2-氯-5-(三氟甲基)吡啶-4-胺 | 1061358-78-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2-氯-5-(三氟甲基)吡啶-4-胺
• 英文名称: 2-chloro-5-(trifluoromethyl)pyridin-4-amine
• 英文别名: 2-Chloro-5-(trifluoromethyl)pyridin-4-amine
• CAS: 1061358-78-8
• 化学式: C₆H₄ClF₃N₂
• 分子量: 196.559
• InChiKey: BVKYVDJDCQLPEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  38.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-氯-5-(三氟甲基)吡啶-4-胺 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium hydride 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 6.0h， 生成 CCT245737游离态
  参考文献：
  名称：

  Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

  摘要：

  Multiparameter optimization of a series of 5((4-aminopyridin-2-yl)amino)pyrazine-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.5b01938
• 作为产物：
  描述：

  2-氯-5-三氟甲基吡啶-4-甲酸 在 叠氮磷酸二苯酯 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 10.0h， 生成 2-氯-5-(三氟甲基)吡啶-4-胺
  参考文献：
  名称：

  Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

  摘要：

  Multiparameter optimization of a series of 5((4-aminopyridin-2-yl)amino)pyrazine-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

  DOI：

  10.1021/acs.jmedchem.5b01938

文献信息

• Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors
  作者：Anmol Gulati、Charles S. Yeung、Blair Lapointe、Solomon D. Kattar、Hakan Gunaydin、Jack D. Scott、Kaleen K. Childers、Joey L. Methot、Vladimir Simov、Ravi Kurukulasuriya、Barbara Pio、Greg J. Morriello、Ping Liu、Haiqun Tang、Santhosh Neelamkavil、Harold B. Wood、Vanessa L. Rada、Michael J. Ardolino、Xin Cindy Yan、Rachel Palte、Karin Otte、Robert Faltus、Janice Woodhouse、Laxminarayan G. Hegde、Paul Ciaccio、Ellen C. Minnihan、Erin F. DiMauro、Matthew J. Fell、Peter H. Fuller、J. Michael Ellis

  DOI：10.1039/d1md00097g

  日期：——

  The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl

  强效、激酶组选择性、脑渗透性 LRRK2 抑制剂的发现是寻求新的、改善帕金森病 (PD) 疾病的治疗方法的广泛研究的重点。在这里，我们描述了吡啶酰胺衍生的铅系列的发现和演变。我们最初的优化工作旨在通过修饰杂芳基 C-H 铰链和接头区域来提高化合物1的效力和 CLK2 脱靶选择性。这导致化合物12在杂芳基苯胺代谢物14之前深入我们的研究操作计划 (ROP)被定性为 Ames 致突变性，阻止其进展。对我们的 ROP 进行了战略性修改，以便尽早降低 Ames 中假定的苯胺代谢物或水解产物的致突变性风险。这导致发现 3,5-二氨基吡啶15和 4,6-二氨基嘧啶16具有低致突变风险（定义为 3 株 Ames 阴性结果）。对关键匹配分子对17和18的分析导致优先考虑 3,5-二氨基吡啶子系列，以进一步优化啮齿动物脑渗透。这些努力最终发现乙基三氟甲基吡唑23具有出色的 LRRK2 效力和扩大的选择性与偏离目标的
• [EN] 5-[[4-[[MORPHOLIN-2-YL]METHYLAMINO]-5-(TRIFLUOROMETHYL)-2-PYRIDYL]AMINO]PYRAZINE-2-CARBONITRILE AND THERAPEUTIC USES THEREOF<br/>[FR] 5-[[4-[[MORPHOLIN-2-YL]MÉTHYLAMINO]-5-(TRIFLUOROMÉTHYL)-2-PYRIDYL]- AMINO]PYRAZINE-2-CARBONITRILE ET UTILISATIONS THÉRAPEUTIQUES DE CELUI-CI
  申请人：CANCER REC TECH LTD

  公开号：WO2013171470A1

  公开（公告）日：2013-11-21

  The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5- (trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as "TFM compounds") which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionising radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

  本发明涉及治疗化合物领域。更具体地，本发明涉及5-[[4-[[吗啡啶-2-基]甲基氨基]-5-(三氟甲基)-2-吡啶基]氨基]吡嗪-2-碳腈化合物（以下简称为“TFM化合物”），其中包括抑制检查点激酶1（CHK1）激酶功能。本发明还涉及包含这些化合物的药物组合物，以及使用这些化合物和组合物，无论是体外还是体内，来抑制CHK1激酶功能，并用于治疗由CHK1介导的疾病和症状，通过抑制CHK1激酶功能得以改善，等等，包括增殖性疾病如癌症等，可选地与另一药剂组合使用，例如，（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或胸苷酸合成酶（TS）抑制剂；（d）微管靶向药物；（e）电离辐射；（f）一个有丝分裂调节因子或有丝分裂检查点调节因子的抑制剂；（g）DNA损伤信号传导物的抑制剂；或（h）DNA损伤修复酶的抑制剂。
• [EN] METHODS FOR SYNTHESIS OF CHK1 INHIBITORS<br/>[FR] MÉTHODES DE SYNTHÈSE D'INHIBITEURS DE CHK1
  申请人：SIERRA ONCOLOGY INC

  公开号：WO2021207210A1

  公开（公告）日：2021-10-14

  The present technology relates to processes, compounds, compositions, and methods useful for coupling reactions. Also, the present disclosure provides for novel intermediates, compositions of matter, and processes relating to the Chk1 inhibitor, SRA737.

  目前的技术涉及到用于偶联反应的过程、化合物、组合物和方法。此外，本公开提供了与Chk1抑制剂SRA737相关的新型中间体、物质组合物和过程。
• INHIBITORS OF FOCAL ADHESION KINASE
  申请人：Liang Congxin

  公开号：US20110046121A1

  公开（公告）日：2011-02-24

  The invention provides inhibitors of focal adhesion kinase, an enzyme involved in the attachment of the cytoskeleton of a cell to an extracellular matrix, which has been implicated in processes such as cell migration, cell proliferation, and cell survival. The inhibitors are derivatives of a 5-substituted 2,4-diaminopyridine wherein the substituents are as defined herein. The invention also provides a method of using the inhibitors in treatment of cancer, and methods of preparation of the inhibitors by use of coupling reactions.

  该发明提供了聚焦粘附激酶的抑制剂，该酶参与细胞的细胞骨架与细胞外基质的附着，已被证实与细胞迁移、细胞增殖和细胞存活等过程有关。这些抑制剂是5-取代的2,4-二氨基吡啶的衍生物，其中取代基如本文所定义。该发明还提供了使用这些抑制剂治疗癌症的方法，以及通过使用偶联反应制备这些抑制剂的方法。
• 5-[[4-[[MORPHOLIN-2-YL]METHYLAMINO]-5-(TRIFLUOROMETHYL)-2-PYRIDYL]AMINO]PYRAZINE-2-CARBONITRILE AND THERAPEUTIC USES THEREOF
  申请人：Cancer Research Technology Limited

  公开号：US20150126471A1

  公开（公告）日：2015-05-07

  The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as “TFM compounds”) which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionising radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

  本发明涉及治疗化合物领域。更具体地，本发明涉及5-[[4-[[吗啡啉-2-基]甲基氨基]-5-(三氟甲基)-2-吡啶基]氨基]吡嗪-2-羧腈化合物（以下简称“TFM化合物”），其抑制检查点激酶1（CHK1）激酶功能等。本发明还涉及包含此类化合物的制药组合物，以及在体内外使用此类化合物和组合物来抑制CHK1激酶功能，以及治疗由CHK1介导的疾病和情况，通过抑制CHK1激酶功能来缓解的疾病和情况等，包括增生性疾病，如癌症等，可选地与另一种药物联合使用，例如：（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或胸腺嘧啶酸合成酶（TS）抑制剂；（d）微管靶向药物；（e）电离辐射；（f）减数分裂调节因子或有丝分裂检查点调节因子的抑制剂；（g）DNA损伤信号传导体的抑制剂；或（h）DNA损伤修复酶的抑制剂。