HRP20202073T1 - Derivati n-(fenilsulfonil)benzamida kao bcl-2 inhibitori - Google Patents
Derivati n-(fenilsulfonil)benzamida kao bcl-2 inhibitori Download PDFInfo
- Publication number
- HRP20202073T1 HRP20202073T1 HRP20202073TT HRP20202073T HRP20202073T1 HR P20202073 T1 HRP20202073 T1 HR P20202073T1 HR P20202073T T HRP20202073T T HR P20202073TT HR P20202073 T HRP20202073 T HR P20202073T HR P20202073 T1 HRP20202073 T1 HR P20202073T1
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- pharmaceutically acceptable
- cancer
- solvate
- image
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic 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
- C07D471/02—Heterocyclic 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
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662371504P | 2016-08-05 | 2016-08-05 | |
| US201762454101P | 2017-02-03 | 2017-02-03 | |
| EP17754889.8A EP3494115B1 (en) | 2016-08-05 | 2017-08-04 | N-(phenylsulfonyl)benzamide derivatives as bcl-2 inhibitors |
| PCT/US2017/045428 WO2018027097A1 (en) | 2016-08-05 | 2017-08-04 | N-(phenylsulfonyl)benzamides and related compounds as bcl-2 inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20202073T1 true HRP20202073T1 (hr) | 2021-02-19 |
Family
ID=59677319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20202073TT HRP20202073T1 (hr) | 2016-08-05 | 2017-08-04 | Derivati n-(fenilsulfonil)benzamida kao bcl-2 inhibitori |
Country Status (27)
| Country | Link |
|---|---|
| US (3) | US10829488B2 (enExample) |
| EP (3) | EP3494115B1 (enExample) |
| JP (2) | JP6651180B2 (enExample) |
| KR (2) | KR102376764B1 (enExample) |
| CN (2) | CN109311871B (enExample) |
| AU (2) | AU2017305508B2 (enExample) |
| CA (1) | CA3031419C (enExample) |
| CY (1) | CY1123859T1 (enExample) |
| DK (1) | DK3494115T3 (enExample) |
| ES (1) | ES2849959T3 (enExample) |
| HR (1) | HRP20202073T1 (enExample) |
| HU (1) | HUE053414T2 (enExample) |
| IL (2) | IL264059B (enExample) |
| LT (1) | LT3494115T (enExample) |
| MX (2) | MX381588B (enExample) |
| MY (1) | MY199409A (enExample) |
| PE (1) | PE20190711A1 (enExample) |
| PH (1) | PH12019500231A1 (enExample) |
| PT (1) | PT3494115T (enExample) |
| RS (1) | RS61821B1 (enExample) |
| RU (2) | RU2722560C1 (enExample) |
| SA (1) | SA519401020B1 (enExample) |
| SG (2) | SG11201900135YA (enExample) |
| SI (1) | SI3494115T1 (enExample) |
| SM (1) | SMT202100025T1 (enExample) |
| WO (1) | WO2018027097A1 (enExample) |
| ZA (2) | ZA201900240B (enExample) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017156398A1 (en) * | 2016-03-10 | 2017-09-14 | Assia Chemical Industries Ltd. | Solid state forms of venetoclax and processes for preparation of venetoclax |
| KR102376764B1 (ko) * | 2016-08-05 | 2022-03-18 | 더 리젠츠 오브 더 유니버시티 오브 미시건 | Bcl-2 억제제로서의 n-(페닐설포닐)벤즈아미드 및 관련 화합물 |
