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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

Pending Publication Date: 2022-07-26
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

[0173] Example 1 Preparation of IRAK4 kinase inhibitor

[0174] The synthetic route is as follows:

[0175]

[0176] step 1:

[0177]

[0178] 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) were added to a 250ml single-necked flask, stirred at room temperature for 3 hours, and added water, extracted with ethyl acetate (100 mL×3), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target product as a yellow solid (8.0 g, yield: 56.1%), LC-MS: 352 [M+H] + .

[0179] Step 2:

[0180]

[0181] In a 100 mL one-neck round bottom flask was added 2 (8.0 g, 22.79 mmol), tert-butyl carbamate (3.20 g, 27.35 mmol), DIEA (5.88 g, 45.58 mmol) and DMF (40.0 mL), at 100 °C The reaction was carried out for 18h. After adding water, it was extracted with ethyl acetate (100 mL x 3), the organic phase...

Embodiment 2

[0210] Example 2 Preparation of IRAK4 kinase inhibitor

[0211] The synthetic route is as follows:

[0212]

[0213] step 1:

[0214]

[0215] 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) were added to a 250ml single-necked flask, stirred at room temperature for 3 hours, and added water, extracted with ethyl acetate (100 mL×3), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target product as a yellow solid (8.0 g, yield: 56.1%), LC-MS: 352 [M+H] + .

[0216] Step 2:

[0217]

[0218] In a 100 mL one-neck round bottom flask was added 2 (8.0 g, 22.79 mmol), tert-butyl carbamate (3.20 g, 27.35 mmol), DIEA (5.88 g, 45.58 mmol) and DMF (40.0 mL), at 100 °C The reaction was carried out for 18h. After adding water, it was extracted with ethyl acetate (100 mL x 3), the organic phase...

Embodiment 3

[0245]Example 3 Preparation of IRAK4 kinase inhibitor

[0246] The synthetic route is as follows:

[0247]

[0248] step 1:

[0249]

[0250] 1 (8.0g, 40.62mmol), dichloromethane (80mL), triethylamine (8.23g, 81.23mmol) and TsCl (9.29g, 48.74mmol) were added to a 250ml single-necked flask, stirred at room temperature for 3 hours, and added water, extracted with ethyl acetate (100 mL×3), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target product as a yellow solid (8.0 g, yield: 56.1%), LC-MS: 352 [M+H] + .

[0251] Step 2:

[0252]

[0253] In a 100 mL one-neck round bottom flask was added 2 (8.0 g, 22.79 mmol), tert-butyl carbamate (3.20 g, 27.35 mmol), DIEA (5.88 g, 45.58 mmol) and DMF (40.0 mL), at 100 °C The reaction was carried out for 18h. After adding water, it was extracted with ethyl acetate (100 mL x 3), the organic phase ...

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PUM

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Abstract

The invention provides a compound with a general formula I, and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, the compound is an IRAK4 kinase inhibitor, and can be used for preventing and / or treating 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 a preparation method and application thereof. Background technique [0002] Interleukin-1 receptor-associated kinase-4 (IRAK4) is an intracellular serine / threonine protein kinase and a member of the IRAK family. IRAK4 kinase is mainly composed of a conserved death domain (DD) at the N-terminal, a hinge region, and a central kinase domain (KD) at the C-terminal. The DD region is the region where IRAK4 binds to the adaptor 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 consists of 12 subregions with typical serine / threonine kinase domain features. The main function of IRAK4 is to phosphorylate its substrates 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): C07D471/14A61K31/437A61K31/4545A61K31/4725A61P37/00A61P37/06A61P29/00A61P35/00A61P7/02A61P9/10A61P3/00
CPCC07D471/14A61P37/00A61P37/06A61P29/00A61P35/00A61P7/02A61P9/10A61P3/00
Inventor 林星雨陆婷婷安娜
Owner ZHUHAI YUFAN BIOTECHNOLOGIES CO LTD
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