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[1,2,4]triazol[1,5-a]pyridine compound as well as preparation method and medical application thereof

A technology of compounds and mixtures, applied in the field of medicine

Active Publication Date: 2018-03-06
NAT INST OF PHARMA R & D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a series of JAK inhibitors have been disclosed, there is still a need to develop compounds with better selectivity and efficacy

Method used

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  • [1,2,4]triazol[1,5-a]pyridine compound as well as preparation method and medical application thereof
  • [1,2,4]triazol[1,5-a]pyridine compound as well as preparation method and medical application thereof
  • [1,2,4]triazol[1,5-a]pyridine compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Example 1: N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine Preparation of -2-yl)-2-oxopyrrolidine-3-carboxamide

[0218]

[0219]

[0220] Step 1: 4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl)thiomorpholine 1,1- Synthesis of Dioxide (Intermediate 1A)

[0221] 4-Bromomethylphenylboronic acid pinacol ester (50.00g, 16.84mmol), 1,1-dioxide thiomorpholine (27.36g, 20.24mmol), potassium carbonate (27.92g, 20.20mmol) were added to 250 mL of N,N-dimethylformamide was added to the reaction flask, and the reaction was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction solution was poured into 1250 mL of ice water, stirred for 30 minutes, and suction filtered to obtain the title product, 47.2 g of white solid, with a yield of 79.7%.

[0222] Step 2: 4-(4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine 1,1-dioxide Synthesis of (Intermediate 1B)

[0223] Add 5-bromo-[1,2,4]triazolo[1...

Embodiment 2

[0228]Example 2: N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine Preparation of -2-yl)pyrrolidine-2-carboxamide

[0229]

[0230] The same preparation method as in Example 1, except that prolyl chloride (using Boc-L-proline as raw material, reference Tetrahedron, 65 (25), 4841-4845; 2009 preparation) replaces 2-oxo-pyrrolidine -3-Formyl chloride to give the title compound.

[0231] ESI-MS[M+H](m / z):455.1.

[0232] 1 H NMR (300MHz, DMSO): δ10.38(s,1H),7.99(m,2H),7.90(m,1H),7.73(m,2H),7.53(m,2H),7.35(m,1H ),3.89(m,1H),3.73(s,2H),3.40(m,2H),3.13(m,4H),2.94(m,4H),1.74(m,4H).

Embodiment 3

[0233] Example 3: N-(5-(4-((1,1-dioxothiomorpholine)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine Preparation of -2-yl)-1-methylazetidine-3-carboxamide

[0234]

[0235] The preparation method is the same as in Example 1, except that 2-oxo-pyrrolidine- 3-Formyl chloride to give the title compound.

[0236] ESI-MS[M+H](m / z):455.1.

[0237] 1 H NMR(300MHz,DMSO):δ10.45(s,1H),8.01(m,2H),7.88(m,1H),7.72(m,2H),7.49(m,2H),7.36(m,1H ),3.73(s,2H),3.31-3.72(m,4H),3.39(m,1H),3.15(m,4H),2.95(m,4H),2.33(s,3H).

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Abstract

The invention relates to a [1,2,4]triazol[1,5-a] pyridine compound as well as a preparation method and medical application thereof. Particularly, the invention relates to the compound shown in a general formula I, the preparation method of the compound, a medicinal composition containing the compound and application of the compound as a Janus kinase inhibitor. The compound and the medicinal composition containing the compound can be used for treating diseases related to the activity of Janus kinase, such as inflammation, autoimmune disease and cancer. The definitions of all substituent groupsin the general formula I are identical with those of the description. (The general formula is shown in the description).

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a new [1,2,4]triazolo[1,5-a]pyridine compound, its preparation method and a pharmaceutical composition containing it, and its use for regulating Janus kinase (JAK) activity and use for the treatment and / or prevention of diseases associated with JAK activity. Background technique [0002] The intracellular signal transmission process is an effective way for cells to respond to external stimuli and ultimately trigger specific biological effects. Cytokines can conduct intracellular signal transmission through a variety of signal transduction pathways, and thus participate in the regulation of many important biological functions related to hematopoietic function and immunity. The Janus kinase (JAK) family of protein tyrosine kinases and the activator of transcription (STAT) play an important role in the process of cytokine signal transduction. [0003] The Janus kinase ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00C07D495/10C07D487/04C07D487/10A61K31/541A61K31/437A61K31/635A61K31/5377A61K31/4545A61K31/496A61P35/00A61P29/00A61P37/06A61P17/06A61P25/00A61P1/04A61P35/02A61P19/02
CPCC07D471/04C07D487/04C07D487/10C07D495/10C07D519/00
Inventor 殷惠军闫旭宗利斌董流欣韩亚超郗青川窦浩帅杨琰
Owner NAT INST OF PHARMA R & D CO LTD
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