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Aromatic heterocyclic lactam compound as well as preparation method and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve problems such as low activity, single structure, and easy drug resistance

Active Publication Date: 2021-03-09
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 an aromatic heterocyclic lactam compound, preparation method and application

Method used

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  • Aromatic heterocyclic lactam compound as well as preparation method and application thereof
  • Aromatic heterocyclic lactam compound as well as preparation method and application thereof
  • Aromatic heterocyclic lactam compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Example 1: (R)-N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(2-(2-((1-methyl-1H-pyridine Azol-5-yl)amino)pyridin-4-yl)-4-oxo-4,6-dihydro-5H-thien[2,3-c]pyrrol-5-yl)propionamide

[0197]

[0198] The first step: (4-bromopyridin-2-yl)(1-methyl-1H-pyrazol-5-yl) tert-butyl carbamate (150mg, 0.42mmol), pinacol borate (119mg, 0.47mmol), potassium acetate (123mg, 1.26mmol) and 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (Pd(dppf)Cl 2 ) (61mg, 0.084mmol) was dissolved in dioxane (10mL), nitrogen was bubbled for 10 minutes, and heated to 80°C for 8 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain (1-methyl-1H-pyrazol-5-yl)(4-(4,4,5,5-tetramethyl-1,3,2- Dioxin-2-yl)pyridin-2-yl)tert-butyl carbamate (yellow oil) was directly used in the next reaction. LC-MS: ESI [M+H]+=401.2; 1 H-NMR(DMSO-d6,400MHz)δ8.34-8.35(m,1H),7.92(s,1H),7.88(s,1H),7.38(d,J=2.0Hz,1H),6.14(d , J=...

Embodiment 2

[0203] Example 2: (R)-N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-(2-(5-methyl-2-((1-methyl Base-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)propane Amide

[0204]

[0205] The first step: tert-butyl (R)-2-(4-oxo4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)propionate (1.0g, 3.8 mmol), bispinacol borate (B 2 pin 2 ) (531 mg, 2.1 mmol), 4,4-di-tert-butylbipyridine (dtbpy) (20 mg, 0.076 mmol) and 1,5-cyclooctadiene methoxyiridium [Ir (cod) OMe] 2 ( 25mg, 0.038mmol) was dissolved in tetrahydrofuran (THF) (20mL), replaced with nitrogen for 10 minutes, and heated to 80°C under the protection of nitrogen to react overnight. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain (R)-2-(4-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxin-2 -yl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)propanoic acid tert-butyl ester (1.4g, red oily substance), directly used in the next reaction. LC-MS:ESI[M+H] ...

Embodiment 3

[0210] Example 3: (2R)-N-(2-hydroxyl-1-(m-toluene)ethyl)-2-(2-(5-methyl-2-((1-methyl-1H-pyrazole -5-yl)amino)pyridin-4-yl)-4-oxo-4,6-dihydro-5H-thiophene[2,3-c]pyrrol-5-yl)propionamide

[0211] Example 3 was synthesized by the same method as Example 1, LC-MS: ESI (M+H) 530.5.

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Abstract

The invention discloses an aromatic heterocyclic lactam compound as well as a preparation method and an application thereof. The invention particularly discloses an aromatic heterocyclic lactam compound shown as a formula (I), or pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a solvate, a polymorphic substance or a prodrug thereof, a preparation method of the aromatic heterocyclic lactam compound and an application of the aromatic heterocyclic lactam compound to pharmacy.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of aromatic heterocyclic lactam 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D513/04C07D491/048C07D519/00A61K31/506A61K31/4439A61K31/444A61P35/00A61P35/02
CPCC07D495/04C07D513/04C07D491/048C07D519/00A61P35/00A61P35/02
Inventor 万惠新潘建峰马金贵
Owner RUDONG RINGENE PHARMA CO LTD
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