4-(tert-butyl)-2-isocyanatothiazole | 1319198-59-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(tert-butyl)-2-isocyanatothiazole
• 英文别名: 4-Tert-butyl-2-isocyanato-1,3-thiazole；4-tert-butyl-2-isocyanato-1,3-thiazole
• CAS: 1319198-59-8
• 化学式: C₈H₁₀N₂OS
• 分子量: 182.246
• InChiKey: GFYIWRFNNNGVIQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  12
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  70.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(tert-butyl)-2-isocyanatothiazole 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 2.0h， 以14 mg的产率得到1-(4-(tert-butyl)thiazol-2-yl)-3-(4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)phenyl)urea
  参考文献：
  名称：

  N-苯基-7,8-二氢-6 H-嘧啶基[5,4-b] [1,4]恶嗪-4-胺衍生物作为新型RET抑制剂的结构优化和构效关系研究其耐药突变体

  摘要：

  RET酪氨酸激酶是甲状腺髓样癌（MTC）的重要治疗靶标，RET的耐药性突变，特别是V804M和V804L，是目前基于RET抑制剂的MTC靶向治疗的主要挑战。在这项调查中，我们报告了N-苯基-7,8-二氢-6 H-嘧啶基[5,4-b] [1,4]恶嗪-4-胺衍生物的结构优化和构效关系研究。新型的RET抑制剂。在所有获得的激酶抑制剂中，1-（5-（叔丁基）异恶唑-3-基）-3-（4-（（6,7,8,9-四氢嘧啶[5,4-b] [1， 4]氧杂氮杂-4-基）氨基）苯基）脲（17d）是一种多激酶抑制剂，可有效抑制RET及其耐药突变体。显示IC 50RET野生型，RET-V804M和RET-V804L的（最大半抑制浓度）值分别为0.010μM，0.015μM和0.009μM。图17d显示了针对各种RET驱动肿瘤细胞系的显着抗生存力。在NIH3T3-RET-C634Y的异种移植小鼠模型中，17d表现出

  DOI：

  10.1016/j.ejmech.2017.09.018
• 作为产物：
  描述：

  一氯频呐酮 以 四氢呋喃 、 乙醇 为溶剂， 反应 12.0h， 生成 4-(tert-butyl)-2-isocyanatothiazole
  参考文献：
  名称：

  Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model

  摘要：

  Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structureactivity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.

  DOI：

  10.1021/acs.jmedchem.6b00604

文献信息

• Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters
  作者：Renée Zindell、Edward R. Walker、John Scott、Patricia Amouzegh、Lifen Wu、Monika Ermann、David Thomson、Micheal B. Fisher、Cody Lee Fullenwider、Heather Grbic、Paul Kaplita、Brian Linehan、Mita Patel、Monica Patel、Sabine Löbbe、Svenja Block、Claudia Albrecht、Mark J. Gemkow、Daw-Tsun Shih、Doris Riether

  DOI：10.1016/j.bmcl.2011.05.068

  日期：2011.7

  A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability. (C) 2011 Elsevier Ltd. All rights reserved.
• Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1<i>H</i>-Pyrazolo[3,4-<i>d</i>]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(<i>tert</i>-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model
  作者：Guo-Bo Li、Shuang Ma、Ling-Ling Yang、Sen Ji、Zhen Fang、Guo Zhang、Li-Jiao Wang、Jie-Min Zhong、Yu Xiong、Jiang-Hong Wang、Shen-Zhen Huang、Lin-Li Li、Rong Xiang、Dawen Niu、Ying-Chun Chen、Sheng-Yong Yang

  DOI：10.1021/acs.jmedchem.6b00604

  日期：2016.9.22

  Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structureactivity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.
• Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants
  作者：Jiao Yang、Kai Chen、Guo Zhang、Qiu-Yuan Yang、Yue-Shan Li、Shen-Zhen Huang、Yan-Lin Wang、Wei Yang、Xiao-Juan Jiang、Heng-Xiu Yan、Jing-Qiang Zhu、Rong Xiang、You-Fu Luo、Wei-Min Li、Yu-Quan Wei、Lin-Li Li、Sheng-Yong Yang

  DOI：10.1016/j.ejmech.2017.09.018

  日期：2018.1

  targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea

  RET酪氨酸激酶是甲状腺髓样癌（MTC）的重要治疗靶标，RET的耐药性突变，特别是V804M和V804L，是目前基于RET抑制剂的MTC靶向治疗的主要挑战。在这项调查中，我们报告了N-苯基-7,8-二氢-6 H-嘧啶基[5,4-b] [1,4]恶嗪-4-胺衍生物的结构优化和构效关系研究。新型的RET抑制剂。在所有获得的激酶抑制剂中，1-（5-（叔丁基）异恶唑-3-基）-3-（4-（（6,7,8,9-四氢嘧啶[5,4-b] [1， 4]氧杂氮杂-4-基）氨基）苯基）脲（17d）是一种多激酶抑制剂，可有效抑制RET及其耐药突变体。显示IC 50RET野生型，RET-V804M和RET-V804L的（最大半抑制浓度）值分别为0.010μM，0.015μM和0.009μM。图17d显示了针对各种RET驱动肿瘤细胞系的显着抗生存力。在NIH3T3-RET-C634Y的异种移植小鼠模型中，17d表现出