N-(3-(2-bromoacetyl)-4-chlorophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide | 902144-67-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-(2-bromoacetyl)-4-chlorophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide
• 英文别名: N-[3-(2-bromoacetyl)-4-chlorophenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide
• CAS: 902144-67-6
• 化学式: C₁₆H₁₁BrClF₃N₂O₂
• 分子量: 435.628
• InChiKey: AINOMKXCSLGOSR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  59.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  碳酸甲丙酯 、 N-(3-(2-bromoacetyl)-4-chlorophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 N-(4-chloro-3-(indolizin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide
  参考文献：
  名称：

  GDC-0449—A potent inhibitor of the hedgehog pathway

  摘要：

  SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.08.049
• 作为产物：
  描述：

  N-(3-acetyl-4-chlorophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide 在 氢溴酸 、 溴 、 溶剂黄146 作用下， 以 苯 为溶剂， 生成 N-(3-(2-bromoacetyl)-4-chlorophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide
  参考文献：
  名称：

  GDC-0449—A potent inhibitor of the hedgehog pathway

  摘要：

  SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.08.049

文献信息

• Quinoxaline Inhibitors of the Hedgehog Signalling
  申请人：Koehler Michael F.T.

  公开号：US20080261989A1

  公开（公告）日：2008-10-23

  The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I wherein A is a carbocycle or heterocycle; X is alkylene, NR 4 C(O), NR 4 C(S), NR 4 C(NH), NR 4 SO, NR 4 SO 2 , NR 4 C(O)NH, NR 4 C(S)NH, C(O)NR 4 , C(S)NR 4 , C(NH)NR 4 , NR 4 PO or NR 4 PO(OH) wherein R 4 is H or alkyl; R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R 2 is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R 3 is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; m is 0-3; n is 0-3; and salts and solvates thereof.

  该发明提供了新型的Hedgehog信号通路抑制剂，可用作治疗恶性肿瘤的治疗剂，其中该化合物具有一般式I，其中A是碳环或杂环；X是烷基，NR4C（O），NR4C（S），NR4C（NH），NR4SO，NR4SO2，NR4C（O）NH，NR4C（S）NH，C（O）NR4，C（S）NR4，C（NH）NR4，NR4PO或NR4PO（OH），其中R4为H或烷基；R1选自由群组，包括烷基，环烷基，芳基或杂环，每个都可以用羟基，卤素，氨基，硝基，烷基，酰基，烷基磺酰基或烷氧基进行取代；R2是卤素，羟基，烷基，酰基或烷氧基，每个都可以用羟基，卤素，氨基，硝基，烷基，酰基，烷基磺酰基或烷氧基进行取代；R3是卤素，羟基，烷基，酰基或烷氧基，每个都可以用羟基，卤素，氨基，硝基，烷基，酰基，烷基磺酰基或烷氧基进行取代；m为0-3；n为0-3；以及其盐和溶剂化合物。
• QUINOXALINE INHIBITORS OF THE HEDGEHOG SIGNALLING PATHWAY
  申请人：Genentech, Inc.

  公开号：EP1745041B1

  公开（公告）日：2012-06-20
• US8273743B2
  申请人：——

  公开号：US8273743B2

  公开（公告）日：2012-09-25
• [EN] QUINOXALINE INHIBITORS OF THE HEDGEHOG SIGNALLING PATHWAY<br/>[FR] INHIBITEURS DE QUINOXALINE DE LA VOIE DE SIGNALISATION HEDGEHOG
  申请人：GENENTECH INC

  公开号：WO2006078283A2

  公开（公告）日：2006-07-27

  [EN] The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agents for treating malignancies where the compounds have the general formula I wherein A is a carbocycle or heterocycle; X is alkylene, NR₄C(O), NR₄C(S), NR₄C(NH), NR₄SO, NR₄SO₂, NR₄C(O)NH, NR₄C(S)NH, C(O)NR₄, C(S)NR₄, C(NH)NR₄, NR₄PO or NR₄PO(OH) wherein R₄ is H or alkyl; R₁ is selected from the group consisting of alkyl, cycloalkyl, aryl or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R₂ is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R₃ is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; m is 0-3; n is 0-3; and salts and solvates thereof.
  [FR] L'invention concerne de nouveaux inhibiteurs de signalisation hedgehog utilisés comme agents thérapeutique dans le traitement de malignités. Lesdits composés sont représentés par la formule générale I dans laquelle A est un carbocycle ou un hétérocycle; X est alkylène, NR4C(O), NR4C(S), NR4C(NH), NR4SO, NR4SO2, NR4C(O)NH, NR4C(S)NH, C(O)NR4, C(S)NR4, C(NH)NR4, NR4PO ou NR4PO(OH), R4 étant H ou alkyle; R1 est sélectionné dans le groupe composé d'alkyle, de cycloalkyle, d'aryle ou d'un hétérocycle, chacun étant éventuellement substitué par hydroxyle, halogène, amino, nitro, alkyle, acyle, alkylsulfonyle ou alkoxy; R2 est halogène, hydroxyle, alkyle, acyle ou alkoxy, chacun éventuellement substitué par hydroxyle, halogène, amino, nitro, alkyle, acyle, alkylsulfonyle ou alkoxy; R3 est halogène, hydroxyle, alkyle, acyle ou alkoxy, chacun éventuellement substitué par hydroxyle, halogène, amino, nitro, alkyle, acyle, alkylsulfonyle ou alkoxy; m est 0-3; et n est 0-3. L'invention concerne également des sels et solvates desdits composés.