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Indole ASK1 small-molecule inhibitor and preparation method and application thereof

A technology of small molecule inhibitors and indoles, which is applied in the field of indole ASK1 small molecule inhibitors and their preparation, and can solve problems such as single structure type

Pending Publication Date: 2020-10-23
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, which needs to be further studied

Method used

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  • Indole ASK1 small-molecule inhibitor and preparation method and application thereof
  • Indole ASK1 small-molecule inhibitor and preparation method and application thereof
  • Indole ASK1 small-molecule inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-2-carboxamide (I-1)

[0045]

[0046] The preparation of the first step 6-aminopyridinecarbohydrazide

[0047]

[0048] Methyl 6-aminopicolinate (5.0 g, 32.9 mmol) was dissolved in MeOH, and N 2 h 4 ·H 2 O (3.22g, 65.8mmol), the reaction solution was heated to reflux for 3h; cooled to room temperature, a solid precipitated out, the filter cake was washed with EA after suction filtration, and the target product (4.5g, 90%) was obtained after vacuum drying.

[0049] ESI-MS m / z:153.1[M+H] + .

[0050] Preparation of the second step 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine

[0051]

[0052] 6-Aminopyridinecarbohydrazide (4.5g, 29.61mmol) was dissolved with anhydrous Dioxane, triethyl orthoformate (5.92mL, 35.53mmol) was added, N 2 React under protection at 75°C for 1h. Add CH via syringe 3 COOH (5.08mL, 88.83mmol), cyclopropylamine (2.05mL, 29.61mmol), reacted at 110°...

Embodiment 2

[0060] 7-Chloro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-2-carboxamide (I- 2) Preparation

[0061]

[0062] Reference for the preparation of 7-chloro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-indole-2-carboxamide Example 1.

[0063] 1 H NMR (300MHz, DMSO-d 6 )δ: 12.06(s, 1H), 10.85(s, 1H), 8.90(s, 1H), 8.26(dd, J=6.3, 0.3Hz, 1H), 8.06(t, J=8.7, 1H), 7.84 (dd, J=7.6,0.6Hz,1H), 7.68(d,J=6.0Hz,1H),7.55(d,J=2.1Hz,1H),7.37(dd,J=5.7,0.6Hz,1H) ,7.12(t,J=7.8Hz,1H),5.54-5.65(m,1H),1.48(d,J=5.1Hz,6H).

[0064] ESI-MS m / z:381.1.[M+H] + .

Embodiment 3

[0066] N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-methoxy-1H-indole-2-carboxamide ( I-3) Preparation

[0067]

[0068] N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-methoxy-1H-indole-2-carboxamide Preparation with reference to Example 1.

[0069] 1H NMR (300MHz, DMSO) δ11.70(s, 1H), 10.56(s, 1H), 8.88(s, 1H), 8.23(d, J=8.3Hz, 1H), 8.02(t, J=7.9Hz ,1H), 7.84(d, J=7.5Hz,1H), 7.63–7.47(m,2H), 6.93(s,1H), 6.75(d,J=8.7Hz,1H), 5.66-6.45(m, 1H), 3.80(s, 3H), 1.47(d, J=6.5Hz, 6H).

[0070] ESI-MS m / z:377.2[M+H] + .

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Abstract

The invention discloses an indole ASK1 small-molecule inhibitor and a preparation method and application thereof. The inhibitor comprises a compound as shown in a general formula (I) and a stereoisomer or pharmaceutically acceptable salt thereof. Experimental data prove that the inhibitor has a certain treatment effect on non-alcoholic steatohepatitis and ulcerative colitis, and has a good application prospect.

Description

technical field [0001] The invention mainly relates to a class of compounds and their preparation methods and applications, in particular to indole ASK1 small molecule inhibitors and their preparation methods and applications. 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 reactions and other physiological processes. The MAPK family includes extracellular signal-regulated kinases (ERKs), P 38 Three major subfamilies of MAPK and JNK. The MAPK family includes three levels of kinases. First, the mitogen-activated protein kinase kinase kinase (MAP3K) is activated by intracellular and extracellular stimuli. The activated MAP3K phosphorylation activates MAP2K, which then activates MAPK. ASK1 belongs to MAP3K5 ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D409/14C07D405/14A61K31/4439A61K31/444A61P29/00A61P1/16A61P1/00
CPCC07D401/14C07D409/14C07D405/14A61P29/00A61P1/16A61P1/00
Inventor 陈亚东侯少华佟宇王雨晨张艳敏杨玥婧万勃亨陈泉威魏然陆涛
Owner CHINA PHARM UNIV
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