5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile | 752238-36-1

• 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: 5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
• 英文别名: 5-chloro-4,6-dimethyl-2-sulfanylidene-1H-pyridine-3-carbonitrile
• CAS: 752238-36-1
• 化学式: C₈H₇ClN₂S
• 分子量: 198.676
• InChiKey: KEJRXJSWOQLISC-UHFFFAOYSA-N

物化性质

• 沸点：
  222.8±50.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile 在 亚硝酸特丁酯 、 potassium hydroxide 、 copper(ll) bromide 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 7-chloro-1,6,8-trimethyl-1H-pyrazolo[3’,4’:4,5]thieno[2,3-b]pyridin-3-amine
  参考文献：
  名称：

  Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands

  摘要：

  This letter describes a focused exercise to explore the role of the beta-amino carboxamide moiety found in all of the first generation M-4 PAMs and question if the NH2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the beta-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH2, generating des-amino congeners and surveyed other functional groups in the beta-position. These modifications led to weak M-4 PAMs with poor DMPK properties. Cyclization of the beta-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M-4 PAMs, many as potent as the classical bicyclic beta-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the beta-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M(4)PAM activity within classical bicyclic M-4 PAM scaffolds.

  DOI：

  10.1016/j.bmcl.2018.12.039
• 作为产物：
  描述：

  2,5-二氯-4,6-二甲基烟腈 在 硫脲 作用下， 以 乙醇 为溶剂， 反应 24.0h， 以29%的产率得到5-chloro-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
  参考文献：
  名称：

  A structure–activity relationship study of the positive allosteric modulator LY2033298 at the M₄ muscarinic acetylcholine receptor

  摘要：

  靶向M4肌酸乙酰胆碱受体的阳性变构调节剂通过其新颖的作用方式，相较于传统的正交配体，提供更高的亚型选择性和作为中枢神经系统药物的独特潜力。

  DOI：

  10.1039/c5md00334b

文献信息

• [EN] SUBSTITUTED 1H-PYRAZOLO[3',4',4,5]THIENO[2,3-B]PYRIDIN-3-AMINE ANALOGS AS POSITIVE ALLOSTERIC MODULATIORS OF THE MUSCARINIC ACETYCHOLINE RECEPTOR M4<br/>[FR] ANALOGUES DE 1H-PYRAZOLO[3',4',4,5]THIÉNO[2,3-B]PYRIDIN-3-AMINE SUBSTITUÉS À TITRE DE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE M4 DE L'ACÉTYLCHOLINE
  申请人：UNIV VANDERBILT

  公开号：WO2013040534A1

  公开（公告）日：2013-03-21

  In one aspect, the invention relates to substituted lH-pyrazolo[3',4':4,5]thieno[2,3- b]pyridin-3 -amine analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代的lH-吡唑并[3',4':4,5]噻吩[2,3-b]吡啶-3-胺类似物，其衍生物和相关化合物，这些化合物可用作肌胆碱受体M4 (mAChR M4)的正变构调节剂；制备这些化合物的合成方法；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治疗与肌胆碱受体功能障碍相关的神经和精神疾病的方法。本文摘要旨在作为在特定领域进行搜索的扫描工具，并不意味着对本发明的限制。
• Synthesis of substituted benzoxazinylthieno[2,3-b]pyridines by the reaction of (3-cyanopyridin-2-ylthio)acetic acids or their amides with o-aminophenyl(diphenyl)carbinol
  作者：E. A. Kaigorodova、L. D. Konyushkin、A. A. Osipova、E. A. Gavrilova、E. V. Gromachevskaya、G. D. Krapivin

  DOI：10.1007/s11172-005-0208-5

  日期：2004.12

  A general method for the synthesis of 3-amino-2-(4,4-diphenyl-4H-3,1-benzoxazin-2-yl)thieno[2,3-b]pyridines was proposed. The method involves reactions of (3-cyanopyridin-2-ylthio)acetic acids or their amides with o-aminophenyl(diphenyl)carbinol in nitromethane in the presence of perchloric acid followed by neutralization of the resulting salts.

  提出了一种合成 3-氨基-2-(4,4-二苯基-4H-3,1-苯并恶嗪-2-基)噻吩并[2,3-b]吡啶的通用方法。该方法包括（3-氰基吡啶-2-基硫基）乙酸或其酰胺与邻氨基苯基（二苯基）甲醇在高氯酸存在下在硝基甲烷中的反应，然后中和所得盐。
• Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines
  作者：E. A. Kaigorodova、A. A. Osipova、L. D. Konyushkin、G. D. Krapivin

  DOI：10.1023/b:rucb.0000037855.13096.6e

  日期：2004.4

  5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2

  2,5-二甲氧基四氢呋喃与 3-氨基噻吩并 [2,3-b] 吡啶的反应提供了许多取代的 3-(1H-吡咯-1-基) 噻吩并 [2,3-b] 吡啶。反应的可能性和产物的产率由噻吩并[2,3-b]吡啶2位取代基的特征决定。2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines 的 Curtius 重排产生 4,5-dihydropyrido[3",2":4,5]thieno[2,3- e]吡咯并[1,2-a]吡嗪-4-酮。4-甲氧基甲基-6-甲基-3-(1H-吡咯-1-基)噻吩并[2,3-b]吡啶-2-羧酸乙酯的分子和晶体结构由X射线衍射分析确定。
• Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition
  作者：Michael R. Wood、Meredith J. Noetzel、James C. Tarr、Alice L. Rodriguez、Atin Lamsal、Sichen Chang、Jarrett J. Foster、Emery Smith、Peter Chase、Peter S. Hodder、Darren W. Engers、Colleen M. Niswender、Nicholas J. Brandon、Michael W. Wood、Mark E. Duggan、P. Jeffrey Conn、Thomas M. Bridges、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2016.07.042

  日期：2016.9

  This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high

  这封信描述了基于不可烯化酮核的一系列新型M 4 PAM的化学优化，该酮核是从MLPCN功能性高通量筛选中鉴定出来的。HTS命中力强，选择性强且具有CNS渗透性；但是，该化合物在体外和体内均高度清除。SAR提供了维持M 4 PAM效力和CNS暴露的类似物。但是，清除率仍然很高。代谢物鉴定研究表明，该系列产品经历了快速且接近定量的还原代谢，转化为相应的没有M 4 PAM活性的仲醇代谢物。
• [EN] ACETAMIDO-AMINO AND ACETAMIDO-SULFUR DERIVATIVES AS DNA POLYMERASE THETA INHIBITORS<br/>[FR] DÉRIVÉS ACÉTAMIDO-AMINO ET ACÉTAMIDO-SOUFRE UTILISÉS EN TANT QU'INHIBITEURS DE L'ADN POLYMÉRASE THÊTA
  申请人：IDEAYA BIOSCIENCES INC

  公开号：WO2022026548A1

  公开（公告）日：2022-02-03

  Disclosed herein are certain acetamido derivatives that are DNA Polymerase Theta (Ροlθ) inhibitors of Formula (I). Also, disclosed are pharmaceutical compositions comprising such compounds and methods of treating diseases treatable by inhibition of Ροlθ such as cancer, including homologous recombination (HR) deficient cancers.

  本文披露了某些醋酰胺衍生物，其为式(I)的DNA聚合酶Theta (Ροlθ)抑制剂。同时，还披露了包括这些化合物的制药组合物和治疗可通过抑制Ροlθ治疗的疾病的方法，例如癌症，包括同源重组(HR)缺陷癌症。