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Aminopyrimidines for inhibiting protein tyrosine kinase activity

A compound and valence technology, applied in the field of medicine, can solve problems such as limiting clinical application

Active Publication Date: 2022-01-04
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these inhibitors effectively inhibit the T790M mutation, they also inhibit the wild-type EGFR (WT EGFR) at the same time, resulting in serious side effects, which limit the clinical application
[0008] The third-generation and subsequent EGFR inhibitors include compounds such as AZD9291 and CO-1686, which irreversibly inhibit EGFR and still have a high effective rate for patients with T790M drug-resistant mutations, but they also have inhibitory effects on wild-type EGFR

Method used

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  • Aminopyrimidines for inhibiting protein tyrosine kinase activity
  • Aminopyrimidines for inhibiting protein tyrosine kinase activity
  • Aminopyrimidines for inhibiting protein tyrosine kinase activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] N-(3-((2-((4-(1-acetylpiperidin-4-yl)oxy)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrim Pyridine-4-yl)amino)phenyl)acrylamide

[0199]

[0200] step 1:

[0201]

[0202] tert-butyl 4-hydroxypiperidine-1-carboxylate (4.70g, 23.3mmol), 4-fluoro-2-methoxynitrobenzene (2g, 11.6mmol), tetrabutylammonium bromide (0.754g, 2.34 mmol) and aqueous potassium hydroxide solution were stirred overnight at 60°C in toluene. The reaction mixture was brought to room temperature, diluted with water and extracted with ethyl acetate. The collected organic phase was dried and purified by column chromatography to obtain yellow oily product tert-butyl 4-(3-methoxy-4-nitrophenoxy)piperidine-1-carboxylate (3.73 g, 91% yield) . 1 H NMR (300MHz, CDCl 3 )(δ / ppm): 8.01(d, J=9.6Hz, 1H), 6.56-6.49(m, 2H), 4.61-4.57(m, 1H), 3.96(s, 3H), 3.75-3.67(m, 2H), 3.44-3.36 (m, 2H), 2.01-1.94 (m, 2H), 1.84-1.76 (m, 2H), 1.45 (s, 9H). LC-MS(APCI): m / z=353.2(M+1) + , Purity: 97.6%.

[0203] Step...

Embodiment 2

[0222] N-(3-((2-((4-(1-acetylpiperidin-4-yl)amino)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrim Pyridine-4-yl)amino)phenyl)acrylamide

[0223]

[0224] step 1:

[0225]

[0226] The synthesis procedure was the same as step 1 of Example 1 to obtain the product tert-butyl 4-(3-methoxy-4-nitrophenylamino)piperidine-1-carboxylate (0.96 g, yield: 93.6%). LC-MS(APCI): m / z=352(M+1) + , Purity: 95.1%.

[0227] Step 2:

[0228]

[0229] The synthesis steps were the same as in Example 1, step 2, to obtain dark blue oily product 4-(4-amino-3-methoxyphenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.19g, yield: 91%) , used directly in the next step.

[0230] Step 3:

[0231]

[0232] The synthesis procedure is the same as that of Example 1 step 3, and the white solid product 4-((4-((4-(3-acrylamide phenylamino)-5-trifluoromethylpyrimidin-2-yl)amino-3-methyl Oxyphenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (89 mg, yield: 54.6%).

[0233] Ste...

Embodiment 3

[0240] N-(3-((2-((4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)amino)-5- (Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide

[0241]

[0242] step 1:

[0243]

[0244] PdCl 2 (dppf) 2 (422mg, 0.052mmol) was added to 4-bromo-2-methoxynitrobenzene (2.0g, 8.62mmol), 4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1,2,5,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and K 2 CO 3 (3.57g, 19.38mmol) in 1,4-dioxane (40mL), heated to 90°C under nitrogen atmosphere and stirred for 14h. Poured into water (150mL), extracted with dichloromethane (50mL x 3), spin-dried, and passed through the column to obtain the yellow solid product 4-(3-methoxy-4-nitrophenyl)-1,2,5,6 - tert-butyl tetrahydropyridine-1-carboxylate (1.6 g, yield: 56%). 1 HNMR (300MHz, CDCl 3 )(δ / ppm): 7.87(d, J=9Hz, 1H), 7.03-7.00(m, 2H), 6.19(s, 1H), 4.13(t, J=3Hz, 2H), 3.99(s, 3H ), 3.67(t, J=6Hz, 2H), 1.53(s, 9H). LC-MS(APCI): m / z=335.2(M+1) + , Purity: 94.6%.

[0245] S...

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Abstract

The present invention relates to aminopyrimidine compounds with inhibitory effect on protein tyrosine kinase activity, as well as their preparation and application. Specifically, the invention discloses an aminopyrimidine compound represented by formula (I) and the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotope Variant pharmaceutical compositions. The compounds of the present invention can be used to treat and / or prevent protein tyrosine kinase related diseases, such as cell proliferative diseases, cancer, immune diseases.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to aminopyrimidine compounds with inhibitory effect on protein tyrosine kinase activity, pharmaceutical compositions containing them, as well as their preparation methods and uses. More specifically, the present invention relates to aminopyrimidine compounds for the treatment of diseases (such as tumors and related diseases) related to disorders of metabolic pathways of protein tyrosine kinases (such as but not limited to EGFR (including HER), ALK, PDGFR), and Its pharmaceutical composition and method of use. Background technique [0002] Protein tyrosine kinase (PTK) is a kind of kinase that catalyzes the transfer of γ-phosphate on ATP to protein tyrosine residues, and can catalyze the phosphorylation of tyrosine residues of various substrate proteins. It plays an important role in cell growth, proliferation and differentiation. Because protein tyrosine kina...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D239/48A61K31/506A61K31/5377A61P35/00A61P35/02
CPCA61K31/506A61K31/5377C07D401/12C07D239/48
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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