| CN110177788B (zh) | 2017-01-07 | 2023-03-24 | 重庆复创医药研究有限公司 | 作为bcl-2选择性凋亡诱导剂的化合物 |
| SI3612531T1 (sl) * | 2017-04-18 | 2022-11-30 | Shanghai Fochon Pharmaceutical Co., Ltd. | Sredstva, ki sprožajo apoptozo |
| CN112437772B (zh) | 2018-04-29 | 2023-11-21 | 百济神州有限公司 | Bcl-2抑制剂 |
| CA3095699A1 (en) * | 2018-07-31 | 2020-02-06 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination product of bcl-2 inhibitor and chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases |
| AU2019315466B2 (en) * | 2018-07-31 | 2022-05-19 | Ascentage Pharma (Suzhou) Co., Ltd. | Synergistic antitumor effect of Bcl-2 inhibitor combined with rituximab and/or bendamustine or Bcl-2 inhibitor combined with CHOP |
| CN110772521A (zh) * | 2018-07-31 | 2020-02-11 | 苏州亚盛药业有限公司 | Bcl-2抑制剂或Bcl-2/Bcl-xL抑制剂与BTK抑制剂的组合产品及其用途 |
| US11478469B2 (en) | 2018-07-31 | 2022-10-25 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination product of BCL-2 inhibitor and MDM2 inhibitor and use thereof in the prevention and/or treatment of diseases |
| EP3706741A4 (en) * | 2018-11-23 | 2022-03-30 | Ascentage Pharma (Suzhou) Co., Ltd. | PHARMACEUTICAL COMPOSITION AND USE THEREOF |
| TWI770503B (zh) * | 2019-05-13 | 2022-07-11 | 大陸商蘇州亞盛藥業有限公司 | 用於預測bcl-2/bcl-xl抑制劑對癌症的功效的方法和組合物 |
| WO2021000899A1 (en) * | 2019-07-02 | 2021-01-07 | Ascentage Pharma (Suzhou) Co., Ltd. | A PHARMACEUTICAL COMBINATION CONTAINING mTOR INHIBITOR AND USE THEREOF |
| US12370197B2 (en) * | 2019-07-31 | 2025-07-29 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination product of a Bcl-2/Bcl-xL inhibitor and a chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases |
| WO2021083135A1 (en) | 2019-10-28 | 2021-05-06 | Beigene, Ltd. | Bcl-2 INHIBITORS |
| WO2021104442A1 (en) * | 2019-11-27 | 2021-06-03 | Ascentage Pharma (Suzhou) Co., Ltd. | Method and compositions for predicting anti-cancer efficacy of compounds targeting apoptosis pathway |
| EP3914251A4 (en) | 2019-12-03 | 2022-03-23 | Ascentage Pharma (Suzhou) Co., Ltd. | N-(PHENYLSULFONYL)BENZAMIDES AND RELATED COMPOUNDS USED AS BCL-2 INHIBITORS |
| CN118542872A (zh) * | 2019-12-04 | 2024-08-27 | 苏州亚盛药业有限公司 | 药物组合及其用途 |
| KR20220100992A (ko) | 2019-12-06 | 2022-07-18 | 록쏘 온콜로지, 인코포레이티드 | 브루톤 티로신 키나제 억제제의 투여 |
| BR112022012283A2 (pt) | 2019-12-20 | 2022-08-30 | Recurium Ip Holdings Llc | Combinações |
| TWI777438B (zh) * | 2020-03-06 | 2022-09-11 | 大陸商蘇州亞盛藥業有限公司 | N- (苯基磺醯基) 苯甲醯胺類化合物的結晶形式 |
| CN115244051B (zh) * | 2020-03-12 | 2024-10-18 | 南京明德新药研发有限公司 | 苯并五元环类化合物 |
| CN116969937B (zh) | 2020-04-15 | 2026-03-24 | 百济神州(苏州)生物科技有限公司 | Bcl-2抑制剂 |
| WO2021227763A1 (en) * | 2020-05-14 | 2021-11-18 | Ascentage Pharma (Suzhou) Co., Ltd. | Hplc analysis method for n- (phenylsulfonyl) benzamide compound |
| CN113880834B (zh) * | 2020-07-01 | 2023-01-20 | 苏州亚盛药业有限公司 | N-(苯基磺酰基)苯甲酰胺类化合物及其中间体的合成方法 |
| CN111537654B (zh) * | 2020-07-07 | 2020-11-10 | 上海亚盛医药科技有限公司 | N-(苯基磺酰基)苯甲酰胺化合物的hplc分析方法 |
