Cdk2/9抑制剂 | 507487-89-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: Cdk2/9抑制剂
• 英文名称: [4-(2-amino-4-methyl-thiazol-5-yl)pyrimidin-2-yl]-(3-nitrophenyl)amine
• 英文别名: 4-(2-amino-4-methylthiazol-5-yl)-N-(3-nitrophenyl) pyrimidin-2-amine；Cdk2/9 inhibitor；iCDK2/9；4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-(3-nitrophenyl)pyrimidine-2-amine；[4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine；4-methyl-5-[2-(3-nitroanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine
• CAS: 507487-89-0
• 化学式: C₁₄H₁₂N₆O₂S
• 分子量: 328.354
• InChiKey: DYTKVFHLKPDNRW-UHFFFAOYSA-N

物化性质

• 沸点：
  590.5±60.0 °C(Predicted)
• 密度：
  1.490±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：12.5 mg/mL（38.07 mM；超声加热至 60°C）

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  151
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Boc-beta-丙氨酸 、 Cdk2/9抑制剂 在 4-二甲氨基吡啶 、 N,N'-二异丙基碳二亚胺 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 24.0h， 生成 ({4-methyl-5-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-thiazol-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  [EN] PYRIMIDINE COMPOUNDS
  [FR] COMPOSES DE PYRIMIDINE

  摘要：

  本发明涉及式(I)的取代嘧啶化合物，它们的制备，含有它们的药物组合物，以及它们作为细胞周期依赖性激酶（CDKs）抑制剂的用途，因此可用于治疗增殖性疾病和/或病毒性疾病。

  公开号：

  WO2004043953A1
• 作为产物：
  描述：

  3-硝基苯基胍硝酸盐 、 3-dimethylamino-1-(2-amino-4-methylthiazol-5-yl)propenone 在 sodium hydroxide 作用下， 以 乙二醇甲醚 为溶剂， 反应 22.0h， 以80%的产率得到Cdk2/9抑制剂
  参考文献：
  名称：

  2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors:  Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity

  摘要：

  Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

  DOI：

  10.1021/jm0309957

文献信息

• Discovery of <i>N</i>-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora Kinase Inhibitors
  作者：Shudong Wang、Carol A. Midgley、Frederic Scaërou、Joanna B. Grabarek、Gary Griffiths、Wayne Jackson、George Kontopidis、Steven J. McClue、Campbell McInnes、Christopher Meades、Mokdad Mezna、Andy Plater、Iain Stuart、Mark P. Thomas、Gavin Wood、Rosemary G. Clarke、David G. Blake、Daniella I. Zheleva、David P. Lane、Robert C. Jackson、David M. Glover、Peter M. Fischer

  DOI：10.1021/jm901913s

  日期：2010.6.10

  compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; Ki values of 8.0 and 9.2 nM for aurora A and B, respectively)

  通过对我们的激酶导向化合物集合的基于细胞的筛选，我们发现N-苯基-4-(噻唑-5-基)嘧啶-2-胺的一个子集是针对癌细胞系的有效细胞毒剂，抑制有丝分裂组蛋白 H3磷酸化，并导致异常的有丝分裂表型。随后证实，这些化合物实际上是极光 A 和 B 激酶的有效抑制剂。结果表明，极光激酶抑制的效力和选择性与这些化合物中苯胺对位取代基的存在相关。先导化合物4-甲基-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine ( 18 ; K i ) 的抗癌作用极光 A 和 B 的值分别为 8.0 和 9.2 nM) 显示来自有丝分裂失败后的细胞死亡和由于细胞抑制极光 A 和 B 激酶而增加的多倍性。初步体内评估表明，化合物18具有口服生物利用度并具有抗癌活性。化合物18 (CYC116) 目前正在癌症患者中进行 I 期临床评估。
• [EN] N-(4-(4-METHYLTHIAZOL-5-YL) PYRIMIDIN-2-YL) -N-PHENYLAMINES AS ANTIPROLIFERATIVE COMPOUNDS<br/>[FR] N-(4-(4-METHYLTHIAZOL-5-YL) PYRIMIDINE-2-YL) -N-PHENYLAMINES COMME COMPOSES A ACTION ANTIPROLIFERANTE
  申请人：CYCLACEL LTD

  公开号：WO2003029248A1

  公开（公告）日：2003-04-10

  The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukaemia, psoriasis and the like.

