Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof

Patent metadata

Field	Value
Publication number	US-10081629-B2
Application number	US-201515303704-A
Country	US
Kind code	B2
Filing date	Mar 31, 2015
Priority date	Apr 14, 2014
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

Amide derivatives and pharmaceutically acceptable salts thereof, preparation method thereof and medicinal application thereof are provided. Specifically, amide derivatives represented by general formula (I) are provided. The amide derivatives represented by general formula (I) can be used as a therapeutic agent, particularly as an inhibitor for microsomal prostaglandin E synthase-1 (mPGES-1), and also to treat and/or prevent diseases or illnesses such as inflammation and/or pain etc. The definition of each substituent group in general formula (I) is the same as the definition in the description.

First claim

The invention claimed is:

1. A compound of formula (III), formula (IV), or formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

wherein:
X is —CH— or N;
each of E, G and W is independently selected from the group consisting of CR a , NR b , and N;
R a and R b are each independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein the alkyl, cycloalkyl and heterocyclyl are each optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7;
each of A, B and Y is —CH—;
R 1 is selected from the group consisting of alkyl and cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted by one or more groups selected from the group consisting of alkyl, halogen and haloalkyl;
R 2 is selected from the group consisting of halogen and haloalkyl;
R 4 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally further substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are each optionally further substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate group;
R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently and optionally further substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate group; or
R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocyclyl, wherein the heterocyclyl optionally contains one or more heteroatoms selected from the group consisting of N, O and S (O) m , and wherein the heterocyclyl is optionally further substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate group;
m is 0, 1 or 2; and
t is 0 or 1.

2. The compound of formula (III), formula (IV), or formula (V), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (VI), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

wherein:
X is —CH— or N;
R b is selected from the group consisting of hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein the alkyl, cycloalkyl and heterocyclyl are each optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ; and
A, B, Y, t, R 1 to R 2 and R 4 to R 7 are as defined in claim 1 .

3. The compound of formula (III), formula (IV), or formula (V), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (VII), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

wherein:
X is —CH— or N;
R b is selected from the group consisting of hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein the alkyl, cycloalkyl and heterocyclyl are each optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
R 8 is selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ; and
A, B, Y, R 1 to R 2 and R 5 to R 7 are as defined in claim 1 .

4. A compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

wherein ring Q is selected from the group consisting of phenyl and pyridine;
R 1 is selected from the group consisting of alkyl and cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted by one or more groups selected from the group consisting of alkyl, halogen and haloalkyl;
R 2 is selected from the group consisting of halogen and haloalkyl;

wherein the group

is selected from the group consisting of:

each R 3 is the same or different and is independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, oxo, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein the alkyl, cycloalkyl and heterocyclyl are each optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —NHS(O) m R 5 , —C(O)R 5 , —NHC(O)R 5 , —NHC(O)OR 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
R 4 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally further substituted by one or more groups selected from the group consisting of halogen, alkoxy, hydroxyl, cyano, nitro, alkyl,

Assignees

• Shanghai hengrui pharmaceutical co ltd
• Jiangsu Hengrui Medicine Co

Inventors

• Li Xin
• He Wei
• Liu Xianbo
• Wang Bin
• Hu Qiyue
• Jin Fangfang
• Dong Qing
• Sun Piaoyang

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title