| CN115697967B (zh) * | 2020-07-10 | 2024-10-22 | 江苏恒瑞医药股份有限公司 | 磺酰苯甲酰胺类衍生物及其偶联物、其制备方法及其应用 |
| CN114057728A (zh) * | 2020-08-06 | 2022-02-18 | 北京诺诚健华医药科技有限公司 | 作为bcl-2抑制剂的杂环化合物 |
| CN114073707A (zh) * | 2020-08-21 | 2022-02-22 | 苏州亚盛药业有限公司 | 治疗系统性红斑狼疮的组合物和方法 |
| CN114073703B (zh) * | 2020-08-21 | 2022-12-30 | 苏州亚盛药业有限公司 | 用于治疗非酒精性脂肪肝炎的组合物和方法 |
| JP2023551056A (ja) * | 2020-11-25 | 2023-12-06 | アセンテージ ファーマ（スーチョウ）カンパニー，リミティド | 固体分散体、医薬製剤、その製造方法及び応用 |
| US20240316069A1 (en) * | 2020-12-28 | 2024-09-26 | Ascentage Pharma (Suzhou) Co., Ltd. | Methods of treating multiple sclerosis |
| CN114835704B (zh) * | 2021-02-01 | 2023-10-27 | 苏州亚盛药业有限公司 | 作为bcl-2抑制剂的磺酰基苯甲酰胺衍生物 |
| US20250319183A1 (en) | 2021-04-07 | 2025-10-16 | David Avigan | Compositions and methods for the treatment of cancer |
| JP2024528174A (ja) | 2021-08-02 | 2024-07-26 | アセンテージ ファーマ（スーチョウ）カンパニー，リミティド | 医薬組合せおよびその使用 |
| JP7765790B2 (ja) * | 2021-12-06 | 2025-11-07 | 杭州和正医薬有限公司 | 抗アポトーシスタンパク質ｂｃｌ－２阻害剤、医薬組成物及びその使用 |
| CN115260191B (zh) * | 2022-09-29 | 2022-12-27 | 上海睿跃生物科技有限公司 | 哌啶类化合物及其制备方法和应用 |
| EP4421075A1 (en) * | 2023-02-27 | 2024-08-28 | KRKA, d.d., Novo mesto | Process for the preparation of venetoclax and intermediates used therein |
| JP2026510567A (ja) | 2023-03-03 | 2026-04-08 | アイオンクチュラ・ソシエテ・アノニム | 血液悪性腫瘍の治療におけるロギノリシブ及びｂｃｌ－２阻害剤の組み合わせ |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1021343A (en) | 1912-01-17 | 1912-03-26 | M A N Mfg Company | Locking-clamp. |
| US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
| WO2005049593A2 (en) | 2003-11-13 | 2005-06-02 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
| US7767684B2 (en) * | 2003-11-13 | 2010-08-03 | Abbott Laboratories | Apoptosis promoters |
| US8624027B2 (en) | 2005-05-12 | 2014-01-07 | Abbvie Inc. | Combination therapy for treating cancer and diagnostic assays for use therein |
| MX2009002422A (es) | 2006-09-05 | 2009-03-20 | Abbott Lab | Inhibidores bcl para tratar exceso de plaquetas. |
| KR20090087491A (ko) | 2006-12-04 | 2009-08-17 | 아보트 러보러터리즈 | 암 치료요법을 위한 동반 진단 검정 |
| UA108193C2 (uk) * | 2008-12-04 | 2015-04-10 | Апоптозіндукуючий засіб для лікування раку і імунних і аутоімунних захворювань | |
| NZ614305A (en) | 2008-12-05 | 2015-03-27 | Abbvie Inc | Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
| RU2538965C2 (ru) | 2009-01-19 | 2015-01-10 | Эббви Инк. | Вызывающие апоптоз средства для лечения рака и иммунных и аутоиммунных заболеваний |
| CA2751293A1 (en) | 2009-02-11 | 2010-08-19 | Abbott Laboratories | Methods and compositions for identifying, classifying and monitoring subject having bcl-2 family inhibitor-resistant tumors and cancers |
| US8546399B2 (en) * | 2009-05-26 | 2013-10-01 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
