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4-Saturated cyclosubstituted aniline protein kinase inhibitor

A protein kinase inhibitor, aniline technology, applied to 4-saturated ring-substituted aniline protein kinase inhibitors, pharmaceutical use of diseases, compounds that regulate anaplastic lymphoma kinase activity, treatment or prevention of protein kinase-related diseases In the field of compounds, it can solve problems such as the incidence of adverse reactions in the digestive tract and the prolongation of QT interval

Active Publication Date: 2017-01-18
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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  • 4-Saturated cyclosubstituted aniline protein kinase inhibitor
  • 4-Saturated cyclosubstituted aniline protein kinase inhibitor
  • 4-Saturated cyclosubstituted aniline protein kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1 5-Chloro-N 2 -(2-isopropoxy-5-methyl-4-(1-(methylenemorpholinyl)cyclopropyl)phenyl)-N 4 Preparation of -(2-(isopropylsulfonyl)phenyl)-2,4-diaminopyrimidine [No. REX-B1]

[0098] The synthetic route is as follows:

[0099]

[0100] Synthetic Scheme 1: Synthesis of intermediate 2-isopropoxy-5-methyl-4-(1-(methylenemorpholinyl)cyclopropyl)aniline (i.e. compound 1-12)

[0101] Step 1: Preparation of intermediate 2-methyl-5-nitro-phenylacetic acid (i.e. compound 1-2)

[0102] Dissolve the raw material 2-methyl-phenylacetic acid (200.0g, 1.33mol) in dichloromethane (700mL), slowly add concentrated sulfuric acid (584mL) below 0°C, continue the reaction for 0.5 hours after the addition, and then add concentrated nitric acid dropwise (30mL), keep the temperature at -2~3°C for 16 hours; after the reaction, pour into 500mL water, extract with dichloromethane, dry and concentrate to obtain compound 1-2 (90.0g), yield: 34.6 %.

[0103] MS m / z [ESI]: 196.1 [M+1].

...

Embodiment 2

[0151] Example 2 5-Chloro-N 2 -(4-(1-((Dimethylamino)methyl)cyclopropyl)-2-isopropoxy-5-methylbenzene)-N 4 Preparation of -(2-(isopropylsulfonyl)phenyl)-2,4-diaminopyrimidine [No. REX-B2]

[0152] The synthetic route is as follows:

[0153]

[0154] As described in the synthetic route provided in this example, in the synthetic scheme 1 "synthesis of compound 1-12", in step 9, dimethylamine is used instead of morpholine in Example 1 for the reaction, and the rest of the synthetic method is the same as that of Example 1 Synthesis scheme 1, the compound 1-12 is obtained, the yield: 22.0%.

[0155] MS m / z [ESI]: 263.4 [M+1].

[0156] In Synthesis Scheme 2 "Synthesis of Compound 2-5", the raw material 2-fluoronitrotoluene (i.e. Compound 2-1) and the rest of the synthesis methods are the same as in Synthesis Scheme 2 of Example 1 to obtain Compound 2-5. Rate: 33%.

[0157] MS m / z [ESI]: 370.2 [M+1].

[0158] In the synthesis scheme 3 "synthesis of the target compound REX-B2...

Embodiment 3

[0160] Example 3 5-Chloro-N 2 -(2-isopropoxy-5-methyl-4-(1-((4-oxopiperidinyl)methyl)cyclopropyl)phenyl)-N 4 Preparation of -(2-(isopropylsulfonyl)phenyl)-2,4-diaminopyrimidine [No. REX-B3]

[0161] The synthetic route is as follows:

[0162]

[0163] As described in the synthetic route provided in this example, in Synthetic Scheme 1, since the raw materials and synthetic methods of "Step 1 to Step 7" in this example are the same as those in "Step 1 to Step 7" in Synthetic Scheme 1 of Example 1 " same, therefore can directly take the compound 1-8 that the synthetic scheme 1 of embodiment 1 makes, synthesize according to the route of step 8 to step 11, obtain intermediate compound 1-12, the preparation process is specifically as follows:

[0164] Step 8: Preparation of intermediate 1-(2-methyl-4-nitro-5-isopropoxy)cyclopropylphenylethanol (ie compound 1-9)

[0165] Compound 1-8 (500mg, 1.7mmol) was dissolved in tetrahydrofuran (50ml), and lithium aluminum hydride (128mg, ...

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PUM

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Abstract

The invention discloses a compound being able to adjust the activity of protein kinase and used for treating or preventing protein kinase related diseases, concretely relates to a 4-saturated cyclosubstituted aniline protein kinase inhibitor belonging to a compound for adjusting the activity of anaplastic lymphoma kinase (ALK), and provides a preparation method of the compound and a pharmaceutical use of the compound 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 4-saturated cyclic group-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 this type of Pharmaceutical use of compounds for the treatment or prevention of diseases 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 signali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D401/12C07D403/12C07D405/12A61K31/506A61K31/505A61K31/5377A61P35/00
CPCC07D239/48C07D401/12C07D403/12C07D405/12
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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