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Regulator containing pyrimidine ring derivatives, and preparation method and application thereof

A compound, cycloalkyl technology, applied in the field of drug synthesis

Pending Publication Date: 2022-05-27
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although there is a large clinical demand for tumors with KRAS mutations, due to the structural characteristics of the RAS protein itself, it is a great difficulty to directly target RAS. So far, there is no drug that directly targets KRAS on the market. Compounds targeting KRAS G12C mutations A major breakthrough has been made recently. Both Amgen's AMG510 and Mirati's MRTX-849 are in phase I clinical trials, and the early clinical results show good curative effect.
The SOS1 inhibitor provides a new treatment method for various KRAS protein mutation cancers, and the inhibitor has also received more and more attention. Many domestic and foreign companies have carried out the research and development of this target, among which Bollinger Ge Ingelheim is making rapid progress. The dominant compound BI-1701963 has entered clinical phase I. The preclinical dominant compound BI-3406 has also shown better in vivo and in vitro activity data, but there is still room for improvement in activity

Method used

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  • Regulator containing pyrimidine ring derivatives, and preparation method and application thereof
  • Regulator containing pyrimidine ring derivatives, and preparation method and application thereof
  • Regulator containing pyrimidine ring derivatives, and preparation method and application thereof

Examples

Experimental program
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Effect test

specific Embodiment approach

[0168] The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

Embodiment 1

[0176] (R)-6-Cyclohexyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4 -amine

[0177]

[0178] The first step: 1-bromo-3-(difluoromethyl)-2-fluorobenzene

[0179]

[0180] 3-Bromo-2-fluorobenzene (formaldehyde) (10.0g, 49.2mmol) and dry dichloromethane (150mL) were added successively to the 250mL there-necked flask, and diethylamine was slowly added dropwise at 0°C under ice bath and nitrogen protection. base sulfur trifluoride (13.3 mL, 98.5 mmol). The reaction solution was stirred at 0 °C for 1 hour, then warmed to room temperature and stirred for 1 hour, quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL×3), and the organic phase was washed with anhydrous sodium sulfate. Dry, filter, spin dry. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1) to give 1-bromo-3-(difluoromethyl)-2-fluorobenzene (6.5 g, 58.6%...

Embodiment 2

[0213] (R)-N-(1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(piperidin-1-yl)pyrido[3,4 -d]pyrimidin-4-amine

[0214]

[0215] The first step: (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethane-1-amine

[0216]

[0217]Using 1-bromo-2-fluoro-3-(trifluoromethyl)benzene as raw material Reference Example 1 from the second step to the fifth step to obtain product (R)-1-(2-fluoro-3-(trifluoromethyl) yl)phenyl)ethane-1-amine.

[0218] MS m / z(ESI): 208.0[M+H] + .

[0219] Step 2: 2-Methyl-6-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0220]

[0221] In a 50 mL reaction flask, 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (1.5 g, 7.9 mmol), piperidine (1.3 g, 15.5 mmol), carbonic acid Potassium (2.1 g, 15.5 mmol) was dissolved in DMF (10 mL), under nitrogen protection, and the reaction was stirred at 90°C for 8 hours. The reaction was stopped, water (20 mL) was added to quench the reaction, concentrated, extracted with ethyl acetate (15 mL×2), the comb...

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PUM

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Abstract

The invention relates to a modifier containing pyrimidine fused ring derivatives as well as a preparation method and application of the modifier. Particularly, the invention relates to a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound serving as an SOS1 inhibitor to treatment of leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, colon cancer and other diseases or symptoms, and substituents in the general formula (I) are as defined in the specification.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a pyrimidocyclic derivative inhibitor and a preparation method and application thereof. Background technique [0002] The RAS (Rat Sarcoma) protein family is encoded by the proto-oncogenes HRAS, NRAS and KRAS, and is divided into four proteins HRAS, NRAS, KRAS4A and KRAS4B. RAS proteins play important roles in a variety of cellular processes. There are two main states of RAS in the body: the inactive state combined with GDP (guanosine diphosphate) and the activated state combined with GTP (guanosine triphosphate). This process is regulated by two types of proteins, guanine nucleotide exchange factor (GEF). ) can promote the release of GDP from RAS protein, make GTP bind to activate RAS, GTPase activating protein (GTPase activating protein, GAP) activates the GTPase activity of RAS protein, hydrolyzes GTP bound to RAS protein into GDP, and makes RAS inactive. ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00C07D471/14C07D495/04C07D405/06C07D405/12C07D487/04C07D498/04C07D491/048C07D491/147A61K31/519A61K31/5383A61P35/00A61P35/02A61P43/00A61P9/00
CPCC07D471/04C07D519/00C07D471/14C07D495/04C07D405/06C07D405/12C07D487/04C07D498/04C07D491/048C07D491/147A61P35/00A61P35/02A61P43/00A61P9/00
Inventor 苏熠东汪军陈晓坡毛枭峰包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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