| ES2546294T7 (es) * | 2009-05-26 | 2024-06-06 | Abbvie Ireland Unlimited Co | Agentes inductores de la apoptosis para el tratamiento de cáncer y enfermedades inmunitarias y autoinmunitarias |
| TWI520960B (zh) | 2010-05-26 | 2016-02-11 | 艾伯維有限公司 | 用於治療癌症及免疫及自體免疫疾病之細胞凋亡誘導劑 |
| KR20180059560A (ko) | 2010-10-29 | 2018-06-04 | 애브비 인코포레이티드 | 아폽토시스―유도제를 포함하는 고체 분산체 |
| WO2012071336A1 (en) | 2010-11-23 | 2012-05-31 | Abbott Laboratories | Salts and crystalline forms of an apoptosis-inducing agent |
| RU2593231C2 (ru) | 2010-11-23 | 2016-08-10 | ЭббВи Айэленд Анлимитед Компани | Способы лечения с использованием селективных ингибиторов bcl-2 |
| WO2017117416A1 (en) | 2015-12-30 | 2017-07-06 | Dexcom, Inc. | System and method for factory calibration or reduced calibration of an indwelling sensor based on sensitivity profile |
| KR102376764B1 (ko) * | 2016-08-05 | 2022-03-18 | 더 리젠츠 오브 더 유니버시티 오브 미시건 | Bcl-2 억제제로서의 n-(페닐설포닐)벤즈아미드 및 관련 화합물 |
-
2017
- 2017-08-04 KR KR1020197002744A patent/KR102376764B1/ko active Active
- 2017-08-04 SI SI201730535T patent/SI3494115T1/sl unknown
- 2017-08-04 ES ES17754889T patent/ES2849959T3/es active Active
- 2017-08-04 MY MYPI2019000239A patent/MY199409A/en unknown
- 2017-08-04 AU AU2017305508A patent/AU2017305508B2/en active Active
- 2017-08-04 SG SG11201900135YA patent/SG11201900135YA/en unknown
- 2017-08-04 CN CN201780035965.6A patent/CN109311871B/zh active Active
- 2017-08-04 WO PCT/US2017/045428 patent/WO2018027097A1/en not_active Ceased
- 2017-08-04 EP EP17754889.8A patent/EP3494115B1/en active Active
- 2017-08-04 EP EP22179906.7A patent/EP4129999A1/en active Pending
- 2017-08-04 RU RU2019105721A patent/RU2722560C1/ru active
- 2017-08-04 US US16/317,056 patent/US10829488B2/en active Active
- 2017-08-04 CN CN201910626474.XA patent/CN110483501B/zh active Active
- 2017-08-04 KR KR1020217026744A patent/KR102429704B1/ko active Active
- 2017-08-04 SM SM20210025T patent/SMT202100025T1/it unknown
- 2017-08-04 PE PE2019000335A patent/PE20190711A1/es unknown
- 2017-08-04 JP JP2019506191A patent/JP6651180B2/ja active Active
- 2017-08-04 PT PT177548898T patent/PT3494115T/pt unknown
- 2017-08-04 CA CA3031419A patent/CA3031419C/en active Active
- 2017-08-04 LT LTEP17754889.8T patent/LT3494115T/lt unknown
- 2017-08-04 HR HRP20202073TT patent/HRP20202073T1/hr unknown
- 2017-08-04 MX MX2019001391A patent/MX381588B/es unknown
- 2017-08-04 EP EP19184604.7A patent/EP3569601B1/en active Active
- 2017-08-04 SG SG10201913643YA patent/SG10201913643YA/en unknown
- 2017-08-04 DK DK17754889.8T patent/DK3494115T3/da active
- 2017-08-04 HU HUE17754889A patent/HUE053414T2/hu unknown
- 2017-08-04 RS RS20201599A patent/RS61821B1/sr unknown
- 2017-08-04 RU RU2020114660A patent/RU2744358C2/ru active
-
2018
- 2018-08-01 US US16/051,816 patent/US10221174B2/en active Active
-
2019
- 2019-01-02 IL IL264059A patent/IL264059B/en active IP Right Grant
