cyclopropyl(2,4-dichloropyridin-3-yl)methanone | 1246350-01-5

• 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
• 英文名称: cyclopropyl(2,4-dichloropyridin-3-yl)methanone
• 英文别名: cyclopropyl-(2,4-dichloropyridin-3-yl)methanone
• CAS: 1246350-01-5
• 化学式: C₉H₇Cl₂NO
• 分子量: 216.067
• InChiKey: GXKYIDYFORHEED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  30
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  cyclopropyl(2,4-dichloropyridin-3-yl)methanone 在 一水合肼 作用下， 以54 %的产率得到4-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine
  参考文献：
  名称：

  一系列吡咯并吡啶酮 MAT2A 抑制剂的开发

  摘要：

  讨论了通过差示扫描荧光测定法发现的变构片段对体内 MAT2a 工具抑制剂的优化。基于结构的药物发现方法，在相对结合自由能计算的辅助下，产生了 AZ'9567 ( 21 )，一种有效的体外抑制剂，具有优异的临床前药代动力学特性。该工具在体外和体内均显示出对甲硫腺苷磷酸化酶 (MTAP) KO 细胞的选择性抗增殖作用，为支持 MAT2a 抑制剂作为 MTAP 缺陷肿瘤的潜在抗癌疗法的实用性提供了进一步的证据。

  DOI：

  10.1021/acs.jmedchem.3c01860
• 作为产物：
  描述：

  2,4-二氯烟醛 在 四丙基高钌酸铵 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 cyclopropyl(2,4-dichloropyridin-3-yl)methanone
  参考文献：
  名称：

  一系列吡咯并吡啶酮 MAT2A 抑制剂的开发

  摘要：

  讨论了通过差示扫描荧光测定法发现的变构片段对体内 MAT2a 工具抑制剂的优化。基于结构的药物发现方法，在相对结合自由能计算的辅助下，产生了 AZ'9567 ( 21 )，一种有效的体外抑制剂，具有优异的临床前药代动力学特性。该工具在体外和体内均显示出对甲硫腺苷磷酸化酶 (MTAP) KO 细胞的选择性抗增殖作用，为支持 MAT2a 抑制剂作为 MTAP 缺陷肿瘤的潜在抗癌疗法的实用性提供了进一步的证据。

  DOI：

  10.1021/acs.jmedchem.3c01860

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：MEDICAL RES COUNCIL TECHNOLOGY

  公开号：WO2010106333A1

  公开（公告）日：2010-09-23

  A compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein R1 is selected from: aryl; heteroaryl; -NHR3; fused aryl-C4-7-heterocycloalkyI; -CONR4R5; -NHCOR6; -C3-7-cycloalkyl; -O-C3-7-cycloalkyl; -NR3R6; and optionally substituted -C1-6 alkyl; wherein said aryl, heteroaryl, fused aryl-C4-7-heterocycloalkyl and C4-7-heterocycloalkyl are each optionally substituted; R2 is selected from hydrogen, aryl, C1-6-alkyl, C2-6-alkenyl, C3-7-cycloalkyl, heteroaryl, C4-7 heterocycloalkyl and halogen, wherein said C1-6-alkyl, C2-6-alkenyl, aryl, heteroaryl and C4-7-heterocycloalkyl are each optionally substituted. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing compounds of formula (I).

  一种具有式（I）的化合物，或其药学上可接受的盐或酯，其中R1选自：芳基；杂环芳基；-NHR3；融合芳基-C4-7-杂环烷基；-CONR4R5；-NHCOR6；-C3-7-环烷基；-O-C3-7-环烷基；-NR3R6；和可选择地取代的-C1-6烷基；其中所述的芳基、杂环芳基、融合芳基-C4-7-杂环烷基和C4-7-杂环烷基均可选择地取代；R2选自氢、芳基、C1-6-烷基、C2-6-烯基、C3-7-环烷基、杂环芳基、C4-7-杂环烷基和卤素，其中所述的C1-6-烷基、C2-6-烯基、芳基、杂环芳基和C4-7-杂环烷基均可选择地取代。进一步涉及制备具有式（I）的化合物的药物组合物、治疗用途和制备方法的其他方面。
• COMPOUNDS
  申请人：Mciver Edward Giles

