(2S)-1-[(5-chloro-2-thienyl)methyl]-8-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (2S)-1-[(5-chloro-2-thienyl)methyl]-8-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one
• 英文别名: (2s)-1-[(5-Chloro-2-Thienyl)methyl]-8-[(3r,5r)-3,5-Dimethylmorpholin-4-Yl]-2-(Trifluoromethyl)-3,4-Dihydro-2h-Pyrimido[1,2-A]pyrimidin-6-One；(8S)-9-[(5-chlorothiophen-2-yl)methyl]-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one
• 化学式: C₁₉H₂₂ClF₃N₄O₂S
• 分子量: 462.923
• InChiKey: MMAAITOCOBQYBQ-BZPMIXESSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  76.6
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-三氟甲基-2-氨基嘧啶 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 sodium hydride 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 正庚烷 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 33.75h， 生成 (2S)-1-[(5-chloro-2-thienyl)methyl]-8-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one
  参考文献：
  名称：

  Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors

  摘要：

  Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.

  DOI：

  10.1021/jm5013352

文献信息

• Novel 2,3-Dihydro-1H-imidazopyrimidin-5-one and this 1,2,3,4-tetrahydropyrimidopyrimidin-6-one Derivatives Comprising a Substituted Morpholine, Preparation Thereof and Pharmaceutical Use Thereof
  申请人：SANOFI

  公开号：US20150148328A1

  公开（公告）日：2015-05-28

  The invention relates to the novel products of formula (I) with p, q=0, 1 or 2; R1=phenyl, pyridyl; —(CH 2 ) m —Ra; alkylene; cycloalkyl; heterocycloalkyl; alkyl; —SO 2 —Rb; —CO—Re; m=1 or 2; Ra=aryl, heteroaryl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—Rb, —C(Rb)═N—ORc, —CO 2 Rd, —CONRxRy; Rb=alkyl, aryl, heteroaryl; Rc=H, alkyl; Rd=alkyl, cycloalkyl; Re=alkyl, cycloalkyl, aryl, heteroaryl; NRxRy with Rx,Ry=H, alkyl, cycloalkyl, alkoxy, phenyl, or form with N a ring with optionally O, N; R2, R3=H, alkyl, CF 3, or form with C a ring with optionally O, S and N; R4=H, F, Cl, CH 3 or CN; the morpholine is substituted with Me, and optionally substituted with F, OH; or is (Formula 1a) and the isomer of configuration R,R (Formula 1b) these products being in all the isomer forms and the salts, as medicaments, in particular as anticancer medicaments.

  本发明涉及公式（I）的新型产物，其中p，q = 0、1或2；R1 = 苯基、吡啶基；—（CH2）m—Ra；烷基；环烷基；杂环烷基；烷基；—SO2—Rb；—CO—Re；m = 1或2；Ra = 芳基、杂芳基、—CO-环烷基、—CO-杂环烷基、—CO—Rb、—C（Rb）═N—ORc、—CO2Rd、—CONRxRy；Rb = 烷基、芳基、杂芳基；Rc = H、烷基；Rd = 烷基、环烷基；Re = 烷基、环烷基、芳基、杂芳基；NRxRy，其中Rx，Ry = H、烷基、环烷基、烷氧基、苯基，或与N形成一个环，该环可以选择性地含有O、N；R2，R3 = H、烷基、CF3，或与C形成一个环，该环可以选择性地含有O、S和N；R4 = H、F、Cl、CH3或CN；吗啡环以Me取代，或以F、OH取代；或为（公式1a），具有R，R构型的异构体（公式1b）。这些产物以所有的异构体形式和盐形式作为药物，特别是作为抗癌药物。
• 2,3-dihydro-1H-imidazo{1,2-a}pyrimidin-5-one and this 1,2,3,4-tetrahydropyrimido{1,2-a}pyrimidin-6-one derivatives comprising a substituted morpholine, preparation thereof and pharmaceutical use thereof
  申请人：SANOFI

  公开号：US10253043B2

  公开（公告）日：2019-04-09

  The invention relates to the novel products of formula (I) with p, q=0, 1 or 2; R1=phenyl, pyridyl; —(CH2)m—Ra; alkylene; cycloalkyl; heterocycloalkyl; alkyl; —SO2 —Rb; —CO—Re; m=1 or 2; Ra=aryl, heteroaryl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—Rb, —C(Rb)═N—ORc, —CO 2 Rd, —CONRxRy; Rb=alkyl, aryl, heteroaryl; Rc=H, alkyl; Rd=alkyl, cycloalkyl; Re=alkyl, cycloalkyl, aryl, heteroaryl; NRxRy with Rx,Ry=H, alkyl, cycloalkyl, alkoxy, phenyl, or form with N a ring with optionally O, N; R2, R3=H, alkyl, CF 3, or form with C a ring with optionally O, S and N; R4=H, F, Cl, CH3 or CN; the morpholine is substituted with Me, and optionally substituted with F, OH; or is (Formula 1a) and the isomer of configuration R,R (Formula 1b) these products being in all the isomer forms and the salts, as medicaments, in particular as anticancer medicaments.

  本发明涉及式（I）的新型产品，其中 p、q=0、1 或 2；R1=苯基、吡啶基；-(CH2)m-Ra；亚烷基；环烷基；杂环烷基；烷基；-SO2 -Rb；-CO-Re；m=1 或 2；Ra=芳基、杂芳基、-CO-环烷基、-CO-杂环烷基、-CO-Rb、-C(Rb)═N-ORC、-CO 2 Rd、-CONRxRy；Rb=烷基、芳基、杂芳基；Rc=H、烷基；Rd=烷基、环烷基；Re=烷基、环烷基、芳基、杂芳基；NRxRy，其中 Rx、Ry=H、烷基、环烷基、烷氧基、苯基，或与 N 形成可选 O、N 的环；R2、R3=H、烷基、CF 3，或与 C 形成可选 O、S 和 N 的环；R4=H、F、Cl、CH3 或 CN；吗啉被 Me 取代，并可选被 F、OH 取代；或者是（式 1a）和构型为 R,R 的异构体（式 1b），这些产品以所有异构体形式和盐类作为药物，特别是抗癌药物。
• Novel 2,3-Dihydro-1h-imidazo{1,2-a}pyrimidin-5-one and this 1,2,3,4-tetrahydropyrimido{1,2-a}pyrimidin-6-one Derivatives Comprising a Substituted Morpholine, Preparation Thereof and Pharmaceutical Use Thereof
  申请人：SANOFI

  公开号：US20190292205A1

  公开（公告）日：2019-09-26

  The invention relates to the novel products of formula (I): with p, q=0, 1 or 2; R1=phenyl, pyridyl; —(CH 2 ) m —Ra; alkylene; cycloalkyl; heterocycloalkyl; alkyl; —SO 2 —Rb; —CO—Re; m=1 or 2; Ra=aryl, heteroaryl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—Rb, —C(Rb)═N—ORc, —CO 2 Rd, —CONRxRy; Rb=alkyl, aryl, heteroaryl; Rc=H, alkyl; Rd=alkyl, cycloalkyl; Re=alkyl, cycloalkyl, aryl, heteroaryl; NRxRy with Rx,Ry=H, alkyl, cycloalkyl, alkoxy, phenyl, or form with N a ring with optionally O, N; R2, R3=H, alkyl, CF 3 , or form with C a ring with optionally O, S and N; R4=H, F, Cl, CH 3 or CN; the morpholine is substituted with Me, and optionally substituted with F, OH; or is and the isomer of configuration R,R these products being in all the isomer forms and the salts, as medicaments, in particular as anticancer medicaments.
• Discovery of (2<i>S</i>)-8-[(3<i>R</i>)-3-Methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2<i>H</i>-pyrimido[1,2-<i>a</i>]pyrimidin-6-one: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors
  作者：Benoit Pasquier、Youssef El-Ahmad、Bruno Filoche-Rommé、Christine Dureuil、Florence Fassy、Pierre-Yves Abecassis、Magali Mathieu、Thomas Bertrand、Tsiala Benard、Cédric Barrière、Samira El Batti、Jean-Philippe Letallec、Véronique Sonnefraud、Maurice Brollo、Laurence Delbarre、Véronique Loyau、Fabienne Pilorge、Luc Bertin、Patrick Richepin、Jérôme Arigon、Jean-Robert Labrosse、Jacques Clément、Florence Durand、Romain Combet、Pierre Perraut、Vincent Leroy、Frédéric Gay、Dominique Lefrançois、François Bretin、Jean-Pierre Marquette、Nadine Michot、Anne Caron、Christelle Castell、Laurent Schio、Gary McCort、Hélène Goulaouic、Carlos Garcia-Echeverria、Baptiste Ronan

  DOI：10.1021/jm5013352

  日期：2015.1.8

  Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.