- 2019-01-14 ZA ZA2019/00240A patent/ZA201900240B/en unknown
- 2019-01-31 MX MX2020013014A patent/MX2020013014A/es unknown
- 2019-01-31 PH PH12019500231A patent/PH12019500231A1/en unknown
- 2019-02-04 SA SA519401020A patent/SA519401020B1/ar unknown
- 2019-07-23 JP JP2019135624A patent/JP7205903B2/ja active Active
- 2019-12-19 ZA ZA2019/08466A patent/ZA201908466B/en unknown
-
2020
- 2020-09-17 US US17/023,426 patent/US11718613B2/en active Active
-
2021
- 2021-01-15 CY CY20211100032T patent/CY1123859T1/el unknown
- 2021-04-06 IL IL282099A patent/IL282099B/en unknown
- 2021-04-06 AU AU2021202113A patent/AU2021202113B2/en active Active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HRP20201681T1 (hr) | Inhibitor aurora a kinaze | |
| HRP20230400T1 (hr) | Benzilamino supstituirani piridopirimidinoni i derivati kao inhibitori sos1 | |
| HRP20210212T1 (hr) | Triciklični spoj kao antikancerogeni agensi | |
| HRP20171151T1 (hr) | Inhibitori cdc7 | |
| HRP20180158T1 (hr) | Spojevi biarilamida kao inhibitori kinaze | |
| HRP20250119T1 (hr) | Kdm1a inhibitor i njegova primjena u terapiji | |
| HRP20250250T1 (hr) | Derivati 7‑benzil‑4‑(2‑metilbenzil)‑2,4,6,7,8,9‑heksahidroimidazo[1,2‑a]pirido[3,4‑e] pirimidin‑5(1h)‑ona, njihove soli i njihova upotreba u terapiji | |
| MX382331B (es) | Derivados de 6,7,8,9-tetrahidro-3h-pirazolo[4,3f] isoquinolina útiles en el tratamiento del cáncer. | |
| PH12017502246A1 (en) | New hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them | |
| HRP20150952T1 (hr) | Određeni triazolopirazini, njihovi pripravci i postupci njihove upotrebe | |
| TN2018000119A1 (en) | Dihydroimidazopyrazinone derivatives useful in the treatment of cancer | |
| ME02470B (me) | Nanočesтice nabijene sa hemoterapeutskim anтitumorskim lekom | |
| HRP20131081T1 (hr) | Kombinirane terapije koje sadrže hinoksalin inhibitor p13k-alfa za uporabu u lijeäśenju kancera | |
| JO3195B1 (ar) | مشتقات أندوليزين جديدة, وطريقة تحضيرهم والتركيبات الصيدلانية التي تحتوي عليهم لعلاج السرطان | |
| EA201691242A1 (ru) | Фармацевтические композиции, содержащие azd9291 | |
| MY199409A (en) | N-(phenylsulfonyl)benzamides and related compounds as bcl-2 inhibitors | |
| HRP20210319T1 (hr) | Kombinacije inhibitora fgfr i inhibitora igf1r | |
| HRP20201264T1 (hr) | Prolijekovi gemcitabina | |
| PH12018500377A1 (en) | Novel annelated benzamides | |
| HRP20150530T1 (hr) | Spojevi korisni za inhibiranje chk1 | |
| SA518390920B1 (ar) | مركبات فينوكسي أسيتاميد معالجة بإضافة حلقة | |
| HRP20210537T1 (hr) | Upotreba inhibitora faktora induciranog hipoksijom | |
| HRP20200662T1 (hr) | Ljekoviti pripravak koji sadrži spoj diamino heterocikličkog karboksamida kao aktivni sastojak | |
| RU2017141536A (ru) | Замещенные производные индол-5-ола и их терапевтические применения | |
| GEAP202115056A (en) | CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE |