Selective JAK1 inhibitor compound as well as preparation method and application thereof

A compound, hydrate technology, applied in non-central analgesics, anti-inflammatory agents, digestive system, etc., can solve problems such as unmet clinical needs, adverse reactions, and unsatisfactory treatment effectiveness

Pending Publication Date: 2021-11-12
MINGHUI PHARMA HANGZHOU LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, RA patients still suffer from disease recurrence, unsatisfactory treatment effectiveness, poor long-term tolerance and some adverse reactions.
More importantly, the quality of life of RA patients, includi

Method used

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  • Selective JAK1 inhibitor compound as well as preparation method and application thereof
  • Selective JAK1 inhibitor compound as well as preparation method and application thereof
  • Selective JAK1 inhibitor compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064]

[0065]

[0066] first step

[0067] To a 10 mL methanol solution of 1a (1.00 g, 4.73 mmol) was added 30% methylamine methanol solution (1.00 g, 9.66 mmol), and reacted at room temperature for 3 hours. Sodium borohydride (361 mg, 9.54 mmol) was added in portions, and the resulting reaction solution was reacted at room temperature overnight. After the reaction was completed, quenched with water (20mL), extracted with ethyl acetate (30mL x 2), combined the organic phases, washed successively with water (20mL x 1) and saturated sodium chloride solution (20mL x 1), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was concentrated under reduced pressure to obtain crude product 1b (1.00 g), yield: 93%.

[0068] 1 H NMR (400MHz, CDCl 3 )δ3.91(s,2H),3.83(s,2H),3.10-3.06(m,1H),2.46-2.41(m,2H),2.32(s,3H),1.87-1.82(m,2H) ,1.43(s,9H).

[0069] second step

[0070] 1b (1.00g,...

Embodiment 2

[0089]

[0090]

[0091] first step

[0092] 1 (50 mg, 0.12 mmol) in 5 mL of hydrogen chloride 1,4-dioxane solution (4M) was reacted at 30° C. overnight. The reaction solution was directly purified by preparative HPLC to obtain 2 (12 mg), yield: 23%.

[0093] 1 H NMR (400MHz, DMSO-d 6 )δ11.62(s,1H),8.17-7.98(m,1H),7.91-7.72(m,1H),7.45-7.25(m,1H),7.13(s,1H),6.57(s,1H) ,6.47(s,1H),6.11(s,1H),5.25-4.96(m,1H),4.23-3.75(m,4H),3.20(dd,J=6.9,3.4Hz,3H),2.60-2.51 (m,4H).

[0094] MS-ESI calculated value [M+1] + 451, the measured value is 451.

Embodiment 3

[0096]

[0097] first step

[0098] To a solution of 3a (1.00 g, 4.22 mmol) and potassium carbonate (637 mg, 4.61 mmol) in 10 mL of N,N-dimethylformamide was added iodomethane (659 mg, 4.64 mmol), and the resulting reaction solution was reacted overnight at room temperature. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3b (486 mg), which was directly used in the next reaction.

[0099] 1 H NMR (400MHz, CDCl 3 )δ7.69-7.63(m,1H),7.46-7.41(m,1H),3.99(s,3H).

[0100] second step

[0101] Under nitrogen protection, 3b (386mg, 1.54mmol), ethynyltrimethylsilane (226mg, 2.30mmol), bistriphenylphosphine palladium dichloride (21mg, 0.03mmol) and cuprous iodide (3mg, 0.15 mmol) in 10 mL of triethylamine was reacted overnight at 80°C. After the reaction was completed, cooled, filtered, a...

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PUM

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Abstract

The invention provides a heterocyclic compound serving as a JAK1 inhibitor and a synthesis and use method, and particularly provides a compound shown in a formula (I), a preparation method of the compound and application of the compound serving as the JAK1 inhibitor. The compound disclosed by the invention shows excellent inhibitory activity on JAK1.

Description

technical field [0001] The present invention relates to a class of compounds as selective JAK1 inhibitors, isomers, solvates and salts of the compounds and medicines with the compounds or their salts as active ingredients, and their therapeutic and / or prophylactic Use in drugs for JAK1-related target diseases such as immune system diseases, rheumatoid arthritis, tumors, etc. Background technique [0002] The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years. JAK plays an important role in cytokine signal transduction. The downstream substrates of the JAK kinase family include signal transducers of transcriptional proteins and Activator (STAT). JAK protein is an important member of this pathway, and the abnormal increase of its activity often leads to the occurrence of diseases. Many diseases are related to the abnormal cell response of JAK-STAT signaling pathway. These diseases include autoimmune diseases, inflamm...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02A61P29/00A61P37/00A61P17/00A61P9/10A61P19/02A61P17/06A61P1/00A61P21/04A61P17/14A61P9/00A61P3/00A61P37/06A61P31/12
CPCC07D487/04A61P35/00A61P35/02A61P29/00A61P37/00A61P17/00A61P9/10A61P19/02A61P17/06A61P1/00A61P21/04A61P17/14A61P9/00A61P3/00A61P37/06A61P31/12
Inventor 李傲P·K·贾达夫姚元山曹国庆
Owner MINGHUI PHARMA HANGZHOU LTD
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