Saturated six-membered ring heterocyclic compound as well as preparation method and application thereof

A technology of compounds and solvates, applied in the field of medicinal chemistry, can solve the problems of unsuccessful development of targeted drugs and low efficacy

Active Publication Date: 2020-12-18
RUDONG RINGENE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more than 30 years have passed since the Kras oncogene was first discovered, and several generations of targeted drugs for common proto-oncogenes such as EGFR and BCL have gone through, but the targeted drug for

Method used

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  • Saturated six-membered ring heterocyclic compound as well as preparation method and application thereof
  • Saturated six-membered ring heterocyclic compound as well as preparation method and application thereof
  • Saturated six-membered ring heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1: (S)-1-(4-(8-(5-methyl-1H-indazol-4-yl)-1-(1-methylpyrrolin-2-yl)-6,7 ,8,9-Tetrahydropyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5-yl)piperazin-1-yl)propan-2 - en-1-one

[0203]

[0204] The first step: tert-butyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (10.4g, 34.3 mmol) and piperazine- Benzyl 1-carboxylate (7.5 g, 34.1 mmol) was dissolved in 1,4-dioxane (200 mL), and DIPEA (13.2 g, 102 mmol) was added. React at room temperature for 2 days, concentrate under reduced pressure, and purify the residue by column chromatography to obtain 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[ 3,4-d]pyrimidine-7(6H)-carboxylate tert-butyl ester (11 g, white solid). LC-MS:ESI[M+H] + =488.5; 1 HNMR (400MHz, DMSO-d 6 ): δ7.33-7.39 (m, 5H), 5.11 (s, 2H), 4.37 (brs, 2H), 3.50 (brs, 10H), 2.63-2.65 (m, 2H), 1.44 (s, 9H).

[0205] The second step: 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]...

Embodiment 2

[0214] Example 2: 1-(4-(8-(5-methyl-1H-indazol-4-yl)-6,7,8,9-tetrahydropyrido[4,3-e][1, 2,4] Triazolo[4,3-a]pyrimidin-5-yl)piperazin-1-yl)prop-2-en-1-one

[0215]

[0216] The first step: 4-(2-hydrazino-7-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate benzyl ester (0.5g, 0.79mmol) was dissolved in dichloromethane (15mL ), trimethyl orthoformate (340mg, 3.2mmol) was added, and after stirring for ten minutes, trifluoroacetic acid (95mg, 0.83mmol) was added. After continuing to stir at room temperature for 1 hour, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain 4-(8-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methoxy)methanol Base)-1H-indazol-4-yl)-6,7,8,9-tetrahydropyrido[4,3-e][1,2,4]triazol[4,3-a]pyrimidine -5-yl)benzylpiperazine-1-carboxylate (320 mg, yellow solid). LC-MS:ESI[M+H] + = 654.7; 1 H NMR(4...

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Abstract

The invention discloses a saturated six-membered ring heterocyclic compound as well as a preparation method and application thereof. The invention discloses a saturated six-membered ring heterocycliccompound shown as a general formula I, or pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorphic substance or prodrug thereof, as well as a preparation method and a pharmaceutical application of the saturated six-membered ring heterocyclic compound. The definition of each group is as described in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of saturated six-membered ring and heterocyclic compounds, a compound capable of inhibiting the activity of Ras mutein, a preparation method and an application. Background technique [0002] RAS was the first oncogene identified in human tumors and was first identified in two murine sarcoma viruses. The RAS gene family has three members, namely Hras, ​​Kras, and Nras. In human tumors, Kras mutations are the most common, accounting for about 85%. Previous studies have shown that the Kras mutation can cause cancer because of a missense mutation in codon 12, which changes the structure of the Kras protein and keeps it active. The role of Ras in signaling pathway transmission is mainly to activate kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and are closely related to the survival, proliferation, migration,...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D498/22A61P35/00A61P35/02A61K31/519A61K31/5383A61K31/496
CPCA61P35/00A61P35/02C07D471/14C07D498/22
Inventor 万惠新查传涛马金贵潘建峰
Owner RUDONG RINGENE PHARMA CO LTD
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