Amide group pyrazol compound used as FGFR irreversible inhibitor

A group, cyano group technology, applied in the field of new pyrazole derivatives, can solve the problems of weak inhibitory effect, insignificant inhibitory effect, reduced tumor inhibitory effect, etc.

Active Publication Date: 2019-10-11
ETERN BIOPHARMA SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although these pan-FGFR inhibitors have strong inhibitory effects on the biological activities of FGFR1, FGFR2 and FGFR3, their inhibitory effects on FGFR4 are much weaker, making such inhibitors effective for tumors that depend on FGFR4 activity (such as: some In addition, both AZD4547 and BGJ398 are reversible inhibitors, and FGFR mutations will produce drug resistance to them, resulting in reduced or even complete loss of tumor inhibitory effect

Method used

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  • Amide group pyrazol compound used as FGFR irreversible inhibitor
  • Amide group pyrazol compound used as FGFR irreversible inhibitor
  • Amide group pyrazol compound used as FGFR irreversible inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220] Example 1: 2-acrylamido-N-(3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-yl)benzamide

[0221]

[0222] Put 76mg (0.31mmol) intermediate A in the round bottom flask, N 2 Add 2ml of dry toluene under protection to dissolve, stir in ice bath for 10min, then add dropwise 0.29ml of trimethylaluminum solution (1.6M, 0.46mmol), react for 1h, add 100mg (0.46mmol) of intermediate B, and stir for 10min Remove the ice bath, react at 60°C for 18h, cool down, add H 2 O quenched the reaction, extracted with ethyl acetate, and the resulting solution was washed with saturated NaCl solution, anhydrous NaCl 2 SO 4 dry. Separation and purification by silica gel column chromatography (gradient elution, dichloromethane:methanol=200:1 to 70:1) to obtain white powdery solid 2-acrylamido-N-(3-(3,5-dimethoxy Phenylethyl)-1H-pyrazol-5-yl)benzamide (Example 1, 67 mg, 52%). 1 H NMR(400MHz,DMSO)δ12.24(s,1H),11.09(s,1H),10.89(s,1H),8.34(d,J=8.3Hz,1H),7.86(d,J=7.8Hz ,1H),7.53(t,J=7.8Hz,1H),7.19(t...

Embodiment 2

[0223] Example 2: 2-acrylamido-N-(5-(3,5-dimethoxyphenethyl)-1H-pyrazol-3-yl)-4-((2-(dimethylamino) Ethyl)(methyl)amino)benzamide

[0224]

[0225] Add 150mg compound A (0.607mmol) in two-necked bottle, N2 After being dissolved by adding 2.2ml of ultra-dry toluene under protection, it was stirred under ice bath for a while, and then 1.3ml of trimethylaluminum solution (1.6M, 2.12mmol) was added slowly, and stirred for another hour under ice bath. One hour later, 194mg of compound C (0.607mmol) was added, and then the reaction system was moved to an oil bath at 110°C to continue stirring. After 10 hours of reaction, the plate was spotted, and the reaction was completed. Add 10 ml of water to the reaction solution to quench the reaction solution, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. Add silica gel to make sand, separate and purify on silica gel column (gradient elution from DCM:MeOH=100:1 to DCM:MeOH=10:1) to obtain m...

Embodiment 3

[0226] Example 3: 2-acrylamido-N-(3-(3,5 dimethoxyphenethyl)-1H-pyrazol-5-yl)-4-((3R,5S)-3,5 -Dimethylpiperazin-1-yl)benzamide

[0227]

[0228] Add compound A (745mg) into 20mL toluene under nitrogen protection, stir for a while under ice-water bath, slowly add 2M toluene solution (4.5ml) of trimethylaluminum, keep stirring in ice-water bath for 0.5-1 hour, add compound D ( 1.3g), the reaction system was transferred to an oil bath and heated to reflux (110-115°C), reacted for 5 hours, LCMS detected that the reaction was complete, the reaction solution was poured into 30mL water to quench, extracted with ethyl acetate, and the organic phase was washed with saturated brine, After drying with anhydrous sodium sulfate, the solvent was spin-dried, and then prepared and lyophilized to obtain a white solid 2-acrylamido-N-(3-(3,5-dimethoxyphenethyl)-1H-pyrazole-5 -yl)-4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzamide (Example 3, 48 mg, 3%). 1 H NMR (400MHz, DMSO-d6)δ12.04(s,1H),10...

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PUM

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Abstract

The invention provides an amide group pyrazol compound used as an FGFR (fibroblast growth factor receptors) irreversible inhibitor and a preparation method and application of the inhibitor. Particularly, the invention provides a compound of formula I, a stereisomer and raceme of the compound, or a pharmaceutically acceptable salt of the compound. The compound of the general formula I has the inhibitory activity of FGFR and can treat cancer induced by FGFR activity or expression quantity.

Description

technical field [0001] The present invention relates to a new class of pyrazole derivatives, including its preparation method, pharmaceutical composition containing the derivatives, and its use as an irreversible inhibitor of fibroblast growth factor receptor (FGFR) in the field of diseases such as cancer therapeutic use. [0002] technical background [0003] The normal growth of cells, tissue repair and remodeling are inseparable from the precise regulation of active growth factors and their receptor specificity. Fibroblast growth factor (FGF) is a kind of structurally related polypeptide consisting of 150-200 amino acids. Its family has about 20 members. It participates in the regulation of development and is expressed in various tissues. Fibroblast growth factor FGF can stimulate proliferation, cell migration and differentiation, and plays an important role in bone and limb development, wound healing, tissue repair, hematopoiesis, angiogenesis and tumorigenesis. [0004...

Claims

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Application Information

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IPC IPC(8): C07D231/40C07D403/12C07D413/12C07D401/12A61K31/415A61K31/496A61K31/4155A61K31/5377A61K31/454A61P35/00A61P35/02
CPCC07D231/40C07D403/12C07D413/12C07D401/12A61P35/00A61P35/02A61K31/415A61K31/4155A61K31/454A61K31/496A61K31/5377
Inventor 朱继东曹恒义糜婷
Owner ETERN BIOPHARMA SHANGHAI CO LTD
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