Aryl or heteroaryl pyridone or pyrimidone derivative as well as preparation method and application thereof

A technology of heteroaryl and alkyl, applied in the field of aryl or heteroaryl pyridone or pyrimidinone derivatives and their preparation, can solve the problems such as no drug approval and listing

Pending Publication Date: 2021-12-17
SUZHOU ZELGEN BIOPHARML +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is still no KRAS-targeted G12C Mutated drug approved

Method used

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  • Aryl or heteroaryl pyridone or pyrimidone derivative as well as preparation method and application thereof
  • Aryl or heteroaryl pyridone or pyrimidone derivative as well as preparation method and application thereof
  • Aryl or heteroaryl pyridone or pyrimidone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0256] The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.

[0257] The present invention also provides a treatment method, which comprises the steps of: administering the compound of formula (I) described in the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate to the subject in need of treatment, Or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12C .

[0258] Compared with the prior art, the present invention has the following main advantages:

[0259] (1) The compound is to KRAS G12C Has a good selective inhibitory effect;

[0260] (2) The compound has better pharmacodynamics, pharm...

Embodiment 1

[0270] Example 1 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4- Preparation of methyl-2-(methylsulfonyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0271]

[0272] Step 1. Preparation of 4-methyl-2-(methylsulfonyl)-3-nitropyridine

[0273] 2-Chloro-4-methyl-3-nitropyridine (3 g, 17.4 mmol) was dissolved in dimethyl sulfoxide (25 ml), and sodium methylsulfinate (2.7 g, 26.2 mmol) was added to the solution. The mixture was stirred at 120°C for 1 hour, quenched with 100 mL of water, and then extracted 3 times with 100 mL of ethyl acetate. The combined organic phases were washed 3 times with 50 mL of brine, then the organic phase was dried and concentrated. The residual solid was slurried with ethanol / methanol / ethyl acetate (40ml / 5ml / 5ml), filtered with suction and dried to obtain the title compound (2.3g, 61%).

[0274] Step 2. Preparation of 4-methyl-2-(methylsulfonyl)pyridin-3-amine

[0275] 4-Methyl-2-(methylsulfonyl)-3-nitropy...

Embodiment 2

[0293] Example 2 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2- Methyl-4-(methylsulfonyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0294]

[0295] LC-MS: m / z 597 (M+H) + . 1 H NMR (400MHz, CDCl 3 )δ8.93(d,J=5.2Hz,1H),

[0296]8.65(brs,1H),7.95-7.89(m,2H),7.26(m,1H),6.72-6.75(m,3H),6.45-6.39(m,1H),5.85-5.81(m,1H), 5.25-4.30(m,3H),4.20-3.50(m,3H),3.30-3.00(m,4H),2.46(d,J=10.0Hz,3H),1.51-1.48(m,3H).

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Abstract

The invention relates to an aryl or heteroaryl pyridone or pyrimidone derivative as well as a preparation method and application thereof. Specifically, the compound has a structure as shown in a formula (I) (See the specification). The invention further discloses a preparation method of the compound and application of the compound as a KRASG12C inhibitor. The compound has a good selective inhibition effect on KRASG12C and has better pharmacodynamic and pharmacokinetic performance and lower toxic and side effects.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to an aryl or heteroaryl pyridone or pyrimidinone derivative and a preparation method and application thereof. Background technique [0002] Lung cancer is one of the important causes of human cancer death. According to cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market in 2016 was about 20.9 billion US dollars, of which the US market accounted for half, followed by Japan, Germany and China. Judging from the existing trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach US$54 billion in 2023 (Nature, 2018; 553(7689):446-454). [0003] At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07F9/6561A61K31/519A61K31/5377A61K31/675A61P35/00
CPCC07D471/04C07F9/65616A61P35/00
Inventor 吕彬华崔大为刘连军
Owner SUZHOU ZELGEN BIOPHARML
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