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Tricyclic derivative inhibitor, preparation method and application thereof

A drug and reaction technology, applied in anti-inflammatory agents, drug combinations, pharmaceutical formulations, etc., can solve the problem that BRAF and MEK inhibitors have not yet been listed

Active Publication Date: 2021-10-08
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, a large number of preclinical research results have proved that resistance to different types of ERK upstream target inhibitors can reverse the drug resistance of BRAF inhibitors and MEK inhibitors by inhibiting ERK activity. Many pharmaceutical companies have been conducting research to clarify Chemicals such as: Genentech, Merck, Lilly, etc., but there are no BRAF and MEK inhibitors researched in China so far.

Method used

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  • Tricyclic derivative inhibitor, preparation method and application thereof
  • Tricyclic derivative inhibitor, preparation method and application thereof
  • Tricyclic derivative inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] Preparation of 6-benzyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one

[0194] The first step: the preparation of 3-bromo-5,6-dinitro-1 hydrogen-indazole

[0195]

[0196] Dissolve 3-bromo-6-nitro-1 hydrogen-indazole (3.0g, 12.4mmol) in 30mL of concentrated sulfuric acid, cool to 0°C, add dropwise to potassium nitrate (1.38g, 13.64mmol) cooled to 0°C ) was dissolved in a solution of concentrated sulfuric acid (30 mL), the dropwise addition was completed, stirred at 0° C. for 30 minutes, the ice-water bath was removed, and stirred overnight at room temperature. The reaction solution was added dropwise to 360 g of ice-water mixture, the precipitate was filtered, washed with water, and sucked dry to obtain the target product 3-bromo-5,6-dinitro-1 hydrogen-indazole (3.2 g, yield 90% ).

[0197] 1 H NMR (400 MHz, DMSO) δ: 14.72 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H).

[0198] The second step: the preparation of 3-bromo-1 hydrogen-indazole-5,6-d...

Embodiment 2

[0225] 6-Benzyl-5-methyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxaline-7- Preparation of ketones

[0226]

[0227] 6-Benzyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (10mg, 0.028mmol) was dissolved in 10mL of methanol, added aqueous formaldehyde (1mL) and acetic acid (1mL), stirred at room temperature for 1 hour, then added reducing agent sodium cyanoborohydride (10mg, 0.16mmol) in a low-temperature ice-water bath, and stirred at room temperature for 5 Hour. After the reaction was completed, methanol was removed, extracted with dichloromethane (2*50mL), and the organic phase was dried and spin-dried to obtain a crude product, which was purified by preparative HPLC to obtain 6-benzyl-5-methyl-3-(pyridin-4-yl )-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (3.5 mg, 34% yield).

[0228] 1H NMR (400MHz, DMSO) δ: 13.10(s, 1H), 10.67(s, 1H), 8.65(d, J=6.0Hz, 2H), 7.94(d, J=6.0Hz, 2H), 7.18-6.91 (m,7H),4.18(t,J=6.3Hz,1H...

Embodiment 3

[0231] 6-Benzyl-5-neopentyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxaline-7 - Preparation of ketones

[0232]

[0233] 6-Benzyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H-pyrazolo[3,4-g]quinoxalin-7-one (20mg, 0.056mmol) was dissolved in MeOH / DCM (12mL, 3:1), acetic acid (1mL) and pivaloylindanedione aldehyde (48.5mg, 0.56mmol) were added, under nitrogen replacement, the reducing agent NaCNBH was added 3 (14 mg, 0.224 mmol), stirred at room temperature for 14 hours. After the reaction was completed, it was quenched with water, and the solvent was removed to obtain a crude product, which was dissolved in dichloromethane (100 mL), and washed with saturated sodium carbonate solution (50 mL*2). The organic layers were combined, dried, concentrated, and purified by HPLC to obtain the white solid product 6-benzyl-5-neopentyl-3-(pyridin-4-yl)-1,5,6,8-tetrahydro-7H- Pyrazolo[3,4-g]quinoxalin-7-one (4 mg, 16.7% yield).

[0234] 1 H NMR (400MHz, DMSO) δ: 13.14(s,...

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Abstract

The present invention relates to tricyclic derivative inhibitor, its preparation method and application. In particular, the present invention relates to a compound represented by general formula (I), its preparation method and pharmaceutical composition containing the compound, and as a protease such as ERK (MAPK) inhibitor in the treatment of cancer, bone disease, inflammatory disease, Uses in immune diseases, nervous system diseases, metabolic diseases, respiratory diseases and heart diseases, wherein each substituent in the general formula (I) is the same as defined in the description.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a triacyclic derivative inhibitor and its preparation method and application. Background technique [0002] Members of the ERK signaling pathway, such as RAS and BRAF, are often mutated in tumors. About 1 / 3 of human tumors express continuously activated mutant RAS, and 8% of tumors express activated BRAF. The mutations and probability statistics related to the ERK signaling pathway in malignant tumors are shown in Table 1. According to statistics, 90% of pancreatic cancer, 50% of colorectal cancer and 30% of lung cancer have RAS mutation; 50% of melanoma, 50% of thyroid cancer and 15% of colorectal cancer have BRAF mutation. [0003] Table 1. Types and probability of ERK signaling pathway-related mutations in different cancers [0004] [0005] Vemurafenib is the first BRAF inhibitor approved by the FDA and is mainly used for the treatment of advanced melanoma, but ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D498/04A61P35/00A61P35/02A61P19/08A61P29/02A61P37/06A61P25/00A61P3/00A61P11/00A61P9/00A61P1/16A61P3/10A61P1/00A61P21/04A61P17/06A61P19/02A61P13/10A61P15/00A61P11/06A61P37/08A61K31/5377A61K31/5383A61K31/4985
CPCY02P20/55
Inventor 刘世强周远锋鲍孟袁逸达刘磊包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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