CA2676173A1 - Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors - Google Patents

Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors Download PDF

Info

Publication number
CA2676173A1
CA2676173A1 CA002676173A CA2676173A CA2676173A1 CA 2676173 A1 CA2676173 A1 CA 2676173A1 CA 002676173 A CA002676173 A CA 002676173A CA 2676173 A CA2676173 A CA 2676173A CA 2676173 A1 CA2676173 A1 CA 2676173A1
Authority
CA
Canada
Prior art keywords
compound
allowed
valance
aryl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002676173A
Other languages
English (en)
French (fr)
Inventor
Brian K. Albrecht
Steven Bellon
Shon Booker
Alan C. Cheng
Derin C. D'amico
Noel D'angelo
Jean-Christophe Harmange
Tae-Seong Kim
Longbin Liu
Mark H. Norman
Aaron C. Siegmund
Markian Stec
Ning Xi
Kevin Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2676173A1 publication Critical patent/CA2676173A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D237/00Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14Oxygen atoms
    • C07D237/16Two oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/02Nasal agents, e.g. decongestants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/04Antipruritics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/06Heterocyclic 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 linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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 linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Obesity (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
CA002676173A 2007-02-16 2008-02-15 Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors Abandoned CA2676173A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US90203007P 2007-02-16 2007-02-16
US60/902,030 2007-02-16
PCT/US2008/002007 WO2008103277A2 (en) 2007-02-16 2008-02-15 Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors

Publications (1)

Publication Number Publication Date
CA2676173A1 true CA2676173A1 (en) 2008-08-28

Family

ID=39563458

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002676173A Abandoned CA2676173A1 (en) 2007-02-16 2008-02-15 Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors

Country Status (7)

Country Link
US (1) US8314087B2 (enExample)
EP (1) EP2114898A2 (enExample)
JP (1) JP2010519204A (enExample)
AU (1) AU2008219166B2 (enExample)
CA (1) CA2676173A1 (enExample)
MX (1) MX2009008531A (enExample)
WO (1) WO2008103277A2 (enExample)

