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5-aminopyrazole formamide derivative as BTK inhibitor, preparation method and pharmaceutical composition thereof

A technology of aminopyrazolecarboxamide and compound is applied in the fields of 5-aminopyrazolecarboxamide derivative derivatives, preparation methods and pharmaceutical compositions thereof, and can solve the problems of increased burden on patients, influence on drug efficacy and the like

Active Publication Date: 2017-11-24
SUZHOU SINOVENT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the administration process, ibrutinib is easily metabolized (oxidatively metabolized into dihydroxylated products by metabolic enzymes or inactivated by other sulfhydryl-containing enzymes, cysteine, glutathione, etc.) Affect the efficacy
Its clinical dosage has reached 560mg per day, which makes the patient's burden aggravated
In addition, ibrutinib also has a certain inhibitory effect on some kinases other than BTK, especially the inhibition of EGFR can lead to severe rash, diarrhea and other adverse reactions

Method used

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  • 5-aminopyrazole formamide derivative as BTK inhibitor, preparation method and pharmaceutical composition thereof
  • 5-aminopyrazole formamide derivative as BTK inhibitor, preparation method and pharmaceutical composition thereof
  • 5-aminopyrazole formamide derivative as BTK inhibitor, preparation method and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(1-cyano-6-methylpiperidin-3-yl)-1H-pyridine Preparation of azole-4-carboxamide (WS-400)

[0115]

[0116] The preparation of the first step 6-methylpiperidin-3-ol

[0117] 5-Hydroxy-2-methylpyridine (1 g, 9 mmol) was dissolved in acetic acid (20 mL), then platinum dioxide (0.25 g) was added. The reaction mixture was shaken overnight under a hydrogen atmosphere at a pressure of 50 psi. The solution was filtered off and spun dry to give crude 6-methylpiperidin-3-ol.

[0118] The preparation of second step 5-hydroxyl-2-methylpiperidine-1-carboxylic acid benzyl ester

[0119] 6-Methylpiperidin-3-ol was dissolved in dichloromethane (100 mL), then triethylamine (7.5 eq) was added dropwise, followed by benzyloxycarbonyl chloride (2 g, 11.2 mmol). The reaction was complete after stirring for 16 hours. After the reaction solution was spin-dried, the residue was purified by silica gel column to obtain the desired product ...

Embodiment 2

[0152] 5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-((3R,6S)-1-cyano-6-methylpiperidine-3- base)-1H-pyrazole-4-carboxamide (WS-401) preparation

[0153]

[0154] The product of the reaction in the fourteenth step of Example 1 can be obtained by chiral resolution to obtain the compound of Example 2. The resolution conditions are: Supercritical fluid chromatography (ChiralPak AD 5μ, 21x 250 mm col, 27% methanol, 70mL / min). MS: m / z 452.2[M+1]

Embodiment 3

[0156]5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-((3S,6R)-1-cyano-6-methylpiperidine-3- base)-1H-pyrazole-4-carboxamide (WS-402) preparation

[0157]

[0158] The product of the fourteenth step reaction in Example 1 can obtain the compound of Example 3 after chiral resolution. The resolution conditions are: Supercritical fluid chromatography (ChiralPak AD 5μ, 21x 250 mm col, 27% methanol, 70mL / min). MS: m / z 452.2[M+1]

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Abstract

The present invention discloses a novel 5-aminopyrazole formamide compound represented by a formula (I), and a stereoisomer, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof, wherein each substituent is defined in the specification. The invention further discloses a preparation method, a pharmaceutical composition and uses of the compound. The formula (I) is defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a novel 5-aminopyrazole carboxamide derivative derivative with high efficiency, good selectivity and good pharmacokinetic properties as a BTK inhibitor and Its preparation method and pharmaceutical composition. Background technique [0002] Protein kinases are the largest family of biological enzymes in the human body, including more than 500 proteins. In particular, for tyrosine kinases, the phenolic functional groups on their tyrosine residues can be phosphorylated, thereby playing an important role in biological signal transduction. The tyrosine kinase family has members that control cell growth, migration and differentiation. Abnormal kinase activity has been elucidated to be closely related to many human diseases, including cancer, autoimmune diseases and inflammatory diseases. [0003] Bruton's tyrosine kinase (BTK) is a cytoplasmic non-receptor ty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/04C07D403/04C07D413/14A61K31/438A61K31/454A61K31/4439A61K31/496A61K31/497A61K31/4545A61K31/5377A61K31/415A61K31/444A61P37/02A61P29/00A61P7/02A61P35/00A61P35/02A61P19/02A61P11/00A61P17/06A61P17/00A61P1/00A61P1/04A61P37/06A61P37/08A61P27/14A61P11/02
CPCC07D401/04C07D401/14C07D403/04C07D413/14A61K31/4439A61K31/444A61K31/454A61K31/4545A61K31/496A61K31/497A61K31/5377C07D403/14A61P35/00Y02P20/55
Inventor 吴予川
Owner SUZHOU SINOVENT PHARMA CO LTD
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