1-[2-[4-(dimethylaminomethyl)-1-piperidyl]ethyl]-3-(p-tolyl)pyrazolo[3,4-d]pyrimidin-4-amine

• 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-[2-[4-(dimethylaminomethyl)-1-piperidyl]ethyl]-3-(p-tolyl)pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: 1-(2-{4-[(dimethylamino)methyl]piperidin-1-yl}ethyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine；1-[2-[4-[(Dimethylamino)methyl]piperidin-1-yl]ethyl]-3-(4-methylphenyl)pyrazolo[3,4-d]pyrimidin-4-amine；1-[2-[4-[(dimethylamino)methyl]piperidin-1-yl]ethyl]-3-(4-methylphenyl)pyrazolo[3,4-d]pyrimidin-4-amine
• 化学式: C₂₂H₃₁N₇
• 分子量: 393.535
• InChiKey: AKSZNKRUJCTEIJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-碘-4-氨基吡唑并[3,4-d]嘧啶 在 palladium diacetate 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 20.84h， 生成 1-[2-[4-(dimethylaminomethyl)-1-piperidyl]ethyl]-3-(p-tolyl)pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  通过 SRC 激酶抑制有效抑制乳腺癌细胞生长的吡唑并嘧啶的快速发现和构效关系，对 ABL 激酶具有卓越的选择性。

  摘要：

  通过以迭代方式结合基于配体的设计和表型筛选，已开发出对 SRC 家族激酶具有高效力和选择性的新型吡唑并嘧啶。化合物来源于混杂激酶抑制剂 PP1，以寻找可能靶向与癌症相关的广谱激酶的类似物。针对 MCF7 乳腺腺癌细胞的表型筛选产生了与靶标无关的结构-活性关系，使后续设计偏向于乳腺癌治疗而不是特定靶标。该策略导致发现了两种具有表型不同抗癌作用模式的强效抗增殖先导物。激酶分析和进一步优化产生了 eCF506，第一个对 SRC 具有亚纳摩尔 IC50 的小分子，需要 3 个数量级的浓度才能抑制 ABL。eCF506 具有出色的水溶性、最佳的 DMPK 特性和口服生物利用度，可阻止斑马鱼胚胎中 SRC 相关的神经丘迁移，而不会引起危及生命的心脏缺陷，并抑制小鼠肿瘤异种移植物中的 SRC 磷酸化。

  DOI：

  10.1021/acs.jmedchem.6b00065

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：UNIV COURT UNIV OF EDINBURGH

  公开号：WO2016185160A1

  公开（公告）日：2016-11-24

  A first aspect of the- invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, (Formula (I)) wherein: R1 is (CH2)mNR11R12;R2 is selected from H, halo, OR13, ΝΗR13, alkyl, alkenyl and alkynyl; R3 is selected from alkyl, alkenyl, alkynyl, aryl, halo, aryloxy, NHCO2R4, NHCONR5R6, NHCOR7, NH-alkyl, NH-alkenyl, NH(CH2);n-aryl, (CH2)p-heteroaryl, (CH2)qCO2R8, (CH2)rCOR9 and NHSO2R10, wherein each alkyl, alkenyl, aryl or heteroaryl moiety in the aforementioned list is optionally further substituted by one or more groups selected from alkyl, halo OH, NH2, alkoxy, aryloxy, alkylamino, arylamino, carboxyl and carboxamide; R4 to R10 and R13 are each independently selected from alkyl, alkenyl and aryl; R11 and R12 are each independently selected from alkyl and alkenyl; or R11 and R:12 are linked together with the nitrogen to which they are attached to form a heterocycloalkyl or heterocycloalkenyl group; n, m, p, q and r are each independently selected from 0, 1, 2,.3. 4, 5 and 6. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing according to the invention.

  该发明的第一个方面涉及化合物的公式(I)，或其药学上可接受的盐或酯，其中：R1为(CH2)mNR11R12；R2选择自H、卤素、OR13、ΝΗR13、烷基、烯基和炔基；R3选择自烷基、烯基、炔基、芳基、卤素、芳氧基、NHCO2R4、NHCONR5R6、NHCOR7、NH-烷基、NH-烯基、NH(CH2);n-芳基、(CH2)p-杂环芳基、(CH2)qCO2R8、(CH2)rCOR9和NHSO2R10，其中上述列表中的每个烷基、烯基、芳基或杂环芳基都可以选择进一步被来自烷基、卤素、羟基、NH2、烷氧基、芳氧基、烷基氨基、芳基氨基、羧基和羧酰胺的一个或多个基团取代；R4至R10和R13各自独立地选择自烷基、烯基和芳基；R11和R12各自独立地选择自烷基和烯基；或者R11和R12与它们附着的氮一起连接以形成杂环烷基或杂环烯基基团；n、m、p、q和r各自独立地选择自0、1、2、3、4、5和6。进一步方面涉及根据该发明制备的药物组合物、治疗用途和制备方法。
• Compounds
  申请人：UNIVERSITY COURT OF THE UNIVERSITY OF EDINBURGH

