JP5756850B2 - フロピリジン化合物およびその使用 - Google Patents
フロピリジン化合物およびその使用 Download PDFInfo
- Publication number
- JP5756850B2 JP5756850B2 JP2013505470A JP2013505470A JP5756850B2 JP 5756850 B2 JP5756850 B2 JP 5756850B2 JP 2013505470 A JP2013505470 A JP 2013505470A JP 2013505470 A JP2013505470 A JP 2013505470A JP 5756850 B2 JP5756850 B2 JP 5756850B2
- Authority
- JP
- Japan
- Prior art keywords
- methylsulfonamido
- cyclopropyl
- methyl
- pyridin
- furo
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (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)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32649110P | 2010-04-21 | 2010-04-21 | |
| US61/326,491 | 2010-04-21 | ||
| PCT/EP2011/056304 WO2011131709A1 (en) | 2010-04-21 | 2011-04-20 | Furopyridine compounds and uses thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2013527842A JP2013527842A (ja) | 2013-07-04 |
| JP2013527842A5 JP2013527842A5 (enExample) | 2014-05-08 |
| JP5756850B2 true JP5756850B2 (ja) | 2015-07-29 |
Family
ID=44010017
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013505470A Expired - Fee Related JP5756850B2 (ja) | 2010-04-21 | 2011-04-20 | フロピリジン化合物およびその使用 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US8324239B2 (enExample) |
| EP (1) | EP2560976B9 (enExample) |
| JP (1) | JP5756850B2 (enExample) |
| CN (1) | CN103025738B (enExample) |
| AR (1) | AR082453A1 (enExample) |
| ES (1) | ES2605039T3 (enExample) |
| TW (1) | TW201139446A (enExample) |
| UY (1) | UY33348A (enExample) |
| WO (1) | WO2011131709A1 (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112013009789A2 (pt) * | 2010-10-26 | 2016-07-19 | Presidio Pharmaceuticals Inc | inibidores do vírus da hepatite c |
| WO2013163466A1 (en) * | 2012-04-25 | 2013-10-31 | Presidio Pharmaceuticals, Inc. | Inhibitors of hepatitis c virus |
| TWI731854B (zh) | 2015-03-23 | 2021-07-01 | 美商共結晶製藥公司 | C型肝炎病毒聚合酶之抑制劑 |
| BR112017023821A2 (pt) | 2015-05-06 | 2018-07-31 | Leidos Biomedical Res Inc | moduladores de k-ras |
| BR112019021899A2 (pt) | 2017-04-20 | 2020-08-18 | The Regents Of The University Of California | moduladores de k-ras |
| KR102659322B1 (ko) * | 2017-05-19 | 2024-04-22 | 엔플렉션 테라퓨틱스, 인코포레이티드 | 피부병 치료를 위한 융합된 헤테로방향족-아닐린 화합물 |
| WO2019204449A1 (en) * | 2018-04-18 | 2019-10-24 | Theras, Inc. | K-ras modulators with a vinyl sulfone moiety |
| CN108727309B (zh) * | 2018-06-20 | 2023-04-07 | 天津全和诚科技有限责任公司 | 一种3-氧杂环丁烷羧酸的合成方法 |
Family Cites Families (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383A (en) | 1846-02-10 | Improvement in condensing steam and feeding steam-boilers | ||
| 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 |
| KR0148748B1 (ko) | 1988-09-16 | 1998-08-17 | 장 크라메르, 한스 루돌프 하우스 | 사이클로스포린을 함유하는 약학조성물 |
| DK0527788T3 (da) | 1990-04-04 | 2004-09-06 | Chiron Corp | Hepatitis C virus protease |
| ATE355380T1 (de) | 1993-04-02 | 2006-03-15 | Rigel Pharmaceuticals Inc | Methode zur selektiven inaktivierung der viralen replication |
| IT1272179B (it) | 1994-02-23 | 1997-06-16 | Angeletti P Ist Richerche Bio | Metodologia per riprodurre in vitro l'attivita' proteolitica della proteasi ns3 del virus hcv. |
| US5703116A (en) | 1995-04-18 | 1997-12-30 | Geron Corporation | Telomerase Inhibitors |
| US5861267A (en) | 1995-05-01 | 1999-01-19 | Vertex Pharmaceuticals Incorporated | Methods, nucleotide sequences and host cells for assaying exogenous and endogenous protease activity |
| JP4191797B2 (ja) | 1995-09-27 | 2008-12-03 | エモリー ユニバーシティー | 組み換えc型肝炎ウイルスrnaレプリカーゼ |
| US5759795A (en) | 1996-03-08 | 1998-06-02 | Schering Corporation | Assay for determining inhibitors of ATPase |
| NZ337703A (en) | 1997-03-05 | 2001-05-25 | Univ Washington | A screening method to identify agents that selectively inhibit Hepatitis C virus replication in viruses that contain an ISDR region |
| CA2312484A1 (en) | 1997-12-11 | 1999-06-17 | Smithkline Beecham Corporation | Hepatitis c virus ns5b truncated protein and methods thereof to identify antiviral compounds |
