Heteroaromatic compound, intermediate, composition and application

A compound and heteroaryl technology, applied in the field of heteroaromatic compounds, can solve problems such as deficiencies, and achieve the effect of high bioavailability

Pending Publication Date: 2021-07-16
山东铂源生物医药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to address defects such as the lack of compounds that simultaneously target A2aR receptors in the prior art. Therefore, the present invention provides a heteroaromatic compound, an intermediate, a composition and an application

Method used

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  • Heteroaromatic compound, intermediate, composition and application
  • Heteroaromatic compound, intermediate, composition and application
  • Heteroaromatic compound, intermediate, composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1. Intermediate compound 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile (8)

[0092]

[0093] Step 1.1. Synthesis of 2-methyl-3-cyanophenylboronic acid pinacol ester (3)

[0094] Add compound 1 (10.00g, 51mmol) into a 500mL three-neck flask, add 100mL 1,4-dioxane, and stir to dissolve. Under nitrogen protection, compound 2 (15.54g, 61mmol), potassium acetate (10.01g, 102mmol) and Pd(dppf)Cl were added sequentially 2 (1.12 g, 1.53 mmol). The reaction was stirred under reflux for 5h, and the temperature was lowered to 25°C. Suction filtration, and the filter cake was washed with 50 mL of ethyl acetate. Add H to the filtrate 2 50 mL each of O and ethyl acetate, stirred for 5 min, separated, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the ethyl acetate phase was combined, and then washed with 30 mL of saturated brine, anhydrous Na 2 SO 4 Dry for 5 minutes, filter with suction, and concentrate under reduced pressure to obtain a ...

Embodiment 2

[0101] Example 2 Compound 3-(2-amino-6-(1-(quinolin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2 - Preparation of methylbenzonitrile (11) (BS001)

[0102] The synthetic route is as follows:

[0103]

[0104] Step 2.1: Synthesis of 2-(azidomethyl)quinoline (10)

[0105] At 25°C, under nitrogen protection, compound 9 (1.00 g, 4.50 mmol) was added into a 50 mL three-neck round bottom flask. Add 10 mL of anhydrous tetrahydrofuran and stir to dissolve. Cool the system down to -10°C, add TMSN dropwise 3 (1.04g, 9.02mmol) and DIPEA (1.16g, 8.98mmol). After the dropwise addition, the temperature of the system was raised to 25° C., and the reaction was stirred for 24 hours. The insoluble matter was removed by suction filtration, the solvent was removed by concentration under reduced pressure, and silica gel column chromatography (n-hexane: ethyl acetate = 10:1) gave 0.515 g of a light yellow liquid (compound 10, yield 62%). MS(ESI)m / z:185.1[M+H] + , 1 H NMR (400MHz, C...

Embodiment 3

[0108] Example 3 3-(2-amino-6-(1-((8-aminoquinolin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine-4- The preparation of -2-methylbenzonitrile hydrochloride (16) (BS002)

[0109] The synthetic route is as follows:

[0110]

[0111] Step 3.1: Synthesis of 2-(bromomethyl)-8-nitroquinoline (13)

[0112] Compound 12 (1.42 g, 10 mmol) was added into a 100 mL three-necked flask, and then 30 mL of carbon tetrachloride was added. N-bromosuccinimide (2.67 g, 15 mmol) and 0.2 g of benzoyl peroxide were added sequentially under stirring at 25°C. Heated to reflux and reacted under reflux for 14 hours. The reaction solution was suction filtered to remove insoluble matter, and concentrated under reduced pressure to obtain 2.1 g of a yellow solid, which was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 3:1) to obtain 1.69 g of a white solid (compound 13, yield 63.5%) . MS(ESI)m / z:222.0,224.0[M+H] + , 1 H NMR (400MHz, CDCl 3 ): δ8.17(d, J=8.5Hz, 1H), 8.08(d...

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PUM

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Abstract

The invention discloses a heteroaromatic compound, an intermediate, a composition and application. The structure of the compound is shown as a formula I, and the compound shows certain inhibitory activity to A2aR receptors and is high in absolute bio-availability.

Description

technical field [0001] The present invention relates to a heteroaromatic compound, intermediate, composition and application. Background technique [0002] In recent years, a variety of immune checkpoint programmed death ligand 1 / programmed death 1 (programmed death ligand 1 / programmed death 1, PDL1 / PD1) and cytotoxic T lymphocyte associated antigen 4 (cytotoxic T lymphocyte associated antigen -4, CTLA-4) drugs have been launched one after another, and immune checkpoint therapy has become one of the most promising strategies in tumor immunotherapy. The first-generation immune checkpoint inhibitors represented by PD-1 / PD-L1 and CTLA-4 monoclonal antibodies have gradually become the cornerstone of tumor immunotherapy. Although the curative effect is obvious, there are still a considerable number of people who are resistant to this type of therapy This also shows from the side that there are other immune tolerance mechanisms in the tumor microenvironment, one of the important ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00A61P25/00A61P9/00A61P3/10C07D401/04C07D213/79C07D215/18C07F7/08
CPCA61P3/10A61P9/00A61P25/00A61P35/00C07D213/79C07D215/18C07D401/04C07D401/14C07F7/0812
Inventor 陆继廷刘明李振刘珂
Owner 山东铂源生物医药有限公司
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