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IRAK4 kinase inhibitor and preparation method thereof

A technology of solvate and alkyl, applied in the field of IRAK4 kinase inhibitor and its preparation

Active Publication Date: 2021-02-02
ZHUHAI YUFAN BIOTECHNOLOGIES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hyperactivation of IRAK4 due to L265P mutation of MyD88 protein in diffuse large B-cell lymphoma

Method used

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  • IRAK4 kinase inhibitor and preparation method thereof
  • IRAK4 kinase inhibitor and preparation method thereof
  • IRAK4 kinase inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] The preparation of embodiment 1IRAK4 kinase inhibitor

[0116] The synthetic route is as follows:

[0117]

[0118] step 1:

[0119]

[0120] Add 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) in a 250ml one-necked bottle, stir at room temperature for 3 hours, add water, extracted with ethyl acetate (100mLx 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, spin-dried, and obtained the target product by column chromatography (petroleum ether: ethyl acetate = 4:1) As a yellow solid (8.0g, yield: 56.1%), LC-MS: 352[M+H] + .

[0121] Step 2:

[0122]

[0123] Add 2 (8.0g, 22.79mmol), tert-butyl carbamate (3.20g, 27.35mmol), DIEA (5.88g, 45.58mmol) and DMF (40.0mL) in a 100mL single-necked round bottom flask, at 100°C Reaction 18h. After adding water, it was extracted with ethyl acetate (100mL x 3), the organic phase was washed with saturated brine (50mL x 2), dried over ...

Embodiment 2

[0152] Preparation of embodiment 2 IRAK4 kinase inhibitor

[0153] The synthetic route is as follows:

[0154]

[0155] step 1:

[0156]

[0157] Add 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) in a 250ml one-necked bottle, stir at room temperature for 3 hours, add water, extracted with ethyl acetate (100mLx 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, spin-dried, and obtained the target product by column chromatography (petroleum ether: ethyl acetate = 4:1) As a yellow solid (8.0g, yield: 56.1%), LC-MS: 352[M+H] + .

[0158] Step 2:

[0159]

[0160] Add 2 (8.0g, 22.79mmol), tert-butyl carbamate (3.20g, 27.35mmol), DIEA (5.88g, 45.58mmol) and DMF (40.0mL) in a 100mL single-necked round bottom flask, at 100°C Reaction 18h. After adding water, it was extracted with ethyl acetate (100mL x 3), the organic phase was washed with saturated brine (50mL x 2), dried over anh...

Embodiment 3

[0187] The preparation of embodiment 3IRAK4 kinase inhibitor

[0188] The synthetic route is as follows:

[0189]

[0190] step 1:

[0191]

[0192] Add 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) in a 250ml one-necked bottle, stir at room temperature for 3 hours, add water, extracted with ethyl acetate (100mLx 3), washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, spin-dried, and obtained the target product by column chromatography (petroleum ether: ethyl acetate = 4:1) As a yellow solid (8.0g, yield: 56.1%), LC-MS: 352[M+H] + .

[0193] Step 2:

[0194]

[0195] Add 2 (8.0g, 22.79mmol), tert-butyl carbamate (3.20g, 27.35mmol), DIEA (5.88g, 45.58mmol) and DMF (40.0mL) in a 100mL single-necked round bottom flask, at 100°C Reaction 18h. After adding water, it was extracted with ethyl acetate (100mL x 3), the organic phase was washed with saturated brine (50mL x 2), dried over ...

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Abstract

The present invention provides a compound represented by a general formula I, and a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof,and the compound is an IRAK4 kinase inhibitor, and can be used for prevention and / or treatment of IRAK4 related diseases, such as autoimmune diseases, inflammatory diseases, cancers, heteroimmune diseases, thromboembolism, atherosclerosis, myocardial infarction and metabolic syndrome.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an IRAK4 kinase inhibitor and its preparation method and application. Background technique [0002] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine / threonine protein kinase in cells and a member of the IRAK family. IRAK4 kinase is mainly composed of a conserved death domain (DD) at the N-terminus, a hinge region, and a central kinase domain (KD) at the C-terminus. The DD region is the region where IRAK4 binds to the adapter protein myeloid differentiation factor 88 (MyD88), which plays an important role in IRAK4's molecular recognition and activation of downstream signaling pathways. The KD region is composed of 12 subregions and has typical serine / threonine kinase domain characteristics. The main function of IRAK4 is to phosphorylate its substrate through the KD region, thereby activating downstream signaling molecules. Studies have shown that IRAK4 is a key...

Claims

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Application Information

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IPC IPC(8): C07D487/14A61K31/4985A61P35/00A61P35/02
CPCC07D487/14A61P35/00A61P35/02A61P11/06C07D471/14A61K31/437A61K31/4985A61K31/5377A61K45/06
Inventor 林星雨陆婷婷
Owner ZHUHAI YUFAN BIOTECHNOLOGIES CO LTD
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