ATE399007T1 - Raf kinase hemmer - Google Patents
Raf kinase hemmerInfo
- Publication number
- ATE399007T1 ATE399007T1 AT98923601T AT98923601T ATE399007T1 AT E399007 T1 ATE399007 T1 AT E399007T1 AT 98923601 T AT98923601 T AT 98923601T AT 98923601 T AT98923601 T AT 98923601T AT E399007 T1 ATE399007 T1 AT E399007T1
- Authority
- AT
- Austria
- Prior art keywords
- raf kinase
- kinase inhibitor
- compounds
- methods
- raf
- Prior art date
Links
- 229940123690 Raf kinase inhibitor Drugs 0.000 title 1
- 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 title 1
- 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 title 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- 102000009929 raf Kinases Human genes 0.000 abstract 1
- 108010077182 raf Kinases Proteins 0.000 abstract 1
- 150000003672 ureas Chemical class 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D417/02—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 containing two hetero rings
- C07D417/12—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 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86302197A | 1997-05-23 | 1997-05-23 | |
| US12642097P | 1997-05-23 | 1997-05-23 | |
| PCT/US1998/010376 WO1998052559A1 (en) | 1997-05-23 | 1998-05-21 | Raf kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ATE399007T1 true ATE399007T1 (de) | 2008-07-15 |
Family
ID=26824631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AT98923601T ATE399007T1 (de) | 1997-05-23 | 1998-05-21 | Raf kinase hemmer |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0986382B1 (de) |
| JP (1) | JP2002500650A (de) |
| AT (1) | ATE399007T1 (de) |
| AU (1) | AU7585598A (de) |
| CA (1) | CA2291065C (de) |
| DE (2) | DE69839639D1 (de) |
| DK (1) | DK0986382T3 (de) |
| ES (1) | ES2153337T3 (de) |
| GR (1) | GR20010300033T1 (de) |
| WO (1) | WO1998052559A1 (de) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7517880B2 (en) | 1997-12-22 | 2009-04-14 | Bayer Pharmaceuticals Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
| DK1056725T3 (da) * | 1997-12-22 | 2006-10-02 | Bayer Pharmaceuticals Corp | Inhibering af raf-kinase ved hjælp af aryl- og heteroaryl-substituerede heterocykliske urinstoffer |
| AU2003204708B2 (en) * | 1997-12-22 | 2006-05-25 | Bayer Healthcare Llc | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
| PL205321B1 (pl) * | 1997-12-22 | 2010-04-30 | Bayer Corp | Zastosowanie podstawionych heterocyklicznych moczników do wytwarzania leku do hamowania kinazy raf, podstawione heterocykliczne moczniki oraz kompozycja farmaceutyczna je zawierająca |
| US7329670B1 (en) | 1997-12-22 | 2008-02-12 | Bayer Pharmaceuticals Corporation | Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas |
| PA8489701A1 (es) * | 1999-01-13 | 2002-11-18 | Bayer Corp | Ureas difenil-(w-carboxiaril substituidas como inhibidores de raf quinasa |
| EP1690853B1 (de) * | 1999-01-13 | 2010-03-10 | Bayer HealthCare LLC | Verwendung von Omega-Carboxyaryl-substituierten Diphenylharnstoffen als raf-Kinase-Inhibitoren |
| US8124630B2 (en) | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| EP2298311B1 (de) | 1999-01-13 | 2012-05-09 | Bayer HealthCare LLC | Omega-carboxyarylsubstituierte-Diphenyl-Harnstoffe als p38-Kinasehemmer |