Families Citing this family (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5580732B2 (ja) 2007-04-03 2014-08-27 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 置換ベンゼン殺菌・殺カビ剤
DE102007025718A1 (de) * 2007-06-01 2008-12-04 Merck Patent Gmbh Pyridazinonderivate
EP2226320A4 (en) * 2007-12-26 2012-07-11 Eisai R&D Man Co Ltd PROCESS FOR THE PRODUCTION OF A HETEROCYCLE-SUBSTITUTED PYRIDINE DERIVATIVE
DE102008019907A1 (de) * 2008-04-21 2009-10-22 Merck Patent Gmbh Pyridazinonderivate
JP5627574B2 (ja) 2008-06-03 2014-11-19 インターミューン, インコーポレイテッド 炎症性および線維性疾患を治療するための化合物および方法
CN103951643B (zh) 2008-07-25 2015-12-09 盐野义制药株式会社 用作hiv整合酶抑制剂的化合物
JP5702293B2 (ja) 2008-11-10 2015-04-15 バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated Atrキナーゼの阻害剤として有用な化合物
KR101678563B1 (ko) 2008-12-11 2016-11-22 비이브 헬쓰케어 컴퍼니 카르바모일피리돈 hiv 인테그라제 억제제를 위한 제조방법 및 중간체
KR101733625B1 (ko) 2008-12-11 2017-05-10 시오노기세야쿠 가부시키가이샤 카르바모일피리돈 hiv 인테그라제 억제제 및 중간체의 합성
BRPI0924084B1 (pt) 2008-12-19 2021-12-21 Vertex Pharmaceuticals Incorporated Derivados de pirazina e composição farmacêutica que os compreende
TWI518084B (zh) 2009-03-26 2016-01-21 鹽野義製藥股份有限公司 哌喃酮與吡啶酮衍生物之製造方法
TW201124078A (en) 2009-12-22 2011-07-16 Du Pont Fungicidal 2-(bicyclic aryloxy) carboxamides
TWI582097B (zh) 2010-03-23 2017-05-11 Viiv醫療保健公司 製備胺甲醯吡啶酮衍生物及中間體之方法
JP2013526538A (ja) 2010-05-12 2013-06-24 バーテックス ファーマシューティカルズ インコーポレイテッド Atrキナーゼ阻害剤として有用な化合物
US8962631B2 (en) 2010-05-12 2015-02-24 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
EP2569287B1 (en) 2010-05-12 2014-07-09 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
AU2011253025A1 (en) 2010-05-12 2012-11-29 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9062008B2 (en) 2010-05-12 2015-06-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2011143422A1 (en) 2010-05-12 2011-11-17 Vertex Pharmaceuticals Incorporated 2 -aminopyridine derivatives useful as inhibitors of atr kinase
US20130102477A1 (en) 2010-06-23 2013-04-25 Ryan D. Morin Biomarkers for non-hodgkin lymphomas and uses thereof
WO2011163527A1 (en) 2010-06-23 2011-12-29 Vertex Pharmaceuticals Incorporated Pyrrolo- pyrazine derivatives useful as inhibitors of atr kinase
JP2013532627A (ja) 2010-07-01 2013-08-19 武田薬品工業株式会社 cMET阻害剤とHGFおよび/またはcMETに対する抗体との組み合わせ
US20130116231A1 (en) * 2010-07-12 2013-05-09 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
JP2013536802A (ja) * 2010-08-31 2013-09-26 メルク・シャープ・エンド・ドーム・コーポレイション チロシンキナーゼ阻害剤
AR082912A1 (es) 2010-09-08 2013-01-16 Sumitomo Chemical Co Metodo para producir compuestos de piridazinona y un intermediario de sintesis
US9175331B2 (en) 2010-09-10 2015-11-03 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
AU2011298987B2 (en) 2010-09-10 2017-09-28 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
WO2012087372A1 (en) 2010-12-22 2012-06-28 E. I. Du Pont De Nemours And Company Fungicidal 2-(bicyclic aryloxy)carboxamides
CN102558147B (zh) * 2010-12-23 2014-09-17 江苏先声药物研究有限公司 化合物、制备方法及应用
EP3323820B1 (en) 2011-02-28 2023-05-10 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
WO2012138938A1 (en) 2011-04-05 2012-10-11 Vertex Pharmaceuticals Incorporated Aminopyrazine compounds useful as inhibitors of tra kinase
JO3363B1 (ar) 2011-04-13 2019-03-13 Epizyme Inc مركبات بنزين مستبدلة بأريل أو أريل غير متجانس
TW201733984A (zh) 2011-04-13 2017-10-01 雅酶股份有限公司 經取代之苯化合物
EP2723745A1 (en) 2011-06-22 2014-04-30 Vertex Pharmaceuticals Inc. Compounds useful as inhibitors of atr kinase
JP2014517079A (ja) 2011-06-22 2014-07-17 バーテックス ファーマシューティカルズ インコーポレイテッド Atrキナーゼ阻害剤として有用な化合物
JP2014522818A (ja) 2011-06-22 2014-09-08 バーテックス ファーマシューティカルズ インコーポレイテッド Atrキナーゼ阻害剤として有用な化合物
IN2014CN02501A (enExample) 2011-09-30 2015-06-26 Vertex Pharma
MX2014003796A (es) 2011-09-30 2015-01-16 Vertex Pharma Compuestos utiles como inhibidores de la cinasa ataxia telangiectasia mutada y rad3 relacionados (atr).
SG10201606774UA (en) 2011-09-30 2016-10-28 Vertex Pharma Processes for making compounds useful as inhibitors of atr kinase
WO2013049720A1 (en) 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2013049719A1 (en) 2011-09-30 2013-04-04 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
