Methods and compositions for targeting PD-L1
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.
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.