JAK kinase inhibitor, preparation method for same, and applications thereof in field of medicine

Patent metadata

Field	Value
Publication number	US-12398141-B2
Application number	US-202017437944-A
Country	US
Kind code	B2
Filing date	Mar 11, 2020
Priority date	Mar 14, 2019
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

Related are a JAK kinase inhibitor, a preparation method for same, and applications thereof in the field of medicine, related to the field of medicinal chemistry. Provided is a novel small molecule JAK inhibitor, which has the structure as represented by formula (II). The compound provides improved efficacy and safeness in preventing or treating a JAK-related indication.

First claim

The invention claimed is:

1. A compound of formula (II), tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof,

wherein,
T is —CN;
R 0 is hydrogen or C 1-3 alkyl;
R 1 is

R 2 is —C(O)R 4 , —C(O)NR 5 R 6 , or —S(O) 2 R 4 ;
R 3 is —H or —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —O—C 1-4 alkyl, —NH 2 , halogen, phenyl or cyano;
R 4 is —C 1-5 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the —C 1-5 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —C 5-6 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano;
wherein the phenyl of R 4 is optionally substituted by R e ;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is —C 1-4 alkyl, —C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl,

—CHF 2 or —CH 2 CF 2 CF 3 , wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano; wherein phenyl is optionally substituted by R e or R g , or R e and R g ;
R e and R g are each independently halogen, —C 1-4 alkyl, alkoxy, 3- to 6-membered cycloalkyl, —NR c R d , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , or —(CH 2 ) n —CN, wherein the —C 1-4 alkyl, alkoxy or cycloalkyl is optionally monosubstituted or disubstituted by the following groups: halogen, —OH, —NH 2 , —C 1-3 alkyl, —O—C 1-4 alkyl, CF 3 , phenyl or cyano;
R f is —C 1-4 alkyl or 3- to 6-membered cycloalkyl, wherein the —C 1-4 alkyl or cycloalkyl is optionally substituted by the following substituents: halogen, —OH, —NH 2 , —C 1-3 alkyl, —O—C 1-4 alkyl, CF 3 , phenyl or cyano;
R c and R d are each independently hydrogen, —C 1-3 alkyl, —C 1-4 alkylene-OH, —C 1-4 alkylene-CF 3 , —C 2-4 alkylene-OCH 3 , 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl; and
n is 0, 1, 2, 3 or 4.

2. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein
R 4 is —C 1-5 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the —C 1-5 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano;
wherein the phenyl of R 4 is optionally substituted by R e ;
R 6 is —C 1-4 alkyl, —C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, or phenyl, wherein the phenyl is optionally substituted by R e or R g , or R e and R g ; wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano; and
R f is —C 1-4 alkyl or 3- to 6-membered cycloalkyl, wherein the —C 1-4 alkyl or cycloalkyl is optionally substituted by the following substituents: halogen, —OH, or —C 1-3 alkyl.

3. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein
R 6 is —(CH 2 ) n —CH 2 CF 3 , —(CH 2 ) n —CF 2 CF 3 , —(CH 2 ) n —CH 2 CN, 4- to 6-membered heterocyclyl or phenyl, wherein the phenyl is optionally substituted by R e or R g , or R e and R g ;
R f is —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted by halogen or —OH; and
Rc and Rd are each independently hydrogen, —C1-3 alkyl, —C1-4 alkylene-OH or —C2-4 alkylene-OCH3; n is 0, 1, 2 or 3.

4. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 3 , wherein
R 3 is H, —CH 3 , or —CH 2 CH 3 ;
R 4 is methyl, ethyl, propyl, —(CH 2 ) n —CH 2 CN, —(CH 2 ) n —CH 2 CF 3 , —CH(OH)—(CH 2 ) n —CH 3 ,

R 5 is H;
R 6 is —(CH 2 ) n —CH 2 CF 3 , —(CH 2 ) n —CF 2 CF 3 , —(CH 2 ) n —CH 2 CN,

R e and R g are each independently —F, —Cl, methyl, ethyl, propyl, —CH(CH 3 )—(CH 2 ) n CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —C(CH 3 ) 2 —(CH 2 ) n CH 3 , —O—(CH 2 ) n CH 3 , —O—(CH 2 ) n CH 2 —O—CH 3 , —(CH 2 ) n OCH 3 , —O—(CH 2 ) n —CH 2 —C(CH 3 ) 2 —OH, —O—(CH 2 ) n —CH 2 —C(CH 3 ) 2 —NH 2 , C 3-6 cycloalkyl, —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , —(CH 2 ) n —CHF 2 , or —(CH 2 ) n —CN;
R f is methyl, ethyl or propyl;
R c and R d are each independently —H, methyl, ethyl or propyl; and
n is 0 or 1.

5. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein the compound is:

6. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein the pharmaceutically acceptable salts are acid addition salts, alkali addition salts, inner salts or betaines.

7. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , and optionally one or more pharmaceutically acceptable carriers and excipients, wherein the pharmaceutical composition also co

Assignees

• Shanghai Synergy Pharmaceutical Sciences Co Ltd
• Zhejiang Huahai Pharm Co Ltd

Inventors

• Xu Xin
• Chen Jia
• Zhang Zhen
• Wang Guan
• Zhang Linli
• Li Qiang
• Xi Chenghao
• Qu Minkai
• Zhang Xiaojuan
• Chen Chunqiao
• Yang Fan
• Xia Xiaoer
• Wang Yijin
• Li Yunfei
• Ge Jian

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · 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

• A61P17/00 Primary

  Drugs for dermatological disorders · CPC title