US8841449B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2013071093A1 (en) 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Pyrazine compounds useful as inhibitors of atr kinase
EP2776421A1 (en) 2011-11-09 2014-09-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
EP2776429A1 (en) 2011-11-09 2014-09-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
EP2776422A1 (en) 2011-11-09 2014-09-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
WO2013075084A1 (en) * 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulators of methyl modifying enzymes, compositions and uses thereof
US9206128B2 (en) * 2011-11-18 2015-12-08 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
CA2862289C (en) 2012-02-10 2019-11-26 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US20140044802A1 (en) 2012-04-05 2014-02-13 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase and combination therapies thereof
DK3628670T3 (da) 2012-04-13 2022-12-05 Epizyme Inc Saltform til ezh2-hæmning
UA112897C2 (uk) 2012-05-09 2016-11-10 Байєр Фарма Акцієнгезелльшафт Біциклічно заміщені урацили та їх застосування для лікування і/або профілактики захворювань
AR092742A1 (es) 2012-10-02 2015-04-29 Intermune Inc Piridinonas antifibroticas
DK2904406T3 (en) 2012-10-04 2018-06-18 Vertex Pharma METHOD OF DETERMINING THE ATR INHIBITION, INCREASED DNA DAMAGE
CN105102432B (zh) 2012-10-15 2019-01-04 Epizyme股份有限公司 经取代的苯化合物
US8912198B2 (en) 2012-10-16 2014-12-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
SMT202000713T1 (it) 2012-12-07 2021-03-15 Vertex Pharma Pirazolo [1,5-a] pirimidine utili come inibitori dell'atr chinasi per il trattamento di malattie del cancro
MX2015008444A (es) 2012-12-28 2015-09-23 Dow Agrosciences Llc Derivados de n-(sustituido)-5-flouro-4-imino-3-metil-2-oxo-3,4-dih idropirimidin-1 (2h)-carboximida.
JP6336480B2 (ja) * 2012-12-28 2018-06-06 アダマ・マクテシム・リミテッド 1−(置換ベンゾイル)−5−フルオロ−4−イミノ−3−メチル−3,4−ジヒドロピリミジン−2(1h)−オンの誘導体
AU2013370493B2 (en) 2012-12-28 2017-08-17 Adama Makhteshim Ltd. N-(substituted)-5-fluoro-4-imino-3-methyl-2-oxo-3,4-dihydropyrimidine-1 (2H)-carboxylate derivatives
KR102309245B1 (ko) 2012-12-31 2021-10-06 아다마 마켓심 리미티드 살진균제로서의 3-알킬-5-플루오로-4-치환된-이미노-3,4-디히드로피리미딘-2(1h)-온 유도체
CA2900652C (en) 2013-02-15 2021-05-04 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
CN107915751A (zh) 2013-02-20 2018-04-17 卡拉制药公司 治疗性化合物和其用途
JP2016512815A (ja) 2013-03-15 2016-05-09 バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated Atrキナーゼの阻害剤として有用な縮合ピラゾロピリミジン誘導体
WO2014151142A1 (en) 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
AU2014306149B2 (en) 2013-08-06 2019-09-19 Imago Biosciences Inc. KDM1A inhibitors for the treatment of disease
WO2015023915A1 (en) 2013-08-15 2015-02-19 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
KR20160068956A (ko) 2013-10-15 2016-06-15 얀센 파마슈티카 엔.브이. RORyT의 퀴놀리닐 조절제
EP3057962B1 (en) 2013-10-16 2023-10-18 Epizyme, Inc. Hydrochloride salt form for ezh2 inhibition
DK3290407T3 (da) 2013-10-18 2020-03-23 Celgene Quanticel Res Inc Bromodomæneinhibitorer
WO2015066482A1 (en) 2013-11-01 2015-05-07 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
EP3066098A1 (de) 2013-11-08 2016-09-14 Bayer Pharma Aktiengesellschaft Substituierte uracile und ihre verwendung
US9695131B2 (en) 2013-11-08 2017-07-04 Bayer Pharma Aktiengesellschaft Substituted uracils as chymase inhibitors
HUE046727T2 (hu) 2013-12-06 2020-03-30 Vertex Pharma Az ATR-kináz inhibitoraként használható vegyület, 2-amino-6-fluoro-N-[5-fluoro-piridin-3-IL]-pirazolo-[1,5-A]-pirimidin-3-karboxamid, ennek elõállítása, különbözõ szilárd formái és ezek radioaktív nyomjelzett származékai
CA2936551A1 (en) 2014-01-24 2015-07-30 Confluence Life Sciences, Inc. Substituted pyrrolopyridines and pyrrolopyrazines for treating cancer or inflammatory diseases
WO2015112847A1 (en) * 2014-01-24 2015-07-30 Confluence Life Sciences, Inc. Arylpyridinone itk inhibitors for treating inflammation and cancer
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
CN107074863B (zh) 2014-06-05 2019-12-03 沃泰克斯药物股份有限公司 Atr激酶抑制剂的制备方法及其不同的固体形式
