Methods and compositions for targeting PD-L1

Patent metadata

Field	Value
Publication number	US-12018015-B2
Application number	US-202217807083-A
Country	US
Kind code	B2
Filing date	Jun 15, 2022
Priority date	Jun 18, 2021
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

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:

each X 1 is selected from the group consisting of CH and N;
X 2 is O;
X 3 is selected from the group consisting of CH, C-halo and N;
Y 1 is selected from the group consisting of N and CH;
Y 2 is selected from the group consisting of N and CH;
Y 3 is selected from the group consisting of N and CH;
Y 4 is selected from the group consisting of N and CH;
Y 5 is selected from the group consisting of N, CH and C—OCH 3 ;
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 selected from the group consisting of —C 1-4 alkyl, —C 1-4 haloalkyl, —CH 2 (C 3-6 monocyclic cycloalkyl), —C 2-4 alkyl(C 1-4 alkoxy), —C 2-4 alkyl (C 1-4 haloalkoxy), —CH 2 (4-6 membered monocyclic heterocyclyl) and —CH 2 (5-6 membered monocyclic heteroaryl);
each R 1b is selected from the group consisting of —N(R m1 )R n1 and —R x1 ;
R 1d is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 and —F;
R 1e is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 and —F;
R 1f is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 and —F;
R 1g is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 and —F;
R 1c is selected from the group consisting of —N(R m1 )R n1 and —R x1 ;
R 2a , R 2b , R 2c , R 2e , R 2g , R 2h 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 , —CH 2 CH 3 , —CH 2 OH, —OCH 3 and —SCH 3 ;
R 3a is selected from the group consisting of H, —CH 3 , —CF 3 and —CHF 2 ;
R 4a is selected from the group consisting of H, halogen, —C 1-4 alkyl, —C 1-4 haloalkyl, —CH 2 R 4b and —C(CH 3 )R 4b ;
R 4b is selected from the group consisting of —N(R m2 )R n2 and —R y1 ;
R 5a is selected from the group consisting of hydrogen, —CH 3 , —C 2-4 alkyl and —C 2-4 haloalkyl;
R 5b is selected from the group consisting of hydrogen, —CH 3 , —C 2-4 alkyl and —C 2-4 haloalkyl;
R 5c is selected from the group consisting of hydrogen, —CH 3 , —C 2-4 alkyl and —C 2-4 haloalkyl;
R 5d is selected from the group consisting of hydrogen, —CH 3 , —C 2-4 alkyl and —C 2-4 haloalkyl;
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, —OH, —CN and —CH 3 ;
R m1 is selected from the group consisting of hydrogen, —C 1-4 alkyl, C 3-6 monocyclic cycloalkyl, C 5-12 bicyclic cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4-7 membered monocyclic heterocyclyl, 8-11 membered fused-heteroaryl, 8-11 membered fused-heterocyclyl and —R x2 ; wherein the monocyclic heteroaryl, the bicyclic heteroaryl the monocyclic heterocyclyl and the bicyclic heterocyclyl contain at least one atom or group of atoms independently selected from the group consisting of O (oxygen), S (sulfur), C(═O), S(═O), S(═O) 2 and N (nitrogen); wherein the —C 1-4 alkyl is optionally substituted with one or two or three substituents independently selected from halogen, cyano, hydroxy, —C 1-4 alkoxy, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(═O)OR Z1 , —C(═O)NHS(═O) 2 R Z3 , —C(═O)N(R Z1 )R Z2 , —S(═O) 2 R Z3 , —S(═O) 2 N(R Z1 )R Z2 , —N(R Z1 )C(═O)R Z3 , —N(R Z1 )S(═O)R Z3 , —N(R Z1 )C(═O)N(R Z2 )R Z3 and —N(R Z1 )S(═O)N(R Z2 )R Z3 ; wherein the C 3-6 monocyclic cycloalkyl, the C 5-12 bicyclic cycloalkyl, the 5- or 6-membered monocyclic heteroaryl, the 4-7 membered monocyclic heterocyclyl, the 8-11 membered fused-heteroaryl and the 8-11 membered fused-heterocyclyl are optionally substituted with one, two, three or four substituents independently selected from halogen, cyano, —C 1-4 alkyl, hydroxy, —C 1-4 alkoxy, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(═O)R Z1 , —C(═O)OR Z1 , —C(═O)NHS(═O) 2 R Z3 , —C(═O)N(R Z1 )R Z2 , —S(═O) 2 R Z3 , —S(═O) 2 N(R Z1 )R Z2 , —N(R Z1 )C(═O)R Z3 , —N(R Z1 )S(═O)R Z3 , —N(R Z1 )C(═O)N(R Z2 )R Z3 and —N(R Z1 )S(═O)N(R Z2 )R Z3 ; and R n1 is hydrogen, —C 1-4 alkyl, —C 1-4 haloalkyl, C 3-6 monocyclic cycloalkyl(CH 2 )— or —C(═O)OR Z4 ;
R m2 is selected from the group consisting of —CH 3 , —C 2-4 alkyl, —C 1-4 haloalkyl and —R y2 , wherein the —C 2-4 alkyl is optionally substituted with hydroxy;
R n2 is selected from the group consisting of H, —C 1-4 alkyl and —C 1-4 haloalkyl;
R x1 is selected from the group consisting of:

wherein R x1 is optionally substituted with one or two substituents independently selected from halogen, cyano, —C 1-4 alkyl, hydroxy, —C 1-4 alkoxy, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(═O)OR z1 , —C(═O)NHS(═O) 2 R Z3 , —C(═O)N(R Z1 )R Z2 , —S(═O) 2 R Z3 , —S(═O) 2 N(R Z1 )R Z2 , —N(R Z1 )C(═O)R Z3 , —N(R Z1 )S(═O)R Z3 , —N(R Z1 )C(═O)N(R Z1 )R Z3 and —N(R Z1 )S(═O) 2 N(R Z2 )R Z3 ;
R x2 is selected from the group consisting of:

R y1 is selected from the group consisting of:

wherein R y1 is optionally substituted with one or two substituents independently selected from halogen, cyano, —C 1-4 alkyl, hydroxy, —C 1-4 alkoxy, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(═O)OR W1 —C(═O)NHS(═O) 2 R W3 , —C(═O)N(R W1 )R W2 , —S(═O) 2 R W3 , —S(═O)N(R W1 )R W2 , —N(R W1 )C(═O)R W3 , —N(R W1 )S(═O)R W3 , —N(R W1 )C(═O)N(R W2 )R W3 and —N(R W1 )S(═O)N(R W2 )R W3 ;
R y2 is selected from the group consisting of:

m 1 , m 2 , m 3 , n 1 , n 2 and n 3 are independently 1 or 2;
m 4 and n 4 are independently 0, 1 or 2;
m 5 and n 5 are independently 1, 2, 3 or 4;
each R X3 is independently selected from the group consisting of hydrogen, halogen, —C 1-4 alkyl, —C 1-4 haloalkyl, —C(═O)R Z3 —C(═O)OR Z1 , —S(═O) 2 R Z1 , —C(═O)N(R Z1 )R Z2 and —S(═O)N(R Z1 )R Z2 ;
each R Y3 is independently selected from the group consisting of hydrogen, halogen, —C 1-4 alkyl, —C 1-4 haloalkyl, —C(═O)R W3 —C(═O)OR W3 , —S(═O) 2 R W3 , —C(═O)N(R W1 )R W2 and —S(═O)N(R W1 )R W2 ;
R Z1 and R Z2 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl and —C 1-4 haloalkyl; or
R Z1 and R Z2 are taken together to form a monocyclic heterocyclyl when attached to the same nitrogen;
R W1 and R W2 are independently selected from the group consisting of

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