噻吩并(3,4-d)异噻唑-3-胺,N-(苯基甲基)-N-(3-(3-(1-哌啶基甲基)苯氧基)丙基)-,1,1-二氧化 | 956489-10-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 噻吩并(3,4-d)异噻唑-3-胺,N-(苯基甲基)-N-(3-(3-(1-哌啶基甲基)苯氧基)丙基)-,1,1-二氧化
• 英文名称: methyl 3-(2,3-diaminopyridin-4-yloxy)benzoate
• 英文别名: Methyl 3-[(2,3-diamino-4-pyridinyl)oxy]benzoate；methyl 3-(2,3-diaminopyridin-4-yl)oxybenzoate
• CAS: 956489-10-4
• 化学式: C₁₃H₁₃N₃O₃
• 分子量: 259.265
• InChiKey: VVVROICWDBXNQS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  噻吩并(3,4-d)异噻唑-3-胺,N-(苯基甲基)-N-(3-(3-(1-哌啶基甲基)苯氧基)丙基)-,1,1-二氧化 、 三光气 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以75%的产率得到methyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)benzoate
  参考文献：
  名称：

  BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring

  摘要：

  We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo-[4,5]pyridin-2-one scaffold and it substituted urea linker. Here, we present it new series of BRAY inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

  DOI：

  10.1021/jm901509a
• 作为产物：
  描述：

  methyl 3-(2-amino-3-nitropyridin-4-yloxy)benzoate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 6.0h， 以64%的产率得到噻吩并(3,4-d)异噻唑-3-胺,N-(苯基甲基)-N-(3-(3-(1-哌啶基甲基)苯氧基)丙基)-,1,1-二氧化
  参考文献：
  名称：

  BRAF Inhibitors Based on an Imidazo[4,5]pyridin-2-one Scaffold and a Meta Substituted Middle Ring

  摘要：

  We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo-[4,5]pyridin-2-one scaffold and it substituted urea linker. Here, we present it new series of BRAY inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of low-nanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series.

  DOI：

  10.1021/jm901509a

文献信息

• [EN] PYRIDO[2,3-B]PYRAZINE-8-SUBSTITUTED COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS PYRIDO[2,3-B]PYRAZINE SUBSTITUÉS EN POSITION 8 ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009077766A1

  公开（公告）日：2009-06-25

  The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain pyrido[2,3-b]pyrazin-8-substituted compounds, as described herein, which, inter alia, inhibit RAF (e.g., B RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明一般涉及用于治疗增殖性疾病、癌症等的治疗化合物领域，更具体地涉及到本文所述的某些吡啶并[2,3-b]吡嗪-8-取代化合物，该化合物在某些情况下抑制RAF（例如BRAF）活性。本发明还涉及包含这些化合物的药物组合物，以及利用这些化合物和组合物在体内外抑制RAF（例如BRAF）活性、抑制受体酪氨酸激酶（RTK）活性、抑制细胞增殖，并用于治疗通过抑制RAF、RTK等而得到改善的疾病和疾患，如癌症（例如结直肠癌、黑色素瘤）等。
• IMIDAZO[4, 5-B]PYRIDIN-2-ONE AND OXAZOLO[4, 5-B]PYRIDIN-2-ONE COMPOUNDS AND ANALOGS THEREOF AS CANCER THERAPEUTIC COMPOUNDS
  申请人：Niculescu-Duvaz Dan

