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JAK inhibitor compound and application thereof

A compound and isomer mixture technology, applied in the field of novel compounds, can solve problems such as unsatisfactory efficacy or safety of JAK inhibitors

Active Publication Date: 2020-09-01
HENAN MEDINNO PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Although some JAK inhibitors have been approved for marketing, and a large number of JAK inhibitors are in the clinical research stage, these JAK inhibitors are not satisfactory in terms of efficacy or safety

Method used

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  • JAK inhibitor compound and application thereof
  • JAK inhibitor compound and application thereof
  • JAK inhibitor compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0509] Example 1: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)methanone (MDI-2)

[0510]

[0511] The synthetic route of target compound 8 (that is, MDI-2):

[0512]

[0513] Synthetic route of intermediate 10

[0514]

[0515] Synthetic route of intermediate 16

[0516]

[0517] Synthetic route of intermediate 20

[0518]

[0519] resolve resolution:

[0520] Synthetic intermediate 1: 6-bromo1H-indazole-3-carbaldehyde

[0521] Sodium nitrite (14.00g, 200mmol) was dissolved in 75ml DMF and 100ml water, cooled to 0°C, under nitrogen protection, 3N HCl (23ml, 68.9mmol) was slowly added dropwise, and the reaction was completed for 10 minutes. At 0°C, a solution of 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise to the reaction solution, and after the addition was complete, the reaction was carried out overnight at room temperature. Extracted 3...

Embodiment 2

[0578] Example 2: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)--4,6-dihydropyrrolo [3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)methanone (MDI-201)

[0579]

[0580] The synthetic route of MDI-201:

[0581]

[0582] resolve resolution:

[0583] Synthetic intermediate MDI-201-1: methyl 5-morpholinepyrazine-2-carboxylate

[0584] Dissolve 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.5g, 8.7mmol) in 10ml DMF, add N,N-diisopropylethylamine (3.0ml, 17.4mmol) and morpholine (0.91g , 10.4mmol), stirred at room temperature overnight, under vigorous stirring, water was added, solids were precipitated, filtered, washed with water, and dried to obtain intermediate MDI-201-1 with a yield of 72.2%.

[0585] Synthetic intermediate MDI-201-2: 5-morpholine pyrazine-2-carboxylic acid

[0586] Dissolve the intermediate MDI-201-1 (1.4g, 6.27mmol) in 20ml of tetrahydrofuran and 20ml of water, add lithium hydroxide (0.32g, 7.53mmol), react at room temperature...

Embodiment 3

[0597] Example 3: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)--4,6-dihydropyrrolo [3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)methanone (MDI-202)

[0598]

[0599] The synthetic route of MDI-202:

[0600]

[0601] resolve resolution:

[0602] Synthetic intermediate MDI-202-1: (2-(6-bromo 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-( (2-(Trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H- Pyrazol-4-yl)methanone

[0603] The intermediate 1-methyl-1H-pyrazole-4-carboxylic acid (16.5mg, 0.13mmol) and N,N-diisopropylethylamine (46.0mg, 0.36mmol) were dissolved in DMF, and HATU (67.8 mg, 0.18mmol), react at room temperature for 10 minutes. Intermediate 2-(6-bromo1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl Base)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-tert-butyl carboxylate (80mg, 0.12mmol) was dissolved in 5ml of dichloromethane, Add 1ml of trifluoroacet...

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Abstract

The invention relates to a JAK inhibitor compound and application thereof. Specifically, the invention discloses a compound shown as a formula (G), or an isotope labeled compound, or an optical isomer, a geometrical isomer, a tautomer or an isomer mixture of the compound, or a pharmaceutically acceptable salt of the compound, or a prodrug of the compound, or a metabolite of the compound. The invention also relates to the medical application of the compound.

Description

technical field [0001] The present invention provides a class of novel pharmaceutically active compounds useful for inhibiting Janus kinase (JAK). The present invention also relates to compositions comprising said compounds, and the use of said compounds and said compositions in the manufacture of medicaments for the treatment and / or prevention of diseases or conditions associated with JAK. Background technique [0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine / threonine kinases. Inappropriate kinase activity due to mutation, overexpression or inappropriate regulation, dysregulation or dysregulation, and overproduction or underproduction of growth factors or cytokines has been implicated in many diseases including, but not limited to, cancer, cardiovascular disease, Allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bo...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/497A61K31/5377A61K31/4188A61K31/454A61K31/501A61K31/496A61K31/4439A61P17/00A61P17/06A61P17/14A61P17/04A61P19/02A61P37/06A61P7/06A61P1/00A61P25/00A61P15/00A61P7/00A61P27/02A61P21/04A61P1/16A61P3/10A61P5/16A61P1/04A61P25/28A61P25/16A61P25/14A61P9/10A61P7/02A61P11/06A61P11/00
CPCC07D487/04C07D519/00A61P17/00A61P37/06A61P1/00A61P25/00A61P27/02A61P3/10A61P11/06A61P11/00A61P37/02A61P35/00A61P37/08A61P1/04A61P1/16A61P5/16A61P7/00A61P7/02A61P7/06A61P9/10A61P15/00A61P17/04A61P17/06A61P17/14A61P19/02A61P21/04A61P25/14A61P25/16A61P25/28A61K31/497A61K31/5377A61K31/416A61K31/454A61K31/4188A61K31/501A61P37/00C07D487/10
Inventor 路良黄海张龙争赵赛赛张霁旋
Owner HENAN MEDINNO PHARM TECH CO LTD