Myers Squibb Company | Substituted indole and indazole compounds |
| US11998537B2 (en) | 2018-10-24 | 2024-06-04 | Bristol-Myers Squibb Company | Substituted indole dimer compounds |
| PL3894411T3 (pl) | 2018-12-13 | 2024-10-07 | F. Hoffmann-La Roche Ag | Pochodne 7-fenoksy-N-(3-azabicyklo[3.2.1]oktan-8-ylo)-6,7-dihydro-5H-pirolo[1,2-b][1,2,4]triazolo-2-aminy i związki pokrewne jako modulatory gamma-sekretazy do leczenia choroby Alzheimera |
| ES2987832T3 (es) | 2019-05-09 | 2024-11-18 | Bristol Myers Squibb Co | Compuestos de benzimidazolona sustituidos |
| KR20220075381A (ko) | 2019-10-01 | 2022-06-08 | 브리스톨-마이어스 스큅 컴퍼니 | 치환된 비시클릭 헤테로아릴 화합물 |
| WO2021067657A1 (en) | 2019-10-04 | 2021-04-08 | Bristol-Myers Squibb Company | Substituted carbazole compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010098495A1 (en) * | 2009-02-26 | 2010-09-02 | Eisai R&D Management Co., Ltd. | Imidazolylpyrazine derivatives |
| WO2010126745A1 (en) * | 2009-04-27 | 2010-11-04 | High Point Pharmaceuticals, Llc | SUBSTITUTED IMIDAZO[1,2-A]PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE AS β-SECRETASE INHIBITORS |
Family Cites Families (63)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69321875T2 (de) * | 1992-05-19 | 1999-06-17 | Adir Et Compagnie, Courbevoie | Benzimidezolderivate mit antidiabetischer und Anti-Plättchenklumpungswirkung |
| US5767144A (en) | 1994-08-19 | 1998-06-16 | Abbott Laboratories | Endothelin antagonists |
| US6114334A (en) | 1995-07-13 | 2000-09-05 | Knoll Aktiengesellschaft | Piperazine derivatives as therapeutic agents |
| CN1156445C (zh) | 1999-06-10 | 2004-07-07 | 沃尼尔·朗伯公司 | 采用二氢异吲哚衍生物抑制淀粉样蛋白聚集和使淀粉样蛋白沉积成像的方法 |
| CA2406383A1 (en) | 2000-04-13 | 2001-10-25 | Mayo Foundation For Medical Education And Research | A.beta.42 lowering agents |
| WO2001087845A2 (en) | 2000-05-15 | 2001-11-22 | Fujisawa Pharmaceutical Co., Ltd. | N-containing heterocyclic compounds and their use as 5-ht antagonists |
| DE10109867A1 (de) | 2001-03-01 | 2002-09-05 | Abbott Gmbh & Co Kg | Verwendung von Triazolverbindungen zur Prophylaxe und Therapie neurodegenerativer Erkrankungen, Hirntrauma und zerebraler Ischämie |
| DE10238002A1 (de) | 2002-08-20 | 2004-03-04 | Merck Patent Gmbh | Benzimidazolderivate |
| BRPI0407913A (pt) | 2003-02-27 | 2006-03-01 | Hoffmann La Roche | antagonistas receptores de ccr-3 |
| WO2004110350A2 (en) | 2003-05-14 | 2004-12-23 | Torreypines Therapeutics, Inc. | Compouds and uses thereof in modulating amyloid beta |
| AU2004265101B2 (en) | 2003-08-14 | 2009-06-11 | F. Hoffmann-La Roche Ag | Gabanergic modulators |
| ATE483708T1 (de) | 2004-03-08 | 2010-10-15 | Prosidion Ltd | Pyrrolopyridin-2-carbonsäurehydrazide als inhibitoren von glykogenphosphorylase |
| US7667041B2 (en) | 2004-05-26 | 2010-02-23 | Eisai R&D Management Co., Ltd. | Cinnamide compound |
| KR20070083781A (ko) | 2004-10-26 | 2007-08-24 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 신나미드 화합물의 비정질체 |
| US7893267B2 (en) * | 2005-03-14 | 2011-02-22 | High Point Pharmaceuticals, Llc | Benzazole derivatives, compositions, and methods of use as β-secretase inhibitors |
| US7572807B2 (en) | 2005-06-09 | 2009-08-11 | Bristol-Myers Squibb Company | Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors |
| US20070078136A1 (en) | 2005-09-22 | 2007-04-05 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful as kinase modulators |
| BRPI0616150A2 (pt) | 2005-09-22 | 2011-06-07 | Sanofi Aventis | derivados de amino-alquil-amida como lìquidos receptores de ccr3 |
| WO2007043786A1 (en) | 2005-10-10 | 2007-04-19 | Seiyang Yang | Dynamic-based verification apparatus for verification from electronic system level to gate level, and verification method using the same |
