Methods and compositions for targeting PD-L1

Patent metadata

Field	Value
Publication number	US-12534450-B2
Application number	US-202418658848-A
Country	US
Kind code	B2
Filing date	May 8, 2024
Priority date	Jun 18, 2021
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

Provided herein are compounds that can be useful as inhibitors of PD-1, PD-L1 or the PD-1/PD-L1 interaction. Also provided herein are pharmaceutical compositions of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of PD-L1 related diseases including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.

First claim

What is claimed is:

1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein:

A 1 is

B 1 is
each X 1 is N;
X 2 is O;
X 3 is CH;
Y 6 is selected from the group consisting of N and CR 5c ;
Y 7 is CR 5e ;
Y 8 is CR 5f ;
each R 1a is —C 1-4 alkyl;
each R 1b is selected from the group consisting of —N(R m1 )R n1 and —R x1 ;
wherein R x1 is selected from the group consisting of:

R 1d , R 1e , R 1f and R 1g are each hydrogen;
R 2a , R 2b , R 2g and R 2h are each hydrogen;
R 2c and R 2e are independently selected from the group consisting of hydrogen and halogen;
R 2d and R 2f are independently selected from the group consisting of hydrogen, halogen, cyano, —CH 3 and —OCH 3 ;
R 5a is selected from the group consisting of hydrogen and —CH 3 ;
R 5b is selected from the group consisting of hydrogen and —CH 3 ;
R 5c is selected from the group consisting of hydrogen and —CH 3 ;
R 5d is selected from the group consisting of hydrogen and —CH 3 ;
R 5e is selected from the group consisting of hydrogen, halogen and —CH 3 ;
R 5f is selected from the group consisting of hydrogen, halogen and —CH 3 ;
R m1 is selected from the group consisting of 4-7 membered monocyclic heterocyclyl and —R x2 ; wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with hydroxy; and R n1 is hydrogen; and wherein
R x2 is selected from the group consisting of:

m 1 , m 2 and m 3 are independently 1 or 2;
m 4 is 0, 1 or 2;
m 5 is 1, 2, 3 or 4;
each R X3 is independently selected from the group consisting of hydrogen, —C 1-4 alkyl, —C(═O) R Z3 and —C(═O) OR Z1 ,
R Z1 and R Z2 are independently selected from the group consisting of hydrogen and —C 1-4 alkyl; and
each R Z3 is independently selected from the group consisting of hydrogen and —C 1-4 alkyl.

2 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and excipient.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —N(R m1 )H, wherein R m1 is the 4-7 membered monocyclic heterocyclyl optionally substituted with hydroxy, and wherein the 4-7 membered monocyclic heterocyclyl contains at least one O (oxygen) atom.

4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R m1 is selected from the group consisting of

5 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f are independently selected from the group consisting of halogen and —CH 3 ; and R 2c and R 2e are each hydrogen.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein B 1 is selected from the group consisting of

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —N(R m1 )H, wherein R m1 is —R x2 , wherein R x2 is selected from the group consisting of

and wherein each R Z1 is hydrogen.

8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the N(R X2 )H, is selected from the group consisting of

9 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f are independently selected from the group consisting of halogen and —CH 3 ; and R 2c and R 2e are each halogen.

10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein B 1 is selected from the group consisting of

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1b is —R x1 , wherein R x1 is selected from the group consisting of:

12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein —R x1 is selected from the group consisting of:

13 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein —R x1 is selected from the group consisting of:

wherein m 1 , m 2 , m 3 , m 4 and m 5 , are each 1.

14 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein —R x1 is selected from the group consisting of:

15 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2d and R 2f are independently selected from the group consisting of halogen and —CH 3 ; and R 2c and R 2e are each hydrogen.

16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein B 1 is selected from the group consisting of

17 . A method for treating hepatitis B in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18 . A method for treating hepatocellular carcinoma (HCC) in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , further comprising administering surgery, radiation therapy, chemotherapy, targeted therapy, immunotherapy, hormonal therapy, or antiviral therapy.

Assignees

• Aligos Therapeutics Inc

Inventors

• Wu Tongfei
• Raboisson Pierre Jean-Marie Bernard
• Gonzalvez Francois
• Stoycheva Antitsa Dimitrova
• Liu Cheng
• Deval Jerome
• Mcgowan David

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

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title