  公开号：US20090325945A1

  公开（公告）日：2009-12-31

  The present invention pertains to certain imidazo[4,5-b]pyridin-2-one and oxazolo[4,5 b]pyridin-2-one compounds and analogs thereof, which, inter alia, inhibit RAF (e.g., B RAF) activity, inhibit cell proliferation, treat cancer, etc., and more particularly to compounds of the formulae: wherein: J is independently —O— or —NR N1− ; R N1 , if present, is independently —H or a substituent; R N2 is independently —H or a substituent; Y is independently —CH═ or —N═; Q is independently —(CH 2 ) j -M-(CH 2 ) k — wherein: j is independently 0, 1 or 2; k is independently 0, 1, or 2; j+k is 0, 1, or 2; M is independently O—, —S—, —NH—, —NMe-, or —CH 2 —; each of R P1 , R P2 , R P5 , and R P4 is independently —H or a substituent; and additionally R P1 and R P2 taken together may be CH═CH—CH═CH—; and additionally R P1 and R P5 taken together may be CH═CH—CH═CH—; L is independently: a linker group formed by a chain of 2, 3, or 4 linker moieties; each linker moiety is independently CH 2 —, —NR N —, —C(═X)—, or —S(═O) 2 —; either: exactly one linker moiety is —NR N —, or: exactly two linker moieties are —NR N —; either: exactly one linker moiety is —C(═X)—, and no linker moiety is —S(═O) 2 —, or: exactly one linker moiety is —S(═O) 2 —, and no linker moiety is —C(═X)—; no two adjacent linker moieties are —NR N —; X is independently ═O or ═S; each R N is independently —H or a substituent; A is independently: C 6-14 carboaryl, C 5-14 heteroaryl, C 3-12 carbocyclic, C 3-12 heterocyclic; and is independently unsubstituted or substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., B-RAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and conditions that are ameliorated by the inhibition of RAF, RTK, etc., proliferative conditions such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明涉及特定的咪唑并[4,5-b]吡啶-2-酮和噁唑并[4,5-b]吡啶-2-酮化合物及其类似物，其中，它们可以抑制RAF（例如B-RAF）活性，抑制细胞增殖，治疗癌症等。特别是本发明涉及以下式的化合物：其中：J独立地为—O—或—NRN1−；RN1（如果存在）独立地为—H或取代基；RN2独立地为—H或取代基；Y独立地为—CH═或—N═；Q独立地为—（CH2）j-M-（CH2）k—，其中：j独立地为0、1或2；k独立地为0、1或2；j+k为0、1或2；M独立地为O—、—S—、—NH—、—NMe-或—CH2—；RP1、RP2、RP5和RP4中的每一个独立地为—H或取代基；并且另外RP1和RP2一起可以是CH═CH—CH═CH—；并且另外RP1和RP5一起可以是CH═CH—CH═CH—；L独立地为：由2、3或4个连接基成的连接基团；每个连接基单元独立地为CH2—、—NRN—、—C（═X）—或—S（═O）2—；要么：恰好有一个连接基单元为—NRN—，或：恰好有两个连接基单元为—NRN—；要么：恰好有一个连接基单元为—C（═X）—，且没有连接基单元为—S（═O）2—，或：恰好有一个连接基单元为—S（═O）2—，且没有连接基单元为—C（═X）—；没有两个相邻的连接基单元为—NRN—；X独立地为═O或═S；每个RN独立地为—H或取代基；A独立地为：C6-14碳基芳基、C5-14杂环芳基、C3-12环烷基、C3-12杂环烷基；并且独立地未取代或取代；以及其药学上可接受的盐、溶剂化合物、酰胺、酯、醚、N-氧化物、化学保护形式和前药。本发明还涉及包含这样的化合物的药物组合物，以及这样的化合物和组合物的使用，无论是在体外还是在体内，来抑制RAF（例如B-RAF）活性，抑制受体酪氨酸激酶（RTK）活性，抑制细胞增殖，并治疗通过抑制RAF、RTK等而改善的疾病和情况，如癌症（例如结肠癌、黑色素瘤）等。
• Pyrido[2,3-b]pyrazin-8-substituted Compounds and Their Use
  申请人：Springer Caroline Joy

  公开号：US20120238568A1

  公开（公告）日：2012-09-20

  The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain pyrido[2,3-b]pyrazin-8-substituted compounds, as described herein, which, inter alia, inhibit RAF (e.g., B-RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明涉及治疗增生性疾病、癌症等的治疗化合物领域，更具体地涉及某些在此处描述的吡啶并[2,3-b]吡嗪-8-取代化合物，它们在诸多方面抑制RAF（例如B-RAF）活性。本发明还涉及包含这些化合物的药物组合物，以及在体外和体内使用这些化合物和组合物来抑制RAF（例如BRAF）活性，抑制受体酪氨酸激酶（RTK）活性，抑制细胞增殖，并用于治疗由于抑制RAF、RTK等而改善的疾病和疾病，如增生性疾病（例如结直肠癌、黑色素瘤）等。
• PYRIDO[2,3-B]PYRAZIN-8-SUBSTITUTED COMPOUNDS AND THEIR USE
  申请人：INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL (THE)

  公开号：US20150182526A1

  公开（公告）日：2015-07-02

  The present invention pertains generally to the field of therapeutic compounds for treating proliferative disorders, cancer, etc., and more specifically to certain pyrido[2,3-b]pyrazin-8-substituted compounds, as described herein, which, inter alia, inhibit RAF (e.g., B-RAF) activity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit RAF (e.g., BRAF) activity, to inhibit receptor tyrosine kinase (RTK) activity, to inhibit cell proliferation, and in the treatment of diseases and disorders that are ameliorated by the inhibition of RAF, RTK, etc., proliferative disorders such as cancer (e.g., colorectal cancer, melanoma), etc.

  本发明涉及治疗增生性疾病、癌症等的治疗化合物领域，更具体地涉及某些在此处描述的吡啶并[2,3-b]吡嗪-8-取代化合物，它们在其他方面抑制RAF（例如B-RAF）活性。本发明还涉及包含这些化合物的药物组合物，以及在体外和体内使用这些化合物和组合物来抑制RAF（例如BRAF）活性，抑制受体酪氨酸激酶（RTK）活性，抑制细胞增殖，并治疗由于抑制RAF，RTK等而改善的疾病和疾患，如癌症（例如结直肠癌，黑色素瘤）等。
• Novel Hinge Binder Improves Activity and Pharmacokinetic Properties of BRAF Inhibitors
  作者：Alfonso Zambon、Delphine Ménard、Bart M. J. M. Suijkerbuijk、Ion Niculescu-Duvaz、Steven Whittaker、Dan Niculescu-Duvaz、Arnaud Nourry、Lawrence Davies、Helen A. Manne、Filipa Lopes、Natasha Preece、Douglas Hedley、Lesley M. Ogilvie、Ruth Kirk、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm100383b

  日期：2010.8.12

  Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A B C system featuring art imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A B C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.