PL3157566T3 (pl) 2014-06-17 2019-10-31 Vertex Pharma Metoda leczenia nowotworu przy użyciu kombinacji inhibitorów chk1 i atr
ES2896400T3 (es) 2014-08-01 2022-02-24 Nuevolution As Compuestos activos frente a bromdominios
CN106573898B (zh) 2014-08-14 2018-11-09 豪夫迈·罗氏有限公司 治疗和预防乙型肝炎病毒感染的新的哒嗪酮和三嗪酮
EP3229836B1 (en) 2014-12-09 2019-11-13 Institut National de la Sante et de la Recherche Medicale (INSERM) Human monoclonal antibodies against axl
HK1245677A1 (zh) 2015-01-23 2018-08-31 Aclaris Therapeutics, Inc. 用於治疗炎症和癌症的杂环itk抑制剂
KR102626978B1 (ko) 2015-02-12 2024-01-18 이마고 바이오사이언시즈 인코포레이티드 질환 치료를 위한 kdm1a 저해제
WO2016135041A1 (en) 2015-02-26 2016-09-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Fusion proteins and antibodies comprising thereof for promoting apoptosis
SG10201912684TA (en) * 2015-06-25 2020-03-30 Taiho Pharmaceutical Co Ltd Therapeutic agent for fibrosis
WO2017019489A1 (en) 2015-07-24 2017-02-02 George Robert Pettit Quinstatin compounds
CA2994478C (en) 2015-08-12 2023-10-03 Neomed Institute Substituted benzimidazoles, their preparation and their use as pharmaceuticals
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
KR102678021B1 (ko) 2015-09-30 2024-06-26 버텍스 파마슈티칼스 인코포레이티드 Dna 손상제와 병용되는, atr 저해제를 포함하는 암 치료용 약제학적 조성물
US20190112317A1 (en) 2015-10-05 2019-04-18 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
PE20181197A1 (es) 2015-10-14 2018-07-23 Bristol Myers Squibb Co 2,4-dihidroxi-nicotinamidas como agonistas del receptor de apelina (apj)
ES2854733T3 (es) 2015-12-16 2021-09-22 Bristol Myers Squibb Co Heteroarilhidroxipirimidinonas como agonistas del receptor APJ
TWI744301B (zh) 2016-03-24 2021-11-01 美商必治妥美雅史谷比公司 做為apj促效劑之6-羥基-4-側氧-1,4-二氫嘧啶-5-甲醯胺
US11390590B2 (en) 2016-08-16 2022-07-19 Imago Biosciences, Inc. Methods and processes for the preparation of KDM1A inhibitors
AU2017324716B2 (en) 2016-09-08 2020-08-13 KALA BIO, Inc. Crystalline forms of therapeutic compounds and uses thereof
MX2019002629A (es) 2016-09-08 2019-10-07 Kala Pharmaceuticals Inc Formas cristalinas de compuestos terapéuticos y usos de los mismos.
AU2017324713B2 (en) 2016-09-08 2020-08-13 KALA BIO, Inc. Crystalline forms of therapeutic compounds and uses thereof
EP3529242A1 (en) 2016-10-19 2019-08-28 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of ezh2
EP3532467A1 (en) * 2016-10-26 2019-09-04 Proteostasis Therapeutics, Inc. Pyridazine derivatives, compositions and methods for modulating cftr
WO2018077227A1 (zh) 2016-10-27 2018-05-03 福建广生堂药业股份有限公司 作为c-MET抑制剂的吡啶酮类化合物
US10316038B2 (en) 2017-01-25 2019-06-11 Aclaris Therapeutics, Inc. Pyrrolopyrimidine ITK inhibitors for treating inflammation and cancer
EP3655396A1 (en) 2017-07-17 2020-05-27 Adama Makhteshim Ltd. Polymorphs of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2-one
CN110117278B (zh) * 2018-02-07 2022-07-19 石家庄以岭药业股份有限公司 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途
KR102684364B1 (ko) 2018-05-11 2024-07-11 이마고 바이오사이언시즈 인코포레이티드 질환의 치료를 위한 kdm1a 저해제
WO2019236625A1 (en) * 2018-06-04 2019-12-12 Ohio State Innovation Foundation Eaat2 activators and methods of using thereof
BR112021008905A2 (pt) 2018-11-06 2021-08-10 Edgewise Therapeutics, Inc. compostos de piridazinona e usos dos mesmos
KR102885525B1 (ko) 2018-11-06 2025-11-13 엣지와이즈 테라퓨틱스, 인크. 피리다지논 화합물 및 이의 용도
AU2019374812B2 (en) 2018-11-06 2025-03-06 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
CN111393375A (zh) * 2020-04-07 2020-07-10 中国药科大学 一种氮取代的六元芳杂环酮类化合物及其药物组合物、制备方法和用途
EP4149621B1 (en) * 2020-05-13 2024-10-30 Edgewise Therapeutics, Inc. Pyridazinone compounds for the treatment of neuromuscular diseases
WO2023189602A1 (ja) 2022-03-30 2023-10-05 石原産業株式会社 ピリダジノン系化合物又はその塩及びそれらを含有する有害生物防除剤
KR20250040894A (ko) 2022-05-25 2025-03-25 이케나 온콜로지, 인코포레이티드 Mek 억제제 및 이의 용도
CN117510470A (zh) * 2022-07-27 2024-02-06 暨南大学 哒嗪酮类化合物及其应用
CN115872976B (zh) * 2022-12-30 2024-05-14 中国药科大学 一种喹啉衍生物、含有其的药物组合物及其用途
WO2025153721A1 (en) * 2024-01-19 2025-07-24 Scenic Biotech Bv Pla2g15 inhibitors
CN121064162B (zh) * 2025-11-05 2026-01-30 中国药科大学 一类2-(2-(喹啉-4-基氧)乙基)哒嗪-3(2h)-酮化合物及其制备方法和应用