| EP1937767B1 (en) | 2005-10-11 | 2013-05-22 | Chemtura Corporation | Diaromatic amines |
| AR056785A1 (es) | 2005-11-10 | 2007-10-24 | Schering Corp | COMPUESTOS DE IMIDAZO[1,2-A]PIRAZINAS, uTILES COMO INHIBIDORES, REGULADORES O MODULADORES DE PROTEINQUINASAS |
| US20090163482A1 (en) | 2006-03-13 | 2009-06-25 | Mchardy Stanton Furst | Tetralines antagonists of the h-3 receptor |
| GB0606774D0 (en) | 2006-04-03 | 2006-05-10 | Novartis Ag | Organic compounds |
| US7893058B2 (en) | 2006-05-15 | 2011-02-22 | Janssen Pharmaceutica Nv | Imidazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases |
| EP2099798A1 (en) | 2006-12-01 | 2009-09-16 | Galapagos N.V. | Imidazolopyridine compounds useful for the treatment of degenerative and inflammatory diseases |
| JP2010512390A (ja) | 2006-12-12 | 2010-04-22 | シェーリング コーポレイション | 三環式系を含むアスパルチルプロテアーゼ阻害剤 |
| US20100298314A1 (en) | 2006-12-20 | 2010-11-25 | Schering Corporation | Novel jnk inhibitors |
| WO2008097538A1 (en) | 2007-02-08 | 2008-08-14 | Merck & Co., Inc. | Therapeutic agents |
| CA2676715A1 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
| CA2676920A1 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperidine derivatives |
| MX2009012177A (es) | 2007-05-07 | 2009-11-23 | Schering Corp | Moduladores de gamma-secretasa. |
| MX2009012163A (es) | 2007-05-11 | 2009-12-01 | Hoffmann La Roche | Hetarilanilinas como moduladores para beta-amiloide. |
| WO2008156580A1 (en) | 2007-06-13 | 2008-12-24 | Merck & Co., Inc. | Triazole derivatives for treating alzheimer's disease and related conditions |
| CL2008001914A1 (es) | 2007-06-29 | 2009-07-17 | Schering Corp | Compuestos heterociclicos de nitrogeno y oxigeno,moduladores de gama secretasa, composicion farmaceutica de dichos compuestos; kit farmaceutico y su uso para prevenir o tratar enfermedades asociadas al sistema nervioso central como alzheimer, sindrome de down, enfermedades neurodegenerativas, inhibir el deposito de proteina amiloide. |
| US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
| EP2200990A1 (en) | 2007-09-06 | 2010-06-30 | Schering Corporation | Gamma secretase modulators |
| GB0720444D0 (en) | 2007-10-18 | 2007-11-28 | Glaxo Group Ltd | Novel compounds |
| AU2008333865A1 (en) | 2007-12-06 | 2009-06-11 | Schering Corporation | Gamma secretase modulators |
| US8426595B2 (en) | 2007-12-11 | 2013-04-23 | Xianhai Huang | Gamma secretase modulators |
| RU2010137300A (ru) | 2008-02-22 | 2012-03-27 | Ф. Хоффманн-Ля Рош Аг (Ch) | Модуляторы бета-амилоида |
| US20100137320A1 (en) | 2008-02-29 | 2010-06-03 | Schering Corporation | Gamma secretase modulators |
| WO2010010188A1 (en) | 2008-07-25 | 2010-01-28 | Galapagos Nv | Novel compounds useful for the treatment of degenerative and inflammatory diseases. |
| EP2340243B1 (en) | 2008-10-17 | 2014-10-08 | Boehringer Ingelheim International GmbH | Heteroaryl substituted indole compounds useful as mmp-13 inhibitors |
| AU2009313527A1 (en) | 2008-11-06 | 2010-05-14 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
| MX2011004954A (es) | 2008-11-10 | 2011-05-30 | Hoffmann La Roche | Moduladores heterociclicos de gamma-secretasa. |
| AU2009322774A1 (en) | 2008-12-03 | 2011-06-30 | Via Pharmaceuticals, Inc | Inhibitors of diacylglycerol acyltransferase |
| PA8854101A1 (es) | 2008-12-18 | 2010-07-27 | Ortho Mcneil Janssen Pharm | Derivados de imidazol bicíclicos sustituidos como moduladores de gamma secretasa |
| TW201030002A (en) | 2009-01-16 | 2010-08-16 | Bristol Myers Squibb Co | Bicyclic compounds for the reduction of beta-amyloid production |
| WO2010089292A1 (en) | 2009-02-06 | 2010-08-12 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
