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Alkenyl-containing pyrimidinecarboxamide compounds, compositions and applications thereof

A compound, formamide technology, applied in the field of medicinal chemistry, can solve the problems of high homology, low selectivity of JAK inhibitors, and small structural differences

Active Publication Date: 2021-01-15
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The ATP binding sites of several subtypes of JAK kinases have high homology and small structural differences, which is an important reason for the low selectivity of JAK inhibitors

Method used

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  • Alkenyl-containing pyrimidinecarboxamide compounds, compositions and applications thereof
  • Alkenyl-containing pyrimidinecarboxamide compounds, compositions and applications thereof
  • Alkenyl-containing pyrimidinecarboxamide compounds, compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 Preparation of 4-(butyl-3-en-1-ylamino)-2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide :

[0071]

[0072] Step 1): Preparation of 2-chloro-4-(butyl-3-en-1-ylamino)pyrimidine-5-carboxamide:

[0073] Dissolve 2,4-dichloropyrimidine-5-carboxamide (400mg, 2.08mmol) and triethylamine (633mg, 6.25mmol) in tetrahydrofuran (10mL), add butyl-3-en-1-amine hydrochloride Salt (225mg, 2.1mmol), react at 25°C for 3 hours. Add saturated brine (200mL), stir for 15 minutes, filter, and wash the filter cake with petroleum ether to obtain 380mg of white solid, MS: 227[M+H] + .

[0074]

[0075] Step 2): 4-(Butyl-3-en-1-ylamino)-2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide preparation:

[0076] Dissolve 2-chloro-4-(butyl-3-en-1-ylamino)pyrimidine-5-carboxamide (70 mg, 0.29 mmol) in sec-butanol (3 mL), add 1-tert-butyl-1H -Pyrazol-4-amine (49mg, 0.35mmol) and trifluoroacetic acid (0.1mL) were blocked at 100°C for 2 hours. The r...

Embodiment 2

[0077] Example 2 Preparation of 2-((1-tert-butyl-1H-pyrazol-4-yl)amino)-4-((2-methallyl)amino)pyrimidine-5-carboxamide:

[0078]

[0079] Operation is the same as in Example 1, with 2-methylpropyl-2-en-1-amine instead of butyl-3-en-1-amine hydrochloride in step 1), to obtain a white solid, 1 H NMR (400MHz, DMSO-d 6) δ10.36(s,1H),10.12(s,1H),8.55(s,1H),8.29–8.09(m,1H), 7.98(s,1H),7.70–7.49(m,2H),4.90 –4.80(m, 2H), 4.10(d, J= 5.7Hz, 2H), 1.76(s, 3H), 1.51(s, 9H). Chemical formula: C 16 h 23 N 7 O, MS: 330(M+H) + .

Embodiment 3

[0080] Example 3 2-((1-(tert-butyl)-1H-pyrazol-4-yl)amino)-4-((3-methylbutyl-2-en-1-yl)amino)pyrimidine- Preparation of 5-formamide:

[0081]

[0082] The operation is the same as in Example 1, and butyl-3-en-1-amine hydrochloride in step 1) is replaced with 3-methylbutyl-2-en-1-amine to obtain a white solid, 1 H NMR (400MHz, DMSO-d 6 )δ10.48 (s,1H),9.94(s,1H),8.51(s,1H),8.36–8.10(m,1H),8.06(s,1H), 7.81–7.40(m,2H),5.41 –5.22(m,1H),4.24–3.92(m,2H),1.71(s,3H),1.67(s,3H),1.50(s,9H).Chemical formula: C 17 h 25 N 7 O, MS: 344 (M+H) + .

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Abstract

The invention relates to a new compound serving as a JAK inhibitor, a composition and an application of the new compound and the composition. Specifically, the invention provides the compound (represented by a formula (1)) with strong JAK inhibitory activity or an isomer, a solvate, a hydrate, a pharmaceutically acceptable salt and a prodrug thereof, and the pharmaceutical composition containing the compound. The invention further discloses the application of the compound or the pharmaceutical composition in preparation of a medicine. The medicine is used for treating autoimmune diseases or cancers.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of alkenyl-containing pyrimidine carboxamide compounds, their isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions thereof, and their Application in the preparation of drugs for treating autoimmune diseases and cancers related to tyrosine kinases JAK1, JAK2, JAK3 and TYK2. Background technique [0002] JAK kinase (Janus kinase) and its downstream effectors, signal transducers and transcriptional activators form an important cytokine signaling pathway - JAK-STAT pathway. Studies have found that the JAK-STAT pathway can be activated by a variety of cytokines, growth factors and receptors, and participate in cell proliferation, differentiation, apoptosis, angiogenesis and immune regulation. JAK kinase is a key kinase in the JAK-STAT signaling pathway. More than 20 years after the enzyme was discovered, the fir...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D405/14A61K31/506A61P35/00A61P35/02A61P27/02A61P17/06A61P17/00A61P17/14A61P19/02A61P1/00A61P9/10A61P37/02A61P1/16
CPCA61P1/00A61P1/16A61P9/10A61P17/00A61P17/06A61P17/14A61P19/02A61P27/02A61P35/00A61P35/02A61P37/02C07D403/12C07D405/14
Inventor 张强刘彦生李兰涛李兴福胡晨明
Owner BEIJING SCITECH MQ PHARMA LTD
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