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Arylamine compound, pharmaceutical composition containing arylamine compound as well as preparation method and application of arylamine compound

A compound and mixture technology, applied in the field of new arylamine compounds, can solve the problems of inhibitors on the market and achieve good inhibitory effect and good pharmacokinetic effects

Pending Publication Date: 2021-03-30
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no inhibitors with RET as the main target are currently on the market

Method used

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  • Arylamine compound, pharmaceutical composition containing arylamine compound as well as preparation method and application of arylamine compound
  • Arylamine compound, pharmaceutical composition containing arylamine compound as well as preparation method and application of arylamine compound
  • Arylamine compound, pharmaceutical composition containing arylamine compound as well as preparation method and application of arylamine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0263] Example 1: 2-(4-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1] Heptane-3-yl)piperidin-1-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 1)

[0264]

[0265] The first step: 3-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (1b )

[0266] 4-Oxopiperidine-1-carboxylate benzyl ester (353mg, 1.5mmol), 1a (200mg, 1.0mmol) and NaBH 3 CN (317mg, 5.0mmol) was placed in a reaction flask, added to methanol (5mL) and AcOH (0.2mL) in sequence, and stirred at room temperature until the raw material was completely converted. After the reaction was completed, saturated ammonium chloride solution (0.1 mL) was added to the reaction system to quench the reaction, the solvent was concentrated under reduced pressure, and purified by Flash column chromatography (PE:EA=1:1) to obtain compound 1b (289 mg). MS (ESI, m / z): 416.3 [M+H] + .

[0267] The second step: tert-butyl 3-...

Embodiment 2

[0278] Example 2: 2-(4-(6-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-3,6-diazabicyclo [3.1.1] Heptane-3-yl)piperidin-1-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 2 )

[0279]

[0280] Compound 1f (30mg, 81μmol), 2a (25mg, 122μmol) and Ti(O i Pr) 4 (92mg, 326μmol) was placed in a reaction flask, THF (2mL) was added, heated to 75°C for 16h under nitrogen protection, and then NaBH(OAc) was added 3 (86mg, 407μmol), the reaction was continued at 75°C until the starting material was completely converted. After the reaction was completed, the reactant was cooled to room temperature, and saturated ammonium chloride solution (0.1 mL) was added to quench the reaction, the reaction solution was concentrated, and the residue was purified by Prep-TLC (DCM:MeOH=10:1) and Prep-HPLC successively. Compound 2 (3 mg) was isolated.

[0281] MS (ESI, m / z): 557.9 [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d 6 )δ11.85(s, 1H), 9.20(s, 1H), 8.65(d, J=4.5Hz,...

Embodiment 3

[0283] Example 3: 6-methyl-2-(4-(6-((6-(5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6- Diazabicyclo[3.1.1]heptane-3-yl)piperidin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 3)

[0284]

[0285] Compound 1f (20mg, 54μmol), 3a (12mg, 65μmol) and Ti(O i pr) 4 (62mg, 217μmol) was placed in a reaction flask, THF (3mL) was added, heated to 75°C under nitrogen protection and stirred for 8h, then NaBH(OAc) was added 3 (58 mg, 271 μmol), the reaction was continued at 75°C until all the starting materials were converted. After the reaction, the reactant was cooled to room temperature, and saturated ammonium chloride solution (0.1 mL) was added to quench the reaction, the reaction solution was concentrated, and the residue was purified by Prep-TLC (DCM:MeOH=10:1) and Prep-HPLC successively. Compound 3 (2 mg) was isolated.

[0286] MS m / z(ESI): 539.9[M+H] + .

[0287] 1 H NMR (400MHz, DMSO-d 6 )δ11.85(s, 1H), 9.18(s, 1H), 8.45(d, J=2.4Hz, 1H), 8.35(d, J=1....

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PUM

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Abstract

The present invention relates to an arylamine compound of a formula (I), a pharmaceutical composition comprising the same, a preparation method of the arylamine compound and application of the pharmaceutical composition in the prevention or treatment of diseases or conditions associated with RET activity.

Description

technical field [0001] The present invention relates to a novel arylamine compound, a pharmaceutical composition containing it, a preparation method thereof and its use for preventing or treating diseases or conditions related to RET (Rearranged during transfection) activity. Background technique [0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins. By mediating the process of cell signal transduction, protein phosphorylation regulates the physiological activities of cells, such as cell survival, proliferation, differentiation, apoptosis and metabolism. Dysregulation of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes. [0003] RET is a proto-oncogene, and the RET protein encoded by it is a transmembrane receptor-type tyrosine protein kinase composed of a cysteine-rich cadherin-like extracellular d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08A61K31/506A61P35/00
CPCC07D471/08A61P35/00
Inventor 陈忠辉韩润丰韩晓军冉茂盛梅红江田强宋宏梅薛彤彤王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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