Methods and compositions for targeting PD-L1

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 hydrogen, —C 1-4 alkyl and —C 1-4 haloalkyl;

R Z3 and R W3 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl and —C 1-4 haloalkyl; and

R Z4 is selected from the group consisting of hydrogen, —C 1-4 alkyl and 5- to 6-membered monocyclic heterocyclyl(CH 2 )— optionally substituted with —C 1-4 alkyl.

2. The compound of claim 1 , wherein A 1 is

and X 1 is N; or A 1 is

X 1 is N; and X 3 is CH.

3. The compound of claim 2 , wherein R 1a is —C 1-4 alkyl.

4. The compound of claim 3 , wherein R 1b is —N( m1 )R n1 ; and R n1 is hydrogen.

5. The compound of claim 4 , wherein R m1 is —C 1-4 alkyl optionally substituted with —C(═O)OR Z1 or 4-7 membered monocyclic heterocyclyl optionally substituted with hydroxy.

6. The compound of claim 4 , wherein R m1 is —R x2 .

7. The compound of claim 6 , wherein —R x2 is

8. The compound of claim 2 , wherein R 1b is —R x1 .

9. The compound of claim 8 , wherein —R x1 is selected from the group consisting of:

10. The compound of claim 9 , wherein —R x1 is selected from the group consisting of:

11. The compound of claim 9 , wherein —R x1 is selected from the group consisting of:

wherein 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 is selected from the group consisting of hydrogen and —C 1-4 alkyl; and R x1 is optionally substituted with one or two halogens.

12. The compound of claim 2 , wherein R 1d is —OH, —CH 3 or —F; R 1e is hydrogen; R 1f is hydrogen; and R 1g is hydrogen; or R 1d is —CH 3 ; R 1e is —CH 3 ; R 1f is hydrogen; and R 1g is hydrogen.

13. The compound of claim 1 , wherein B 1 is

wherein Y 6 is CR 5c ; or wherein B 1 is

wherein R 5d is hydrogen or —CH 3 ; Y 7 is CR 5e , wherein R 5e is hydrogen; and Y 8 is CR 5f , wherein R 5f is hydrogen.

14. The compound of claim 13 , wherein R 5a is —CH 3 ; R 5b is —CH 3 ; and R 5d is —CH 3 .

15. The compound of claim 1 , wherein R 2a , R 2b , R 2c , R 2e , R 2g and R 2h are each hydrogen; and R 2d and R 2f are each halogen; or wherein R 2a , R 2b , R 2e , R 2g and R 2h are each hydrogen; and R 2c , R 2d and R 2f are each halogen; or wherein R 2a , R 2b , R 2c , R 2g and R 2h are each hydrogen; and R 2d , R 2e and R 2f are each halogen; or wherein R 2a , R 2b , R 2c , R 2e , R 2g and R 2h are each hydrogen; R 2f is halogen; and R 2d is —CH 3 .

16. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

17. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

18. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

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

20. 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.

21. 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.