| TWI461425B (zh) | 2009-02-19 | 2014-11-21 | Janssen Pharmaceuticals Inc | 作為伽瑪分泌酶調節劑之新穎經取代的苯并唑、苯并咪唑、唑并吡啶及咪唑并吡啶衍生物類 |
| RU2515976C2 (ru) | 2009-02-26 | 2014-05-20 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Азотсодержащие конденсированные гетероциклические соединения и их применение в качестве ингибиторов продукции бета-амилоида |
| JP2012051807A (ja) | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | アリールイミダゾール化合物 |
| EP2403835A1 (en) | 2009-03-03 | 2012-01-11 | Pfizer Inc. | Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators |
| EP2410529A1 (en) | 2009-03-16 | 2012-01-25 | Panasonic Corporation | Application running device |
| US20120029190A1 (en) * | 2009-04-03 | 2012-02-02 | Douglas Burdi | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
| WO2010145883A1 (en) | 2009-05-07 | 2010-12-23 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Novel substituted indazole and aza-indazole derivatives as gamma secretase modulators |
| JP2010274429A (ja) | 2009-05-26 | 2010-12-09 | Ihi Corp | アライメントステージ |
| EA021047B1 (ru) | 2009-07-15 | 2015-03-31 | Янссен Фармасьютикалз, Инк. | Замещенные производные триазола и имидазола в качестве модуляторов гамма-секретазы |
| MX2012008260A (es) | 2010-01-15 | 2012-08-17 | Janssen Pharmaceuticals Inc | Novedosos derivados de triazol sustituidos como moduladores de la gamma secretasa. |
| TW201307347A (zh) * | 2010-11-01 | 2013-02-16 | Arqule Inc | 經取代苯並－咪唑並－吡啶並－二氮呯化合物 |
| AU2012230348A1 (en) | 2011-03-24 | 2013-08-29 | Cellzome Limited | Novel substituted triazolyl piperazine and triazolyl piperidine derivatives as gamma secretase modulators |
| JP5767393B2 (ja) | 2011-03-31 | 2015-08-19 | ファイザー・インク | 新規二環式ピリジノン |
| WO2013010904A1 (en) | 2011-07-15 | 2013-01-24 | Janssen Pharmaceuticals, Inc. | Novel substituted indole derivatives as gamma secretase modulators |
-
2012
- 2012-07-12 WO PCT/EP2012/063667 patent/WO2013010904A1/en not_active Ceased
- 2012-07-12 KR KR1020147003465A patent/KR101913135B1/ko not_active Expired - Fee Related
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- 2012-07-12 BR BR112014000713A patent/BR112014000713A2/pt active Search and Examination
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- 2012-07-13 AR ARP120102548A patent/AR087182A1/es not_active Application Discontinuation
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- 2014-01-13 IL IL230422A patent/IL230422B/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010098495A1 (en) * | 2009-02-26 | 2010-09-02 | Eisai R&D Management Co., Ltd. | Imidazolylpyrazine derivatives |
| WO2010126745A1 (en) * | 2009-04-27 | 2010-11-04 | High Point Pharmaceuticals, Llc | SUBSTITUTED IMIDAZO[1,2-A]PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE AS β-SECRETASE INHIBITORS |
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| TW201315736A (zh) | 2013-04-16 |
| CN103874702A (zh) | 2014-06-18 |
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| BR112014000713A2 (pt) | 2017-01-10 |
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| WO2013010904A1 (en) | 2013-01-24 |
| KR101913135B1 (ko) | 2018-10-30 |
| US9115143B2 (en) | 2015-08-25 |
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| IN2014MN00258A (enExample) | 2015-09-25 |
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| EP2731948A1 (en) | 2014-05-21 |
| CN103874702B (zh) | 2015-12-09 |
| US20140148450A1 (en) | 2014-05-29 |
| KR20140063595A (ko) | 2014-05-27 |
| EA201490287A1 (ru) | 2014-05-30 |
| IL230422B (en) | 2018-03-29 |
| CA2841102C (en) | 2019-08-13 |
| AR087182A1 (es) | 2014-02-26 |
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