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Boronyl-substituted aniline protein kinase inhibitors

A protein kinase inhibitor, aniline technology, applied in the fields of boron-substituted aniline protein kinase inhibitors, compounds that regulate the activity of anaplastic lymphoma kinase, pharmaceutical use of diseases, and compounds for treating or preventing diseases related to protein kinases , can solve the problems such as the incidence of gastrointestinal adverse reactions and the prolongation of QT interval

Active Publication Date: 2020-12-29
HANGZHOU LEISUO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the remarkable efficacy of the drug, due to the characteristics of tumor heterogeneity and the adaptation of tumor cells to environmental pressure, more and more research reports have shown that tumor drug resistance and continued disease progression are almost the inevitable fate of such patients; in addition, now There are serious adverse reactions of drugs, such as high incidence of gastrointestinal adverse reactions, liver toxicity and QT interval prolongation, which also limit the application of this type of drugs

Method used

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  • Boronyl-substituted aniline protein kinase inhibitors
  • Boronyl-substituted aniline protein kinase inhibitors
  • Boronyl-substituted aniline protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1 7-((5-chloro-2-((2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl)amine)4-pyrimidinyl)amine)benzo Preparation of [c][1,2]oxo-1(3H)boronic acid [No. REX-C1]

[0092] The synthetic route is as follows:

[0093]

[0094] Synthetic Scheme 1: Synthesis of intermediate 7-((2,5-dichloropyrimidinyl)amino)benzo[c][1,2]oxo1(3H)boronic acid (i.e. compound 1-5)

[0095] Step 1: Preparation of 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl)benzylacetic acid (ie compound 1-2)

[0096] Dissolve the raw material 2-bromo-3-nitrobenzylacetic acid (compound 1-1, 11.3g, 40.0mmol) in 1,4-dioxane (150.0mL), slowly add potassium acetate (13.7g, 140.0mmol ), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (2.6g, 3.0mmol), bis(pinacolate) diboron (15.2g, 60.0mmol), nitrogen replacement, keep the temperature at React at 90-95°C for 16 hours; after the reaction, pour it into 500.0 mL of water, extract with ethyl acetate, dry, concentrate, and separate by silica gel column ...

Embodiment 2

[0124] Example 2 4-((5-chloro-2-((2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl)amine)4-pyrimidinyl)amine)benzo Preparation of [c][1,2]oxo-1(3H)boronic acid [No. REX-C2]

[0125] The synthetic route is as follows:

[0126]

[0127] As described in the synthetic route provided in this example, in Synthesis Scheme 1 "Synthesis of Compound 1-5", the raw material 2-bromo-6-nitrobenzylacetic acid in step 1 replaces the 2-bromo-3-nitrobenzylacetic acid in Example 1 Nitrobenzylacetic acid was reacted, and the rest of the synthesis method was the same as the synthesis scheme 1 of Example 1. Compound 1-5 was obtained after multi-step reaction, and the yield was 28.0%.

[0128] MS m / z [ESI]: 296.4 [M+1].

[0129] In Synthesis Scheme 2 "Synthesis of Compound 2-4", the raw material 2-chloro-4-fluoro-5-nitrotoluene (i.e. Compound 2-1), and the rest of the synthesis methods are the same as in Synthesis Scheme 2 of Example 1, namely Compound 2-4 was obtained with a yield of 62.8%.

[...

Embodiment 3

[0133] Example 3 7-((5-trifluoromethoxy-2-((2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl)amine)4-pyrimidinyl) Preparation of amine) benzo [c] [1,2] oxo 1 (3H) boronic acid [No. REX-C3]

[0134] The synthetic route is as follows:

[0135]

[0136] As described in the synthetic route provided in this example, in Synthesis Scheme 1 "Synthesis of Compound 1-5", the raw material 2,4-dichloro-5-trifluoromethylpyrimidine in Step 4 replaces 2,4 in Example 1 , 6-trichloropyrimidine was reacted, and the rest of the synthesis method was the same as the synthesis scheme 1 of Example 1. After the multi-step reaction, compound 1-5 was obtained, and the yield was 31.0%.

[0137] MS m / z [ESI]: 296.4 [M+1].

[0138] In Synthesis Scheme 2 "Synthesis of Compound 2-4", the raw material 2-chloro-4-fluoro-5-nitrotoluene (i.e. Compound 2-1), and the rest of the synthesis methods are the same as in Synthesis Scheme 2 of Example 1, namely Compound 2-4 was obtained with a yield of 62.8%.

[013...

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Abstract

The present invention discloses a compound capable of regulating protein kinase activity and used for treating or preventing protein kinase-related diseases, particularly relates to a boryl-substituted aniline-based protein kinase inhibitor, belongs to the compound capable of regulating the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of the compounds, and pharmaceutical uses of the compounds in treatment or prevention of ALK-related diseases.

Description

technical field [0001] The present invention relates to compounds that regulate the activity of protein kinases and are used for treating or preventing diseases related to protein kinases. Specifically, the present invention relates to a boron-substituted aniline protein kinase inhibitor, which belongs to the compound that regulates the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of this type of compound, and the use of this type of compound for A pharmaceutical use for treating or preventing a disease associated with ALK. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. It is characterized by abnormal proliferation of cells or mutant cells. The proliferation, apoptosis, and metastasis of tumor cells are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cells. In these signaling pathways, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00
Inventor 王永辉高羽军周娟朱研刘万登王栋沈锡明吴耀东李春启
Owner HANGZHOU LEISUO PHARMA
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