5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide | 1428569-85-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide
• 英文别名: GDC-0339；Gdc-0339；5-amino-N-[5-[(4R,5R)-4-amino-5-fluoroazepan-1-yl]-1-methylpyrazol-4-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxamide
• CAS: 1428569-85-0
• 化学式: C₂₀H₂₂F₃N₇OS
• 分子量: 465.502
• InChiKey: NHXVGMQFCYBLTL-ZWNOBZJWSA-N

物化性质

• 密度：
  1.61±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥ 52 mg/mL（111.71 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  143
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  tert-butyl di(but-3-en-1-yl)carbamate 在 盐酸 、 potassium fluoride 、 sodium azide 、 Hoveyda-Grubbs catalyst second generation 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 水 、 铁粉 、 氯化铵 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三苯基膦 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 二氧化碳 、 水 、 二甲基亚砜 为溶剂， 反应 122.58h， 生成 5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide
  参考文献：
  名称：

  Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma

  摘要：

  Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

  DOI：

  10.1021/acs.jmedchem.8b01857

文献信息

• CYCLIC ETHER PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20140088117A1

  公开（公告）日：2014-03-27

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I的环醚吡唑-4-基-杂环基-羧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2为环醚，X为噻唑基、吡啶基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I化合物进行体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE
  申请人：GENENTECH, INC.

  公开号：US20130079321A1

  公开（公告）日：2013-03-28

  Pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  Formula I中的吡唑-4-基杂环基-羧酰胺化合物，包括其立体异构体、几何异构体、互变异构体和药学上可接受的盐，其中X为噻唑基、吡啶基、吡啶基或嘧啶基，用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用Formula I化合物进行体外、原位和体内诊断、预防或治疗哺乳动物细胞中的这类疾病或相关病理条件的方法。
• [EN] OXEPAN-2-YL-PYRAZOL-4-YL-HETEROCYCLYL-CARBOXAMIDE COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS OXÉPAN-2-YL-PYRAZOL-4-YL-HÉTÉROCYCLYLE-CARBOXAMIDE ET LEURS MÉTHODES D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2015140189A1

  公开（公告）日：2015-09-24

  Oxepan-2-yl pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  氧杂环戊烷-2-基吡唑-4-基杂环基甲酰胺化合物的化学式I，包括立体异构体、几何异构体、互变异构体和其药用可接受的盐，其中X为噻唑基、吡啶基、吡啶基或嘧啶基，用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用化合物I的方法，用于体外、原位和体内诊断、预防或治疗哺乳动物细胞中的这类疾病，或相关的病理条件。
• USP7 small-molecule inhibitors interfere with ubiquitin binding
  作者：Lorna Kategaya、Paola Di Lello、Lionel Rougé、Richard Pastor、Kevin R. Clark、Jason Drummond、Tracy Kleinheinz、Eva Lin、John-Paul Upton、Sumit Prakash、Johanna Heideker、Mark McCleland、Maria Stella Ritorto、Dario R. Alessi、Matthias Trost、Travis W. Bainbridge、Michael C. M. Kwok、Taylur P. Ma、Zachary Stiffler、Bradley Brasher、Yinyan Tang、Priyadarshini Jaishankar、Brian R. Hearn、Adam R. Renslo、Michelle R. Arkin、Frederick Cohen、Kebing Yu、Frank Peale、Florian Gnad、Matthew T. Chang、Christiaan Klijn、Elizabeth Blackwood、Scott E. Martin、William F. Forrest、James A. Ernst、Chudi Ndubaku、Xiaojing Wang、Maureen H. Beresini、Vickie Tsui、Carsten Schwerdtfeger、Robert A. Blake、Jeremy Murray、Till Maurer、Ingrid E. Wertz

  DOI：10.1038/nature24006

  日期：2017.10.26

  isotopic labels and measuring USP7 binding by nuclear magnetic resonance. This preferential binding protracted the depolymerization kinetics of Lys48-linked ubiquitin chains relative to Lys63-linked chains. In summary, engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly

  泛素系统调节真核生物中必需的细胞过程。泛素作为单体或链与底物蛋白质连接，泛素修饰的拓扑结构调节底物与特定蛋白质的相互作用。因此，泛素化指导各种底物的命运，包括蛋白酶体降解。去泛素酶从底物中切割泛素，并与疾病有关。例如，泛素特异性蛋白酶7（USP7）调节p53肿瘤抑制因子和其他对肿瘤细胞存活至关重要的蛋白质的稳定性。然而，开发选择性的去泛素酶抑制剂一直是具有挑战性的，并且没有用小分子抑制剂解决共晶体结构。在这里，使用基于核磁共振的筛选和基于结构的设计，我们描述了选择性USP7抑制剂GNE-6640和GNE-6776的开发。这些化合物可通过化学治疗剂和靶向化合物（包括PIM激酶抑制剂）诱导肿瘤细胞死亡并增强细胞毒性。结构研究表明，GNE-6640和GNE-6776非共价地靶向距催化半胱氨酸12Å的USP7。这些化合物减弱了泛素结合，从而抑制了USP7去泛素酶的活性。GNE-6640和GNE-6
• Cyclic Ether Pyrazol-4-YL-Heterocyclyl-Carboxamide Compounds And Methods Of Use
  申请人：Genentech, Inc.

  公开号：US20160213652A1

  公开（公告）日：2016-07-28

  Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 2 is a cyclic ether and X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  公式I中的环氧杂环基卡氧酰胺化合物，包括立体异构体、几何异构体、互变异构体和其药学上可接受的盐，其中R2是环氧杂环基，X是噻唑基、吡嗪基、吡啶基或嘧啶基，可用于抑制Pim激酶，并用于治疗由Pim激酶介导的癌症等疾病。公开了使用公式I中的化合物进行哺乳动物细胞中的体外、原位和体内诊断、预防或治疗此类疾病或相关病理条件的方法。