Family Cites Families (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3009A (en) * 1843-03-21 Lard-lamp
US3956287A (en) * 1973-11-07 1976-05-11 Richardson-Merrell Inc. 7-[(2-Oxo-1-pyridinyl)acylamino]cephalosporin derivatives
CH629240A5 (de) * 1976-09-02 1982-04-15 Henkel Kgaa Mittel zum faerben von keratinhaltigem material.
US4673735A (en) * 1982-04-15 1987-06-16 Sandoz Ltd. Azo compounds having at least one 6-hydroxypyrid-2-one coupling component radical metal complexes thereof and intermediates therefor
EP0092520B1 (de) * 1982-04-15 1986-11-12 Sandoz Ag Basische Verbindungen, deren Herstellung und Verwendung
JP2762522B2 (ja) 1989-03-06 1998-06-04 藤沢薬品工業株式会社 血管新生阻害剤
US5112946A (en) 1989-07-06 1992-05-12 Repligen Corporation Modified pf4 compositions and methods of use
US5892112A (en) 1990-11-21 1999-04-06 Glycomed Incorporated Process for preparing synthetic matrix metalloprotease inhibitors
FR2670208B1 (fr) 1990-12-07 1993-08-13 Pf Medicament Derives de phenyl-1 dihydro 1-4 arylalcoylamino-3 oxo-4 pyridazines, leur preparation et leur application en therapeutique.
CZ403592A3 (en) * 1992-02-20 1993-12-15 Hoechst Ag Arylcarbonylaminoalkyldihydrooxopyridines, process of their preparation and their use
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
PT669929E (pt) 1992-11-13 2007-04-30 Immunex Corp Ligando de elk, uma citoquina
BR9307570A (pt) * 1992-12-02 1999-05-25 Pfizer Diéteres de catecol como inibidores seletivos de pdeiv
US5629327A (en) 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
US5516658A (en) 1993-08-20 1996-05-14 Immunex Corporation DNA encoding cytokines that bind the cell surface receptor hek
US5700823A (en) 1994-01-07 1997-12-23 Sugen, Inc. Treatment of platelet derived growth factor related disorders such as cancers
AU702522B2 (en) 1994-04-15 1999-02-25 Amgen, Inc. HEK5, HEK7, HEK8, HEK11, new EPH-like receptor protein tyrosine kinases
US6303769B1 (en) 1994-07-08 2001-10-16 Immunex Corporation Lerk-5 dna
US5919905A (en) 1994-10-05 1999-07-06 Immunex Corporation Cytokine designated LERK-6
US6057124A (en) 1995-01-27 2000-05-02 Amgen Inc. Nucleic acids encoding ligands for HEK4 receptors
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5880141A (en) 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
CO4950519A1 (es) 1997-02-13 2000-09-01 Novartis Ag Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion
RS49779B (sr) 1998-01-12 2008-06-05 Glaxo Group Limited, Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze
ES2324846T3 (es) 1998-03-04 2009-08-17 Bristol-Myers Squibb Company Inhibidores de la proteina tirosina quinasa de imidazopirazina heterociclo-sustituida.
IL139934A0 (en) 1998-05-29 2002-02-10 Sugen Inc Pyrrole substituted 2-indolinone derivatives and pharmaceutical compositions containing the same
UA60365C2 (uk) 1998-06-04 2003-10-15 Пфайзер Продактс Інк. Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця
CA2336848A1 (en) 1998-07-10 2000-01-20 Merck & Co., Inc. Novel angiogenesis inhibitors
EP1109555A4 (en) 1998-08-31 2001-11-21 Merck & Co Inc Novel angiogenesis inhibitors
CA2359244C (en) 1999-01-13 2013-10-08 Bayer Healthcare Llc .omega.-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
TW506993B (en) * 1999-03-15 2002-10-21 Ciba Sc Holding Ag Reactive dyes, processes for their preparation and process for dyeing or printing a fibre material
JP4673977B2 (ja) 1999-03-30 2011-04-20 ノバルティス アーゲー 炎症性疾患治療用フタラジン誘導体
