1-methyl-1H-pyrazole-3-carbonyl azide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-methyl-1H-pyrazole-3-carbonyl azide
• 英文别名: 1-Methylpyrazole-3-carbonyl azide；1-methylpyrazole-3-carbonyl azide
• 化学式: C₅H₅N₅O
• 分子量: 151.128
• InChiKey: XDEYLEXQQIUXQQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  49.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-methyl-1H-pyrazole-3-carbonyl azide 以 甲苯 为溶剂， 反应 1.0h， 生成 3-Isocyanato-1-methylpyrazole
  参考文献：
  名称：

  Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts

  摘要：

  The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number-of-diverse structures have been reported to inhibit CDKs and GSK-3 beta. in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates: for further development as anticancer agents.

  DOI：

  10.1021/jm3008536
• 作为产物：
  描述：

  1-甲基-1H-吡唑-3-甲酰氯 在 sodium azide 作用下， 以 水 为溶剂， 反应 1.0h， 生成 1-methyl-1H-pyrazole-3-carbonyl azide
  参考文献：
  名称：

  Novel Tetrahydropyrido[1,2-a]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts

  摘要：

  The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number-of-diverse structures have been reported to inhibit CDKs and GSK-3 beta. in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates: for further development as anticancer agents.

  DOI：

  10.1021/jm3008536

文献信息

• [EN] ISOINDOLINONE COMPOUNDS<br/>[FR] COMPOSÉS D'ISO-INDOLINONE
  申请人：MONTE ROSA THERAPEUTICS

  公开号：WO2021069705A1

  公开（公告）日：2021-04-15

  Disclosed herein is a compound or pharmaceutically acceptable salts or stereoisomers thereof of of formula I wherein X1 is linear or branched C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkyl C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 alkyl C6-10 aryl, C1-6 alkyl 5-10 membered heteroaryl, wherein X1 is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-C1- 6alkyl, -OC(O)-C1-6alkyl, -OC(O)-C1-4alkylamino, -C(O)O-C1-6alkyl, -COOH, - CHO, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-6 alkoxy or C1-6 alkylhydroxy; X2 is hydrogen, C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C1-4alkyl-4-8 membered heterocycloalkyl or C6 aryloxy, wherein X2 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, NH2, NMe2 or 5-6 membered heterocycloalkyl; n is 0, 1 or 2.

  本公开涉及一种化合物或药用可接受盐或其立体异构体，其化学式为I，其中X1为直链或支链的C1-6烷基，C3-6环烷基，-C1-6烷基C3-6环烷基，C6-10芳基，5-10成员杂芳基，C1-6烷基C6-10芳基，C1-6烷基5-10成员杂芳基，其中X1未取代或取代为一个或多个卤素，直链或支链的C1-6烷基，直链或支链的C1-6杂烷基，CF3，CHF2，-O-CHF2，-O-(CH2)2-OMe，OCF3，C1-6烷基氨基，-CN，-N(H)C(O)-C1-6烷基，-OC(O)-C1-6烷基，-OC(O)-C1-4烷基氨基，-C(O)O-C1-6烷基，-COOH，-CHO，-C1-6烷基C(O)OH，-C1-6烷基C(O)O-C1-6烷基，NH2，C1-6烷氧基或C1-6烷基羟基；X2为氢，C6-10芳基，5-10成员杂芳基，-O-(5-10成员杂芳基)，4-8成员杂环烷基，C1-4烷基4-8成员杂环烷基，-O-(4-8成员杂环烷基)，-O-C1-4烷基-(4-8成员杂环烷基)，-OC(O)-C1-4烷基-4-8成员杂环烷基或C6芳氧基，其中X2未取代或取代为一个或多个直链或支链的C1-6烷基，NH2，NMe2或5-6成员杂环烷基；n为0、1或2。
• [EN] PHARMACEUTICAL COMPOSITIONS FOR USE IN THE PREVENTION AND TREATMENT OF A DISEASE OR DISORDER CAUSED BY OR ASSOCIATED WITH ONE OR MORE PREMATURE TERMINATION CODONS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES DESTINÉES À ÊTRE UTILISÉES POUR PRÉVENIR OU TRAITER UNE MALADIE OU UN TROUBLE PROVOQUÉ PAR OU ASSOCIÉ À UN OU PLUSIEURS CODONS DE TERMINAISON PRÉMATURÉS
  申请人：MONTE ROSA THERAPEUTICS AG

  公开号：WO2022200857A1

  公开（公告）日：2022-09-29

  The present disclosure relates to a. compound of formula I or a. pharmaceutically acceptable salt thereof Formula I wherein A is Formula II X1is linear or branched C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X1is unsubstituted or substituted with one or more of halogen, linear or branched C1-6alkyl, linear or branched C1-6heteroalkyl, CF3, CHF2, CMeF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6alkylamino, -CN, -N(H)C(O)-C1-6alkyl, - OC(O)-C1-6alkyl, -OC(O)-C1-4alkylamino, -C(O)O-C1-6alkyl, -COOH, -CHO, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-6alkoxy or Cue alkylhydroxy; or X1together with X4forms a 4-8 membered heterocycloalkyl, which is unsubstituted or substituted with one or more of halogen, linear or branched -C1-6alkyl, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, C1-6alkylamino, -CN, -N(H)C(O)-C1-6alkyl, -OC(O)-C1-6alkyl, -C(O)O-C1-6alkyl, -COOH, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-4alkylhydroxy, or C1-4alkoxy; X2is hydrogen, C3-6cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, 4-8 membered heterocycloalkyl, wherein X2is unsubstituted or substituted with one or more of linear or branched Cue alkyl, -C1-4alkoxy, NH2, NMe2, halogen, CF3, CHF2, CMeF2, -O-(CH2)2-OMe, OCF3, OCHF2, CM alkylhydroxy, X3is -NH-, -O-; X4is -NH-, - CH2-; L1is a covalent bond, C1-6alkyl, which is unsubstituted or substituted with one or more of C1-4alkyl, halogen; L2is a covalent bond, Cue alkyl, which is unsubstituted or substituted with one or more of CM alkyl, halogen; L3is a covalent bond, -O-, - C1-4alkoxy or C1-6alkyl, which is unsubstituted or substituted with one or more of C1-4alkyd, halogen, for use in the prevention and treatment of a disease or disorder caused by or associated with one or more premature termination codons in a monotherapy or in a combined therapy with an aminoglycoside or a. pharmaceutically acceptable salt thereof.

  本公开涉及式I的化合物或其药学上可接受的盐，其中A为式II，X1为线性或支链C1-6烷基，C3-6环烷基，C6-10芳基，5-10成员杂芳基，4-8成员杂环烷基，其中X1未取代或取代有卤素，线性或支链C1-6烷基，线性或支链C1-6杂烷基，CF3，CHF2，CMeF2，-O-CHF2，-O-(CH2)2-OMe，OCF3，C1-6烷基氨基，-CN，-N(H)C(O)-C1-6烷基，-OC(O)-C1-6烷基，-OC(O)-C1-4烷基氨基，-C(O)O-C1-6烷基，-COOH，-CHO，-C1-6烷基C(O)OH，-C1-6烷基C(O)O-C1-6烷基，NH2，C1-6烷氧基或Cue烷基羟基；或X1与X4共同形成未取代或取代有卤素，线性或支链C1-6烷基，CF3，CHF2，CMeF2，-O-(CH2)2-OMe，OCF3，OCHF2，C1-6烷基氨基，-CN，-N(H)C(O)-C1-6烷基，-OC(O)-C1-6烷基，-C(O)O-C1-6烷基，-COOH，-C1-6烷基C(O)OH，-C1-6烷基C(O)O-C1-6烷基，NH2，C1-4烷基羟基或C1-4烷氧基的4-8成员杂环烷基；X2为氢，C3-6环烷基，C6-10芳基，5-10成员杂芳基，4-8成员杂环烷基，其中X2未取代或取代有线性或支链Cue烷基，-C1-4烷氧基，NH2，NMe2，卤素，CF3，CHF2，CMeF2，-O-(CH2)2-OMe，OCF3，OCHF2，CM烷基羟基，X3为-NH-，-O-；X4为-NH-，-CH2-；L1为共价键，C1-6烷基，未取代或取代有C1-4烷基，卤素；L2为共价键，Cue烷基，未取代或取代有CM烷基，卤素；L3为共价键，-O-，-C1-4烷氧基或C1-6烷基，未取代或取代有C1-4烷基，卤素，用于单一疗法或与氨基糖苷类药物或其药学上可接受的盐联合疗法预防和治疗由一个或多个过早终止密码子引起或相关的疾病或障碍。
• Novel Tetrahydropyrido[1,2-<i>a</i>]isoindolone Derivatives (Valmerins): Potent Cyclin-Dependent Kinase/Glycogen Synthase Kinase 3 Inhibitors with Antiproliferative Activities and Antitumor Effects in Human Tumor Xenografts
  作者：Rajâa Boulahjar、Aziz Ouach、Chiurato Matteo、Stephane Bourg、Myriam Ravache、Rémy le Guével、Séverine Marionneau、Thibauld Oullier、Olivier Lozach、Laurent Meijer、Christiane Guguen-Guillouzo、Saïd Lazar、Mohamed Akssira、Yves Troin、Gérald Guillaumet、Sylvain Routier

  DOI：10.1021/jm3008536

  日期：2012.11.26

  The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number-of-diverse structures have been reported to inhibit CDKs and GSK-3 beta. in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC50 < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates: for further development as anticancer agents.
• Advances in tetrahydropyrido[1,2- a ]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors
  作者：Rajâa Boulahjar、Aziz Ouach、Stéphane Bourg、Pascal Bonnet、Olivier Lozach、Laurent Meijer、Christiane Guguen-Guillouzo、Rémy Le Guevel、Saïd Lazar、Mohamed Akssira、Yves Troin、Gérald Guillaumet、Sylvain Routier

  DOI：10.1016/j.ejmech.2015.06.046

  日期：2015.8

  An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine iso-indolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSM as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro Kinase activities and the best effects were obtained with lung and colon cell lines. (C) 2015 Elsevier Masson SAS. All rights reserved.