1-(4-((2,3-diaminopyridin-4-yl)oxy)-2-(phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea | 884340-53-8

• 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: 1-(4-((2,3-diaminopyridin-4-yl)oxy)-2-(phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea
• 英文别名: 1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-[4-(2,3-diaminopyridin-4-yl)oxy-2-phenylphenyl]urea
• CAS: 884340-53-8
• 化学式: C₂₅H₁₉ClF₃N₅O₂
• 分子量: 513.906
• InChiKey: QCUAZPOTTNVGNK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  115
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(4-((2,3-diaminopyridin-4-yl)oxy)-2-(phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea 、 三光气 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 以15%的产率得到1-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yloxy)-2-(phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea
  参考文献：
  名称：

  Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring

  摘要：

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

  DOI：

  10.1021/jm900242c
• 作为产物：
  描述：

  1-(4-(2-amino-3-nitropyridin-4-yloxy)-2-phenylphenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 5.0h， 以99%的产率得到1-(4-((2,3-diaminopyridin-4-yl)oxy)-2-(phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea
  参考文献：
  名称：

  Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring

  摘要：

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

  DOI：

  10.1021/jm900242c

文献信息

• Imidazo[4,5-B]Pyridin-2-One and Oxazolo[4,5-B]Pyridin-2-One Compounds and Analogs Thereof as Therapeutic Compounds
  申请人：Niculescu-Duvaz Dan

  公开号：US20070287838A1

  公开（公告）日：2007-12-13

  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 formula (I): 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 P3 , and R P4 is independently —H or a substituent; and additionally R P1 and R P2 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 —; exactly one linker moiety is —NR N —, or: exactly two linker moieties are —NR N —; 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.

  本发明涉及某些咪唑并[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，其中包括抑制RAF（例如B-RAF）活性、抑制细胞增殖、治疗癌症等功能，更具体地，涉及式（I）的化合物：其中：J独立地是—O—或—NRN1—；RN1，如果存在，独立地是—H或取代基；RN2独立地是—H或取代基；Y独立地是—CH═或—N═；Q独立地是—（CH2）j-M-（CH2）k—，其中：j独立地是0、1或2；k独立地是0、1或2；j+k为0、1或2；M独立地是—O—、—S—、—NH—、—NMe—或—CH2—；RP1、RP2、RP3和RP4中的每一个独立地是—H或取代基；并且RP1和RP2一起可以是—CH═CH—CH═CH—；L独立地是：由2、3或4个连接基成的连接基团；每个连接基独立地是—CH2—、—NRN—、—C（═X）—或—S（═O）2—；恰好一个连接基是—NRN—，或：恰好两个连接基是—NRN—；恰好一个连接基是—C（═X）—，且没有连接基是—S（═O）2—；或：恰好一个连接基是—S（═O）2—，且没有连接基是—C（═X）—；没有两个相邻的连接基是—NRN—；X独立地是═O或═S；每个RN独立地是—H或取代基；A独立地是：C6-14碳基芳基、C5-14杂环芳基、C3-12环烷基、C3-12杂环基；并且独立地是未取代或取代的；以及其药学上可接受的盐、溶剂化物、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制药组合物，以及这样的化合物和组合物的使用，无论在体内还是体外，用于抑制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，并用于治疗由于抑制RAF、RTK等而改善的疾病和病况，如增殖性疾病，如癌症（例如结肠癌、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 THERAPEUTIC COMPOUNDS
  申请人：Cancer Research Technology Limited

  公开号：EP1812433A1

  公开（公告）日：2007-08-01
• US7625922B2
  申请人：——

  公开号：US7625922B2

  公开（公告）日：2009-12-01
• [EN] IMIDAZO[4,5-B]PYRIDIN-2-ONE AND OXAZOLO[4,5-B]PYRIDIN-2-ONE COMPOUNDS AND ANALOGS THEREOF AS THERAPEUTIC COMPOUNDS<br/>[FR] COMPOSES D'IMIDAZO[4,5-B]PYRIDIN-2-ONE ET OXAZOLO[4,5-B]PYRIDIN-2-ONE ET LEURS ANALOGUES UTILISES A DES FINS THERAPEUTIQUES
  申请人：CANCER REC TECH LTD

  公开号：WO2006043090A1

  公开（公告）日：2006-04-27

  [EN] 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, [FR] La présente invention concerne certains composés d'imidazo[4,5-b]pyridin-2-one et d'oxazolo[4,5-b]pyridin-2-one et leurs analogues qui, entres autres, inhibent l'activité RAF (B-RAF, par ex.), inhibent la prolifération cellulaire, traitent les cancers, etc. L'invention concerne plus particulièrement les composés de formule (I) dans laquelle J est indépendamment -O- ou -NR
• Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
  作者：Delphine Ménard、Ion Niculescu-Duvaz、Harmen P. Dijkstra、Dan Niculescu-Duvaz、Bart M. J. M. Suijkerbuijk、Alfonso Zambon、Arnaud Nourry、Esteban Roman、Lawrence Davies、Helen A. Manne、Frank Friedlos、Ruth Kirk、Steven Whittaker、Adrian Gill、Richard D. Taylor、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm900242c

  日期：2009.7.9

  BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number Of Substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit (V600E)BRAF kinase activity in vitro and oncogqnic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.