| US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
| JPWO2002051849A1 (ja) | 2000-12-26 | 2004-04-22 | 第一製薬株式会社 | Cdk4活性阻害剤 |
| WO2002072549A1 (en) | 2001-03-12 | 2002-09-19 | Millennium Pharmaceuticals, Inc. | Functionalized heterocycles as modulators of chemokine receptor function and methods of use therefor |
| EP2335700A1 (en) | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
| US7429593B2 (en) | 2001-09-14 | 2008-09-30 | Shionogi & Co., Ltd. | Utilities of amide compounds |
| WO2004078163A2 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| ATE375349T1 (de) | 2002-08-02 | 2007-10-15 | Merck & Co Inc | Substituierte furo(2,3-b)pyridin derivate |
| US20050069522A1 (en) | 2002-08-12 | 2005-03-31 | Richard Colonno | Combination pharmaceutical agents as inhibitors of HCV replication |
| BR0315233A (pt) | 2002-10-09 | 2005-08-23 | Scios Inc | Derivados de azaindol como inibidores de p38 cinase |
| HN2003000348A (es) | 2002-11-01 | 2008-10-14 | Viropharma Inc | Compuestos de benzofurano, composiciones y metodos para tratamiento y profilaxis de infeccion virales de hepatitis c y enfermedades asociadas. |
| MXPA05010802A (es) | 2003-04-25 | 2005-12-14 | Univ Cardiff | Compuestos heterociclicos para el uso en el tratamiento de infecciones virales. |
| AU2004259012C1 (en) | 2003-07-23 | 2012-08-02 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
| US7511145B2 (en) | 2003-08-01 | 2009-03-31 | Genelabs Technologies, Inc. | Bicyclic heteroaryl derivatives |
| UY28526A1 (es) | 2003-09-24 | 2005-04-29 | Boehringer Ingelheim Pharma | Miméticos de glucocorticoides, métodos de preparación composiciones farmacéuticas y usos de los mismos |
| TW200528459A (en) | 2004-01-06 | 2005-09-01 | Achillion Pharmaceuticals Inc | Azabenzofuran substituted thioureas; inhibitors of viral replication |
| WO2005072412A2 (en) | 2004-01-29 | 2005-08-11 | Elixir Pharmaceuticals, Inc. | Anti-viral therapeutics |
| TW200538120A (en) | 2004-02-20 | 2005-12-01 | Kirin Brewery | Compound having TGF-beta inhibitory activity and pharmaceutical composition containing same |
| JPWO2005082905A1 (ja) | 2004-02-26 | 2007-08-02 | 協和醗酵工業株式会社 | 二環性複素環化合物 |
| US7846959B2 (en) | 2004-05-07 | 2010-12-07 | Exelixis, Inc. | Raf modulators and methods of use |
| JP5026963B2 (ja) | 2004-06-22 | 2012-09-19 | 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 | カルシウムチャネル調整用の複素環誘導体 |
| TW200618800A (en) | 2004-08-03 | 2006-06-16 | Uriach Y Compania S A J | Heterocyclic compounds |
| GB0420719D0 (en) | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
| JP2008517896A (ja) | 2004-10-21 | 2008-05-29 | ファイザー・インク | C型肝炎ウイルスプロテアーゼの阻害剤並びにそれを用いた組成物及び治療 |
| EP1948137A2 (en) | 2005-11-10 | 2008-07-30 | Wyeth a Corporation of the State of Delaware | Pharmaceutical formulations containing 5-cyclopropyl-2(4-fluorophenyl)-6-(2-hydroxyethyl)(methylsulfonyl) amino-n-methyl-1-benzofuran-3-carboxamide and method of making same |
| US20070208053A1 (en) | 2006-01-19 | 2007-09-06 | Arnold Lee D | Fused heterobicyclic kinase inhibitors |
| WO2008011557A2 (en) | 2006-07-20 | 2008-01-24 | Borchardt Allen J | Heteroaryl inhibitors of rho kinase |
| WO2008057857A1 (en) | 2006-11-01 | 2008-05-15 | Bristol-Myers Squibb Company | MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF |
| EP2094692B1 (en) | 2006-11-01 | 2012-11-28 | Bristol-Myers Squibb Company | Modulators of glucocorticoid receptor, ap-1 and/or nf-kappab activity and use thereof |
| MX2009008439A (es) | 2007-02-12 | 2009-08-13 | Intermune Inc | Nuevos inhibidores de la replicacion del virus de hepatitis c. |
| TW200900408A (en) | 2007-03-02 | 2009-01-01 | Kyowa Hakko Kogyo Kk | Fused pyridine derivative |
| PE20090142A1 (es) | 2007-04-11 | 2009-02-19 | Merck & Co Inc | Derivados de furo[2,3-b] piridina sustituidos como moduladores del receptor canabinoide-1 |
| GB0707000D0 (en) | 2007-04-12 | 2007-05-30 | Istituto Di Ricerche D Biolog | Antiviral agents |
