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A kind of substituted pyridine amide compound and application thereof

A compound and composition technology, applied in the field of medicine, can solve problems such as inability to reduce pain

Active Publication Date: 2021-04-30
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although nutraceuticals such as chondroitin and glucosamine sulfate are proven safe and effective options for the treatment of osteoarthritis, recent clinical trials have shown that these two treatments do not reduce pain associated with osteoarthritis

Method used

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  • A kind of substituted pyridine amide compound and application thereof
  • A kind of substituted pyridine amide compound and application thereof
  • A kind of substituted pyridine amide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1 N-(5-(4-((1,1-dioxo-4-thiomorpholine-2,2,6,6-d4)methyl)phenyl)-[1,2, 4] Triazolo[1,5-a]pyridin-2-yl)cyclopropanylcarboxamide (compound 13)

[0160]

[0161] Step 1: Synthesis of 1-(6-bromopyridin-2-yl)-3-ethoxycarbonyl-thiourea (compound 3).

[0162] At 5°C, ethoxycarbonyl isothiocyanate (6.80 mL, 57.8 mmol) was slowly added dropwise to 2-amino-6-bromopyridine (10.0 g, 57.8 mmol) in dichloromethane (100 mL) within 15 minutes. ) solution, after the dropwise addition, the reaction solution was warmed up to room temperature, and stirred overnight. The solvent was removed under reduced pressure, the solid was filtered, washed with petroleum ether, and dried in vacuo to obtain 16.9 g of yellow solid, yield: 96.1%.

[0163] Step 2: Synthesis of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Compound 4).

[0164] DIPEA (27.0mL, 165.6mmol) was added dropwise to a solution of hydroxylamine hydrochloride (19.2g, 276.0mmol) in ethanol / methanol (v:v=1:1, 170mL) a...

Embodiment 2

[0177] Example 2 N-(5-(4-((1,1-dioxo-4-thiomorpholinyl)methyl-d)phenyl-[1,2,4]triazolo [1,5-a]pyridin-2-yl)cyclopropanyl formamide (compound 18)

[0178]

[0179] Step 1: N-(5-(4-formylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanylcarboxamide (compound 15) synthesis.

[0180] N 2 Under protection, 1,4-dioxane (12mL) and water (4mL) were injected into N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2- base) cyclopropanyl formamide (560mg, 2.00mmol), (4-formylphenyl) boronic acid (360mg, 2.40mmol), Pd(dppf)Cl 2 (70mg, 0.10mmol), potassium carbonate (850mg, 6.00mmol) mixture, the reaction was carried out at 90°C overnight (16h). Cool to the greenhouse, filter with diatoms, wash the filter cake with dichloromethane, dry the filtrate with anhydrous sodium sulfate, remove the solvent, and carry out column separation of the concentrated solution (eluent: dichloromethane / methanol (v / v)=25: 1), to obtain 450 mg beige solid, yield: 73.5%. LC-MS(APCI):m / z=307.1(M+H) + . ...

Embodiment 3

[0187] Example 3 N-(5-(4-((1,1-dioxo-4-thiomorpholine)methyl-d2)phenyl)-[1,2,4]triazolo [1,5-a]pyridin-2-yl)cyclopropanylformamide (Compound 24)

[0188]

[0189] Step 1: Synthesis of 4-carboxymethyl phenylboronic acid (compound 20).

[0190] Concentrated sulfuric acid (0.5 mL) was added dropwise to 4-carboxyphenylboronic acid (3.50 g, 21.09 mmol) in anhydrous methanol (50 mL), and the mixture was refluxed overnight under nitrogen protection. The reaction solution was concentrated under reduced pressure, 50 mL of water was added, extracted with ethyl acetate (50x 3), the organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid 4.1 g, yield: 100%. LC-MS(APCI):m / z=181.1(M+H) + ; 1 H NMR (300MHz, DMSO-d 6 ): δ7.89(s,4H),7.52(s,4H),3.83(s,3H).

[0191] Step 2: Synthesis of methyl 4-(2-(cyclopropanylcarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzoate...

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Abstract

A substituted pyridine amide compound and its application. Specifically disclosed are deuterated pyridine amide compounds represented by formula (I) and compounds containing the compound, or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvate pharmaceutical composition. The compound can be used as a JAK inhibitor, and is further applicable to the preparation of medicines for treating JAK-related diseases (such as autoimmune diseases, etc.).

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to a deuterated pyridine amide compound and its use, more specifically, to a pyridine amide compound and its use as a JAK inhibitor, or for treating and preventing diseases related to JAK enzymes. Background technique [0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Four JAK family members have been described in the prior art: JAK1, JAK2, JAK3 and TYK2. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, and subsequently STATs are phosphorylated and then migrate into the nucleus to regulate transcription. JAK-STAT intracellular signaling works with interferons, most interleukins, and a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL. [0003] Cartila...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D487/04A61K31/437A61P19/02
CPCC07D487/04A61K31/437C07D471/04
Inventor 王义汉任兴业
Owner SHENZHEN TARGETRX INC
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