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ASK1 inhibitor, derivative, preparation method, pharmaceutical composition and application thereof

A technology of derivatives and inhibitors, applied in the field of ASK1 inhibitors and its derivatives, can solve the problems of non-alcoholic steatohepatitis not reaching the clinical endpoint and single structure type

Active Publication Date: 2021-02-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure type of small molecule inhibitors of ASK1 is relatively single at present, and only GS-4997 has been clinically tested for related diseases
However, GS-4997 failed to meet clinical endpoints in two phase III clinical trials on nonalcoholic steatohepatitis (NASH)

Method used

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  • ASK1 inhibitor, derivative, preparation method, pharmaceutical composition and application thereof
  • ASK1 inhibitor, derivative, preparation method, pharmaceutical composition and application thereof
  • ASK1 inhibitor, derivative, preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: 3-(3-(4-cyclopropyl-1H-imidazol-1-yl)phenyl)-5-(4-isopropyl-4H-1,2,4-triazole-3- base)-1H-indazole (compound I-1) synthesis

[0117]

[0118] 1. 4-cyclopropyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H- Synthesis of Imidazole (Compound 1-1)

[0119]

[0120] (1) Synthesis of 2-((3 bromophenyl)amino)-1-cyclopropyl-1-ethanone (compound 3)

[0121] m-Bromoaniline (3.0g, 17.5mmol) was dissolved in DMF, added K 2 CO 3 (2.9g, 21mmol), KI (2.9g, 17.5mmol), stirred at room temperature for 30min, added 2-bromo-1-cyclopropylethan-1-one (4.25g, 26.2mmol) and reacted at 60°C for 3h. The end of the reaction was detected by TLC, the reaction solution was diluted with water, and then extracted with EA, which was dried and spin-dried, and the target product (3 g, 68%) was obtained by silica gel column chromatography. ESI-MS m / z:254.0[M+H] + .

[0122] (2) Synthesis of 1-(3-bromophenyl)-4-cyclopropyl-1H-imidazole-2-thiol (compound 4)

[0123] 2...

Embodiment 2

[0144] Example 2: N-cyclopropyl-3-(5-(4-isopropyl-4H-1,2,4-triazol-3-yl)-1H-indazol-3-yl)benzamide Synthesis of (I-14)

[0145]

[0146] 1. Synthesis of N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (compound 1-2)

[0147]

[0148] (1) Synthesis of 3-bromo-N-cyclopropylbenzamide (compound 9)

[0149] Take 3-bromobenzoic acid (500mg, 2.5mmol), HATU (1.43mmol, 3.75mmol) and DIEA (806mg, 6.25mmol), dissolve it in DMF, stir at room temperature for 15min, add cyclopropylamine (171mg, 3mmol), and react at room temperature for 3h ; The end of the reaction was detected by TLC, the reaction solution was diluted with water, extracted and dried with EA, and the target product (400mg, 67%) was obtained by silica gel column chromatography. ESI-MS m / z:240.0[M+H] + .

[0150] (2) N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (compound 1-2) synthesis

[0151] Take 3-bromo-N-cyclopropylbenzamide (400mg, 1.67mmol), biboronic acid pin...

Embodiment 3

[0157] Example 3: 3-(5-(4-isopropyl-4H-1,2,4-triazol-3-yl)-1H-indazol-3-yl)benzamide (compound I-20) Synthesis

[0158]

[0159] 1. Synthesis of 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (compound 1-3)

[0160]

[0161] (1) Synthesis of 3-(3-bromophenyl)pyridine (compound 10)

[0162] Take 1,3-dibromobenzene (343mg, 1.46mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ( 300mg, 1.46mmol), Pd (pph 3 ) 4 (168mg, 0.146mmol) and K 2 CO 3 (404mg, 2.92mmol), with Dioxane / H 2 O was dissolved at 5:1, reacted overnight at 80°C; TLC detected the end of the reaction, removed the insolubles by suction filtration, washed the filter cake with EA, diluted the filtrate with water, extracted the reaction solution with water, and extracted with EA, dried and spin-dried the EA, and obtained by silica gel column chromatography Target product (300 mg, 89%). ESI-MS m / z:234.0[M+H] + .

[0163] (2) 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)...

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Abstract

The invention discloses an ASK1 inhibitor, a derivative, a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown as a formula I. The ASK1 inhibitor derivative relates to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomer, the diastereoisomer, the enantiomer, the tautomer and the solvate of the compound. The ASK1 inhibitor and the derivative thereof have an efficient inhibition effect on ASK1 kinase, and can be used for preparing drugsfor ASK1 kinase related diseases, the prepared drugs can play a drug effect at a molecular level and a cellular level, the application is wide, and the synthesis method of the compound is simple, convenient and easy to operate.

Description

technical field [0001] The present invention relates to an ASK1 inhibitor and its derivatives, preparation method, pharmaceutical composition and application, in particular to an ASK1 inhibitor which can be prepared as an ASK1 inhibitor drug and its derivatives, preparation method, pharmaceutical composition and application . Background technique [0002] Apoptosis signal-regulated kinase 1 (ASK1) belongs to the mitogen-activated protein kinase (MAPK) family, and the MAPK signaling pathway is one of the important signal transduction systems in organisms, involved in mediating cell proliferation, differentiation, apoptosis, and inflammation Physiological processes such as reactions. The MAPK family includes three subfamilies of extracellular signal-regulated kinase (ERK), p38MAPK and JNK. The MAPK family includes three levels of kinases. First, mitogen-activated protein kinase (MAP3K) is activated by intracellular and extracellular stimuli. The activated MAP3K phosphorylate...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D403/04C07D409/14C07D413/14C07D401/14C07D405/14A61K31/4196A61K31/5377A61K31/4439A61P25/00A61P9/00A61P29/00A61P3/00
CPCC07D403/14C07D403/04C07D409/14C07D413/14C07D401/14C07D405/14A61P25/00A61P9/00A61P29/00A61P3/00Y02A50/30
Inventor 陈亚东侯少华佟宇杨玥婧陈泉威万勃亨魏然陆涛
Owner CHINA PHARM UNIV
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