7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one | 884340-50-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one
• 英文别名: 7-(4-aminophenyloxy)-3-N-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one；7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2-one
• CAS: 884340-50-5
• 化学式: C₁₃H₁₂N₄O₂
• 分子量: 256.264
• InChiKey: IIFNJFDKVOANIO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  80.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one 、 2-氟-5-三氟甲基苯基异氰酸酯 以 四氢呋喃 为溶剂， 反应 14.0h， 以93%的产率得到1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-(3-methyl-2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yloxy)phenyl)urea
  参考文献：
  名称：

  吡咯并咪唑酮类化合物是v-Raf小鼠肉瘤肉瘤病毒癌基因同源物B1（BRAF）的新型强效抑制剂

  摘要：

  BRAF是一种丝氨酸/苏氨酸激酶，在多种癌症（包括50％至70％的黑色素瘤）中都会发生突变，并且已被证实可作为治疗靶标。我们已经设计并合成了含有吡啶并咪唑酮作为新型铰链结合支架的BRAF突变体抑制剂。已经获得对突变BRAF具有低纳摩尔效能（对于化合物5i为12nM ）和对突变BRAF黑色素瘤细胞系WM266.4具有低微摩尔细胞效能的化合物。该系列得益于极低的新陈代谢，以及可以通过咪唑酮的NH基团的甲基化来调节的药代动力学（PK），从而使化合物具有更少的H-供体和更好的PK谱。这些化合物在治疗突变型BRAF黑色素瘤中具有巨大潜力。

  DOI：

  10.1021/jm801509w
• 作为产物：
  描述：

  tert-butyl 4-(2,3-dihydro-3-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl-oxy)phenylcarbamate 在 三氟乙酸 、 水 、 sodium carbonate 作用下， 反应 1.5h， 以27%的产率得到7-(4-aminophenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one
  参考文献：
  名称：

  吡咯并咪唑酮类化合物是v-Raf小鼠肉瘤肉瘤病毒癌基因同源物B1（BRAF）的新型强效抑制剂

  摘要：

  BRAF是一种丝氨酸/苏氨酸激酶，在多种癌症（包括50％至70％的黑色素瘤）中都会发生突变，并且已被证实可作为治疗靶标。我们已经设计并合成了含有吡啶并咪唑酮作为新型铰链结合支架的BRAF突变体抑制剂。已经获得对突变BRAF具有低纳摩尔效能（对于化合物5i为12nM ）和对突变BRAF黑色素瘤细胞系WM266.4具有低微摩尔细胞效能的化合物。该系列得益于极低的新陈代谢，以及可以通过咪唑酮的NH基团的甲基化来调节的药代动力学（PK），从而使化合物具有更少的H-供体和更好的PK谱。这些化合物在治疗突变型BRAF黑色素瘤中具有巨大潜力。

  DOI：

  10.1021/jm801509w

文献信息

• Development of Novel, Highly Potent Inhibitors of V-RAF Murine Sarcoma Viral Oncogene Homologue B1 (BRAF): Increasing Cellular Potency through Optimization of a Distal Heteroaromatic Group
  作者：Bart M. J. M. Suijkerbuijk、Ion Niculescu-Duvaz、Catherine Gaulon、Harmen P. Dijkstra、Dan Niculescu-Duvaz、Delphine Ménard、Alfonso Zambon、Arnaud Nourry、Lawrence Davies、Helen A. Manne、Frank Friedlos、Lesley M. Ogilvie、Douglas Hedley、Filipa Lopes、Natasha P. U. Preece、Javier Moreno-Farre、Florence I. Raynaud、Ruth Kirk、Steven Whittaker、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm900607f

  日期：2010.4.8

  We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A−B−C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an

  我们描述了一系列新型V-RAF鼠肉瘤病毒癌基因同源物B1（BRAF）抑制剂的设计，合成和优化，该激酶的突变体形式（V600E）与几种类型的癌症有关，发生频率特别高在黑色素瘤中。我们先前所述的具有三方A-B-C系统的抑制剂（其中A是铰链结合吡啶并[4,5- b ]咪唑啉酮系统，B是芳基间隔基团，C是杂芳族基团）对纯化的V600E有效体外进行BRAF，但在伴随的细胞测定中效力较弱。本文评估将不同的芳族杂环取代为基于苯基的C环，作为提高这些抑制剂细胞效价的潜在手段。取代的吡唑，尤其是3-叔丁基-丁基-1-芳基-1 H-吡唑类可增加细胞效能，而对分离的V600E BRAF的效能无不利影响。因此，已经合成了以低纳摩尔浓度抑制V600E BRAF，其在细胞中的下游信号传导的化合物（如通过细胞外调节激酶（ERK）磷酸化的减少来测量）以及突变型BRAF依赖性细胞的增殖。伴随的好处是良好的口服生物利用度和体内高血浆浓度。
• 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：US07625922B2

  公开（公告）日：2009-12-01

  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 —NRN1—; RN1, if present, is independently —H or a substituent; RN2 is independently —H or a substituent; Y is independently —CH═ or —N═; Q is independently —(CH2)j—M—(CH2)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 —CH2—; each of RP1, RP2, RP3, and RP4 is independently —H or a substituent; and additionally RP1 and RP2 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 —CH2—, —NRN—, —C(═X)—, or —S(═O)2—; exactly one linker moiety is —NRN—, or: exactly two linker moieties are —NRN—; 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 —NRN—; X is independently ═O or ═S; each RN is independently —H or a substituent; A is independently: C6-14carboaryl, C5-14heteroaryl, C3-12carbocyclic, C3-12heterocyclic; 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，治疗癌症等作用，更具体地，是式（I）的化合物：其中：J独立地为—O—或—NRN1—；如果存在，RN1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、RP3和RP4中每一种独立地为—H或取代基；并且另外，RP1和RP2在一起可以是—CH═CH—CH═CH—；L独立地为：由2、3或4个连接基团形成的连接基团；每个连接基团独立地为—CH2—、—NRN—、—C（═X）—或—S（═O）2—；正好一个连接基团为—NRN—或：正好两个连接基团为—NRN—；正好一个连接基团为—C（═X）—，且没有连接基团为—S（═O）2—；或：正好一个连接基团为—S（═O）2—，且没有连接基团为—C（═X）—；没有相邻的两个连接基团为—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烷基芳基、C5-14杂环芳基、C3-12环烷基、C3-12杂环基；并且独立地为未取代或取代；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，以及在体内外使用这样的化合物和组合物来抑制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 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