ES2219290T3 (es) * 1999-03-30 2004-12-01 Ciba Specialty Chemicals Holding Inc. Colorantes reactivos, procedimiento para su preparacion y su empleo.
ATE324444T1 (de) 1999-06-07 2006-05-15 Immunex Corp Tek-antagonisten
US6521424B2 (en) 1999-06-07 2003-02-18 Immunex Corporation Recombinant expression of Tek antagonists
CN100376567C (zh) 1999-11-05 2008-03-26 阿斯特拉曾尼卡有限公司 作为vegf抑制剂的喹唑啉衍生物
DK1233943T3 (da) 1999-11-24 2011-08-15 Sugen Inc Ioniserbare indolinon derivater og anvendelse deraf som PTK ligander
US6515004B1 (en) 1999-12-15 2003-02-04 Bristol-Myers Squibb Company N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases
US6727225B2 (en) 1999-12-20 2004-04-27 Immunex Corporation TWEAK receptor
EP1259595B1 (en) 2000-02-25 2007-04-04 Immunex Corporation Integrin antagonists
DE60125026T2 (de) 2000-03-23 2007-06-28 Takeda Pharmaceutical Co. Ltd. Fluorisochinolinderivate, verfahren zu ihrer herstellung und ihre anwendung
JP2001335579A (ja) * 2000-03-23 2001-12-04 Takeda Chem Ind Ltd フロイソキノリン誘導体、その製造法および用途
US6630500B2 (en) 2000-08-25 2003-10-07 Cephalon, Inc. Selected fused pyrrolocarbazoles
ES2556946T3 (es) 2000-12-21 2016-01-21 Novartis Ag Pirimidinaminas como moduladores de la angiogénesis
US6995162B2 (en) 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US20020147198A1 (en) 2001-01-12 2002-10-10 Guoqing Chen Substituted arylamine derivatives and methods of use
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7105682B2 (en) 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
ES2195785B1 (es) * 2002-05-16 2005-03-16 Almirall Prodesfarma, S.A. Nuevos derivados de piridazin-3(2h)-ona.
US7307088B2 (en) 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
TWI329112B (en) 2002-07-19 2010-08-21 Bristol Myers Squibb Co Novel inhibitors of kinases
CN1688549A (zh) * 2002-08-23 2005-10-26 麒麟麦酒株式会社 具有TGFβ抑制活性的化合物和含所述化合物的药用组合物
US20060205790A1 (en) * 2002-10-22 2006-09-14 Coe Diane M Medicinal arylethanolamine compounds
WO2005000818A1 (en) * 2003-06-27 2005-01-06 Warner-Lambert Company Llc 5-substituted-4-`(substituted phenyl)!amino!-2-pyridone deviatives for use as mek inhibitors
EP1714654A4 (en) * 2004-02-09 2011-02-16 Nissan Chemical Ind Ltd MEDICAMENT FOR INHIBITING VASCULAR INTIMATE HYPERPLASIA
JP2008537748A (ja) * 2005-04-06 2008-09-25 エクセリクシス、インコーポレイテッド c−Metモジュレーター及び使用方法
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Alternative amide derivatives and methods of use
US20090227588A1 (en) * 2005-12-05 2009-09-10 Roman Wolfgang Fleck Substituted pyrazole compounds useful as soluble epoxide hyrolase inhibitors
US20090170847A1 (en) * 2006-01-23 2009-07-02 Seung Chul Lee Imidazopyridine Derivatives Inhibiting Protein Kinase Activity, Method for the Preparation Thereof and Pharmaceutical Composition Containing Same
JP2009537602A (ja) * 2006-05-22 2009-10-29 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 薬剤として用いるための置換ピラジノン誘導体
DE102006037478A1 (de) 2006-08-10 2008-02-14 Merck Patent Gmbh 2-(Heterocyclylbenzyl)-pyridazinonderivate
WO2008038841A1 (en) * 2006-09-30 2008-04-03 Japan Tobacco Inc. Thiadiazolone derivative and use thereof
CN102442941A (zh) * 2006-12-14 2012-05-09 安斯泰来制药有限公司 用作crth2拮抗剂和抗过敏剂的多环酸化合物
JP5419706B2 (ja) * 2006-12-20 2014-02-19 タケダ カリフォルニア インコーポレイテッド グルコキナーゼアクチベーター
TWI407960B (zh) 2007-03-23 2013-09-11 Jerini Ag 小分子緩激肽b2受體調節劑
US8258134B2 (en) * 2008-04-16 2012-09-04 Hoffmann-La Roche Inc. Pyridazinone glucokinase activators
TWI367598B (en) * 2008-06-23 2012-07-01 Ind Tech Res Inst Antenna radome