  公开号：US10294227B2

  公开（公告）日：2019-05-21

  A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, (Formula (I)) wherein: R1 is (CH2)mNR11R12; R2 is selected from H, halo, OR13, NHR13, alkyl, alkenyl and alkynyl; R3 is selected from alkyl, alkenyl, alkynyl, aryl, halo, aryloxy, NHCO2R4, NHCONR5R6, NHCOR7, NH-alkyl, NH-alkenyl, NH(CH2);n-aryl, (CH2)p-heteroaryl, (CH2)qCO2R8, (CH2)rCOR9 and NHSO2R10, wherein each alkyl, alkenyl, aryl or heteroaryl moiety in the aforementioned list is optionally further substituted by one or more groups selected from alkyl, halo OH, NH2, alkoxy, aryloxy, alkylamino, arylamino, carboxyl and carboxamide; R4 to R10 and R13 are each independently selected from alkyl, alkenyl and aryl; R11 and R12 are each independently selected from alkyl and alkenyl; or R11 and R:12 are linked together with the nitrogen to which they are attached to form a heterocycloalkyl or heterocycloalkenyl group; n, m, p, q and r are each independently selected from 0, 1, 2, 3, 4, 5 and 6. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing according to the invention.

  本发明的第一个方面涉及一种式（I）化合物或其药学上可接受的盐或酯，（式（I））其中：R1 是 (CH2)mNR11R12； R2 选自 H、卤素、OR13、NHR13、烷基、烯基和炔基； R3 选自烷基、烯基、炔基、芳基、卤素、芳氧基、NHCO2R4、NHCONR5R6、NHCOR7、NH-烷基、NH-烯基、NH(CH2)；n-芳基、(CH2)p-杂芳基、(CH2)qCO2R8、(CH2)rCOR9 和 NHSO2R10，其中上述清单中的每个烷基、烯基、芳基或杂芳基可任选地被一个或多个选自烷基、卤代 OH、NH2、烷氧基、芳氧基、烷基氨基、芳基氨基、羧基和羧酰胺的基团进一步取代；R4 至 R10 和 R13 各自独立地选自烷基、烯基和芳基；R11 和 R12 各自独立地选自烷基和烯基；或 R11 和 R：12 与它们所连接的氮连接在一起，形成杂环烷基或杂环烯基；n、m、p、q 和 r 各自独立地选自 0、1、2、3、4、5 和 6。其他方面涉及根据本发明制备的药物组合物、治疗用途和工艺。
• COMPOUNDS
  申请人：UNIVERSITY COURT OF THE UNIVERSITY OF EDINBURGH

  公开号：US20180127422A1

  公开（公告）日：2018-05-10

  A first aspect of the-invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, (Formula (I)) wherein: R 1 is (CH 2 ) m NR 11 R 12 ; R 2 is selected from H, halo, OR 13 , NHR 13 , alkyl, alkenyl and alkynyl; R 3 is selected from alkyl, alkenyl, alkynyl, aryl, halo, aryloxy, NHCO 2 R 4 , NHCONR 5 R 6 , NHCOR 7 , NH-alkyl, NH-alkenyl, NH(CH 2 ); n -aryl, (CH 2 ) p -heteroaryl, (CH 2 ) q CO 2 R 8 , (CH 2 ) r COR 9 and NHSO 2 R 10 , wherein each alkyl, alkenyl, aryl or heteroaryl moiety in the aforementioned list is optionally further substituted by one or more groups selected from alkyl, halo OH, NH 2 , alkoxy, aryloxy, alkylamino, arylamino, carboxyl and carboxamide; R 4 to R 10 and R 13 are each independently selected from alkyl, alkenyl and aryl; R 11 and R 12 are each independently selected from alkyl and alkenyl; or R 11 and R: 12 are linked together with the nitrogen to which they are attached to form a heterocycloalkyl or heterocycloalkenyl group; n, m, p, q and r are each independently selected from 0, 1, 2, .3. 4, 5 and 6. Further aspects relate to pharmaceutical compositions, therapeutic uses and process for preparing according to the invention.
• Rapid Discovery and Structure–Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase
  作者：Craig Fraser、John C. Dawson、Reece Dowling、Douglas R. Houston、Jason T. Weiss、Alison F. Munro、Morwenna Muir、Lea Harrington、Scott P. Webster、Margaret C. Frame、Valerie G. Brunton、E. Elizabeth Patton、Neil O. Carragher、Asier Unciti-Broceta

  DOI：10.1021/acs.jmedchem.6b00065

  日期：2016.5.26

  Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary

  通过以迭代方式结合基于配体的设计和表型筛选，已开发出对 SRC 家族激酶具有高效力和选择性的新型吡唑并嘧啶。化合物来源于混杂激酶抑制剂 PP1，以寻找可能靶向与癌症相关的广谱激酶的类似物。针对 MCF7 乳腺腺癌细胞的表型筛选产生了与靶标无关的结构-活性关系，使后续设计偏向于乳腺癌治疗而不是特定靶标。该策略导致发现了两种具有表型不同抗癌作用模式的强效抗增殖先导物。激酶分析和进一步优化产生了 eCF506，第一个对 SRC 具有亚纳摩尔 IC50 的小分子，需要 3 个数量级的浓度才能抑制 ABL。eCF506 具有出色的水溶性、最佳的 DMPK 特性和口服生物利用度，可阻止斑马鱼胚胎中 SRC 相关的神经丘迁移，而不会引起危及生命的心脏缺陷，并抑制小鼠肿瘤异种移植物中的 SRC 磷酸化。