N-(4-(2-chloroethoxy)-3-((allyloxy)methyl)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine | 1312603-57-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-(4-(2-chloroethoxy)-3-((allyloxy)methyl)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine
• 英文别名: [3-allyloxymethyl-4-(2-chloroethoxy)phenyl]-[4-(3-allyloxymethylphenyl)pyrimidin-2-yl]amine；N-[4-(2-chloroethoxy)-3-(prop-2-enoxymethyl)phenyl]-4-[3-(prop-2-enoxymethyl)phenyl]pyrimidin-2-amine
• CAS: 1312603-57-8
• 化学式: C₂₆H₂₈ClN₃O₃
• 分子量: 465.98
• InChiKey: NZZMLGVBVLOFRX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  33
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  65.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(4-(2-chloroethoxy)-3-((allyloxy)methyl)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 盐酸 作用下， 以 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 5.5h， 生成 11-(2-Piperidin-1-ylethoxy)-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(24),2(27),3,5,8(26),9,11,16,21(25),22-decaene
  参考文献：
  名称：

  Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

  摘要：

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.

  DOI：

  10.1021/jm200326p
• 作为产物：
  描述：

  3-羟甲基苯硼酸 在 盐酸 、 四丁基硫酸氢铵 、 palladium diacetate 、 sodium carbonate 、 三苯基膦 、 potassium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 正丁醇 为溶剂， 反应 22.0h， 生成 N-(4-(2-chloroethoxy)-3-((allyloxy)methyl)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine
  参考文献：
  名称：

  Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

  摘要：

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.

  DOI：

  10.1021/jm200326p

文献信息

• Activated Hoveyda‐Grubbs Olefin Metathesis Catalysts Derived from a Large Scale Produced Pharmaceutical Intermediate – Sildenafil Aldehyde
  作者：Louis Monsigny、Jakub Piątkowski、Damian Trzybiński、Krzysztof Woźniak、Tomasz Nienałtowski、Anna Kajetanowicz、Karol Grela

  DOI：10.1002/adsc.202100669

  日期：2021.10.5

  Sil-II’ was confirmed in a set of diverse metathesis reactions including ring-closing metathesis (RCM) and cross-metathesis (CM) of complex polyfunctional substrates of medicinal chemistry interest, including a challenging macrocyclization of the Pacritinib precursor. Compatibility of the new catalyst with various green solvents was checked and metathesis of Sildenafil and Tadalafil-based substrates was successfully

  在一组烯烃复分解反应中获得、表征和筛选了两种 EWG 活化的 Hoveyda-Grubbs 型钌配合物（Sil-II和Sil-II'）。这些催化剂是由市售的药物结构单元西地那非醛方便地合成，只需两步。稳定性和催化活性测试表明，体积较大的带有 NHC 配体的催化剂Sil-II'明显比其较小的 NHC 类似物Sil-II更稳定和更高效。催化剂Sil-II' 的良好应用概况在一系列不同的复分解反应中得到证实，包括具有药物化学意义的复杂多功能底物的闭环复分解 (RCM) 和交叉复分解 (CM)，包括 Pacritinib 前体的具有挑战性的大环化。检查了新催化剂与各种绿色溶剂的相容性，并成功地在丙酮中进行了基于西地那非和他达拉非的底物的复分解。通过动力学实验研究了Sil-II'引发的机制，揭示螯合烷氧基部分（从i PrO 到 EtO）的空间位阻的减少有利于交换引发途径，而不是其他流行的第二代的典型解离途径Hoveyda-Grubbs
• Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines
  作者：Eugene Guorong Yang、Nurulhuda Mustafa、Eng Chong Tan、Anders Poulsen、Pondy Murugappan Ramanujulu、Wee Joo Chng、Jeffrey J. Y. Yen、Brian W. Dymock

  DOI：10.1021/acs.jmedchem.6b00157

  日期：2016.9.22

  Blockage of more than one oncoptotein or pathway is now a standard approach in modem cancer therapy. Multiple inhibition is typically achieved with two or more drugs. Herein, we describe a pharmacophore Merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vorinostat, to create bispecific single molecules with both JAK and HDAC targeted inhibition. A preferred ether hydroxamate, 51, inhibits JAK2 and HDAC6 with low nanomolar potency, is <100 nM potent against HDACs 2 and potent against HDACs 1, 8, and 11, and >50-, fold selective for JAK2 in a panel of 97 kinases. Broad cellular antiproliferative potency is supported by demonstration of JAK-STAT and HDAC pathway blockade in several hematological cell lines, inhibition of colony formation in HEL cells, and analysis of apoptosis. This study provides new tool compounds for further exploration of dual JAK-HDAC pathway inhibiton achieved with a single molecule.
• Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma
  作者：Anthony D. William、Angeline C.-H. Lee、Stéphanie Blanchard、Anders Poulsen、Ee Ling Teo、Harish Nagaraj、Evelyn Tan、Dizhong Chen、Meredith Williams、Eric T. Sun、Kee Chuan Goh、Wai Chung Ong、Siok Kun Goh、Stefan Hart、Ramesh Jayaraman、Mohammed Khalid Pasha、Kantharaj Ethirajulu、Jeanette M. Wood、Brian W. Dymock

  DOI：10.1021/jm200326p

  日期：2011.7.14

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.