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N-(azaaryl) cyclic lactam-1-carboxamide derivative and its preparation method and application

A technology of heteroaryl and aryl, applied in the field of N-cyclic lactam-1-carboxamide derivatives and its preparation

Active Publication Date: 2020-12-08
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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  • N-(azaaryl) cyclic lactam-1-carboxamide derivative and its preparation method and application
  • N-(azaaryl) cyclic lactam-1-carboxamide derivative and its preparation method and application
  • N-(azaaryl) cyclic lactam-1-carboxamide derivative and its preparation method and application

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Experimental program
Comparison scheme
Effect test

preparation example Construction

[0162] 1. Preparation of intermediates

[0163] Intermediate A1: 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Preparation of pyrazole

[0164]

[0165] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (582 mg, 3.0 mmol) dissolved in N,N-dimethyl Dimethylformamide (5 mL), 1-bromo-2-methoxyethane (798 mg, 6.0 mmol), cesium carbonate (2.9 g, 9.0 mmol) and sodium iodide (224 mg, 1.5 mmol) were added. The reaction was stirred at 70° C. for 3 hours, then poured into water (50 mL), extracted with ethyl acetate (40 mL×2), the organic phases were combined and washed with brine (40 mL), dried over sodium sulfate and filtered, and the filtrate was concentrated to give 1-(2 -Methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole crude (240 mg, yield 32%). MS m / z(ESI):253[M+H] + .

[0166] Intermediate A2: 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl ) Preparation of ethyl) morpholine

[0167]

...

Embodiment 1

[0424] Example 1: 3,3-Dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxo) Preparation of pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide

[0425]

[0426] The first step: preparation of 3,3-dimethyl-2-carbonylpyrrolidine-1-carbonyl chloride

[0427]

[0428] In an ice bath, a solution of 3,3-dimethylpyrrolidin-2-one (200mg, 1.75mmol) and pyridine (415mg, 5.26mmol) in dichloromethane (5mL) was dropped into triphosgene (172mg, 0.58 mmol) in dichloromethane (5 mL). The reaction was stirred at 5°C for 30 minutes. The reaction solution was directly used in the next step without any treatment.

[0429] The second step: 3,3-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxo) Preparation of pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide

[0430]

[0431]In an ice bath, a solution of 3,3-dimethyl-2-carbonylpyrrolidine-1-carbonyl chloride (0.33 mmol) in dichloromethane (10 mL) obtained in the previous step was dropped into 6-methy...

Embodiment 9

[0444] Example 9: N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxo)-6-methylpyridin-2-yl)-3,3-dimethyl Preparation of yl-2-carbonylpyrrolidine-1-carboxamide

[0445]

[0446] The first step: tert-butyl 4-(4-((6-(3,3-dimethyl-2-carbonylpyrrolidin-1-carboxalylamino)-2-methylpyridin-3-yl )Oxo)pyridin-2-yl)-1H-pyrazole-1-carboxylate

[0447]

[0448] Triphosgene (88mg, 0.296mmol) was dissolved in dichloromethane (2mL), and 3,3-dimethylpyrrolidin-2-one (100mg, 0.885mmol) and pyridine (209mg, 2.655mmol) were added under ice-cooling. Chloromethane (2 mL) solution and the reaction was stirred for 0.5 h under ice bath. It was then added to tert-butyl 4-(4-((6-amino-2-methylpyridin-3-yl)oxo)pyridin-2-yl)-1H-pyrazole-1 under ice bath - carboxylate (90 mg, 0.245 mmol) and pyridine (20 mg, 0.25 mmol) in dichloromethane (2 mL) and the reaction was stirred at room temperature for 1 hour. It was then poured into water (30mL), then extracted with dichloromethane (20mL×2), the organic phase...

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Abstract

An N-(azaaryl) cyclic lactam-1-carboxamide derivative with a structure of formula (1) and its preparation method and application, the definition of each substituent is as described in the specification and claims. The compound 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, glial cell Drugs for tumors, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastases from primary tumor sites, or bone metastatic cancers are expected to be developed into CSF1R inhibitor drugs.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to an N-(azaaryl) cyclic lactam-1-carboxamide derivative and a preparation method and application thereof. [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) (Expe...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14C07D417/14A61K31/4439A61K31/497A61P35/00A61P37/00A61P3/00
CPCA61K31/4439A61K31/497A61P3/00A61P35/00A61P37/00C07D401/14C07D413/14C07D417/14C07D407/14
Inventor 赵保卫张鸣鸣喻红平杨舒群陈椎徐耀昌
Owner ABBISKO THERAPEUTICS CO LTD
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