| WO2008128995A1 (en) | 2007-04-23 | 2008-10-30 | Janssen Pharmaceutica N.V. | 4-alkoxypyridazine derivatives as fast dissociating dopamine 2 receptor antagonists |
| KR101596524B1 (ko) | 2007-06-29 | 2016-02-22 | 길리애드 사이언시즈, 인코포레이티드 | 항바이러스 화합물 |
| WO2009027732A1 (en) | 2007-08-24 | 2009-03-05 | Astrazeneca Ab | 5-6-bicyclic heteroaromatic compounds with antibacterial activity |
| WO2009041591A1 (ja) | 2007-09-28 | 2009-04-02 | Kyowa Hakko Kirin Co., Ltd. | 縮環ピリジン誘導体 |
| CN101910145A (zh) | 2008-02-14 | 2010-12-08 | 弗·哈夫曼-拉罗切有限公司 | 抗病毒的杂环化合物 |
| US8546410B2 (en) | 2008-05-05 | 2013-10-01 | Abbvie Inc. | Heteroaryl-fused macrocyclic pyrimidine derivatives |
| WO2009137500A1 (en) | 2008-05-05 | 2009-11-12 | Wyeth | 6-substituted benzofuran compounds to treat infection with hepatitis c virus |
| US8048887B2 (en) | 2008-09-11 | 2011-11-01 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US8198449B2 (en) | 2008-09-11 | 2012-06-12 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
-
2011
- 2011-04-19 US US13/089,764 patent/US8324239B2/en active Active
- 2011-04-19 AR ARP110101347A patent/AR082453A1/es unknown
- 2011-04-20 EP EP11715244.7A patent/EP2560976B9/en not_active Not-in-force
- 2011-04-20 TW TW100113755A patent/TW201139446A/zh unknown
- 2011-04-20 ES ES11715244.7T patent/ES2605039T3/es active Active
- 2011-04-20 JP JP2013505470A patent/JP5756850B2/ja not_active Expired - Fee Related
- 2011-04-20 WO PCT/EP2011/056304 patent/WO2011131709A1/en not_active Ceased
- 2011-04-20 CN CN201180030410.5A patent/CN103025738B/zh not_active Expired - Fee Related
- 2011-04-25 UY UY0001033348A patent/UY33348A/es not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| TW201139446A (en) | 2011-11-16 |
| US8324239B2 (en) | 2012-12-04 |
| AR082453A1 (es) | 2012-12-12 |
| JP2013527842A (ja) | 2013-07-04 |
| EP2560976B9 (en) | 2017-06-07 |
| CN103025738B (zh) | 2015-08-19 |
| ES2605039T3 (es) | 2017-03-10 |
| CN103025738A (zh) | 2013-04-03 |
| US20120015907A1 (en) | 2012-01-19 |
| EP2560976B1 (en) | 2016-08-24 |
| EP2560976A1 (en) | 2013-02-27 |
| WO2011131709A1 (en) | 2011-10-27 |
| UY33348A (es) | 2011-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5756850B2 (ja) | フロピリジン化合物およびその使用 | |
| ES2634095T3 (es) | Compuestos antivíricos | |
| RU2720237C2 (ru) | Композиции, содержащие бензопиперазин, в качестве ингибиторов бромодоменов вет | |
| US8552047B2 (en) | Hepatitis C virus inhibitors | |
| TW200938191A (en) | Hepatitis C virus inhibitors | |
| CA2828478A1 (en) | Serine/threonine kinase inhibitors | |
| EA037883B1 (ru) | Противовирусные соединения | |
| TW201121955A (en) | Hepatitis C virus inhibitors | |
| BR112014028221A2 (pt) | compostos antivirais, composição farmacêutica que os compreende e uso | |
| AU2015247706A1 (en) | Potent and selective inhibitors of hepatitis C virus | |
| WO2014209726A1 (en) | Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases | |
| US9549921B2 (en) | Heterocyclic compounds and methods of use thereof for the treatment of hepatitis C | |
| JP5650324B2 (ja) | 2,3,5−三置換チオフェン化合物およびそれらの使用 | |
| RU2830596C1 (ru) | Биарильные производные в качестве ингибиторов белок-белкового взаимодействия yap/taz-tead | |
| TW201247656A (en) | 2,3,5-trisubstituted thiophene compounds and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140320 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140320 |
|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20140822 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20140902 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150120 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20150122 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150416 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150519 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150601 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5756850 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |