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Polycyclic derivative inhibitor as well as preparation method and application thereof

A technology of heterocyclic group and cycloalkyl group is applied in the field of polycyclic derivative inhibitors and their preparation, which can solve the problem of low selectivity and the like

Active Publication Date: 2020-08-04
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no TYK2 selective inhibitor on the market. Early JAK inhibitors mainly compete for the combination of the kinase domain and ATP, so the general problem of low selectivity

Method used

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  • Polycyclic derivative inhibitor as well as preparation method and application thereof
  • Polycyclic derivative inhibitor as well as preparation method and application thereof
  • Polycyclic derivative inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] 6-(cyclopropylcarboxamide)-4-((4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino) -N-(methyl-d 3 ) Preparation of pyridazine-3-carboxamide

[0189]

[0190] Step 1: Preparation of 4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

[0191]

[0192] 5-Bromo-4-methoxypyridin-3-amine (2.02g, 10mmol), bis-pinacolyldiborane (3.05g, 12mmol), [1,1'-bis(diphenylphosphine) Ferrocene] palladium dichloride dichloromethane complex (816.6mg, 1mmol), potassium acetate (2.45g, 25mmol), mixed in dioxane (20mL), the reaction system nitrogen replacement three times, 100 ° C reaction overnight, cooled to room temperature, concentrated the reaction solution under reduced pressure, and the residue was water and CH 2 Cl 2 Separation, the organic phase was separated and washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and then column chromatographed to obta...

Embodiment 2

[0215] 6-(cyclopropylcarboxamide)-4-((3-methoxy-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-4-yl)amino) -N-(methyl-d 3 ) Preparation of pyridazine-3-carboxamide

[0216]

[0217] 6-(cyclopropylcarboxamide)-4-((3-methoxy-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-4-yl)amino) -N-(methyl-d 3 ) The preparation of pyridazine-3-carboxamide refers to Example 1.

[0218] MS m / z(ESI):427.2[M+H] + .

Embodiment 3

[0220] 6-(cyclopropylcarboxamide)-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino) -N-(methyl-d 3 ) Preparation of pyridazine-3-carboxamide

[0221]

[0222] 6-(cyclopropylcarboxamide)-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino) -N-(methyl-d 3 ) The preparation of pyridazine-3-carboxamide refers to Example 1.

[0223] MS m / z(ESI):427.2[M+H] + .

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PUM

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Abstract

The invention relates to a polycyclic derivative inhibitor as well as a preparation method and application thereof. Particularly, the invention relates to a compound represented by a general formula,the preparation method of the compound, a pharmaceutical composition containing the compound and the application of the compound as an intracellular non-receptor tyrosine kinase to mediation of signaltransduction and activation of various cell factors. The compound plays a key role in the biological process of participating in immunoregulation, immune cell proliferation and the like, is closely related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and the like, and has the same substituent groups in the following general formula (I) as defined in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a polycyclic derivative inhibitor and its preparation method and application. Background technique [0002] Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3, and TYK2, each of which mediates different types of cytokine signaling pathways, and JAK-1, JAK-2, and TYK-2 are found in various human tissue cells Expression, JAK-3 is mainly expressed in various hematopoietic tissue cells. The common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and the receptor is phosphorylated, and the phosphorylated t...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D409/14C07D417/14C07D403/12C07D403/14C07D471/04C07D498/04C07D487/04C07D487/08C07D471/08C07D473/16C07D405/14A61P29/00A61P19/02A61P17/00A61P17/06A61P1/04A61P37/06A61K31/501A61K31/437A61K31/5365A61K31/4375A61K31/5025A61K31/519A61K31/52
CPCC07D401/14C07D409/14C07D417/14C07D403/12C07D403/14C07D471/04C07D498/04C07D487/04C07D487/08C07D471/08C07D473/16C07D405/14A61P29/00A61P19/02A61P17/00A61P17/06A61P1/04A61P37/06Y02P20/55
Inventor 高鹏曾蜜王少宝修文华
Owner SHANGHAI HANSOH BIOMEDICAL
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