Also Published As

Publication number Publication date
AU2008219166B2 (en) 2013-05-16
JP2010519204A (ja) 2010-06-03
US8314087B2 (en) 2012-11-20
US20080280917A1 (en) 2008-11-13
AU2008219166A1 (en) 2008-08-28
MX2009008531A (es) 2009-08-26
WO2008103277A2 (en) 2008-08-28
EP2114898A2 (en) 2009-11-11
WO2008103277A3 (en) 2009-04-16

Similar Documents

Publication Publication Date Title
AU2008219166B2 (en) Nitrogen-containing heterocyclyl ketones and their use as c-Met inhibitors
CA2711101C (en) Fused heterocyclic derivatives and methods of use as c-met inhibitors
EP2118069B1 (en) Bis-aryl amide derivatives useful for the treatment of cancer
AU2007338795B2 (en) Substituted heterocycles and methods of use
EP1881976B1 (en) Substituted amide derivatives as protein kinase inhibitors
AU2007272783B2 (en) Fused heterocyclic derivatives and methods of use
EP1827434B1 (en) Quinolines and quinazoline analogs and their use as medicaments for treating cancer
AU2006265835B2 (en) Bis-aryl kinase inhibitors and their use in the treatment of inflammation, angiogenesis and cancer
WO2008079291A2 (en) Substituted heterocycles and methods of use
AU2009248839B2 (en) Heterocycles as protein kinase inhibitors
HK1116161B (en) Substituted amide derivatives as protein kinase inhibitors

Legal Events

Date Code Title Description
EEER Examination request

Effective date: 20130211

FZDE Discontinued

Effective date: 20160216