| EP1140840B1 (de) | 1999-01-13 | 2006-03-22 | Bayer Pharmaceuticals Corp. | -g(v)-carboxyaryl substituierte diphenyl harnstoffe als raf kinase inhibitoren |
| ME00275B (me) * | 1999-01-13 | 2011-02-10 | Bayer Corp | ω-KARBOKSIARIL SUPSTITUISANI DIFENIL KARBAMIDI KAO INHIBITORI RAF KINAZE |
| UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
| MXPA01008440A (es) | 1999-02-22 | 2002-04-24 | Boehringer Ingelheim Pharma | Derivados heterociclicos policiclos como agentes anti-inflamatorios.. |
| EP1159273A1 (de) | 1999-03-02 | 2001-12-05 | Boehringer Ingelheim Pharmaceuticals Inc. | Verbindungen, verwendbar als reversible inhibitoren von cathepsin s |
| SK12832001A3 (sk) | 1999-03-12 | 2002-01-07 | Boehringer Ingelheim Pharmaceuticals, Inc. | Protizápalové látky, spôsob ich výroby, farmaceutický prostriedok s ich obsahom a ich použitie |
| ATE309237T1 (de) | 1999-03-12 | 2005-11-15 | Boehringer Ingelheim Pharma | Aromatische heterozyklische verbindungen als antientzündungwirkstoffe |
| HN2000000051A (es) * | 1999-05-19 | 2001-02-02 | Pfizer Prod Inc | Derivados heterociclicos utiles como agentes anticancerosos |
| US6573409B1 (en) | 1999-07-02 | 2003-06-03 | The Nutrasweet Company | Process for the preparation of 3,3-dimethylbutanal |
| DE60024830T2 (de) | 1999-07-09 | 2006-06-14 | Boehringer Ingelheim Pharma | Verfahren zur herstellung heteroarylsubstituierter ureaverbindungen |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| US6525046B1 (en) | 2000-01-18 | 2003-02-25 | Boehringer Ingelheim Pharmaceuticals, Inc. | Aromatic heterocyclic compounds as antiinflammatory agents |
| US6608052B2 (en) | 2000-02-16 | 2003-08-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
| US6414013B1 (en) * | 2000-06-19 | 2002-07-02 | Pharmacia & Upjohn S.P.A. | Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention |
| DE10050492A1 (de) * | 2000-10-11 | 2002-04-25 | Morphochem Ag | Verfahren zur Herstellung von 5-Oxo-2,5-dihydro-furan-2-carbonsäureamiden und 6-Oxo-3,6-dihydro-2H-pyran-2-carbonsäureamiden |
| WO2002044156A2 (en) | 2000-11-29 | 2002-06-06 | Glaxo Group Limited | Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors |
| US7235576B1 (en) | 2001-01-12 | 2007-06-26 | Bayer Pharmaceuticals Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US7371763B2 (en) | 2001-04-20 | 2008-05-13 | Bayer Pharmaceuticals Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
| EP1392661A1 (de) | 2001-05-16 | 2004-03-03 | Boehringer Ingelheim Pharmaceuticals Inc. | Diarylharnstoffderivate, die sich als entzündungshemmende mittel eignen |
| CA2448626A1 (en) | 2001-05-25 | 2002-12-05 | Boehringer Ingelheim Pharmaceuticals, Inc. | Carbamate and oxamide compounds as inhibitors of cytokine production |
| CA2450007C (en) | 2001-06-11 | 2012-04-17 | Shire Biochem Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
| EP1709965A3 (de) * | 2001-07-11 | 2006-12-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Methode zur Behandlung von zytokinvermittelten Erkrankungen |
| MXPA04005137A (es) * | 2001-12-03 | 2005-06-03 | Bayer Pharmaceuticals Corp | Compuestos de aril urea en combinacion con otros agentes citostaticos para el tratamiento de canceres humanos. |
