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Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1

A fused, selected technique, for use in conditions or diseases, in the field of preparation of compounds as defined herein, capable of solving problems such as inactivity

Active Publication Date: 2019-07-30
CANCER RES TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At non-shock temperatures in humans and other vertebrates, HSF1 is constitutively produced but inactive and bound by the protein HSP90

Method used

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  • Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1
  • Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1
  • Fused 1,4-dihydrodioxin derivatives as inhibitors of heat shock transcription factor 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0786] Example 1, N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-amido)-2-methylphenyl)quinoline-6- Formamide

[0787] 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 3.34 g, 8.79 mmol) was added to 6- A solution of quinolincarboxylic acid (1.34 g, 7.74 mmol) and N,N-diisopropylethylamine (DIEA, 2.76 mL, 15.8 mmol) in dry DMF (40 mL). The reaction mixture was stirred for 6 min, after which compound 2 (2.00 g, 7.03 mmol) was added. The reaction mixture was stirred overnight at rt, diluted with water and the resulting precipitate was isolated by filtration, washed with water and dried to afford the title compound (3.09 g, 100%) as an off-white solid. 1 H NMR(500MHz,DMSO)δ10.18(s,1H),10.08(s,1H),9.02(dd,J=4.2,1.7Hz,1H),8.67(d,J=2.0Hz,1H),8.54 (dd, J=8.4,1.9Hz,1H),8.29(dd,J=8.8,2.1Hz,1H),8.15(d,J=8.8Hz,1H),7.88(d,J=2.2Hz,1H) ,7.65(dd,J=8.3,4.2Hz,1H),7.59(dd,J=8.2,2.2Hz,1H),7.54(d,J=2.2Hz,1H),7.51(dd,J=8.4,2.2 Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 6...

Embodiment 2 to Embodiment 48

[0789] According to the procedure used in Example 1, by substituting the appropriate carboxylic acid for 6-quinolinecarboxylic acid, the following compounds were synthesized:

Embodiment 2

[0790] Example 2, N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-amido)-2-methylphenyl)isoquinoline-7-methyl Amide

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PUM

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Abstract

The present invention relates to compounds of formula I, wherein A 1 、A 2 , R 4 and Q are as defined herein. The compounds of the present invention are inhibitors of heat shock factor 1 (HSF1). In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and / or prevention of proliferative diseases such as cancer. The invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising these compounds.

Description

[0001] introduction [0002] The present invention relates to novel compounds that act as inhibitors of heat shock factor 1 (HSF1) activity. The invention also relates to processes for the preparation of the compounds defined herein, pharmaceutical compositions comprising them, and their use in the treatment of HSF1 -mediated conditions or diseases such as cancer, autoimmune and viral diseases. [0003] Background of the invention [0004] Cancer arises from uncontrolled and unregulated cell proliferation. Precisely what causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research in recent decades. This research has led to the identification of many molecular targets associated with key metabolic pathways known to be associated with malignancy. [0005] Heat shock factor 1 (HSF1) is one such target molecule. HSF1 is a master regulator of the heat shock response, in which multiple genes are induced in respo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D319/08C07D405/12C07D407/12C07D409/12C07D417/12C07D417/14C07D471/04C07D487/08C07D491/056A61P35/00A61K31/357A61K31/404A61K31/428A61K31/436
CPCC07D405/14C07D319/18C07D407/12C07D409/12C07D417/12C07D417/14C07D471/04C07D487/08C07D491/056C07D405/12A61P31/12A61P35/00A61P35/02A61P37/02A61P43/00A61K31/357A61K31/404A61K31/428A61K31/436C07D319/08
Inventor 基思·琼斯卡尔·拉伊尼古拉·切萨姆马修·奇斯曼阿黛尔·伊利萨·帕斯夸库尔特·戈登·派克保罗·弗兰克·福尔德
Owner CANCER RES TECH LTD
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