4-[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester | 1330596-37-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester
• 英文别名: Tert-butyl 4-[[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-yl]amino]piperidine-1-carboxylate
• CAS: 1330596-37-6
• 化学式: C₂₁H₂₇N₇O₄S
• 分子量: 473.556
• InChiKey: PTJDEKVTBKUWLR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  140
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester 在 盐酸 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 生成 {3-[2-(3-methylbutylamino)pyrimidin-5-yl]imidazo[1,2-b]pyridazin-6-yl}-(1-methylpiperidin-4-yl)amine
  参考文献：
  名称：

  Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

  摘要：

  A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.017
• 作为产物：
  描述：

  4-[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 生成 4-[3-(2-methylsulfonylpyrimidin-5-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

  摘要：

  A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.017

文献信息

• [EN] FUSED HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF MALARIA<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES CONDENSÉS POUR UTILISATION DANS LE TRAITEMENT DU PALUDISME
  申请人：MEDICAL RES COUNCIL TECHNOLOGY

  公开号：WO2011101640A1

  公开（公告）日：2011-08-25

  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein: R1 is -NR3R4 or -OR5; R2 is selected from aryl, heteroaryl, fused aryl- heterocycloalkyl and fused heteroaryl-heterocycloalkyl each of which may be optionally substituted by one or more R8 groups; R3 is H or alkyl; R4 is: (i) cycloalkyl optionally substituted by one or more -NR11R12, -NHCO2R11, -NHCOR11 and -NHSO2R11 groups; or (ii) -(CH2)n-heterocycloalkyl, wherein said heterocycloalkyl is a 4, 5 or 6-membered nitrogen-containing group optionally containing one or more CO groups, wherein said heterocycloalkyl is optionally substituted by one or more one or more (CH2)nR7 groups; (iii) -(CH2)n-heteroaryl, wherein said heteroaryl group is optionally substituted by one or more R7 groups; or (iv) alkyl substituted by one or more -NR11R12groups; or R3 and R4 are linked together with the nitrogen to which they are attached to form a 4, 5 or 6-membered heterocycloalkyl group optionally containing one or two further groups selected from CO, O, N and S, and which is optionally further substituted by one or more R7 groups; R5 is selected from alkyl, -(CH2)n-heteroaryl and -(CH2)n-heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl groups are each optionally substituted by one or more R7 groups; each R11 and R12 is independently H or alkyl; and each n is independently an integer from O to 6; for use in treating or preventing a disorder associated with CDPK. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of PfCDPK1.

  发明的第一个方面涉及式(I)的化合物，或其药学上可接受的盐或酯，其中：R1为-NR3R4或-OR5；R2选自芳基、杂环芳基、融合芳基-杂环烷基和融合杂环芳基-杂环烷基，每种基可能被一个或多个R8基取代；R3为H或烷基；R4为：(i) 可选地被一个或多个-NR11R12、-NHCO2R11、-NHCOR11和-NHSO2R11基取代的环烷基；或(ii) -(CH2)n-杂环烷基，其中所述杂环烷基是一个含氮的4、5或6成员环基，可选地含有一个或多个CO基团，其中所述杂环烷基可被一个或多个( )nR7基团取代；(iii) -( )n-杂芳基，其中所述杂芳基可被一个或多个R7基团取代；或(iv) 被一个或多个-NR11R12基团取代的烷基；或R3和R4与它们连接到的氮一起形成一个含有一个或两个进一步选择自CO、O、N和S的4、5或6成员杂环烷基基团，可选地进一步被一个或多个R7基团取代；R5选自烷基、-( )n-杂芳基和-( )n-杂环烷基，其中所述杂芳基和杂环烷基基团可选地被一个或多个R7基团取代；每个R11和R12独立地为H或烷基；每个n独立地为0到6的整数；用于治疗或预防与CDPK相关的疾病。进一步方面涉及所述化合物在治疗各种治疗性疾病中的使用，更特别地作为PfCDPK1的抑制剂。