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Pyrazolo[1,5a]pyrimidine derivatives as modulators of IRAK4

A technology of compounds and medicinal salts, applied in the field of compounds that inhibit interleukin-1 receptor-related kinase 4, can solve the problems of defective production of cytokines, increased susceptibility to infection, etc.

Inactive Publication Date: 2021-11-02
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Similarly, IRAK4-null mice are defective in TLR- and IL-1-mediated cytokine production and display increased susceptibility to infection

Method used

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  • Pyrazolo[1,5a]pyrimidine derivatives as modulators of IRAK4
  • Pyrazolo[1,5a]pyrimidine derivatives as modulators of IRAK4
  • Pyrazolo[1,5a]pyrimidine derivatives as modulators of IRAK4

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0554] Example 1: N-(7-(4-(hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4] (oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0555]

[0556] Step A: (1-(6-nitro-3,4-dihydro-2H-benzo[b][1,4] Azin-7-yl)piperidin-4-yl)methanol

[0557]

[0558] Commercially available 7-fluoro-6-nitro-3,4-dihydro-2H-benzo[b][1,4] Oxazine (300mg, 1.51mmol), piperidin-4-ylmethanol (183mg, 1.59mmol) and N-ethyl-N-isopropylpropan-2-amine (391mg, 3.03mmol) in N-methyl-2 - The mixture in pyrrolidone (5 mL) was stirred at 120°C for 18 hours. After cooling to room temperature, the mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined and washed with water and brine. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as the eluting solvent to obtain (1-(6-nitro-3,4-dihydro-2H-benzene and[b][1,4] Azin-7-yl)piper...

Embodiment 2

[0565] Example 2: N-(7-(4-(hydroxymethyl)piperidin-1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4] (oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0566]

[0567] Step A: 7-(4-(Hydroxymethyl)piperidin-1-yl)-6-nitro-2H-benzo[b][1,4] Azin-3(4H)-one

[0568]

[0569] In a sealed tube, the 7-fluoro-6-nitro-4H-1,4-benzo Oxin-3-one (300mg, 1.41mmol), 4-piperidinylmethanol (162mg, 1.41mmol) and N,N-diisopropylethylamine (342mg, 2.82mmol) in 4-methyl-2- The mixture in pentanone (5 mL) was stirred at 30°C for 16 hours. Water and ethyl acetate (2 x 30 mL) were added. The organic phases were combined and washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluent to give 7-(4-(hydroxymethyl)piperidin-1-yl)-6-nitro-2H -Benzo[b][1,4] Azin-3(4H)-one (400 mg, 92%) as a yellow solid. MS(ESI): m / z=308.2[M+1] + .

[0570] Step B: 6-Amino-7-(4-(hydroxymethyl)p...

Embodiment 3

[0576] Example 3: trans-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1,3-di Alk-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0577]

[0578] Step A: 2-Trimethylsilylethyl N-(2,2-dimethoxyethyl)carbamate

[0579]

[0580] To a mixture of 2,2-dimethoxyethylamine (608.0 mg, 5.78 mmol) and triethylamine (1.07 mL, 7.71 mmol) in THF (10 mL) was added 1-[2-(tri Methylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (1.0 g, 3.86 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (150 mL) and the organic phase was washed with water and brine, dried over sodium sulfate and concentrated to give 2-trimethylsilyl N-(2,2-dimethoxyethyl)carbamate Ethyl ester (945 mg), a colorless oil, was used directly in the next step without further purification. 1 HNMR (400MHz, CDCl 3 )δ4.76(brs,1H),4.33(t,J=5.6Hz,1H),4.12(t,J=8.4Hz,2H),3.36(s,6H),3.27(t,J=5.6Hz, 2H)...

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Abstract

Described herein are compounds of formula (0), formula (I) and formula (II) and methods of use as interleukin-1 receptor-associated kinase (IRAK4) inhibitors.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 271,171, filed December 22, 2015, U.S. Provisional Application No. 62 / 279,459, filed January 15, 2016, and U.S. Provisional Application No. 62 / 279,459, filed September 22, 2016. 62 / 398,341 interests. [0003] field of invention [0004] The present invention relates to compounds useful for inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4). [0005] Background of the invention [0006] Cell surface receptors containing TIR-domain (Toll-Interleukin 1 receptor-domain) such as Toll-like receptor (TLR) and IL-1 and IL-18 receptors play a key role in innate immunity, And it is related to the pathogenesis of autoimmunity. For example, TLRs recognize pathogenic or endogenous ligands and provide the necessary signals for dendritic cell maturation and antigen presentation to T cells. Similarly, proteins that mediate signaling by these receptors have also be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61P29/00
CPCC07D519/00C07D487/04A61P37/02A61P29/00A61P35/00
Inventor M·C·布赖恩冯健文A·戈比J·R·小基弗A·科列斯尼科夫C·恩杜巴库A·G·奥利韦罗J·德罗布尼克梁军N·拉贾帕克萨
Owner F HOFFMANN LA ROCHE & CO AG
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