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Kras-G12C inhibitor heterocyclic compounds

A compound, -NH2 technology, applied in organic chemistry, drug combination, organic chemical methods, etc., can solve problems such as low activity, low blood drug concentration, and short half-life

Active Publication Date: 2021-03-30
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In some other patents (WO2019213516A1), various substituent groups such as amino, alkoxy, and halogen have been introduced. These compounds either have low activity, or have defects such as too short half-life or low blood concentration.

Method used

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  • Kras-G12C inhibitor heterocyclic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-1-[2-(2,2-difluorocyclopropyl)-4-methylpyridin-3-yl ]-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyridin[2,3-d]pyrimidin-2(1H)-one

[0070]

[0071] Step A: 1-Methyl-2-nitro-3-vinylpyridine

[0072]

[0073] Under nitrogen protection, 2-bromo-3-nitro-4-methylpyridine (1 g), Pd(dppf)Cl 2 (337 mg), potassium carbonate (2 g), and potassium ethylene trifluoroborate (0.94 g) were dissolved in a mixed solvent of 1,4-dioxane / water (35 mL / 5 mL), and the system was heated to 120°C Stir overnight. Cool to room temperature, concentrate under reduced pressure, add ethyl acetate to dissolve the residue, filter with celite, concentrate the filtrate under reduced pressure, and separate the residue by silica gel column chromatography (EtOAc / PE = 1 / 5) to obtain the product (603 mg).

[0074] Step B: 2-(2,2-Difluorocyclopropyl)-4-methyl-3-nitropyridine

[0075]

[0076] Under nitrogen protection, 1-methyl-2-nitro-3-vinylpyridine (100 mg), ...

Embodiment 2

[0114] 4-((S)-2-acryloyl-2-methylpiperazin-1-yl)-1-[2-(difluoromethyl)-4-methylpyridin-3-yl]-6-fluoro -7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0115]

[0116] Step A: 2,4-Dimethyl-3-nitropyridine

[0117]

[0118] Under nitrogen protection, 2-bromo-4-methyl-3-nitropyridine (2.4 g), trimethylboroxane (2.8 g), Pd(dppf)Cl 2 (0.4 g) and potassium carbonate (4.6 g) dispersed in 1,4-dioxane (30 mL) and H2 O (5 mL) in a mixed solvent, then heated to 120 °C and refluxed for 3 hours. Cooled to room temperature, the reaction mixture was filtered with celite, the filtrate was extracted with ethyl acetate and water, the organic phases were combined, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (EtOAc / PE = 1 / 5) to obtain the product ( 1.6g).

[0119] 1 H NMR (400 MHz, CDCl 3 ), 8.42 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.8Hz, 1H), 2.52 (s, 3H), 2.31 (s, 3H).

[0120] Step B: 4-Methyl-3-nitrobenzaldehy...

Embodiment 3

[0157] 4-((S)-2-acryloyl-2-methylpiperazin-1-yl)-1-[2-(1,1-difluoroethyl)-4-methylpyridin-3-yl] -6-fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0158]

[0159] Step A: 2-(1-Ethoxyvinyl)-4-methyl-3-nitropyridine

[0160]

[0161] Under nitrogen protection, 2-bromo-4-methyl-3-nitropyridine (1.1 g), tributyl(1-ethoxyvinyl)tin (2.2 g) and Pd(dppf)Cl 2 (0.2 g) was dispersed in 1,4-dioxane (30 mL), then heated to 120°C and refluxed for 24 hours. Cool to room temperature, add saturated KF aqueous solution (50 mL) and continue stirring for 1 hour, then filter the reaction mixture with Celite, extract the filtrate with ethyl acetate (50 mL×3), combine the organic phases, concentrate under reduced pressure, and the residue The product (0.9 g) was isolated by silica gel column chromatography (EtOAc / PE = 1 / 5).

[0162] 1 H NMR (400 MHz, CDCl 3 ), 8.49 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 5.2Hz, 1H), 5.15 (d, J = 2.8 Hz, 1H), 4.49 (d, J = 2.8 Hz, 1H), 3.87...

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Abstract

The invention relates to Kras-G12C inhibitor heterocyclic compounds and a preparation method thereof, and application of the compounds in prevention and treatment of tumor diseases such as lung cancer, colorectal cancer and pancreatic cancer. In the preparation process, the compounds provided by the invention are obtained through a series of reactions such as a condensation reaction, an intramolecular cyclization reaction, a chlorination reaction, an SN2 reaction, a coupling reaction, deprotection and the like.

Description

technical field [0001] This application relates to a new type of KRAS-G12C inhibitor, its preparation method and the preventive and therapeutic use of this type of compound in tumor diseases, such as lung cancer, colorectal cancer and pancreatic cancer. The present invention also relates to a pharmaceutical composition containing the compound represented by formula (I) and a preparation method, as well as the preventive and therapeutic use of the compound in tumor diseases, such as lung cancer and colorectal cancer. Background technique [0002] RAS proteins are a class of small G proteins that bind to GTP / GDP and have GTP hydrolase activity. As a molecular switch, RAS activates downstream signaling pathways such as MAPK and PI3K-AKT by binding to GTP, thereby regulating cell growth, proliferation, differentiation, apoptosis and other life processes, and its mutation is closely related to the occurrence and development of cancer. It has three family members: HRAS, KRAS and ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07B2200/07C07B2200/13C07D471/04
Inventor 张英利张晓军李继军陈昌俊陈志峰孙颖慧刘爽李红娟朱岩
Owner SHOUYAO HLDG BEIJING CO LTD
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