TWI667236B - 作為蛋白激酶抑制劑的胺基噻唑化合物 - Google Patents
作為蛋白激酶抑制劑的胺基噻唑化合物 Download PDFInfo
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- TWI667236B TWI667236B TW107120014A TW107120014A TWI667236B TW I667236 B TWI667236 B TW I667236B TW 107120014 A TW107120014 A TW 107120014A TW 107120014 A TW107120014 A TW 107120014A TW I667236 B TWI667236 B TW I667236B
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| EP3801529B1 (en) | 2018-05-25 | 2023-10-11 | OncoCube Therapeutics LLC | Highly potent tacc3 inhibitor as a novel anticancer drug candidate |
| EP4058447A4 (en) * | 2019-11-14 | 2023-12-27 | A2A Pharmaceuticals, Inc. | ISOXAZOLE DERIVATIVES DIRECTED AGAINST TACC3 AS ANTICANCER AGENTS |
| US11299489B1 (en) | 2020-11-19 | 2022-04-12 | National Health Research Institutes | Thiazole compounds as protein kinase inhibitors |
| CN117460724A (zh) * | 2021-04-12 | 2024-01-26 | A2A制药有限公司 | 用于治疗癌症的组合物和方法 |
| KR20250005157A (ko) | 2022-03-24 | 2025-01-09 | 에이2에이 파마수티칼스, 잉크. | 암 치료를 위한 조성물 및 방법 |
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| TWI434834B (zh) * | 2011-03-04 | 2014-04-21 | Nat Health Research Institutes | 作為蛋白質激酶抑制劑之吡唑化合物及噻唑化合物、其醫藥組成物及用途 |
| CN106279143A (zh) * | 2015-05-11 | 2017-01-04 | 天津国际生物医药联合研究院 | 噻唑杂环类化合物及其制备方法和应用 |
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| WO2006135604A2 (en) * | 2005-06-09 | 2006-12-21 | Merck & Co., Inc. | Inhibitors of checkpoint kinases |
| GB0610909D0 (en) * | 2006-06-05 | 2006-07-12 | Merck Sharp & Dohme | Therapeutic treatment |
| AU2007296743B2 (en) | 2006-09-11 | 2012-02-16 | Curis, Inc. | Tyrosine kinase inhibitors containing a zinc binding moiety |
| TW200906825A (en) | 2007-05-30 | 2009-02-16 | Scripps Research Inst | Inhibitors of protein kinases |
| KR101924247B1 (ko) * | 2011-07-27 | 2019-02-22 | 에이비 사이언스 | 선택적 프로테인 키나제 저해제로서 옥사졸 및 티아졸 유도체 |
| WO2013143466A1 (zh) * | 2012-03-27 | 2013-10-03 | 广东东阳光药业有限公司 | 作为欧若拉激酶抑制剂的取代嘧啶衍生物 |
| WO2018106643A1 (en) * | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
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| TWI434834B (zh) * | 2011-03-04 | 2014-04-21 | Nat Health Research Institutes | 作為蛋白質激酶抑制劑之吡唑化合物及噻唑化合物、其醫藥組成物及用途 |
| CN106279143A (zh) * | 2015-05-11 | 2017-01-04 | 天津国际生物医药联合研究院 | 噻唑杂环类化合物及其制备方法和应用 |
Non-Patent Citations (1)
| Title |
|---|
| Francini, Cinzia Maria, et al. "Identification of aminoimidazole and aminothiazole derivatives as Src family kinase inhibitors." ChemMedChem 10.12 (2015): 2027-2041. * |
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| TWI770858B (zh) * | 2020-03-06 | 2022-07-11 | 財團法人國家衛生研究院 | 嘧啶化合物及其醫藥用途 |
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| ES2949616T3 (es) | 2023-10-02 |
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| JP2020523348A (ja) | 2020-08-06 |
| NZ759327A (en) | 2021-08-27 |
| MX2019014845A (es) | 2020-08-06 |
| CA3064081C (en) | 2023-03-21 |
| MY201291A (en) | 2024-02-15 |
| BR112019026577A8 (pt) | 2023-04-11 |
| MX393992B (es) | 2025-03-24 |
| AU2018284249B2 (en) | 2021-06-24 |
| EP3638237A4 (en) | 2021-01-13 |
| JP6979595B2 (ja) | 2021-12-15 |
| ZA202000107B (en) | 2020-12-23 |
| CA3064081A1 (en) | 2018-12-20 |
| CN110831596A (zh) | 2020-02-21 |
| US20180353509A1 (en) | 2018-12-13 |
| EP3638237A1 (en) | 2020-04-22 |
| WO2018231910A1 (en) | 2018-12-20 |
| RU2019137573A (ru) | 2021-05-24 |
| TW201906836A (zh) | 2019-02-16 |
| EP3638237B1 (en) | 2023-04-19 |
| AU2018284249A1 (en) | 2019-12-12 |
| KR20200014350A (ko) | 2020-02-10 |
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