  本发明涉及2-取代的4-杂环芳基嘧啶，它们的制备，包含它们的药物组合物以及它们作为细胞周期依赖性激酶（CDKs）的抑制剂的用途，因此可用于治疗增生性疾病，如癌症、白血病、牛皮癣等。
• Therapeutic applications of 2-substituted 4-heteroarylpyrimidines
  申请人：Wang Shudong

  公开号：US20050282843A1

  公开（公告）日：2005-12-22

  The present invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein (A) one of X and Y is S, and the other is N; or one of X and Y is NH or N—R 5 , and the other is C—R 6 ; “a” is a single bond; “b”, “c”, “d”, “e” and “f” are single or double bonds so as to form a heteroaryl ring; R 1 is is R 7 with the proviso that R 1 is other than H or Me; or (B) one of X and Y is S, and the other is NH or N—R 5 ; “a” and “d” are each double bonds; “b”, “c”, “e” and “f” are each single bonds; R 1 is oxo; and R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H or R 7 ; R 7 is a group (CH 2 ) n —R 8 , wherein n is 0, 1, 2, 3 or 4 and wherein R 8 is selected from alkyl, aryl, heteroaryl, heterocycloalkyl, F, Cl, Br, I, CF 3 , NO 2 , CN, OH, O-alkyl, O-aryl, O-heteroaryl, O-heterocycloalkyl, CO-alkyl, CO-aryl, CO-heteroaryl, CO-heterocycloalkyl, COO-alkyl, NH 2 , NH-alkyl, NH-aryl, N(alkyl) 2 , NH-heteroaryl, NH-heterocycloalkyl, COOH, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CONH-aryl, CONH-heteroaryl, CONH-heterocycloalkyl, SO 3 H, SO 2 -alkyl, SO 2 -aryl, SO 2 -heteroaryl, SO 2 -heterocycloalkyl, SO 2 NH 2 , SO 2 NH-alkyl, SO 2 N(alkyl) 2 , SO 2 NH-aryl, SO 2 NH-heteroaryl, or SO 2 NH-heterocycloalkyl, wherein said alkyl, aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted with one or more groups selected from halogeno, NO 2 , OH, O-methyl, NH 2 , COOH, CONH 2 and CF 3 ; in the preparation of a medicament for treating diabetes. The compounds of the invention also have applications in the treatment of CNS disorders, alopecia, cardiovascular disorders and stroke.

  本发明涉及使用公式I的化合物或其药学上可接受的盐，其中(A) X和Y中的一个是S，另一个是N；或者X和Y中的一个是NH或N-R5，另一个是C-R6；“a”是单键；“b”，“c”，“d”，“e”和“f”是单键或双键，以形成杂环芳基环；R1是R7，但R1不是H或Me；或(B) X和Y中的一个是S，另一个是NH或N-R5；“a”和“d”均为双键；“b”，“c”，“e”和“f”均为单键；R1是氧代；R2，R3，R4，R5和R6均独立地为H或R7；R7是(CH2)n-R8基团，其中n为0、1、2、3或4，而R8是选自烷基、芳基、杂芳基、杂环烷基、F、Cl、Br、I、CF3、NO2、CN、OH、O-烷基、O-芳基、O-杂芳基、O-杂环烷基、CO-烷基、CO-芳基、CO-杂芳基、CO-杂环烷基、COO-烷基、NH2、NH-烷基、NH-芳基、N(烷基)2、NH-杂芳基、NH-杂环烷基、COOH、CONH2、CONH-烷基、CON(烷基)2、CONH-芳基、CONH-杂芳基、CONH-杂环烷基、SO3H、SO2-烷基、SO2-芳基、SO2-杂芳基、SO2-杂环烷基、SO2NH2、SO2NH-烷基、SO2N(烷基)2、SO2NH-芳基、SO2NH-杂芳基或SO2NH-杂环烷基的基团，其中所述的烷基、芳基、杂芳基和杂环烷基基团可以选择地用一种或多种从卤代、NO2、OH、O-甲基、NH2、COOH、CONH2和CF3中选择的基团进行取代；用于制备治疗糖尿病的药物。本发明的化合物还可用于治疗中枢神经系统疾病、脱发、心血管疾病和中风。
• N-(4-(4-methylthiazol-5-yl)pyrimidin-2-yl)-N-phenylamines as antiproliferative compounds
  申请人：——

  公开号：US20040259894A1

  公开（公告）日：2004-12-23

  The present invention relates to 2-substituted 4-heteroaryl-pyrimidines, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like.

  本发明涉及2-取代的4-杂环芳基嘧啶、它们的制备、含有它们的药物组合物以及它们作为细胞周期蛋白依赖性激酶（CDKs）的抑制剂的用途，因此可用于治疗增殖性疾病，如癌症、白血病、牛皮癣等。
• Anti-viral compounds
  申请人：Wang Shudong

  公开号：US20050288307A1

  公开（公告）日：2005-12-29

  The present invention relates to the use of 2-substituted 4-heteroaryl-pyrimidines and related compounds in the treatment of viral disorders.

  本发明涉及使用2-取代的4-杂环基嘧啶和相关化合物治疗病毒性疾病。