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Inhibitor containing fused ring derivative as well as preparation method and application thereof

A kind of compound, heterocyclic group technology, applied in the field of drug synthesis

Pending Publication Date: 2020-12-15
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because many EGFR inhibitors have a strong inhibitory effect on wild-type EGFR, leading to clinical side effects such as skin rashes, and the inhibitory activity against EGFR exon 20 insertion mutations and HER2 exon 20 insertion mutation targets also needs to be improved, so the EGFR and HER2 exon 20 mutations have obvious effects and compounds with high selectivity for wild-type EGFR are still in great demand and have good market prospects

Method used

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  • Inhibitor containing fused ring derivative as well as preparation method and application thereof
  • Inhibitor containing fused ring derivative as well as preparation method and application thereof
  • Inhibitor containing fused ring derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment

[0217] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The mensuration of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0218] Agilent 1200 Infinity Series mass spectrometer was used for LC-MS determination. HPLC determination using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and Waters2695-2996 high pressure liquid chromatography (Gimini C18 150 × 4.6 mm column).

[0219] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates. The specifications used for TLC are 0.15 mm to 0.20 mm, and the s...

Embodiment 6

[0223] N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((6-(4-fluorophenoxy)-8-phenylpyrido[3,2- d] pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0224]

[0225] The first step: 3-amino-4-bromo-6-chloromethyl picolinate

[0226]

[0227] N-Bromosuccinimide (10.5 g, 59.0 mmol) was added portionwise to 3-amino-6-chloromethylpicolinic acid methyl ester (10 g, 53.6 mmol) in N,N-dimethylformamide (75 mL) solution, the reaction solution was heated to 50 ° C for 5 hours. After cooling, ethyl acetate (150 mL) was dissolved, washed with brine (50 mL*6), the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product. The crude product was separated by column (petroleum ether:ethyl acetate=5:1) to obtain the product 3-amino-4-bromo-6-chloromethylpicolinic acid methyl ester (4.6 g, yield: 32%).

[0228] MS m / z(ESI):264.9[M+H] + .

[0229] The second step: 3-amino-6-chloro-4-phenylmethylpicolinic acid methyl ester

[0230] ...

Embodiment 13

[0270] N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)-5-carbonyl-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl )amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0271]

[0272] The first step: 2,4-dichloro-7-hydroxyfuro[3,4-d]pyrimidin-5(7H)-one

[0273]

[0274] At room temperature, 2,4-dichloro-5-carboxypyrimidine (2.0g, 10.4mmol) was dissolved in tetrahydrofuran (20mL), nitrogen was replaced, and then the reaction system was placed in a dry ice acetone bath, and diisopropylamino Lithium (2.0M in THF, 7.8mL, 15.6mmol) was added dropwise to the reaction system, reacted for 20 minutes, then N,N-dimethylformamide (0.37g, 50.2mmol) was added dropwise to the reaction system, stirred One hour. Then it was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was separated by column chromatography to obtain 2,4-dichloro-7-hydroxy...

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PUM

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Abstract

The invention relates to an inhibitor containing fused ring derivative as well as a preparation method and application thereof. Particularly, the invention relates to a compound as shown in a generalformula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a kinase inhibitor, particularly as a receptor tyrosine kinase inhibitor (TKI), more particularly as an EGFR (epidermal growth factor receptor) or HER2 (human epidermal growth factor receptor 2) inhibitor to treatment of cancer, inflammation, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and other related diseases. Each substituent in the general formula (I) is the same as the definition in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an inhibitor containing a ring derivative and its preparation method and application. Background technique [0002] There are a variety of signaling pathways interacting in cells to control cell proliferation, growth, migration and apoptosis. Abnormal activation of signaling pathways can lead to tumorigenesis. Receptor tyrosine kinases play an important role in the regulation of cells. Epidermal growth factor receptor (EGFR) is a member of the transmembrane protein tyrosine kinase ErbB receptor family (including ErbB1, ErbB2, ErbB3, ErbB4), through the binding of its ligand epidermal growth factor (EGF), it can Form homodimers on receptors, or form heterodimers with other receptors in the ErbB family (such as ErbB2, ErbB3, ErbB4), leading to the activation of EGFR tyrosine kinase activity. Activated EGFR can phosphorylate different substrates, thereby activating the d...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04C07D239/84C07D491/048C07D473/00C07D473/32C07D239/70C07D403/12C07D519/00C07D401/12C07D491/056C07D401/14A61K31/519A61K31/52A61K31/517A61P35/00A61P29/00A61P1/16A61P3/10A61P9/00A61P31/18A61P35/02
CPCC07D471/04C07D487/04C07D239/84C07D491/048C07D473/00C07D473/32C07D239/70C07D403/12C07D519/00C07D401/12C07D491/056C07D401/14A61P35/00A61P29/00A61P1/16A61P3/10A61P9/00A61P31/18A61P35/02
Inventor 王峰李凯龙黄志强蔡家强
Owner SHANGHAI HANSOH BIOMEDICAL
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