Compound as mTOR inhibitor and use thereof

Patent metadata

Field	Value
Publication number	US-11649231-B2
Application number	US-202017080497-A
Country	US
Kind code	B2
Filing date	Oct 26, 2020
Priority date	Apr 26, 2018
Publication date	May 16, 2023
Grant date	May 16, 2023

Abstract

The present invention relates to a novel compound as an mTOR inhibitor and a use thereof and, more specifically, to a novel compound represented by formula 1 that exhibits mTOR inhibitory activity and a pharmaceutical composition comprising same as an active ingredient for preventing or treating brain diseases associated with an mTOR pathway.

First claim

What is claimed is:

1. A compound defined by Chemical Formula 1 or pharmaceutically acceptable salt thereof:

wherein R1 is hydrogen; substituted or unsubstituted C1-C5 straight or branched alkyl; C2-C5 alkenyl; C3-C10 heteroarylalkyl; or C1-C5 hydroxyalkyl;
R2 is hydrogen; C1-C5 straight or branched alkyl;
R3 is hydrogen; substituted or unsubstituted C1-C5 straight or branched alkyl;
C6-C15 aryl; or C3-C15 heteroaryl;
X is oxygen, sulfur, or nitrogen;
Y1 and Y2 are each independently oxygen or sulfur; and
n is 0, 1, or 2; and
wherein the compound defined by Chemical Formula 1 or pharmaceutically acceptable salt thereof is selected from the group consisting of (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-(2-furylmethyl)-5-[(1-methylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-methyl-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-allyl-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]-3-methyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]-3-ethyl-2-thioxo-thiazolidin-4-one, (5Z)-3-allyl-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]-3-methyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]-3-ethyl-2-thioxo-thiazolidin-4-one, (5Z)-3-allyl-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-4-yl]methylene]-3-methyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-4-yl]methylene]-3-ethyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(p-tolyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-methyl-5-[[1-(p-tolyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-ethyl-5-[[1-(p-tolyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-allyl-5-[[1-(p-tolyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-isopropylphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-ethyl-5-[[1-(4-isopropylphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-butylphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-butylphenyl)pyrazol-4-yl]methylene]-3-ethyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3,4-dimethylphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3,4-dimethylphenyl)pyrazol-4-yl]methylene]-3-ethyl-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-methoxyphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-naphthyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-ethyl-5-[[1-(2-naphthyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-(2-hydroxyethyl)-5-[[1-(2-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-3-(2-hydroxyethyl)-5-[[1-(3-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[(5-methyl-1-phenyl-pyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(2-fluorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3-fluorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(4-fluorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione (5Z)-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(p-tolyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(4-isopropylphenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(4-butylphenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3,4-dimethylphenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(2-methoxyphenyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(2-naphthyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3-pyridyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[(3-methyl-1-phenyl-pyrazol-4-yl)methylene]thiazolidine-2,4-dione, (5Z)-5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-3-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-pyridyl)pyrazol-3-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-pyridyl)pyrazol-3-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-phenylpyrazol-3-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(2-pyridyl)pyrazol-3-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3-pyridyl)pyrazol-3-yl]methylene]thiazolidine-2,4-dione, and (5Z)-5-[[1-(4-pyridyl)pyrazol-3-yl]methylene]thiazolidine-2,4-dione.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-fluorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-chlorophenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(4-isopropylphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-methoxyphenyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-pyridyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[(5-methyl-1-phenyl-pyrazol-4-Amethylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(3-pyridyl)pyrazol-4-yl]methylene]thiazolidine-2,4-dione, (5Z)-5-[[1-(2-pyridyl)pyrazol-3-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(3-pyridyl)pyrazol-3-yl]methylene]-2-thioxo-thiazolidin-4-one, (5Z)-5-[[1-(2-pyridyl)pyrazol-3-yl]methylene]thiazolidine-2,4-dione, and (5Z)-5-[[1-(4-pyridyl)pyrazol-3-yl]methylene]thiazolidine-2,4-dione.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is the potassium salt of (5Z)-5-[(1-phenylpyrazol-4-yl)methylene]-2-thioxo-thiazolidin-4-one.

5. A method for preparing the compound of claim 1 or pharmaceutically acceptable salt thereof using Reaction Scheme 1:

wherein R 1 , R 2 , R 3 , X, Y 1 , Y 2 and n are described in claim 1 .

6. A pharmaceutical composition comprising the compound of claim 1 or pharmaceutically acceptable salt thereof as an active

Assignees

• Medicinal Bioconvergence Res Ct
• Univ Yonsei Iacf

Inventors

• Kim Sunghoon
• Kim Jong Hyun
• Han Gyoonhee
• Han Jung Min
• Lee Chulho

Classifications

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title