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Pyrimidine-4 (3H)-ketone heterocyclic compound, preparation method thereof and application of pyrimidine-4 (3H)-ketone heterocyclic compound in medicine

A compound and heteroaromatic ring technology, applied to pyrimidine-4(3H)-one heterocyclic compound, its preparation and its application in medicine, can solve the problem of poor cell permeability, low bioavailability, selective Sexual problems, etc.

Inactive Publication Date: 2021-07-20
BEIJING INNOCARE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high protein sequence homology of the PTP catalytic site and the high hydrophilicity of the PTP catalytic pocket, SHP2 catalytic site inhibitors have poor selectivity, poor cell permeability and low bioavailability.

Method used

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  • Pyrimidine-4 (3H)-ketone heterocyclic compound, preparation method thereof and application of pyrimidine-4 (3H)-ketone heterocyclic compound in medicine
  • Pyrimidine-4 (3H)-ketone heterocyclic compound, preparation method thereof and application of pyrimidine-4 (3H)-ketone heterocyclic compound in medicine
  • Pyrimidine-4 (3H)-ketone heterocyclic compound, preparation method thereof and application of pyrimidine-4 (3H)-ketone heterocyclic compound in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] (R)-5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decane-8-yl )-3-methylpyrimidin-4(3H)-one

[0108]

[0109]

[0110] first step

[0111] 2-Chloro-5-iodopyrimidin-4(3H)-one

[0112] Dissolve 2,4-dichloro-5-iodopyrimidine 1a (8.0g, 29.1mmol) in tetrahydrofuran (100mL), add sodium hydroxide solution (1N, 45mL) at 0°C, and warm the reaction mixture to room temperature, stirring for 16 hours . The pH was adjusted to acidic with citric acid, and extracted with ethyl acetate (60 mL×3). The combined organic phases were washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, and precipitated under reduced pressure to obtain the target product 2-chloro-5-iodopyrimidin-4(3H)-one 1b (6.7g, solid), yield: 91%.

[0113] MS m / z(ESI):257[M+1]

[0114] second step

[0115] 2-Chloro-5-iodo-3-methylpyrimidin-4(3H)-one

[0116] 2-Chloro-5-iodopyrimidin-4(3H)-one 1b (5.6g, 21.7mmol) was dissolved in THF (100mL), methyl iodide (3.7g, 26m...

Embodiment 2

[0143] (R)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-3-methyl-5-((1-methyl-1H-pyrrolo[2,3- b] pyridin-4-yl)thio)pyrimidin-4(3H)-one

[0144]

[0145]

[0146] first step

[0147] 3-((1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)propanoic acid ethyl ester

[0148] To 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine 2a (200mg, 0.95mmol), ethyl 3-mercaptopropionate (255mg, 1.9mmol), N,N-diiso In a mixture of propylethylamine (368mg, 2.85mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (55mg, 0.095mmol) and dioxane (10mL) Tris(dibenzylideneacetone)dipalladium (87mg, 0.095mmol) was added, heated to 100°C under nitrogen protection, and reacted for 2 hours. Cool down to room temperature, add water (10 mL), and extract with ethyl acetate (20 mL×3). The organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the solvent was precipitated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl aceta...

Embodiment 3

[0164] (R)-5-((1H-indazol-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-3-methylpyrimidine- 4(3H)-keto

[0165]

[0166] first step

[0167] Ethyl 3-((1H-indazol-4-yl)thio)propionate

[0168] To a solution of 4-bromo-1H-indazole 3a (500 mg, 2.53 mmol) in dioxane (20 mL) was added ethyl 3-mercaptopropionate (680 mg, 5.06 mmol), N,N-diisopropylethyl Amine (979mg, 7.59mmol), tris(dibenzylideneacetone)dipalladium (231mg, 0.253mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (219mg, 0.397 mmol). The reaction mixture was heated to 100°C under nitrogen for 2 hours. Cool down to room temperature, precipitate under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether=2.6 / 1) to obtain the target product 3-((1H-indazol-4-yl)thio)propionic acid Ethyl ester 3b (560 mg, solid), yield: 89%.

[0169] MS m / z(ESI):251[M+1]

[0170] second step

[0171] Sodium 1H-indazole-4-thiolate

[0172] To a solution of ethyl 3-...

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Abstract

The invention relates to pyrimidine-4 (3H)-ketone heterocyclic compounds suitable for inhibiting or regulating SHP2, a preparation method of the pyrimidine-4 (3H)-ketone heterocyclic compounds and application of the pyrimidine-4 (3H)-ketone heterocyclic compounds in medicine. Specifically, the invention relates to a compound as shown in a general formula (I) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof, a method for treating and / or preventing related diseases mediated by SHP2, especially cancers by using the compound or the pharmaceutically acceptable salt thereof, and a preparation method of the compound or the pharmaceutically acceptable salt thereof. The invention also relates to application of the compound or the pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt thereof in preparation of drugs for treating and / or preventing SHP2-mediated related diseases. Wherein each substituent in the general formula (I) is as defined in the specification.

Description

technical field [0001] The present invention relates to a novel pyrimidin-4(3H)-one heterocyclic compound or a pharmaceutically acceptable salt thereof for regulating or inhibiting SHP2 activity, a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and the The preparation method of the compound or its pharmaceutically acceptable salt and the compound or its pharmaceutically acceptable salt or the pharmaceutical composition containing said compound or its pharmaceutically acceptable salt are used in the preparation for treatment and / or prevention caused by SHP2 Use in medicine for related disorders mediated, in particular cancer, and methods of use thereof. Background technique [0002] SHP2 (Src Homology 2 domain-containing Phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 (Protein Tyrosine Phosphatase Nonreceptor type 11) gene. SHP2 contains two SH2 domains (Src Homology domain), a PTP domain ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D401/14C07D491/107C07D519/00A61K31/506A61P35/02A61P35/00A61P43/00
CPCC07D471/04C07D401/14C07D491/107C07D519/00A61P35/02A61P35/00A61P43/00A61K31/506A61K45/06A61K2300/00A61K31/513
Inventor 不公告发明人
Owner BEIJING INNOCARE PHARMA TECH CO LTD