| ES2425739T3 (es) | 2002-02-11 | 2013-10-17 | Bayer Healthcare Llc | Sorafenib-tosilato para el tratamiento de enfermedades caracterizadas por angiogénesis anormal |
| DK1580188T3 (da) | 2002-02-11 | 2012-02-06 | Bayer Healthcare Llc | Forbindelser af arylurea som kinaseinhibitorer |
| ES2299689T3 (es) | 2002-02-25 | 2008-06-01 | Boehringer Ingelheim Pharmaceuticals Inc. | Compuestos de cicloalquil-uera fusionada con benzo 1,4-disustituido, utiles para el tratamiento de enfermedades por citoquinas. |
| EP1707205A2 (de) | 2002-07-09 | 2006-10-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Pharazeutische zusammensetzungen aus anticholinergica und p38 kinase hemmern zur behandlung von erkrankungen der atemwege |
| NZ540878A (en) | 2003-01-14 | 2008-06-30 | Cytokinetics Inc | Compounds, compositions and methods |
| US7902192B2 (en) | 2003-05-15 | 2011-03-08 | Arqule, Inc. | Inhibitors of P38 and methods of using the same |
| CA2526636C (en) | 2003-05-20 | 2012-10-02 | Bayer Pharmaceuticals Corporation | Diaryl ureas for diseases mediated by pdgfr |
| BR122016015715B8 (pt) | 2003-07-23 | 2021-05-25 | Bayer Healthcare Llc | composições farmacêuticas de metilamida de ácido 4[4-[3-(4-cloro-3-trifluorometilfenil)-ureido]-3-fluorofenóxi)-piridina-2-carboxílico |
| WO2005016909A1 (en) * | 2003-08-15 | 2005-02-24 | Astrazeneca Ab | Substituted thiophenes and uses thereof |
| TW200530236A (en) | 2004-02-23 | 2005-09-16 | Chugai Pharmaceutical Co Ltd | Heteroaryl phenylurea |
| EP2295427A1 (de) | 2004-04-30 | 2011-03-16 | Bayer HealthCare, LLC | Substituierte Pyrazolyl-harnstoff-derivate zur Behandlung von Krebs |
| EP2862859B1 (de) | 2004-06-17 | 2018-07-25 | Cytokinetics, Inc. | Verbindungen, zusammensetzungen und verfahren |
| WO2006010082A1 (en) | 2004-07-08 | 2006-01-26 | Arqule, Inc. | 1,4-disubstituted naphtalenes as inhibitors of p38 map kinase |
| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| WO2006044869A1 (en) | 2004-10-19 | 2006-04-27 | Arqule, Inc. | Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 map kinase |
| WO2006062982A2 (en) | 2004-12-07 | 2006-06-15 | Locus Pharmaceuticals, Inc. | Urea inhibitors of map kinases |
| WO2006062984A2 (en) | 2004-12-07 | 2006-06-15 | Locus Pharmaceuticals, Inc. | Inhibitors of protein kinases |
| GB0428082D0 (en) | 2004-12-22 | 2005-01-26 | Welcome Trust The Ltd | Therapeutic compounds |
| PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
| BRPI0608840B8 (pt) | 2005-03-07 | 2021-05-25 | Batyer Healthcare Ag | composição farmacêutica compreendendo uma difenil uréia substituída por ômega-carboxiarila, e seu processo de preparação |
| CA2607359C (en) | 2005-05-13 | 2011-08-09 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
| US7538223B2 (en) | 2005-08-04 | 2009-05-26 | Cytokinetics, Inc. | Compounds, compositions and methods |
| JP5072595B2 (ja) | 2005-08-05 | 2012-11-14 | 中外製薬株式会社 | マルチキナーゼ阻害剤 |
| TW200808321A (en) | 2005-12-15 | 2008-02-16 | Cytokinetics Inc | Certain chemical entities, compositions and methods |
| US7825120B2 (en) | 2005-12-15 | 2010-11-02 | Cytokinetics, Inc. | Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas |
| EP1959962A2 (de) | 2005-12-16 | 2008-08-27 | Cytokinetics, Inc. | Bestimmte chemische stoffe, zusammensetzungen und verfahren |
| US7989455B2 (en) | 2005-12-19 | 2011-08-02 | Cytokinetics, Inc. | Compounds, compositions and methods |
| EP1992344A1 (de) | 2007-05-18 | 2008-11-19 | Institut Curie | P38 Alpha als therapeutisches Target für Erkrankungen, die mit einer FGFR3- Mutation assoziiert sind |
| CN102627657B (zh) * | 2012-03-09 | 2015-01-07 | 苏州施亚生物科技有限公司 | 3-(4-甲氧基-苄基)-1h-嘧啶-2,4-二酮衍生物的合成方法 |
| US9629851B2 (en) | 2013-09-20 | 2017-04-25 | Stitching Het Nederlands Kanker Institut—Antoni Van Leeuwenhoek Ziekenhuis | ROCK in combination with MAPK pathway |
| WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
| US20170027940A1 (en) | 2014-04-10 | 2017-02-02 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
| CN106470974B (zh) | 2014-04-17 | 2019-07-16 | 韩国巴斯德研究所 | 用于治疗病毒感染的化合物 |
| WO2015178770A1 (en) | 2014-05-19 | 2015-11-26 | Stichting Het Nederlands Kanker Instituut | Compositions for cancer treatment |
| EP3533791B1 (de) * | 2016-10-26 | 2020-12-30 | Ishihara Sangyo Kaisha, Ltd. | Verfahren zur herstellung von 3-methyl-2-thiophencarbonsäure |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61268678A (ja) * | 1985-05-17 | 1986-11-28 | バイエル・アクチエンゲゼルシヤフト | 生産増進剤 |
| US5597719A (en) * | 1994-07-14 | 1997-01-28 | Onyx Pharmaceuticals, Inc. | Interaction of RAF-1 and 14-3-3 proteins |
| US5773459A (en) * | 1995-06-07 | 1998-06-30 | Sugen, Inc. | Urea- and thiourea-type compounds |
| EP1019040B1 (de) * | 1997-05-23 | 2004-09-29 | Bayer Corporation | Arylharnstoffderivate zur behandlung von inflammatorischen oder immunomodulatorischen erkrankungen |
-
1998
- 1998-05-21 AT AT98923601T patent/ATE399007T1/de not_active IP Right Cessation
- 1998-05-21 DE DE69839639T patent/DE69839639D1/de not_active Expired - Lifetime
- 1998-05-21 JP JP55061898A patent/JP2002500650A/ja active Pending
- 1998-05-21 AU AU75855/98A patent/AU7585598A/en not_active Abandoned
- 1998-05-21 WO PCT/US1998/010376 patent/WO1998052559A1/en not_active Ceased
- 1998-05-21 DK DK98923601T patent/DK0986382T3/da active
- 1998-05-21 EP EP98923601A patent/EP0986382B1/de not_active Expired - Lifetime
- 1998-05-21 ES ES98923601T patent/ES2153337T3/es not_active Expired - Lifetime
- 1998-05-21 CA CA2291065A patent/CA2291065C/en not_active Expired - Fee Related
- 1998-05-21 DE DE0986382T patent/DE986382T1/de active Pending
-
2001
- 2001-06-29 GR GR20010300033T patent/GR20010300033T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0986382A1 (de) | 2000-03-22 |
| EP0986382B1 (de) | 2008-06-25 |
| GR20010300033T1 (en) | 2001-06-29 |
| CA2291065A1 (en) | 1998-11-26 |
| ES2153337T1 (es) | 2001-03-01 |
| DE986382T1 (de) | 2001-01-25 |
| EP0986382A4 (de) | 2001-04-11 |
| WO1998052559A1 (en) | 1998-11-26 |
| ES2153337T3 (es) | 2008-11-01 |
| CA2291065C (en) | 2010-02-09 |
| DE69839639D1 (en) | 2008-08-07 |
| JP2002500650A (ja) | 2002-01-08 |
| AU7585598A (en) | 1998-12-11 |
| DK0986382T3 (da) | 2008-10-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| UEP | Publication of translation of european patent specification |
Ref document number: 0986382 Country of ref document: EP |
|
| REN | Ceased due to non-payment of the annual fee |