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US 2021/0137918 A1Published application
3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (chk1) inhibitors, and their preparations and applications
AssigneePharmaengine, Inc.
InventorsXiong CAI, Changgeng QIAN, Yanong Daniel WANG
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Abstract
The present invention provides compounds of formula (I) which are potent inhibitors of Chk1 and have the structural formula below: wherein R1, R2, R3, R4, and R5 are as defined herein. Pharmaceutical compositions comprising the compounds, uses thereof and their preparation process are also provided.
Claims34
A compound of formula (I):
- wherein:
- R1 is halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted aryl, —NO2, —OH, —C(O)R, —C(O)OR, —C(O)N(R′)(R″), or —N(R′)(R″);
- R2 and R3 are each independently —H, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, —NO2—OH, or —N(R′)(R″), or R2 and R3 together with the carbon atom to which they are attached form an unsubstituted or substituted carbon cyclic or heterocyclic ring;
- R4 is —H, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted aryl, —OH, —C(O)R, —C(O)OR, —C(O)N(R′)(R″), or —N(R′)(R″);
- R5 is —CN, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkoxy, —NO2, —OH or —N(R′)(R″);
- R is unsubstituted or substituted alkyl;
- and
- R′ and R″ are each independently —H or unsubstituted or substituted alkyl,
- or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.
6 more elements
A compound, which is selected from:
- 5-(5-(2-(3-aminopropoxy)-3-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-((5-(6-(3-aminopropoxy)-3-fluoro-2-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-aminopropoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-aminopropoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-aminopropoxy)-6-methoxy)-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-aminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(3-methylaminopropoxy)-4-chloro-6-methoxyphenyl)-1H-pyrazo-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(3-methylaminopropoxy)-4-bromo-6-methoxyphenyl)-1-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(3-methylaminopropoxy)-4-methyl-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(3-methylaminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazo-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-chloro-4-chloro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-bromo-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-6-methoxy-4-methylphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-(5-(3-fluoro-6-methoxy-2-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-((5-(3-fluoro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-(5-(4-fluoro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-H-pyrazol-3-ylamino)pyrazine-2-carbonitrile;
- 5-((5-(4-chloro-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-((5-(4-bromo-2-methoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-((5-(2-methoxy-4-methyl-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-((5-(2,4-dimethoxy-6-((1-((methylamino)methyl)cyclopropyl)methoxy)phenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile;
- 5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-methyl-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 5-(5-(2-(2-hydroxy-3-aminopropoxy)-4,6-dimethoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine-2-carbonitrile;
- 2-methyl-5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine;
- 2-chloro-5-(5-(2-(3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine;
- 2-methyl-5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino) pyrazine;
- 2-chloro-5-(5-(2-(3-methylaminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- 2-methyl-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- 2-chloro-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- 2-methyl-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- 2-chloro-5-(5-(2-((1-(aminomethyl)cyclopropyl)methoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- 2-methyl-5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-3H-pyrazol-3-ylamino)pyrazine;
- 2-chloro-5-(5-(2-(2-hydroxy-3-aminopropoxy)-4-fluoro-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine;
- ethyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxyphenoxy) propylcarbamate;
- 2-amino-N-(3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxyphenoxy)propyl)acetamide;
- or
- 1-(((3-(2-(3-((5-cyanopyrazin-2-yl)amino)-1H-pyrazol-5-yl)-5-fluoro-3-methoxyphenoxy) propyl)carbamoyl)oxy)ethyl isobutyrate;
- or a pharmaceutically acceptable salt, geometric isomer, enantiomer, distereomer, racemate, prodrug, solvate, or hydrate thereof.
39 more elements
Dependencies are inferred from the claim text.