2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one | 1421693-04-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one
• 英文别名: 2-chloro-4-methyl-1-(4-methyl-2-(methylamino)thiazol-5-yl)pent-2-en-1-one；2-chloro-3-(dimethylamino)-1-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]prop-2-en-1-one
• CAS: 1421693-04-0
• 化学式: C₁₀H₁₄ClN₃OS
• 分子量: 259.76
• InChiKey: HMGFRMYNLROIJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  73.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one 在 盐酸 、 水 作用下， 以 甲醇 、 乙二醇甲醚 为溶剂， 反应 3.0h， 生成 5-[5-chloro-2-(3-piperazin-1-ylanilino)pyrimidin-4-yl]-N,4-dimethyl-1,3-thiazol-2-amine
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f
• 作为产物：
  描述：

  3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one 在 N-氯代丁二酰亚胺 作用下， 以 甲醇 为溶剂， 反应 0.67h， 以43%的产率得到2-chloro-3-(dimethylamino)-1-(4-methyl-2-(methylamino)thiazol-5-yl)prop-2-en-1-one
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f

文献信息

• [EN] THERAPEUTIC COMPOUNDS<br/>[FR] COMPOSÉS THÉRAPEUTIQUES
  申请人：CANCER REC TECH LTD

  公开号：WO2013156780A1

  公开（公告）日：2013-10-24

  The present invention relates to compounds of formula (I): wherein R1 is NH2 or NHMe; R2 is halo; and one of R3 or R4 is hydrogen and the other is selected from –SO2NH2, -SO2NHMe or –SO2NMe2, -SO2NHEt, or -SO2NEt2; or a pharmaceutically acceptable salt or solvate thereof. The compounds of formula (I) are inhibitors of protein kinases, especially cyclic dependent kinases (CDKs) such as CDK9. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which protein kinase/CDK activity is implicated.

  本发明涉及公式（I）的化合物：其中R1为NH2或NHMe；R2为卤素；而R3或R4中的一个为氢，另一个选自-SO2NH2，-SO2NHMe或-SO2NMe2，-SO2NHEt或-SO2NEt2；或其药学上可接受的盐或溶剂。公式（I）的化合物是蛋白激酶抑制剂，特别是环依赖性激酶（CDKs），如CDK9。本发明还涉及制备这些化合物的过程，包括它们的制药组合物以及它们在治疗增殖性疾病，如癌症，以及其他涉及蛋白激酶/CDK活性的疾病或病情中的应用。
• THERAPEUTIC COMPOUNDS
  申请人：CHANGZHOU LE SUN PHARMACEUTICALS LIMITED

  公开号：US20150105413A1

  公开（公告）日：2015-04-16

  The present invention relates to compounds of formula (I): wherein R 1 is NH 2 or NHMe; R 2 is halo; and one of R 3 or R 4 is hydrogen and the other is selected from —SO 2 NH 2 , —SO 2 NHMe or —SO 2 NMe 2 , —SO 2 NHEt, or —SO 2 NEt 2 ; or a pharmaceutically acceptable salt or solvate thereof. The compounds of formula (I) are inhibitors of protein kinases, especially cyclic dependent kinases (CDKs) such as CDK9. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which protein kinase/CDK activity is implicated.

  本发明涉及式（I）的化合物： 其中，R1为NH2或NHMe；R2为卤素；R3或R4中的一个为氢，另一个选自—SO2NH2、—SO2NHMe或—SO2NMe2、—SO2NHEt或—SO2NEt2；或其药学上可接受的盐或溶剂。式（I）的化合物是蛋白激酶抑制剂，特别是环状依赖性激酶（CDKs），如CDK9。本发明还涉及制备这些化合物的方法、包含它们的药物组合物以及它们在治疗增生性疾病（如癌症）以及其他涉及蛋白激酶/CDK活性的疾病或病况中的用途。
• Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents
  作者：Hao Shao、David W. Foley、Shiliang Huang、Abdullahi Y. Abbas、Frankie Lam、Pavel Gershkovich、Tracey D. Bradshaw、Chris Pepper、Peter M. Fischer、Shudong Wang

  DOI：10.1016/j.ejmech.2021.113244

  日期：2021.3
• US9062039B2
  申请人：——

  公开号：US9062039B2

  公开（公告）日：2015-06-23