6-chloro-2-morpholin-4-ylpyrimidine-4-carboxylic acid methyl ester | 873450-42-1

• 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: 6-chloro-2-morpholin-4-ylpyrimidine-4-carboxylic acid methyl ester
• 英文别名: Methyl 6-chloro-2-morpholinopyrimidine-4-carboxylate；methyl 6-chloro-2-morpholin-4-ylpyrimidine-4-carboxylate
• CAS: 873450-42-1
• 化学式: C₁₀H₁₂ClN₃O₃
• 分子量: 257.677
• InChiKey: OFRFEWZFJKXDAY-UHFFFAOYSA-N

物化性质

• 沸点：
  432.7±55.0 °C(Predicted)
• 密度：
  1.363±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  64.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-chloro-2-morpholin-4-ylpyrimidine-4-carboxylic acid methyl ester 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium tetrahydroborate 、 四丁基碘化铵 、 sodium hydride 、 sodium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 5-(6-(1-(ethylsulfonyl)cyclopropyl)-2-morpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

  摘要：

  The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C-4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3K alpha/beta/gamma/delta (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50= 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C-4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

  DOI：

  10.1021/acsmedchemlett.8b00167
• 作为产物：
  描述：

  吗啉 、 2,6-二氯嘧啶-4-甲酸甲酯 以 二氯甲烷 为溶剂， 生成 6-chloro-2-morpholin-4-ylpyrimidine-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

  摘要：

  The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C-4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3K alpha/beta/gamma/delta (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50= 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C-4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

  DOI：

  10.1021/acsmedchemlett.8b00167

文献信息

• [EN] 2 -MORPHOLINOPYRIMIDINES AND THEIR USE AS PI3 KINASE INHIBITORS<br/>[FR] 2-MORPHOLINOPYRIMIDINES ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE KINASE PI3
  申请人：HOFFMANN LA ROCHE

  公开号：WO2009066084A1

  公开（公告）日：2009-05-28

  Morpholino pyrimidines of formula (I): wherein R1 is selected from -Y-R6 and -NR4R5; R2 is a N-containing monocyclic heteroaryl group which is selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl, thienyl, triazolyl and tetrazolyl and which is unsubstituted or substituted by halo, -CN, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, - N(C(O)R11)2, -NR10C(O)NR10R11, -SO2R10R11, -SO2NR10R11, -C(=O)OR10, -C(=O)NR10R11, halo-C1 -C6 alkyl and unsubstituted C1-C12 alkyl; R3 is selected from H, C1-C6 alkyl and C1-C6 alkoxy; Y is selected from a direct bond, -(CR2)m-, C2-C6 alkenylene, C2-C6 alkynylene, -(CR2)p-O-(CR2) t-, -(CR2)p-NR-(CR2) t, -(CR2)p-NR-(CR2)n-C(O)-, -(CR2)p-NR-C(O)- (CR2)n-, -(CR2)p-C(O)-NR-(CR2) t, -(CR2)p-C(O)-(CR2)n-NR-(CR2)t,- and -(CR2)p- C(O)-(CR2)n-; R6 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted, C1-C6 alkyl, -NR2, -OR, -NR(CO)R and - C(O)NR2; R4 and R5, which are the same or different, are both C1-C6 alkyl which is unsubstituted or substituted, or R4 and R5 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted; each R, which are the same or different when more than one is present in a given group, is independently H, C1-C6 alkyl which is unsubstituted or substituted or a 5- to 12-membered aryl or heteroaryl group which is unsubstituted or substituted; R10 and R11, which are the same or different, are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C8 cycloalkyl; n is 0 or an integer of 1 to 6; m is an integer of 1 to 6; p is 0 or an integer of 1 to 6; and t is 0 or an integer of 1 to 6, with the proviso that t is an integer of 2 to 6 when R6 is linked to Y through a constituent O or N atom of R6; and the pharmaceutically acceptable salts thereof, subject to various provisos, have activity as inhibitors of PI3K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour, particularly that associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.

  式(I)的吗哥啉嘧啶，其中R1从-Y-R6和-NR4R5中选择；R2是一种含氮的单环杂环芳基，选择自吡啶基、异噁唑基、咪唑基、吡唑基、吡咯基、噻唑基、吡啶嗪基、嘧啶基、吡嗪基、噁唑基、呋喃基、噻吩基、三唑基和四唑基，未取代或取代为卤素、-CN、-NR10R11、-OR10、-C(O)R10、-NR10C(O)R11、-N(C(O)R11)2、-NR10C(O)NR10R11、-SO2R10R11、-SO2NR10R11、-C(=O)OR10、-C(=O)NR10R11、卤代-C1-C6烷基和未取代的C1-C12烷基；R3从H、C1-C6烷基和C1-C6烷氧基中选择；Y从直接键、-(CR2)m-、C2-C6烯基、C2-C6炔基、-(CR2)p-O-(CR2)t-、-(CR2)p-NR-(CR2)t、-(CR2)p-NR-(CR2)n-C(O)-、-(CR2)p-NR-C(O)-(CR2)n-、-(CR2)p-C(O)-NR-(CR2)t、-(CR2)p-C(O)-(CR2)n-NR-(CR2)t和-(CR2)p-C(O)-(CR2)n-中选择；R6从未饱和的5-至12成员碳环或杂环环中选择，饱和的5、6或7成员N含杂环基，未取代或取代，C1-C6烷基，-NR2，-OR，-NR(CO)R和-C(O)NR2中选择；R4和R5，相同或不同，均为未取代或取代的C1-C6烷基，或R4和R5与它们连接的氮原子形成未取代或取代的饱和的5、6或7成员N含杂环基；每个R，当在给定的基团中存在多个时，相同或不同，独立地为H，未取代或取代的C1-C6烷基或未取代或取代的5-至12成员芳基或杂环基；R10和R11，相同或不同，独立地选择自H，C1-C6烷基，C2-C6烯基，C2-C6炔基和C3-C8环烷基；n为0或1至6的整数；m为1至6的整数；p为0或1至6的整数；t为0或1至6的整数，但当R6通过R6的一个成分O或N原子与Y连接时，t为2至6的整数；以及其药学上可接受的盐，受各种规定限制，具有PI3K抑制剂的活性，因此可用于治疗由于异常细胞生长、功能或行为引起的疾病和紊乱，特别是与PI3激酶相关的癌症、免疫紊乱、心血管疾病、病毒感染、炎症、代谢/内分泌紊乱和神经系统紊乱。还描述了合成这些化合物的方法。
• IL-12 MODULATORY COMPOUNDS
  申请人：Sun Lijun

  公开号：US20100256132A1

  公开（公告）日：2010-10-07

  The invention relates to heterocyclic compounds, compositions including the compounds and methods of using and methods of making thereof. The compounds (and compositions) are useful, inter alia, in modulating IL-12 production and processes mediated by IL-12.

  本发明涉及杂环化合物、包括该化合物的组合物以及使用和制备该化合物的方法。该化合物（和组合物）在调节IL-12产生和由IL-12介导的过程中具有实用性。
• 2-morpholin-4,6-disubstituted pyrimidine derivative, and preparation method and pharmaceutical use thereof
  申请人：Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

  公开号：US10227324B2

  公开（公告）日：2019-03-12

  Disclosed is a 2-morpholin-4,6-disubstituted pyrimidine derivative as shown in formula (1) below, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutical composition thereof and a use thereof, wherein the definition of each group is as shown in the description. The compound has a PI3K kinase inhibition activity, and has a relatively high inhibitive ability and a low cytotoxicity against PIK3CA mutant breast cancer cell strains T47D and MCF-7.

  公开了一种如下式（1）所示的2-吗啉-4,6-二取代嘧啶衍生物及其药学上可接受的盐、溶液剂、立体异构体或原药，以及其药物组合物及其用途，其中各基团的定义如说明书所示。该化合物具有 PI3K 激酶抑制活性，对 PIK3CA 突变乳腺癌细胞株 T47D 和 MCF-7 具有相对较高的抑制能力和较低的细胞毒性。
• [EN] 2-MORPHOLIN-4,6-DISUBSTITUTED PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF<br/>[FR] DÉRIVÉ DE PYRIMIDINE DISUBSTITUÉ EN 2-MORPHOLIN-4,6 ET PROCÉDÉ DE PRÉPARATION ET UTILISATION PHARMACEUTIQUE ASSOCIÉS<br/>[ZH] 2-吗啉-4,6-二取代的嘧啶衍生物、其制法与医药上的用途
  申请人：SHANGHAI HAIYAN PHARMACEUTICAL TECHNOLOGY CO LTD

  公开号：WO2016095833A1

  公开（公告）日：2016-06-23

  一种如下式(I)所示的2-吗啉-4,6-二取代的嘧啶衍生物、其药学上可接受的盐、溶剂化物、立体异构体或其前药，其药物组合物及其应用，其中各基团定义如说明书中所示。所述化合物具有PI3K激酶抑制活性，对PIK3CA突变型乳腺癌细胞株T47D和MCF-7具有较高的抑制性和低细胞毒性。
• WO2006/53227
  申请人：——

  公开号：——

  公开（公告）日：——