Macrolide derivatives, preparation method and application thereof

Patent metadata

Field	Value
Publication number	US-12410191-B2
Application number	US-202017612315-A
Country	US
Kind code	B2
Filing date	May 20, 2020
Priority date	May 21, 2019
Publication date	Sep 9, 2025
Grant date	Sep 9, 2025

Abstract

Provided are a macrolide derivative represented by formula (I), a preparation method thereof, and an application of the macrolide derivative as an inhibitor of one or more protein kinases of TRK, ALK and ROS1,

First claim

The invention claimed is:

1. A compound represented by general formula (I) or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:
ring A is selected from bicyclic heteroaryl;
ring B is selected from bicyclic aryl, bicyclic heteroaryl and bicyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of aryl or heteroaryl and monocyclic heterocyclyl or monocyclic cycloalkyl;
L 1 is selected from —(CR a R b ) m —, wherein any one of —(CR a R b )— is optionally further replaced by —N(R c )—, —O— or —S(O) r —;
L 2 is selected from —(CR d R e ) n —, wherein any one of —(CR d R e )— is optionally further replaced by —N(R f )—, —O— or —S(O) r —;
each R a , R b , R d and R e are the same or different and are each independently selected from hydrogen atom, deuterium, halogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and —NR 5 R 6 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
alternatively, R a and R b together with the same carbon atom bound therewith form a C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
alternatively, any two R a together with different carbon atoms respectively bound therewith form a C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 of and —NR 5 C(O)R 6 ;
alternatively, R d and R e together with the same carbon atom bound therewith form a C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
alternatively, any two R d together with different carbon atoms respectively bound therewith form a C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
each R c and R f are the same or different, and are each independently selected from hydrogen atom, alkyl and cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy and cycloalkyl; and R c and R f are preferably selected from hydrogen atom;
alternatively, when one —(CR a R b )— is replaced by —N(R c )—, R a or R b and R c together with the carbon atom and nitrogen atom respectively bound therewith form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 of and —NR 5 C(O)R 6 ;
alternatively, when one —(CR d R e )— is replaced by —N(R′)—, R d or R c and R f together with the carbon atom and nitrogen atom respectively bound therewith form a 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the 3-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
each R 1 and R 2 are the same or different, and are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ; preferably, R 1 and R 2 are each independently selected from hydrogen atom, halogen, amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl and alkoxyalkyl; and more preferably, R 1 and R 2 are each independently selected from hydrogen atom, amino, cyano, F, Cl, Br, methyl, hydroxymethyl, halomethyl and methoxymethyl;
R 3 is selected from hydrogen atom, alkyl and cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy and cycloalkyl;
R 4 , R 5 and R 6 are each independently selected from hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
alternatively, R 5 and R 6 together with the atom bound therewith form a 4-8 membered heterocyclyl, wherein the 4-8 membered heterocyclyl internally contains one or more N, O or S(O) r , and the 4-8 membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
R 7 , R 1 and R 9 are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and carboxylate;
m and n are the same or different and are each independently selected from 1, 2, 3 and 4;
p and q are the same or different and are each independently selected from 0, 1, 2, 3, 4 and 5; and
r is selected from 0, 1 and 2.

2

Assignees

• Zhejiang Hisun Pharm Co Ltd
• Shanghai Aryl Pharmtech Co Ltd

Inventors

• Chen Youxi
• Gong Liang
• Zhu Xingwu
• Xiang Qing
• Mao Wentao
• Ye Cheng
• Hu taishan
• Chen Lei
• Jiang Guoping

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D498/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title