A class of furolactam compounds, preparation method and use

A compound and alkyl technology, applied in the field of medicinal chemistry, can solve the problems of low activity, single structure, easy drug resistance, etc., and achieve the effects of good ERK kinase inhibitory activity, novel structure, and excellent cell proliferation inhibitory activity

Active Publication Date: 2021-08-17
RUDONG RINGENE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the defects of existing ERK inhibitors such as single structure, low activity and easy drug resistance, and provide a furolactam compound, preparation method and use

Method used

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  • A class of furolactam compounds, preparation method and use
  • A class of furolactam compounds, preparation method and use
  • A class of furolactam compounds, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1: (R)-N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(2-(5-methyl-2-((1-methyl Base-1H-pyrazol-5-yl)amino)pyridin-4-yl)-4-oxo-6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)propionamide

[0164]

[0165] The first step: (4-chloro-5-methylpyridin-2-yl) (1-methyl-1H-pyrazol-5-yl) tert-butyl carbamate (5g, 15.5mmol), pinacol Borate (15.8g, 62.1mmol) was dissolved in dimethyl sulfoxide DMSO (50mL), and Pd-XPhos-G2 (1.2g, 1.5mmol), 2-dicyclohexylphosphine-2',4' were added under nitrogen protection , 6'-triisopropylbiphenyl XPhos (1.4g, 3.0mmol) and potassium acetate (3g, 31mmol), heated to 75 degrees overnight. The solution was cooled to room temperature, filtered, and the residue was purified by column chromatography to obtain (2-((tert-butoxycarbonyl)(1-methyl-1H-pyrazol-5-yl)amino)-5-methylpyridine-4 -yl) pinacol borate (2 g, white solid). LC-MS:ESI[M+H] + = 415.3.

[0166] The second step: (2-((tert-butoxycarbonyl)(1-methyl-1H-pyrazol-5-yl)amino)-5-methylpyridin-4-...

Embodiment 2

[0169] Example 2: (R)-N-((6-(dimethylamino)pyridin-2-yl)methyl)-2-(2-(5-methyl-2-((1-methyl- 1H-pyrazol-5-yl)amino)pyridin-4-yl)-4-oxo-6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)propionamide

[0170] It was synthesized by the same method as in Example 1, LC-MS: ESI (M+H) 529.4. 1 H-NMR (DMSO-d6, 400MHz) 8.76(s, 1H), 8.33-8.37(m, 1H), 8.04(s, 1H), 7.44(t, J=7.6Hz, 1H), 7.31(d, J =5.6Hz,1H),7.13(s,1H),7.07(s,1H),6.46(t,J=8.4Hz,2H),6.24(s,1H),5.14-5.19(m,1H),4.21 (d,J=6.0Hz,2H),3.63-3.70(m,5H),3.00-3.10(m,2H),2.98(s,6H),2.38(s,3H),1.37(d,J=7.2 Hz, 3H).

Embodiment 3

[0171] Example 3: (R)-N-((6-(dimethylamino)pyridin-2-yl)methyl)-2-(2-(2-((1-methyl-1H-pyrazole- 5-yl)amino)pyridin-4-yl)-4-oxo-6,7-dihydrofuro[3,2-c]pyridin-5(4H)-yl)propionamide

[0172] Synthesized by the same method as in Example 1, LC-MS: ESI (M+H) 515.5. 1 H-NMR (DMSO-d6, 400MHz) 9.52(br s, 1H), 8.63(t, J=5.6Hz, 1H), 8.12(d, J=6.0Hz, 1H), 7.82(t, J=8.0Hz ,1H),7.61(s,1H),7.47(d,J=2.0Hz,1H),7.29(d,J=5.6Hz,1H),7.13(s,1H),6.98(d,J=8.4Hz ,1H),6.67(d,J=7.2Hz,1H),6.34(d,J=2.0Hz,1H),5.07-5.09(m,1H),4.38-4.40(m,2H),3.68-3.71( m, 5H), 3.18 (s, 6H), 3.12 (t, J=7.2Hz, 2H), 1.38 (d, J=7.2Hz, 3H).

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Abstract

The invention discloses a class of furolactam compounds, a preparation method and application. The present invention specifically discloses a class of furolactam compounds shown in formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers, and tautomers thereof , solvates, polymorphs or prodrugs, processes for their preparation and their use in pharmacy.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of furolactam compounds, a preparation method and application. Background technique [0002] Extracellular signal-regulated kinases (ERKs) are a class of serine / threonine protein kinases discovered in the 1990s and are one of the important subfamilies of the MAPKs family of mitogen-activated protein kinases. Activated ERK can transmit extracellular signals to the nucleus, promote the phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Ras-Raf-MEK-ERK signal transduction is the center of the signaling network involved in regulating cell growth, development and differentiation, so ERK has various biological effects such as regulating cell proliferation, differentiation, migration, invasion and apoptosis. [0003] The Ras / Raf / MEK / ERK pathway is the main signaling pathway related t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/048A61K31/506A61K31/444A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D491/048
Inventor 万惠新潘建峰马金贵沈竞康
Owner RUDONG RINGENE PHARMA CO LTD
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