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IRAK4 kinase inhibitor as well as preparation and application thereof

A solvate, alkyl technology, applied in the field of medicinal chemistry, can solve the problem of redundant host defense against natural infection

Active Publication Date: 2021-03-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although IRAK4 occupies an extremely important position in innate immunity, studies have shown that the TIR-MyD88-IRAK4 signaling pathway is essential for the protective immunity of a small number of pyogenic bacteria, but it is redundant for the host defense of most natural infections

Method used

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  • IRAK4 kinase inhibitor as well as preparation and application thereof
  • IRAK4 kinase inhibitor as well as preparation and application thereof
  • IRAK4 kinase inhibitor as well as preparation and application thereof

Examples

Experimental program
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preparation example Construction

[0077] Preparation of compounds of the present invention

[0078] The following reaction schemes illustrate the preparation of the compounds of the present invention.

[0079] Reaction Scheme I

[0080]

[0081] The general synthetic method of a class of compounds of the present invention is shown in Reaction Scheme I. Including the following steps:

[0082] 1. Compound 1a / 1b was obtained by Grignard reaction with methylmagnesium bromide at -78°C to obtain compound 2a / 2b;

[0083] 2. Compound 2a / 2b undergoes a ring-closing reaction under the condition of potassium tert-butoxide to obtain compound 3a / 3b;

[0084] 3. Compound 3a / 3b undergoes nitration reaction under the action of nitric acid to obtain compound 4a / 4b

[0085] 4. Compound 4a undergoes a Suzuki coupling reaction under the action of a palladium catalyst, and compound 4b undergoes a substitution reaction under the action of a base to obtain different forms of formula 5;

[0086] 5. Compound 5 can be reduced u...

Embodiment 1

[0160] 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzo Furan-5-yl)oxazole-4-carboxamide (I-1)

[0161]

[0162] Step 1: Preparation of (1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

[0163]

[0164] 6-Fluoro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (200 mg, 94.7 μmol), 4-hydroxymethylpiperidine (218 mg, 1.89 mmol) were dissolved in N , N-dimethylformamide (5mL), potassium carbonate (262mg, 1.89mmol) was added, reacted at 40°C for two hours, TLC detected that the reaction was complete, added ethyl acetate (25mL) and water for extraction, the ethyl acetate layer was washed with water, Wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, concentrate to dryness, and put directly into the next reaction.

[0165] Step 2: Preparation of (1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

[0166]

[0167] Dissolve the reaction product of the p...

Embodiment 2

[0175] (R)-N-(6-(3-aminopiperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-(2-amino Pyridin-4-yl)oxazole-4-carboxamide trifluoroacetate (I-2)

[0176]

[0177] Step 1: R)-(4-(4-((6-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2,2-dimethyl-2,3-di Preparation of tert-butyl hydrobenzofuran-5-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

[0178]

[0179] (R)-(4-(4-((6-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)-2,2 -Dimethyl-2,3-dihydrobenzofuran-5-yltert-butyl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate tert-butyl. 1 H NMR (400MHz, Chloroform-d) δ10.15(s,1H),8.65(s,1H),8.41(d,J=5.2Hz,1H),8.37(s,1H),8.31(s,1H) ,7.99(s,1H),7.63(dd,J=5.2,1.5Hz,1H),6.60(s,1H),3.14(s,1H),3.02(s,2H),2.77(s,3H), 1.90(s,1H),1.67(s,3H),1.55(s,9H),1.47(s,6H),1.19(s,9H).

[0180] Step 2: (R)-N-(6-(3-aminopiperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-2-( Preparation of 2-aminopyridin-4-yl)oxazole-4-carboxamide trifluoroacetate

[0181] (R)-(4-(4-((6-(3-((tert-butoxyca...

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Abstract

The invention provides an IRAK4 kinase inhibitor as well as preparation and application thereof, and particularly provides a compound shown as a formula (I) in the specification, a stereoisomer, a geometrical isomer, a tautomer, pharmaceutically acceptable salt, a prodrug, a hydrate or a solvate of the compound, and a preparation method and application of the compound. Compared with an IRAK4 inhibitor in the prior art, the compound of the invention has the advantage that the activity of the compound is obviously improved, so the compound can be used for preparing drugs used for preventing and / or treating IRAK4-mediated related diseases such as cancer, inflammatory diseases and autoimmune diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a compound with IRAK4 kinase inhibitory activity and its preparation and application. Background technique [0002] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine / threonine kinase located directly within the interleukin-1 (IL-1) receptor family (IL-1, IL-18 and IL-33 receptors) and Toll-like receptors (TLRs, except TLR3), are key signaling nodes for transducing innate immunity. Upon ligand binding, IL-1 family receptors and TLRs recruit the scaffold adapter protein myeloid differentiation primary response gene 88 (MyD88) through the conserved Toll / IL receptor (TIR) ​​domain. MyD88 in turn recruits IRAK4 using the homotypic interaction of the death domain, thereby activating downstream signaling pathways such as NF-κB and AP-1. IRAK4 has a dual role as a kinase and a backbone, and it mediates downstream signaling pathways by forming a lar...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D491/107C07D487/04A61P35/00A61P37/02A61P29/00A61P9/10A61P7/02A61P35/02A61P19/02A61P11/00A61P17/00A61P17/06A61P1/04A61P1/00A61K31/4545A61K31/5377A61K31/4439A61K31/496A61K31/538A61K31/444A61K31/4985
CPCC07D413/14C07D491/107C07D487/04A61P35/00A61P37/02A61P29/00A61P9/10A61P7/02A61P35/02A61P19/02A61P11/00A61P17/00A61P17/06A61P1/04A61P1/00A61K31/4439A61K31/444A61K31/4545A61K31/496A61K31/4985A61K31/5377A61K31/538C07D231/56C07D471/04
Inventor 段文虎丁健陈运谢华张惠斌周金培
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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