Azaheteroaryl derivative with csf1r inhibitory activity, preparation method and application thereof

A technology of heterocyclic group and alkyl group, applied in the field of drug synthesis

Active Publication Date: 2020-09-15
ABBISKO THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Small-molecule kinase inhibitors generally have selectivity issues, especially with respect to other members of the same kinase family

Method used

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  • Azaheteroaryl derivative with csf1r inhibitory activity, preparation method and application thereof
  • Azaheteroaryl derivative with csf1r inhibitory activity, preparation method and application thereof
  • Azaheteroaryl derivative with csf1r inhibitory activity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0192] 1. Preparation of intermediates

[0193] 1, Preparation of 5-bromo-N-isopropyl-4-methoxypyrimidin-2-amine (intermediate A1)

[0194]

[0195] 5-Bromo-2-chloro-4-methoxypyrimidine (2.4 g, 10.8 mmol), isopropylamine (6 mL, 72.4 mmol) and DIPEA (4 mL, 21.6 mmol) were added to the sealed tube, tetrahydrofuran (20 mL) was added, The reaction mixture was heated to 80°C for 5 hours. After cooling, the crude product was separated by column chromatography to obtain 5-bromo-N-isopropyl-4-methoxypyrimidin-2-amine (2.3 g, yield 88%).

[0196] 2. Preparation of (2-(isopropylamino)-4-methoxypyrimidin-5-yl)boronic acid (intermediate B1)

[0197]

[0198] 5-Bromo-N-isopropyl-4-methoxypyrimidin-2-amine (4.4g, 18mmol) was dissolved in dimethylformamide (30mL), and biboronic acid pinacol ester (13.7g, 53.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.6g, 3.6mmol) and potassium acetate (10.6g, 107.8mmol), then evacuated to nitrogen at room temperature Thre...

Embodiment 1

[0301] Example 1, 5-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-2-(isopropylamino ) Preparation of pyrimidin-4(3H)-one

[0302]

[0303] 5-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-N-isopropyl-4-methoxy Pyrimidin-2-amine (30 mg, 0.08 mmol) was dissolved in acetic acid (3 mL), and 40% aqueous hydrobromic acid (0.085 mL, 0.6 mmol) was added. The reaction solution was stirred at 90°C for 6 hours. After the reaction solution was cooled, it was basified with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by plate chromatography [eluent: dichloromethane to dichloromethane / methanol (10:1)] to obtain 5 -(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-2-(isopropylamino)pyrimidine-4( 3H)-Kone (6.9 mg, 24% yield). MS m / z(ESI):375[M+H] + .

[0304] 1 H NMR (400MHz, DMSO-d 6 )δ11.44(s,1H),10.73(s,1H),8.74–8.57(m,1H),8.18(d,J=4.7Hz,1...

Embodiment 7

[0310] Example 7, 5-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-2-(isopropylamino )-3-methylpyrimidin-4(3H)-one preparation

[0311]

[0312] The first step: tert-butyl 3-((6-(2-(isopropylamino)-6-carbonyl-1,6-dihydropyrimidin-5-yl)-2-methylpyridin-3-yl )methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0313]

[0314] 5-(5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-yl)-2-(isopropylamino)pyrimidine- 4(3H)-Kone (45 mg, 0.12 mmol) was dissolved in tetrahydrofuran (3 mL), di-tert-butyl dicarbonate (39 mg, 0.18 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) were added , and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried and concentrated, and separated by column chromatography [eluent: petroleum ether ~ petroleum ether / ethyl acetate (1:1)] to obtain tert-butyl 3-((6- (2-(isopropylamino)-6-carbonyl-1,6-dihyd...

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Abstract

The invention provides an azaaryl derivative with CSF1R inhibitory activity, its preparation method and application. The series of compounds of the present invention have the structure of the following formula (I), and the definition of each substituent is as described in the specification and claims. The series of compounds of the present invention can be widely used in the preparation of drugs for the treatment of cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, especially for the treatment of ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma Drugs for cell tumors, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastases from primary tumor sites, or bone metastatic cancers are expected to be developed into a new generation of CSF1R inhibitor drugs.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to an azaaryl derivative with CSF1R inhibitory activity, its preparation method and application. [0002] technical background [0003] The full name of CSF1R (cFMS) is colony stimulating factor-1 receptor. CSF1R and cKIT, FLT3, PDGFR-a&b belong to the same three types of growth hormone receptor family. The receptor is a membrane protein expressed on the surface of macrophages and monocytes. Its extracellular segment can bind to macrophage colony-stimulating factor, and its intracellular segment tyrosine kinase can activate macrophages and monocytes downstream Cell growth and reproduction signaling pathways, including MAPK, PI3K, etc. Therefore, the CSF1R signaling pathway has an important impact on the development and differentiation of macrophages, monocytes, and the physiological functions of tumor-associated macrophages (Tumor-Associated Macrophage, TAM). [0004] Tumo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/4375
CPCA61K31/4375C07D471/04C07D519/00A61P35/00A61P37/00C07D487/04A61P35/02
Inventor 张鸣鸣赵保卫喻红平陈椎徐耀昌
Owner ABBISKO THERAPEUTICS CO LTD
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