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Pyridazinone BTK inhibitors and application thereof

A solvate and compound technology, applied in the field of medicinal chemistry, can solve problems such as unsatisfactory selectivity, drug resistance, and multiple side effects

Inactive Publication Date: 2019-01-11
NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] It is currently known that the selectivity of BTK inhibitors is not ideal. In addition to inhibiting BTK, it also inhibits various other kinases (such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.), resulting in more side effects; at the same time , BTK binding site mutations often lead to drug resistance

Method used

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  • Pyridazinone BTK inhibitors and application thereof
  • Pyridazinone BTK inhibitors and application thereof
  • Pyridazinone BTK inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The preparation of embodiment 1 (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid o-chlorobenzyl ester

[0034]

[0035] Weigh 5-amino-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate (50mmol) and DIPEA (100mmol) into a reaction flask, add 300ml of dichloromethane, and slowly add it dropwise under stirring at room temperature O-chlorobenzyl chloroformate (51mmol), after dropping, continue to stir at room temperature for 1h, stop the reaction, concentrate the reaction mixture, add 70ml of ethyl acetate, wash with dilute aqueous hydrochloric acid (0.2-0.3N) and saturated brine, anhydrous sulfuric acid Dry over sodium, filter, and concentrate to give the title compound, which is used directly in the next step.

[0036] ESI–MS:[M+H] + m / z 417.

Embodiment 2

[0037] Example 2 Preparation of (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid p-chlorobenzyl ester

[0038]

[0039] Weigh triphosgene (5mmol) into a reaction bottle, add 100ml of toluene, add dropwise 20ml of tetrahydrofuran solution dissolved with p-chlorophenol (5mmol) and pyridine (10ml) at 0°C, after the drop is completed, continue to react at room temperature for 8h, concentrate the reaction solution, added 40ml of dichloromethane, suspended to dryness, and obtained p-chlorobenzyl chloroformate, which was directly used in the next step.

[0040] Using tert-butyl 5-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate and p-chlorobenzyl chloroformate as raw materials, the title compound was obtained by the same method as in Example 1.

[0041] ESI–MS:[M+H] + m / z 417.

Embodiment 3

[0042] Example 3 Preparation of 2H-phthalazin-1-one

[0043]

[0044] Step 1: Weigh dimethoxymethylbenzene (500mmol) into a reaction flask, add tetrahydrofuran (800ml) to dissolve, add s-BuLi (565mmol) under nitrogen protection at 60°C, and store the reaction solution at -60°C Stir for 1h.

[0045] Step 2: Weigh dry ice (50mmol) into a reaction flask, add tetrahydrofuran (200ml), add n-BuLi (5ml), stir for 2h under nitrogen protection, add the mixture of step 1, continue stirring for 30min, stop the reaction, add water 1000ml, adjust the pH to 2 with concentrated hydrochloric acid, separate the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and recrystallize to obtain 2-dimethoxymethylbenzoic acid .

[0046] Step 3: Weigh the product obtained in Step 2 (400mmol), acetic acid (93mmol), and hydrazine (600mmol) into a reaction flask, add 300ml of isopropanol, under nitrogen ...

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Abstract

The invention relates to the field of medicinal chemistry, relates to pyridazinone BTK inhibitors and an application thereof, and concretely relates to pyridazinone BTK inhibitors represented by formula (I), a preparation method thereof, a medicinal composition containing the compounds, and a use of the compounds or the medicinal composition in the treatment of Bruton's tyrosine kinase-related diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to phthalazinone BTK inhibitors and applications thereof, in particular to phthalazinone BTK inhibitors, a preparation method thereof, a pharmaceutical composition containing the compound, and its application in the treatment of Bruton casein Use in amino acid kinase-associated diseases. Background technique [0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family. It consists of a unique N-terminal domain, namely PH (pleckstrin homology) domain, TH (Tec homology) homology region, SH3 (Srchomology3) domain, SH2 (Src homology2) domain and catalytic domain, also known as SH1 / TK (Srchomologyl / Tyrosine kinase) domain or kinase domain composition (Akinleye et al: Ibrutiniband novel BTK inhibitors in clinical development. Journal of Hematology & Oncology 2013, 6: 59). During the normal development of B lymphocytes, the correct expression of different protein regions of the...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/502A61P35/00
CPCA61P35/00C07D401/12
Inventor 郭程杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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