Di(hetero)aryl macrocyclic compound for inhibiting protein kinase activity

Patent metadata

Field	Value
Publication number	US-11358973-B2
Application number	US-201917047877-A
Country	US
Kind code	B2
Filing date	Apr 10, 2019
Priority date	Apr 16, 2018
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

A di(hetero)aryl macrocyclic compound having an inhibitory effect on protein kinase activity, preparation and the use thereof. Specifically, disclosed are a di(hetero)aryl macrocyclic compound represented by formula (I), or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug or an active metabolite thereof, a pharmaceutical composition comprising said compound and the derivative thereof, and methods of using the same, including methods of treating cancers, pain, neurological diseases, autoimmune diseases and inflammation.

First claim

What is claimed is:

1. A compound of formula (I):

wherein,
A 1 is CR 1 ;
A 2 is CR 2 ;
A 3 is CR 3 ;
A 4 is CR 4 ;
wherein R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, —CN, and —NO 2 ;
L 1 is C(R 1a )(R 2a );
L 2 is C(R 1b )(R 2b );
X is selected from O, S, and N(R 1c );
Y is selected from O, S, N(R 1d ) and C(R 1d )(R 2d );
W is selected from O, S, and N(R 1e );
R is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
m is selected from 1, 2, 3, 4 and 5;
n is selected from 1, 2 and 3;
wherein,
R 1a and R 2a are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1a , R 2a together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1b and R 2b are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1c is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1d and R 2d are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1d , R 2d together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1e is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated; and
substituents on different atoms in -(L 2 ) n -W— can be connected to form a-3- to 10-membered heterocyclyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof;
wherein,
“3- to 7-membered heterocyclyl” is a radical of a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms;
“5- to 10-membered heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.

2. The compound according to claim 1 , which is a compound of formula (III-1) or (III-2):

wherein,
A 1 is CR 1 ;
A 4 is CR 4 ;
wherein R 1 , R 3 and R 4 are independently selected from H, D, halogen, —CN, and —NO 2 ;
X is O;
Y is selected from N(R 1d ) and C(R 1d )(R 2d );
W is selected from O and NH;
m is selected from 1, 2 and 3;
R 1a and R 2a are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1a , R 2a together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
and wherein,
R 1d and R 2d are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1d , R 2d together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

3. The compound according to claim 1 , which is a compound of formula (IV-1) or (IV-2):

wherein,
R 3 is selected from H, D, halogen, —CN, and —NO 2 ;
X is O;
Y is selected from NH, CH 2 and C(Me)(Me); wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
m is selected from 1, 2 and 3;
R 1a and R 2a are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1a , R 2a together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated; and
R 1b is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

4. The compound according to claim 1 , which is a compound of formula (VI-1) or (VI-2):

wherein,
R 3 is selected from H, D, and halogen;
R 1a and R 2a are each independently selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated; and
R 1b is selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof.

5. The compound according to claim 1 , which is a compound of formula (I′):

A 1 is CR 1 ;
A 2 is CR 2 ;
A 3 is CR 3 ;
A 4 is CR 4 ;
wherein R 1 , R 2 , R 3 and R 4 are independently selected from H, D, halogen, —CN, and —NO 2 ;
L 1 is C(R 1a )(R 2a );
X is selected from O, S, and N(R 1c );
Y is selected from O, S, N(R 1d ) and C(R 1d )(R 2d );
L 3 is C(R 1f )(R 2f );
L 4 is C(R 1g )(R 2g );
L 5 is C(R 1h )(R 2h );
R is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
m is selected from 1, 2, 3, 4 and 5;
n is selected from 1, 2 and 3;
wherein,
R 1a and R 2a are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1a , R 2a together with the atom to which they are attached form a C 3-7 cycloalkyl; wherein the above groups are optionally substituted by one or more D atoms until completely deuterated;
R 1d and R 2d are each independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; or R 1d , R 2d together with the atom

Assignees

• Shenzhen Targetrx Inc

Inventors

• Wang Yihan
• Zhao Jiuyang
• Ai Yixin

Classifications

• C07C271/18

  to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms · CPC title

• C07D207/20

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/529

  forming part of bridged ring systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title