  公开号：US20100317646A1

  公开（公告）日：2010-12-16

  A compound of formula I, or a pharmaceutically acceptable salt or ester thereof, wherein R 1 is selected from: aryl; heteroaryl; —NHR 3 ; fused aryl-C 4-7 -heterocycloalkyl; —CONR 4 R 5 ; —NHCOR 6 ; —C 3-7 -cycloalkyl; —O—C 3-7 -cycloalkyl; —NR 3 R 6 ; and optionally substituted —C 1-6 alkyl; wherein said aryl, heteroaryl, fused aryl-C 4-7 -heterocycloalkyl and C 4-7 -heterocycloalkyl are each optionally substituted; R 2 is selected from hydrogen, aryl, C 1-6 -alkyl, C 2-6 -alkenyl, C 3-7 -cycloalkyl, heteroaryl, C 4-7 heterocycloalkyl and halogen, wherein said C 1-6 -alkyl, C 2-6 -alkenyl, aryl, heteroaryl and C 4-7 -heterocycloalkyl are each optionally substituted; R 3 is selected from aryl, heteroaryl, C 4-7 -heterocycloalkyl, C 3-7 -cycloalkyl, fused aryl-C 4-7 -heterocycloalkyl and C 1-6 -alkyl, each of which is optionally substituted; R 4 and R 5 are each independently hydrogen, or optionally substituted C 3-7 -cycloalkyl, aryl, heteroaryl, C 1-6 -alkyl or C 3-6 -heterocycloalkyl; or R 4 and R 5 together with the N to which they are attached form a C 3-6 -heterocycloalkyl ring; each R 6 is independently selected from C 1-6 -alkyl, C 3-7 cycloalkyl, C 4-7 -heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted each R 7 is selected from hydrogen, optionally substituted C 1-6 -alkyl and C 3-7 -cycloalkyl; each of R 8 and R 9 is independently hydrogen or optionally substituted C 1-6 -alkyl; or R 8 and R 9 together with the N to which they are attached form a C 4-6 -heterocycloalkyl; each R 10 is selected from C 3-7 -cycloalkyl and optionally substituted C 1-6 -alkyl; each R 11 is independently selected from C 1-6 -alkyl, C 3-7 -cycloalkyl, C 1-6 alkyl-C 3-7 -cycloalkyl, C 4-7 -heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted; A is selected from halogen, —NR 4 SO 2 R 5 , —CN, —OR 6 , —NR 4 R 5 , —NR 7 R 11 , hydroxyl, —CF 3 , —CONR 4 R 5 , —NR 4 COR 5 , —NR 7 (CO)NR 4 R 5 , —NO 2 , —CO 2 H, —CO 2 R 6 , —SO 2 R 6 , —SO 2 NR 4 R 5 , —NR 4 COR 5 , —NR 4 COOR 5 , C 1-6 -alkyl and —COR 6 . Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing compounds of formula I.

  化合物I的公式，或其药学上可接受的盐或酯，其中R1选自：芳基；杂环芳基；—NHR3；融合的芳基-C4-7-杂环烷基；—CONR4R5；—NHCOR6；—C3-7-环烷基；—O—C3-7-环烷基；—NR3R6；和可选择取代的—C1-6烷基；其中所述的芳基，杂环芳基，融合的芳基-C4-7-杂环烷基和C4-7-杂环烷基均可选择取代；R2选自氢，芳基，C1-6-烷基，C2-6-烯基，C3-7-环烷基，杂环芳基，C4-7-杂环烷基和卤素，其中所述的C1-6-烷基，C2-6-烯基，芳基，杂环芳基和C4-7-杂环烷基均可选择取代；R3选自芳基，杂环芳基，C4-7-杂环烷基，C3-7-环烷基，融合的芳基-C4-7-杂环烷基和C1-6-烷基，每种均可选择取代；R4和R5各自独立地选自氢，或可选择取代的C3-7-环烷基，芳基，杂环芳基，C1-6-烷基或C3-6-杂环烷基；或R4和R5与它们连接的N一起形成C3-6-杂环烷基环；每个R6各自独立地选自C1-6-烷基，C3-7-环烷基，C4-7-杂环烷基，芳基和杂环芳基，每种均可选择取代；每个R7选自氢，可选择取代的C1-6-烷基和C3-7-环烷基；每个R8和R9各自独立地选自氢或可选择取代的C1-6-烷基；或R8和R9与它们连接的N一起形成C4-6-杂环烷基；每个R10选自C3-7-环烷基和可选择取代的C1-6-烷基；每个R11各自独立地选自C1-6-烷基，C3-7-环烷基，C1-6-烷基-C3-7-环烷基，C4-7-杂环烷基，芳基和杂环芳基，每种均可选择取代；A选自卤素，—NR4SO2R5，—CN，—OR6，—NR4R5，—NR7R11，羟基，—CF3，—CONR4R5，—NR4COR5，—NR7（CO）NR4R5，—NO2，—CO2H，—CO2R6，—SO2R6，—SO2NR4R5，—NR4COR5，—NR4COOR5，C1-6-烷基和—COR6。进一步方面涉及公式I化合物的制药组合物，治疗用途和制备过程。
• Development of a Series of Pyrrolopyridone MAT2A Inhibitors
  作者：Stephen J. Atkinson、Sharan K. Bagal、Argyrides Argyrou、Sean Askin、Tony Cheung、Elisabetta Chiarparin、Muireann Coen、Iain T. Collie、Ian L. Dale、Claudia De Fusco、Keith Dillman、Laura Evans、Lyman J. Feron、Alison J. Foster、Michael Grondine、Vasudev Kantae、Gillian M. Lamont、Scott Lamont、James T. Lynch、Sten Nilsson Lill、Graeme R. Robb、Jamal Saeh、Marianne Schimpl、James S. Scott、James Smith、Bharath Srinivasan、Sharon Tentarelli、Mercedes Vazquez-Chantada、David Wagner、Jarrod J. Walsh、David Watson、Beth Williamson

  DOI：10.1021/acs.jmedchem.3c01860

  日期：2024.3.28

  The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect

  讨论了通过差示扫描荧光测定法发现的变构片段对体内 MAT2a 工具抑制剂的优化。基于结构的药物发现方法，在相对结合自由能计算的辅助下，产生了 AZ'9567 ( 21 )，一种有效的体外抑制剂，具有优异的临床前药代动力学特性。该工具在体外和体内均显示出对甲硫腺苷磷酸化酶 (MTAP) KO 细胞的选择性抗增殖作用，为支持 MAT2a 抑制剂作为 MTAP 缺陷肿瘤的潜在抗癌疗法的实用性提供了进一步的证据。