Pyrazole derivative compound and use thereof

Patent metadata

Field	Value
Publication number	US-11254676-B2
Application number	US-201816646883-A
Country	US
Kind code	B2
Filing date	Sep 13, 2018
Priority date	Sep 13, 2017
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

Provided is a compound represented by Formula 1 having an inhibitory activity on lysine-specific demethylase-1 (LSD1), an optical isomer, a solvate, a tautomer, or a pharmaceutically acceptable salt thereof, which is effective in preventing or treating a disease caused by abnormal activation of LSD1.

First claim

The invention claimed is:

1. A compound of the following Formula 4, an optical isomer, or a tautomer, or a pharmaceutically acceptable salt thereof:

wherein, in Formula 4,
A is hydrogen or a C 1 -C 4 alkyl group,
W(s) are each independently a halogen,
n is a natural number from 1 to 4,
Y is a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted N-linked pyrrolidinyl group, or a substituted or unsubstituted N-linked piperidinyl group, wherein the substituted C 3 -C 6 cycloalkyl group is a C 3 -C 6 cycloalkyl group in which at least one hydrogen is substituted with a functional group each independently selected from halogen and a hydroxy group, and the substituted N-linked pyrrolidinyl group and the substituted N-linked piperidinyl group are each a N-linked pyrrolidinyl group and a N-linked piperidinyl group, respectively, in which at least one ring hydrogen atom is substituted with a functional group each independently selected from a C 1 -C 4 alkyl group, halogen, a C 1 -C 4 alkoxy group, a hydroxy group, and a C 1 -C 10 heterocyclic group, and
Z is a substituted or unsubstituted N-linked pyrrolidinyl group, a substituted or unsubstituted N-linked piperidinyl group, or a substituted or unsubstituted N-linked azepanyl group, wherein at least one substituent of the substituted N-linked pyrrolidinyl group, the substituted N-linked piperidinyl group, or the substituted N-linked azepanyl group is selected from an amino group, a C 1 -C 4 alkylamino group, a C 1 -C 4 alkyl group, a halogen, a C 1 -C 4 alkoxy group, and a C 1 -C 10 heterocyclic group.

2. The compound of claim 1 , an optical isomer, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein
A is hydrogen,
W(s) are fluorine,
n is a natural number of 1,
Y is a substituted or unsubstituted N-linked pyrrolidinyl group or a substituted or unsubstituted N-linked piperidinyl group, wherein the substituted N-linked pyrrolidinyl group and the substituted N-linked piperidinyl group are each a N-linked pyrrolidinyl group and a N-linked piperidinyl group, respectively, in which at least one ring hydrogen atom is substituted with a functional group each independently selected from a C 1 -C 4 alkyl group, a halogen, a C 1 -C 4 alkoxy group, and a hydroxy group, and
Z is a substituted N-linked piperidinyl group or a unsubstituted piperidinyl group in which at least one substituent is substituted with a functional group selected from an amino group, a C 1 -C 4 alkylamino group, a C 1 -C 4 alkyl group, a halogen, and a C 1 -C 4 alkoxy group.

3. A compound selected from Compounds 1) to 113), an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof:
1) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-cyclopropylphenyl)-1H-pyrazole-5-yl)benzonitrile
2) (R)-4-(1-(4-cyclopropylphenyl)-3-(3-methylaminopiperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
3) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazole-5-yl)benzonitrile
4) (R)-4-(1-(4-cyclopropyl-2-fluorophenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
5) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
6) (R)-4-(1-(4-cyclopropyl-2-fluorophenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
7) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(4-(cyclopropylphenyl)-1H-pyrazole-5-yl)benzonitrile
8) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
9) 4-(3-((3R,5R)-3-amino-5-methylpiperidine-1-carbonyl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
10) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-cyclopropyl-2,6-difluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
11) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(4-cyclopropyl-2,6-difluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
12) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(2-chloro-4-cyclopropylphenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
13) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(2-chloro-4-cyclopropylphenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
14) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-phenyl-1H-pyrazole-5-yl)benzonitrile
15) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(pyridine-2-yl)-1H-pyrazole-5-yl)benzonitrile
16) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-fluorophenyl)-1H-pyrazole-5-yl)benzonitrile
17) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-chlorophenyl)-1H-pyrazole-5-yl)benzonitrile
18) (R)-4-(1-(4-chlorophenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
19) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(3-chlorophenyl)-1H-pyrazole-5-yl)benzonitrile
20) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-bromophenyl)-1H-pyrazole-5-yl)benzonitrile
21) (R)-4-(1-(4-bromophenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
22) (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
23) (S)-4-(3-(3-(methylamino)pyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
24) (S)-4-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
25) (R)-4-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
26) (R)-4-(3-(3-(methylamino)pyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
27) (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
28) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
29) (R)-4-(3-(3-(methylamino)piperidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
30) (R)-4-(3-(3-(dimethylamino)piperidine-1-carbonyl)-1-(p-tolyl)-1H-pyrazole-5-yl)benzonitrile
31) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(m-tolyl)-1H-pyrazole-5-yl)benzonitrile
32) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(o-tolyl)-1H-pyrazole-5-yl)benzonitrile
33) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-ethylphenyl)-1H-pyrazole-5-yl)benzonitrile
34) (R)-4-(1-(4-ethylphenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
35) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-isopropylphenyl)-1H-pyrazole-5-yl)benzonitrile
36) (R)-4-(1-(4-isopropylphenyl)-3-(3-(methylamino)piperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
37) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(2-fluoro-4-isopropylphenyl)-1H-pyrazole-5-yl)benzonitrile
38) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(2-fluoro-4-isopropylphenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
39) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(2-fluoro-4-isopropylphenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
40) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(tert-butyl)phenyl)-1H-pyrazole-5-yl)benzonitrile
41) (R)-4-(1-(4-(tert-butyl)phenyl-3-(3-methylaminopiperidine-1-carbonyl)-1H-pyrazole-5-yl)benzonitrile
42) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(tert-butyl)-2-fluorophenyl)-1H-pyrazole-5-yl)benzonitrile
43) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(tert-butyl-2-fluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
44) (R)-4-(3-(3-aminoazepane-1-carbonyl)-1-(4-(tert-butyl-2-fluorophenyl)-1H-pyrazole-5-yl)-2-fluorobenzonitrile
45) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole-5-yl)benzonitrile
46) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole-5-yl)benzonitrile
47) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)benzonitrile
48) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(2-fluoro-4-methylphenyl)-1H-pyrazole-5-yl)benzonitrile
49) (R)-4-(3-(3-aminopiperidine-1-carbonyl)-1-(3-fluoro-4-methoxyphe

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Bae In Hwan
• Kim Ji Sook
• Kim Won Jeoung
• Park Chang Hee
• Song Ji Young
• Ahn Young Gil

Classifications

• C07D401/06 Primary

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

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title