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MST1 kinase inhibitor and application thereof

A technology of kinase inhibitors and solvates, which is applied in the field of MST1 kinase inhibitors and their uses, and can solve the problems of not showing selectivity

Active Publication Date: 2020-04-21
HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Organometallic ruthenium MST1 inhibitor 9E (Anand R, et al.Toward the Development of a Potent and Selective Organoruthenium Mammalian Sterile20Kinase Inhibitor.J.Med.Chem.2009, 52, 1602-1611) is a multi-target inhibitor reported in 2009 , IC for MST1 inhibitory activity 50 Up to 45nM, although he achieved relatively good selectivity (8-25 times) in the same family, but did not show selectivity in other related kinases PIM1 and GSK3β (IC 50 0.6nM and 13nM, respectively)

Method used

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  • MST1 kinase inhibitor and application thereof
  • MST1 kinase inhibitor and application thereof
  • MST1 kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: 4-((7-(2,6-difluorophenyl)-5,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl ) Amino)benzenesulfonamide

[0130]

[0131] 2-Amino-2-(2,6-difluorophenyl)acetic acid methyl ester (A2): Add 3-2-amino-2-(2,6-difluorophenyl)acetic acid (2.0 g) was added methanol (30 mL), followed by the dropwise addition of thionyl chloride (1.2 mL) under ice-cooling. The reaction system was reacted overnight at 85°C. After the reaction, the system was evaporated to dryness under reduced pressure to obtain a white solid, which was directly used in the next step.

[0132] Methyl 2-((2-chloro-5-nitropyrimidin-4-yl)amino)-2-(2,6-difluorophenyl)acetate (A3): Add 2-amino- Add acetone (30 ml) and potassium carbonate (2.2 g) after 2-(2,6-difluorophenyl) methyl acetate (2 g), then cool the system to -10°C with an ice-salt bath, then slowly add 2,4-Dichloro-5-nitropyrimidine (3.1 g) in acetone. The reaction was stirred overnight at room temperature. After the reaction was com...

Embodiment 2

[0136] Example 2: 4-((5,8-dimethyl-6-oxo-7-phenyl-5,6,7,8-tetrahydropteridin-2-yl)amino)benzenesulfonate Amide

[0137]

[0138] The synthesis of the compound of Example 2 was accomplished using a procedure similar to that described in Example 1. MS (ESI) m / z (M+1)+: 425.14.

Embodiment 3

[0139] Example 3: 4-((7-benzyl-5,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzenesulfonate Amide

[0140]

[0141] Synthesis of the compound of Example 3 was accomplished using a procedure similar to that described in Example 1. MS (ESI) m / z (M+1)+: 439.15.

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Abstract

The present invention relates to a kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present invention also relates to pharmaceutical compositions comprising the kinase inhibitor, and uses and methods of using these compound and compositions to inhibit tyrosine kinase activity of one or more selected from MST1 or mutations thereof in a cell or subject, and to prevent or treat disorders associated with MST1 or mutated kinase thereof in a subject.

Description

technical field [0001] The present invention relates to compounds useful as inhibitors of mammalian Ste20-like kinase 1 (MST1), as well as compositions comprising the compounds and uses thereof. Background technique [0002] MST1 kinase has a variety of biological functions such as regulating cell proliferation, growth, apoptosis and organ size. Studies have found that the abnormal expression of MST1 protein is closely related to major diseases such as tumors, nervous system diseases, heart diseases, autoimmune diseases and diabetes. Therefore, MST1 can be used as a potential target for diagnosis, prognosis and treatment. The mammalian sterile line 20-like kinase 1 (mammalian sterile 20-like kinase 1, MST1) gene was cloned from the lymphatic cDNA library by PCR in 1995 when studying the homologues of Saccharomyces cerevisiae Ste20 and humans. The structure and function of yeast Ste20 are similar, so it was named MST1. MST1 kinase belongs to the class of mammalian Ste20-re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/00C07D475/12A61P1/00A61P1/04A61P1/16A61P3/10A61P5/14A61P5/38A61P7/00A61P7/06A61P9/00A61P11/06A61P15/14A61P17/00A61P19/02A61P19/08A61P21/04A61P27/02A61P29/00A61P37/02A61P37/06A61K31/519A61K31/635
CPCC07D475/00C07D475/12A61P3/10A61P29/00A61P37/02A61P1/00A61P19/08A61P1/04A61P11/06A61P17/00A61P15/14A61P37/06A61P5/14A61P1/16A61P5/38A61P7/00A61P21/04A61P7/06A61P9/00A61P19/02A61P27/02A61K31/519A61K31/5377A61K31/635
Inventor 刘青松刘静吴云汪文亮王蓓蕾齐紫平王俊杰王文超亓爽王黎
Owner HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI
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