Fused cyanopyridine compound and preparation method and application thereof

A technology of cyanopyridines and compounds, applied in the field of medicinal chemistry, can solve problems such as little effect and failure to develop targeted drugs

Active Publication Date: 2020-12-29
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 K-Ras 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 K

Method used

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  • Fused cyanopyridine compound and preparation method and application thereof
  • Fused cyanopyridine compound and preparation method and application thereof
  • Fused cyanopyridine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160]Example 1: (S)-4-(4-acryloylpiperazin-1-yl)-7-(5-methyl-1H-indazol-4-yl)-2-((1-methylpyrrole) Alk-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-3-carbonitrile

[0161]

[0162]Step 1: Dissolve Intermediate 1 (9.5g, 31.7mmol) and N-Boc-piperazine (8.81g, 47.4mmol) in 1,4-dioxane (100mL), add diisopropylethylamine (DIEA ) (8.18g, 63.4mmol), the temperature was raised to 90 degrees and reacted overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and used saturated sodium bicarbonate NaHCO3The aqueous solution is slurried, filtered, and the filter cake is dried and then slurried with ethyl acetate for purification to obtain 4-(7-benzyl-3-cyano-2-hydroxy-5,6,7,8-tetrahydro-1,7-naphthalene (Pyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (3.5 g, dark green solid). LC-MS: ESI[M+H]+=450.4;1H NMR (400MHz, DMSO_d6): δ11.53 (brs, 1H), 7.28-7.34 (m, 5H), 3.62 (s, 2H), 3.23-3.42 (m, 10H), 2.40-2.56 (m, 4H) ,1.42(s,9H).

[0163]Step 2: ...

Embodiment 2

[0168]Example 2: 4-(4-Acryloylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-2-(((S)-1-methylpyrrole) Alk-2-yl)methoxy)-1,8-naphthyridine-3-carbonitrile

[0169]

[0170]The first step: 2,4-Dichloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1,8-naphthyridine-3-carbonitrile (670mg, 1.8mmol), 1-Cbz-piperazine (306 mg, 1.4 mmol) and DIEA (1.2 g, 9.3 mmol) were dissolved in 1.4-dioxane (20 mL) and reacted at room temperature overnight. The reaction solution was diluted with 100 mL ethyl acetate, washed twice with water, dried, and concentrated under reduced pressure to obtain 4-(2-chloro-3-cyano-6-fluoro-7-(2-fluoro-6-6-methoxy) (Phenyl)-1,8-naphthyridin-4-yl)piperazine-1-carboxylic acid benzyl ester (605 mg, red solid). LC-MS: ESI[M+H]+= 550.6.

[0171]The second step: the 4-(2-chloro-3-cyano-6-fluoro-7-(2-fluoro-6-6-methoxyphenyl)-1,8-naphthyridin-4-yl) Benzyl piperazine-1-carboxylate (605mg, 1.1mmol) was dissolved in TFA (2.5mL) and water (0.5mL), heated to 120°C and reacted overnight. The...

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Abstract

The invention discloses a fused cyanopyridine compound shown as a general formula I-1 or I-2, or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, a tautomer, a torsional isomer, a solvate, a polymorphic substance or a prodrug thereof, and a preparation method and a pharmaceutical application of the fused cyanopyridine compound, wherein the definition of each group is shown in the specification.

Description

Technical field[0001]The invention belongs to the field of medicinal chemistry, and specifically relates to a class of condensed cyanopyridine compounds, compounds with the activity of inhibiting Ras mutein, preparation methods and uses.Background technique[0002]Ras was the first oncogene identified in human tumors, and was first discovered in two murine sarcoma viruses. The RAS gene family has three members, namely H-Ras, K-Ras, and N-Ras. In human tumors, K-Ras mutations are the most common, accounting for about 85%. Previous studies have shown that the K-Ras mutation can cause cancer because of a missense mutation in codon 12, which changes the structure of the K-Ras protein and keeps it in an active state. The role of Ras in signal pathway transmission is mainly to activate kinases that control gene transcription, thereby regulating cell differentiation and proliferation, and is closely related to tumor cell survival, proliferation, migration, metastasis and angiogenesis. Accord...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D401/14A61K31/496A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/14C07D471/04
Inventor 万惠新查传涛马金贵潘建峰
Owner RUDONG RINGENE PHARMA CO LTD
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