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Substituted heteroaromatic ring dihydropyrimidinone derivative as well as preparation method and medical application thereof

A pharmacy and prodrug technology, applied in the field of medicine, can solve problems such as cancer, prolong cell signal transduction, prolong protein activation time, etc., and achieve the effects of low toxicity and side effects, good selectivity and high activity

Active Publication Date: 2021-02-23
GENFLEET THERAPEUTICS (SHANGHAI) INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Any mutation in RAS will affect the interaction of RAS with GAP, and the ability of GTP to convert to GDP, this mutation will lead to the prolongation of protein activation time, which prolongs cell signaling, which in turn causes cells to continue to grow and divide
Since this signaling causes cells to grow and divide, overactivated RAS signaling can eventually lead to cancer

Method used

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  • Substituted heteroaromatic ring dihydropyrimidinone derivative as well as preparation method and medical application thereof
  • Substituted heteroaromatic ring dihydropyrimidinone derivative as well as preparation method and medical application thereof
  • Substituted heteroaromatic ring dihydropyrimidinone derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Example 1 Preparation of (S)-7-acryloyl-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-5a,6 ,7,8,9-Hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]-naphthalene- 11(12H)-Kone (Z1)

[0172]

[0173] Step 1: Dissolve 2,4,6-trichloronicotinic acid (8g, 35.5mmoL) in 150mL of dichloromethane, cool down to 0°C, add oxalyl chloride (9.3ml, 106.6mmol), drop after 30 minutes Add DMF (0.5ml), rise to room temperature and react for 1h. After the reaction is completed, concentrate and dilute with 150mL of dichloromethane, lower to 0°C, slowly add 8mL of ammonia water dropwise, stir at room temperature for 2h, after the reaction is completed, concentrate, and dilute with ethyl acetate Slurry and filter to obtain 6g (6.5g, yield: 82%) of crude product 2,4,6-trichloronicotinamide. ES-API:[M+H] + = 224.9.

[0174] Step 2: Dissolve 2-isopropyl-4-methylpyridin-3-amine (4.4g, 29.1mmol) in 80mL tetrahydrofuran, under nitrogen protection, add LiH...

Embodiment 2

[0183] Example 2 Preparation of (S)-7-acryloyl-12-(2-isopropyl-4-methylpyridin-3-yl)-2-(5-methyl-1H-indazol-4-yl) -5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de ]naphthalene-11-(12H)-one (Z2)

[0184]

[0185] Step 1: Add (S)-2-chloro-12-(2-isopropyl-4-methylpyridin-3-yl)-11-oxo-5a,6,8,9,11,12-hexa Hydrogen-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]-naphthalene-7(5H)-carboxylic acid tertiary Butyl ester (130mg, 0.247mmoL), (5-methyl-1H-indazol-4-yl) boronic acid (86.8mg, 0.493mmol), Pd(PPh 3 ) 4 (28.5mg, 0.0247mmol) and potassium carbonate (68g, 0.493mmol) were dissolved in 2ml dioxane and 0.2ml water, replaced with nitrogen, reacted at 120°C for 1.5h, cooled to room temperature, filtered, passed through water and saturated saline Washing, concentration, and column chromatography to obtain (S)-12-(2-isopropyl-4-methylpyridin-3-yl)-2-(5-methyl-1H-indazol-4-yl )-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenz...

Embodiment

[0189] Compounds Z3, Z5 to Z10 and Z15 were prepared with reference to the similar methods of compound Z1 or Z2, wherein the starting materials of each compound can be prepared by commercially available or with reference to existing methods well known to those skilled in the art, and the similar synthetic methods of intermediates It is easily obtained by those skilled in the art by referring to existing methods.

[0190]

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PUM

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Abstract

The invention discloses a substituted heteroaromatic ring dihydropyrimidinone derivative with selective inhibition effect on KRAS gene mutation or a pharmaceutically acceptable salt, a stereoisomer, asolvate or a prodrug thereof. The substituted heteroaromatic ring dihydropyrimidinone derivative is shown as a formula (I), and each group in the formula is as defined in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound and application of the compound in preparation of cancer drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a substituted heteroaromatic dihydropyrimidinone derivative, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom. Background technique [0002] Lung cancer is the cancer with the highest incidence rate in the world. In China, the incidence rate of lung cancer ranks first among all cancers. It is also the cancer with the highest incidence and mortality in China. According to the data released by the American Cancer Society in 2016, about 1.8 million people suffer from lung cancer, and nearly 80% of lung cancers are non-small cell lung cancer (NSCLC). The RAS are a group of closely related monomeric globular proteins (21 kDa molecular weight) of 188-189 amino acids that bind either guanosine diphosphate GDP or guanosine triphosphate GTP. Members of the RAS subfamily include HRAS, KRAS, and NRAS. RAS acts as a molecu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/22C07D471/22C07D471/04C07D487/04A61K31/553A61K31/551A61K31/519A61P35/00
CPCC07D498/22C07D471/22C07D471/04C07D487/04A61P35/00C07B2200/07
Inventor 周福生蒋涛何宛蔡礼健杨华彬刘柱博兰炯
Owner GENFLEET THERAPEUTICS (SHANGHAI) INC
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