Selective Janus kinase 2 (JAK2) inhibitor and application thereof

A technology selected from, solvate, applied in the field of JAK2 inhibitors and its applications, can solve the problems of side effects, multiple target effects, and low selectivity of inhibitors

Inactive Publication Date: 2019-10-25
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research on the above-mentioned JAK2 inhibitors for the treatment of immune inflammation and myeloproliferative carcinoma has achieved good results, but its safety needs to be further evaluated in clinical research, and some inhibitors have low selectivity and are not effective against various targets. All points will affect and cause side effects, so it is very important for the research of highly selective and efficient targeting JAK2 inhibitors

Method used

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  • Selective Janus kinase 2 (JAK2) inhibitor and application thereof
  • Selective Janus kinase 2 (JAK2) inhibitor and application thereof
  • Selective Janus kinase 2 (JAK2) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1 prepares compound WWQ-131

[0085] 1) Synthesis of 1-(2-chloro-5-fluorophenyl)ethanol

[0086]

[0087] Put the raw material (1g, 5.8mmol) in a 50mL reaction flask, dissolve in anhydrous methanol, protect with argon, stir in an ice bath for 30 minutes, then slowly add NaBH 4 (331mg, 8.7mmol), gradually raised to room temperature, stirred at room temperature, TLC tracked the spot plate, and the reaction was completed in 6 hours, quenched with water in an ice bath, spin off methanol, extracted three times with DCM and water, and used for the organic phase Saturated saline was extracted three times, the organic phase was collected, dried with anhydrous sodium sulfate, filtered with suction, and the organic phase was spin-dried to obtain a colorless oily liquid, 960 mg, with a yield of 95%. 1 H NMR (400MHz, CDCl 3 ):δ7.25(dd,J 1 =2.4Hz,J 2 =6.8Hz,1H),7.20(dd,J 1 =4.0Hz,J 2 =5.2Hz,1H),6.83(td,J 1 =2.8Hz,J 2 =8.4Hz, 1H), 5.15(q, J=6.4Hz, 1H), 2.06(s, 1...

Embodiment 2

[0103] Embodiment 2 prepares WWQ-133

[0104] 1) 3-[1-(2,6-dichlorophenyl)ethoxy]-2-nitropyridine

[0105]

[0106] Weigh raw materials 1-(2,6-dichlorophenyl)ethanol (1g, 5.23mmol), 3-hydroxy-2-nitropyridine (807mg, 5.75mmol), triphenylphosphine (1.647g, 6.27mmol) In a 50mL two-necked bottle, add THF to dissolve it. Under argon protection, DIAD (1.236mL, 6.27mmol) was slowly added dropwise under stirring in an ice bath. 50:1), 804 mg of white solid was obtained, and the yield was 48.5%. 1 H NMR (400MHz, CDCl 3 ):δ8.01(dd,J 1 =1.2Hz,J 2 =3.2Hz,1H),7.36-7.33(m,1H),7.32(s,1H),7.30(s,1H),7.23(dd,J=0.8,7.6Hz,1H),7.18(t,J= 8.0Hz, 1H), 6.13(q, J=6.4Hz, 1H), 1.85(d, J=6.8Hz, 3H). GC-MS: m / z=312.1.

[0107] 2) 3-[1-(2,6-dichlorophenyl)ethoxy]-2-aminopyridine

[0108]

[0109] Weigh 3-[1-(2,6-dichlorophenyl)ethoxy]-2-nitropyridine (804mg, 2.56mmol), iron powder (360mg, 6.41mmol) into a 50mL two-necked bottle, add It was dissolved with EtOH, refluxed at 90°C for 30 minute...

Embodiment 3

[0119] Embodiment 3 prepares WWQ-153

[0120] 4-{3-[1-(2,6-dichloro-3-fluorophenyl)methoxy]-2-aminopyridine}pyrazole-1-piperidine

[0121]

[0122] 43mg of white solid was obtained, the yield was 45.1%, melting point: 195.0-196.5°C. 1 H NMR (400MHz, CDCl 3 ): δ7.87(d,J=2.0Hz,1H),7.67(s,1H),7.60(s,1H),7.52(dd,J 1 =2.8Hz,J 2 =6.4Hz,1H),7.39(dd,J 1 =2.4Hz,J 2 =5.6Hz,1H),7.07(d,J=1.6Hz,1H),5.15(s,2H),4.69(s,2H),4.28-4.21(m,1H),3.26(d,J=12.8Hz ,2H),2.78(td,J 1 =2.0Hz,J 2 =12.4Hz,2H),2.19(dd,J 1 =2.0Hz,J 2 =12.4Hz, 2H), 1.98-1.88(m, 2H), 1.83(s, 1H). 13 C NMR (100MHz, CDCl 3 ): δ153.4, 148.6, 140.8, 136.7, 135.8, 130.2, 129.8, 127.7, 126.4, 126.2, 122.9, 122.4, 119.7, 115.2, 63.5, 59.9, 45.7, 34.0. HRMS (ESI) (m / z): [M +H] + calcd for C 20 h 20 Cl 2 FN 5 O, 436.1062; found, 436.1100. HPLC purity: 97.76%, retention time = 10.879min.

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Abstract

The invention relates to a selective Janus kinase 2 (JAK2) inhibitor and application thereof. Specifically, the invention relates to a compound shown as the following formula I (please see the specifications for the formula) and application of the compound to treatment of JAK2 mediated related diseases and preparation of drugs for treating the JAK2 mediated related diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to JAK2 inhibitors and applications thereof. Background technique [0002] JAKs (Janus kinase) is a cytoplasmic non-receptor soluble protein tyrosine kinase. The JAKs family has four family members, namely JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase). JAK1, JAK2, and TYK2 are widely present in various tissues and cells in vivo, while JAK3 is mainly expressed in hematopoietic tissues. Among them, JAK2 consists of 1132 amino acids with a relative molecular mass of 13493, and its coding gene is located in zone 4, zone 2, short arm of chromosome 9. JAK2 consists of seven JAK homology regions (JAK homology, JH) of different lengths from the N-terminus to the C-terminus. There are two homologous kinase domains JH1 and JH2 at the C-terminus; five homology regions JH3-JH7 at the N-terminus . JH1 is located at the carboxyl terminal, which is the cat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14C07D405/14C07D213/73C07D401/10A61K31/496A61K31/4545A61K31/4439A61K31/444A61P35/00A61P35/02A61P29/00A61P31/04A61P31/10A61P31/12A61P19/02A61P21/04A61P7/06A61P31/14A61P31/20
CPCC07D401/04C07D401/14C07D405/14C07D213/73C07D401/10A61P35/00A61P35/02A61P29/00A61P31/04A61P31/10A61P31/12A61P19/02A61P21/04A61P7/06A61P31/14A61P31/20C07B2200/07C07D401/12C07D413/04C07D417/04C07D471/04C07D487/04C07D213/74Y02A50/30A61K31/4439A61K31/444A61K31/4545A61K31/496A61K31/519A61K31/5377A61P31/00C07D413/10
Inventor 李洪林徐玉芳王婉琪赵振江朱丽丽齐甜甜
Owner EAST CHINA UNIV OF SCI & TECH
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