Inhibitors with ALK and EGFR dual activity, and preparation method and application thereof

A phenyl, amino technology, applied in the field of drug synthesis, can solve the problems of limited dosage, poor selectivity, tumor recurrence, etc.

Inactive Publication Date: 2016-12-07
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drug resistance of half of the patients is due to the secondary mutation of the EGFR gatekeeper gene residue T790M, which reduces the affinity of the drug and the target and produces drug resistance, resulting in tumor recurrence or disease progression
[0006] In view of the importance and prevalence of this mutation in drug resistance in lung cancer EGFR-targeted therapy, several drug R&D companies (Pfizer, BI, AZ, etc.) are trying to develop second-generation small molecule EGFR inhibitors, by inhibiting EGFR

Method used

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  • Inhibitors with ALK and EGFR dual activity, and preparation method and application thereof
  • Inhibitors with ALK and EGFR dual activity, and preparation method and application thereof
  • Inhibitors with ALK and EGFR dual activity, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: N-(5-((4-((5-chloro-2-(isopropylsulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino) - Preparation of 2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0070]

[0071] The first step: the preparation of 4-chloro-2-(isopropylthio)aniline

[0072]

[0073] Put 5-chloro-2-aminothiophenol (500mg, 3.13mmol), potassium carbonate (973mg, 7.04mmol) in a 50mL round bottom bottle, add 15ml DMF, add isopropyl bromide (0.5mL) under stirring , the mixture was stirred overnight at room temperature, 50 ml of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain a light yellow oily viscous liquid (0.520 g).

[0074] The second step: the preparation of 4-chloro-2-(isopropylsulfonyl)aniline

[0075]

[0076] 4-Chloro-2-(isopropylthio)aniline (520mg, 3.33mmol) and m-chloroperoxybenzoic acid ...

Embodiment 2

[0099] Example 2: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(isopropylsulfonyl)-5-(tri Preparation of fluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0100]

[0101] The first step: preparation of isopropyl (2-nitro-4-(trifluoromethyl)phenyl)sulfane

[0102]

[0103] Take a 100mL single-necked bottle, add 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1g) and 15mL DMF, add potassium carbonate (3.3g) and isopropylthiol (0.72g) to the above solution respectively , stirred at 50°C for 3 hours, cooled to 0°C, added 2ml of NaOH (1M) aqueous solution, extracted with ethyl acetate, dried, and concentrated to give a white solid (2.5g).

[0104] 1 H NMR (400MHz, CDCl3) δ8.44(s, 1H), 7.76(d, J=8.5Hz, 1H), 7.76(d, J=8.5Hz, 1H), 7.58(d, J=8.5Hz, 1H ),7.58(d,J=8.5Hz,1H),3.62(dt,J=13.3,6.7Hz,1H),3.62(dt,J=13.3,6.7Hz,1H),1.44(d,J=6.7Hz ,6H).

[0105] The second step: the preparation of 1-(isopropylsulfonyl)-2-nitro-4-(tri...

Embodiment 3

[0128] Example 3: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(isopropylsulfonyl)-5-methyl Preparation of phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0129]

[0130] The first step: the preparation of 1-(isopropylsulfonyl)-4-methyl-2-nitrobenzene

[0131]

[0132] 2-Fluoro-5-methylnitrobenzene (3.0 g, 19.355 mmol) was dissolved in DMF (50 mL), and isopropylthiol (2.95 g, 38.71 mmol) and potassium carbonate (8.01 g, 58.065 mmol) were added. The reaction was stirred at 60°C for 2 hours, and LCMS showed that the reaction was complete. The reaction solution was dissolved in dichloromethane, washed with water and saturated sodium chloride, the organic phase was dried and filtered, concentrated, the residue was dissolved in DCM (100 mL), and m-chloroperoxybenzoic acid (8.35 g, 48.387 mmol) was added in portions. Stir for 16 hours, LCMS shows that the reaction is complete, the reaction solution is quenched with saturated sodi...

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Abstract

The invention discloses inhibitors with ALK and EGFR dual activity, and a preparation method and an application thereof, and relates to N-(3-((4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2-yl)amino)phenyl)acryloylamide analogs represented by formula (I), and stereoisomers or pharmaceutically acceptable salts thereof. The series of compounds have epidermal growth factor receptor (EGFR) L858R EGFR mutant, T790MEGFR mutant and exon 19 deleted active mutant inhibition activity, and also have ALK inhibition activity, so the series of compounds can be used to treat EGFR mutant and ALK activity individually or partially mediated diseases, can be widely applied to medicines for preventing and treating cancers and especially non-small cell lung cancers, and is hopeful to be developed into new generation EGFR or/and ALK inhibitors.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to an inhibitor with dual activities of ALK and EGFR, its preparation method and application. Background technique [0002] EGFR (Epidermal Growth Factor Receptor) is a member of the transmembrane protein tyrosine kinase erbB receptor family. EGFR can form homodimers on the cell membrane by binding to its ligands, such as epidermal growth factor (EGF), or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4) . The formation of these dimers can cause phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in cells. These intracellular signaling pathways play important roles in cell proliferation, survival and anti-apoptosis. Dysregulation of EGFR signaling pathway, including increased expression of ligands and receptors, EGFR gene amplification and mutation, can promote malignant tran...

Claims

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Application Information

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IPC IPC(8): C07D239/48A61K31/505A61K31/506A61P35/00A61P35/02
CPCC07D239/48
Inventor 仝朝龙崔媛媛危明松包如迪喻红平徐耀昌
Owner SHANGHAI HANSOH BIOMEDICAL
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