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Macrocyclic JAK2 inhibitor and application thereof

A CH2, SO2 technology, applied in the direction of anti-inflammatory agents, antiviral agents, non-central analgesics, etc., can solve problems such as increased infection risk

Pending Publication Date: 2021-02-05
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among JAK inhibitors, the lack of selectivity for JAK2 leads to some side effects, notably an increased risk of infection

Method used

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  • Macrocyclic JAK2 inhibitor and application thereof
  • Macrocyclic JAK2 inhibitor and application thereof
  • Macrocyclic JAK2 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Embodiment 1 prepares compound WYL-1

[0101] 1) Synthesis of 1-(5-fluoro-2-methylphenyl)-1-ethanol

[0102]

[0103] In anhydrous THF solution of 5-fluoro-2-methylbenzaldehyde (5.00g, 0.036mol) was added dropwise 3.0M methylmagnesium bromide diethyl ether solution (13.3mL, 0.04mol) under ice-bath conditions, After the dropwise addition, the ice bath was removed, and the mixture was transferred to room temperature to react for 1.5 h, and the progress of the reaction was monitored by TLC. After the reaction is complete, use saturated NH 4 Aqueous Cl solution quenched the reaction. The reaction solution was extracted three times with ethyl acetate and the organic phases were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 5.03 g (90.13%) of a colorless oily liquid.

[0104] 1 H NMR (400MHz, CDCl 3 )δ7.15(dd, J=10.2Hz, 2.8Hz, 1H), 6.99(dd, J=8.3Hz, 5.8Hz, 1H), 6.78-6.75(m, 1H), 5.03-4.95(m, 1H) ,2.20(s,3H),1.84(s,1H),1...

Embodiment 2

[0129] Embodiment 2 prepares compound WYL-2

[0130]

[0131] WYL-2 was synthesized by the method of synthesizing WYL-1 to obtain 23 mg (3.76%) of light red solid.

[0132] mp:249.8-251.5℃. 1 H NMR (400MHz, CDCl 3 )δ7.46(d, J=1.6Hz, 1H), 7.40(d, J=1.8Hz, 1H), 7.33(dd, J=8.7Hz, 5.9Hz, 1H), 7.17(dd, J=13.1, 4.6Hz, 2H), 6.94-6.89(m, 1H), 5.36-5.30(m, 1H), 4.74(s, 2H), 4.37(d, J=15.7Hz, 1H), 4.07(d, J=15.6 Hz,1H),3.67(s,3H),1.67(d,J=6.5Hz,3H). 13 C NMR (101MHz, DMSO-d 6 )δ162.44,160.03,155.17,150.39,140.39,138.82,131.82,128.20,128.00,117.89,115.37,112.39,107.38,75.15,49.07,45.30,38.43,21.90:( +H) + calcd for C 18 h 19 FN 5 O, 340.1574; found 3340.1575. HPLC purity: 96.7%, retention time = 13.15min.

Embodiment 3

[0133] Embodiment 3 prepares compound WYL-3

[0134] 1) Synthesis of (4-hydroxypyrimidin-2-yl) tert-butyl carbamate

[0135]

[0136] Dissolve 2-aminopyrimidin-4-ol (1.00g, 0.01mmol) in 20mL of pyridine, and add (Boc) dropwise to the reaction solution at 65°C 2 O (2.94g, 0.014mol), after the dropwise addition, the temperature was raised to 85°C for 4h, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was extracted with EA, the organic phase was washed with acid water, and passed through a silica gel column to obtain 1.06 g (53.65%) of a white solid.

[0137] 1 H NMR (400MHz, DMSO-d 6 )δ11.28(s,2H),7.70(d,J=6.8Hz,1H),5.93(d,J=6.8Hz,1H),1.48(s,9H).LC-MS(ESI):m / z:212.1(M+H) + .

[0138] 2) 4-((2-(1-((5-bromo-2-nitro-pyridin-3-yl)oxy)ethyl)-4-fluorobenzyl)oxy)pyrimidin-2-amine synthesis

[0139]

[0140] 5-Bromo-3-(1-(2-(bromomethyl)-5-fluorophenyl)ethoxy)-2-nitropyridine (0.11g, 0.25mmol), (4-hydroxypyrimidine-...

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Abstract

The invention relates to a macrocyclic JAK2 inhibitor and an application thereof. Specifically, the invention relates to a compound shown as a formula I and an application of the compound in treatingJAK2-mediated related diseases and preparing medicines for treating the JAK2-mediated related diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; in particular, the present invention relates to novel JAK2 inhibitors and applications thereof. Background technique [0002] JAK kinase (Janus Kinase) is a non-receptor tyrosine kinase first discovered in the early 1990s, and plays an important role in the signal transduction process mediated by various cytokine receptors. Together with its downstream signal converters and activators of transcription (STATs), JAKs are involved in many important physiological functions such as innate immunity, inflammation and hematopoiesis. Dysregulation of this signaling pathway has been implicated in the pathogenesis of immune diseases and cancer. Therefore, JAKs are attractive targets for the treatment of various diseases. [0003] Signaling of the JAK / STAT pathway begins with the binding of ligands (such as growth factors, interferons or interleukins) to specific transmembrane receptors. A varie...

Claims

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Application Information

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IPC IPC(8): C07D498/18A61P35/00A61P35/02A61P19/02A61P29/00A61P31/14A61P31/20A61P31/22A61P31/16A61P31/04A61P31/12A61P7/06A61P21/04A61K31/519A61K31/439
CPCC07D498/18A61P35/00A61P35/02A61P19/02A61P29/00A61P31/14A61P31/20A61P31/22A61P31/16A61P31/04A61P31/12A61P7/06A61P21/04Y02A50/30
Inventor 李洪林赵振江朱丽丽王艳玲葛欢贺欢
Owner EAST CHINA UNIV OF SCI & TECH
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