Kinase inhibitor, and preparation and application of kinase inhibitor

A solvate and compound technology, applied in the field of kinase inhibitors and its preparation and application, can solve the problems of long synthetic route and single optical isomer

Active Publication Date: 2018-08-07
CHENGDU DIAO PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The fastest-growing small-molecule Pim inhibitor LGH447 has entered phase II clinical research, but the compound has a long synthetic route and can only be obtained through 15 steps of reaction (US2010056576A1, CN102203079A); and the compound molecule has three chiral centers, requiring Chiral separation is required to obtain single optical isomers

Method used

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  • Kinase inhibitor, and preparation and application of kinase inhibitor
  • Kinase inhibitor, and preparation and application of kinase inhibitor
  • Kinase inhibitor, and preparation and application of kinase inhibitor

Examples

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preparation example Construction

[0164] In the preparation of compounds of the present invention, it may be necessary to protect certain interfering functional groups (e.g., primary or secondary amines) of intermediates. The requirements for such protecting groups vary depending on the nature of the particular functional group and the conditions of the preparation method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyleneoxycarbonyl (Fmoc), and the like. Suitable hydroxy protecting groups include allyl, acetyl, silyl, benzyl, trityl, p-methoxybenzyl, and the like. Such protecting groups can be easily determined by those skilled in the art (for details, refer to Protective Groups in Organic Synthesis, John Wiley & Sons, New York, Third Edition, 1999).

[0165] Reaction Scheme 1 below provides a representative procedure for the preparation of compounds of formula (I). It should be understood that these reaction steps and c...

Embodiment 1

[0198] Example 1, (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazolo [4,5-c]pyridin-4-amine

[0199] Preparation of (S)-1-(3-aminopyridin-4-yl)piperidin-3-yl-carbamic acid tert-butyl ester

[0200]

[0201] Step 1, preparation of (S)-1-(3-nitropyridin-4-yl)piperidin-3-yl-carbamic acid tert-butyl ester

[0202] 4-Chloro-3-nitropyridine (475.6mg, 3mmol), (S)-3-tert-butyloxycarbonylaminopiperidine (600.8mg, 3mmol) and DIPEA (387.7mg, 3.0mmol) were sequentially added to a 50mL circle Bottom flask, add 10mL of ethanol, and stir at room temperature for 5h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the ethyl acetate phase (50 mL×3) was washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to o...

Embodiment 2

[0223] Example 2, (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-phenylthiazolo[4,5-c]pyridine- 4-amine

[0224] Preparation of 4-chloro-2-phenylthiazolo[4,5-c]pyridine

[0225]

[0226] Step 1, preparation of 3-amino-4-mercaptopyridine

[0227] Dissolve 4-chloro-3-nitro-pyridine (7.9g, 49.8mmol) in 50mL ethanol, slowly add 50mmol concentrated hydrochloric acid, stir at room temperature; then weigh NaHS·H 2O (13.69g, 184.8mmol) was added to the reaction mixture, stirred at room temperature for 40min; then sodium hydrosulfate (32.21g, 185.1mmol) was weighed and dissolved in water, and the aqueous sodium hydrosulfite solution was added to the reaction mixture, stirred at 80°C for 12h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, separated and purified by silica gel column chromatography (the impurities were first eluted with dichloromethane:methanol=5:1, and then the crude product was obtained by elution with dichlorometh...

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Abstract

The invention provides a compound shown as a formula (I), or a stereoisomer, a tautomer, nitrogen oxide, metabolite, a prodrug, pharmaceutically acceptable salt or solvate of the compound, and application of the compound to preparing drugs or drug compositions for treating Pim kinase-mediated diseases.

Description

technical field [0001] The present invention relates to the compound of formula (I) as a Pim kinase inhibitor, and its application in the preparation of medicine or pharmaceutical composition for treating diseases mediated by Pim kinase, such as cancer and immune-related diseases. Background technique [0002] Pim (Proviral Integration Moloney virus) gene is a family of proto-oncogenes encoding a group of serine / threonine kinases (ie Pim1, Pim2 and Pim3). Pim kinases belong to the calcium ion / calmodulin-dependent protein kinase superfamily and are highly conserved during multicellular evolution. Pim1 - / - Pim2 - / - Pim3 - / - Mice were viable and fertile, but they were markedly reduced in size and impaired in response to hematopoietic growth factors; however, mice lacking only one of the Pim isoforms showed no significant phenotypic differences, suggesting that Pim proteins There is functional redundancy among family members to a certain extent (Mikkers, H. et al., Mol. Cell...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D471/04C07D498/04A61K31/4545A61K31/506A61K31/444A61K31/437A61K31/5377A61K31/496A61K31/4985A61K31/497A61P35/00A61P37/02
CPCC07D471/04C07D498/04C07D513/04
Inventor 郭娜何倩邓塔代川杨巧陈爽范波
Owner CHENGDU DIAO PHARMA GROUP
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