Methods and compositions for targeting PD-L1

Patent metadata

Field	Value
Publication number	US-11760764-B2
Application number	US-202117303089-A
Country	US
Kind code	B2
Filing date	May 19, 2021
Priority date	May 22, 2020
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

The present disclosure related to compounds that can be useful as inhibitors of PD-1, PD-L1 or the PD-1/PD-L1 interaction. Also disclosed herein are pharmaceutical compositions of that can include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and uses of or 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:
R 1a is selected from the group consisting of:

Ring A 1a , Ring A 3a and Ring A 4a are independently selected from the group consisting of:
a monocyclic C 5-7 cycloalkyl substituted with R 3a1 ;
a bicyclic C 6-12 cycloalkyl substituted with R 3a2 ;
a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl;
a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl; and
a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens;
wherein Ring A 1a , Ring A 2a , Ring A 3a and Ring A 4a is optionally further substituted;
wherein when R 1a is

and Ring A 1a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3a3 is present;
wherein when R 1a is

and Ring A 3a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3a3 is present;
wherein when R 1a is

then Ring A 4a cannot be a monocyclic C 5-7 cycloalkyl substituted with R 3a1 or a bicyclic C 6-12 cycloalkyl substituted with R 3a2 ; and
wherein when R 1a is

and Ring A 4a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3a3 is present;
X 1a , X 2a and X 3a are independently N or CR 4a1 ;
X 5a , X 6a and X 7a are independently N or CR 4a3 ;
R 1b is selected from the group consisting of:

Ring A 1b , Ring A 3b and Ring A 4b are independently selected from the group consisting of:
a monocyclic C 5-7 cycloalkyl substituted with R 3b1 ;
a bicyclic C 6-12 cycloalkyl substituted with R 3b2 ;
a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl;
a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b6 ; wherein a carbon of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R 3b8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl; and
a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3b9 or R 3b10 ; wherein R 3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens;
wherein Ring A 1b , Ring A 2b , Ring A 3b and Ring A 4b is optionally further substituted;
wherein when R 1b is

and Ring A 1b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3b3 is present;
wherein when R 1b is

and Ring A 3b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3b3 is present;
wherein when R 1b is

then Ring A 4b cannot be a monocyclic C 5-7 cycloalkyl substituted with R 3b1 or a bicyclic C 6-12 cycloalkyl substituted with R 3b2 ; and
wherein when R 1b is

and Ring A 4b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R 3b3 is optional;
X 1b , X 2b and X 3b are independently N or CR 4b1 ;
X 5b , X 6b and X 7b are independently N or CR 4b3 ;
R 3a1 , R 3a2 , R 3a9 , R 3b1 , R 3b2 and R 3b9 are independently selected from the group consisting of —OH, —N(R m )R n , —C 1-4 alkyl-N(R m )R n , —OC 2-4 alkyl-N(R m )R n ,

R 3a3 , R 3b3 , R 3a6 and R 3b6 are independently selected from the group consisting of —R x1 , C 1-4 alkyl, C 3-7 cycloalkyl, —C(═O)C 1-4 alkyl and -Het a1 , wherein the —C 3-7 cycloalkyl, the —C(═O)C 1-4 alkyl and the -Het a1 is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —C 1-4 alkyl, —OH, —N(R m )R n , —C 1-4 alkoxy, —C(═O)OH, —C(═O)OC 1-4 alkyl, —C(═O)NHS(═O) 2 C 1-4 alkyl, —NHC(═O)C 1-4 alkyl and —C(═O)N(R m )R n , wherein the —C 1-4 alkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, —N(R m )R n , C 1-4 alkoxy, —C(═O)OH, —C(═O)OC 1-4 alkyl, —C(═O)NHS(═O) 2 C 1-4 alkyl, —NHC(═O)C alkyl and —C(═O)N(R m )R n ;
R 3a4 , R 3a7 , R 3b4 and R 3b7 are independently selected from the group consisting of -halogen, —C 1-4 alkyl, —C 3-7 cycloalkyl, —OH, —OC 1-4 alkyl, —N(R m )R n , —C 1-4 alkyl(R m )R n , —C(═O)OH, —C 1-4 alkyl-C(═O)OH, —C(═O)OC 1-4 alkyl and —C 1-4 alkyl-C(═O)OC 1-4 alkyl; wherein the —C 1-4 alkyl, is optionally substituted with one or two substituents selected from the group consisting of -halogen, —OH, —C 1-4 alkoxy, —C(═O)OH, —C(═O)OC 1-4 alkyl, —C(═O)NHS(═O) 2 C 1-4 alkyl, —NHC(═O)C 1-4 alkyl and C(═O)N(R m )R n , and wherein the —C 3-7 cycloalkyl and the —OC 1-4 alkyl is optionally substituted with one or two substituents selected from the group consisting of -halogen, —OH, —C 1-4 alkyl, —C 1-4 alkoxy, C(═O)OH, —C(═O)OC 1-4 alkyl, —C(═O)NHS(═O) 2 C 1-4 alkyl, —NHC(═O)C 1-4 alkyl and —C(═O)N(R m )R n ,
R 3a5 , R 3a8 , R 3b5 and R 3b8 are independently selected from the group consisting of —C(═O)OH, —C 1-4

Assignees

• Aligos Therapeutics Inc

Inventors

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

Classifications

• C07D217/04 Primary

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  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

• A61P31/20

  for DNA viruses · CPC title

• C07C211/42

  with six-membered aromatic rings being part of the condensed ring systems · CPC title