Methods and compositions for targeting PD-L1
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.
1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
X 1 is N or CH;
Ring A is selected from the group consisting of:
a monocyclic C 5-7 cycloalkyl substituted with R 2a1 ;
a bicyclic C 6-12 cycloalkyl substituted with R 2a2 ;
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 2a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 2a4 or R 2a5 , and wherein when R 2a5 is present, R 2a5 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 2a6 ;
a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 2a7 or R 2a8 , wherein when R 2a8 is present, R 2a8 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; and
wherein Ring A is optionally further substituted;
Y 1 is N or —CR 8 , wherein R 8 is selected from the group consisting of hydrogen, —C 1-4 alkyl, and —C 1-4 haloalkyl;
R 1 and R 6a1 are independently selected from the group consisting of —C 1-4 alkyl, —C 1-4 haloalkyl, -monocyclic C 3-6 cycloalkyl, —(C 1-4 alkyl)monocyclic C 3-6 cycloalkyl, 4-6 membered monocyclic heterocyclic ring, aryl(C 1-4 alkyl) and —(C 1-4 alkyl) 5- or 6-membered monocyclic heteroaryl; wherein the —C 3-6 cycloalkyl, the 4-6 membered monocyclic heterocyclyl, the aryl(C 1-4 alkyl) and the -5- or 6-membered monocyclic heteroaryl(C 1-4 alkyl) is optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 3-6 monocyclic cycloalkyl and C 1-4 alkoxy;
R 2a1 , R 2a2 and R 2a7 are independently selected from the group consisting of amino, —N(R m1 )R n1 , —(C 3-6 monocyclic cycloalkyl)N(R m2 )R n2 , -R x1 and —(C 1-4 alkyl)R x1 ,
R m1 and R m2 are independently 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 heteroatom independently selected from the group consisting of O, S, C(═O), S(═O), S(═O) 2 and N; wherein the —C 1-4 alkyl is optionally substituted with one or two or three substituents independently selected from the group consisting of 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 Z1 ; wherein the C 3-6 monocyclic cycloalkyl, the C 3-6 monocyclic cycloalkyl(C 1-4 alkyl), the 5- or 6-membered monocyclic heteroaryl, the 4-7 membered monocyclic heterocyclyl, the 8-11 membered fused-heteroaryl, the 8-11 membered fused-heterocyclyl and the 4-7 membered monocyclic heterocyclyl(CH 2 ) are optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, —C 1-4 alkyl, hydroxy, —C 1-4 alkoxy, —C 1-4 haloalkyl, —C 1 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 ; and R n1 and R n2 is hydrogen, —C 1-4 alkyl, —C 1-4 halolkyl or C 3-6 monocyclic cycloalkyl(CH 2 );
R 2a3 and R 2a6 are independently selected from the group consisting of hydrogen, —C 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 and the monocyclic heterocyclyl contain at least one heteroatom independently selected from the group consisting of O, S, C(═O), S(═O), S(═O) 2 and N; wherein the —C 1-4 alkyl, the —C 3-6 monocyclic cycloalkyl, the —C 3-6 monocyclic cycloalkyl(C 1-4 alkyl), the 5- or 6-membered monocyclic heteroaryl, the 4-7 membered monocyclic heterocyclyl and the 4-7 membered monocyclic heterocyclyl(CH 2 ) are optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, hydroxy, —C 1-4 alkoxy, —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 , —NHC(═O)R Z3 , —NHC(═O)N(R Z1 )R Z3 and —N(R Z1 )S(═O) 2 N(R Z2 )R Z3 ;
R 2a4 is selected from the group consisting of halogen, —C 1-4 alkyl, —C(═O)OR Z4 , —OR Z4 , —N(R m3 )R n3 and —C 3-7 cycloalkyl; wherein the —C 1-4 alkyl and the —C 3-7 cycloalkyl are optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, hydroxy, —C 1-4 alkoxy, —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 , —NHC(═O)R Z3 , —NHC(═O)N(R Z1 )R Z3 and —N(R Z1 )S(═O) 2 N(R Z2 )R Z3 ; wherein R m3 and R n3 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl and —C 3-6 monocyclic cycloalkyl; and R Z4 is selected from the group consisting of hydrogen, —C 1-4 alkyl, —C 1-4 haloalkyl and —C 3-6 cycloalkyl;
R 2a5 and R 2a8 are independently selected from the group consisting of —C 1-4 alkyl, —C(═O)OR Z5 , —C 3-6 monocyclic cycloalkyl and —(C 1-4 alkyl)R x1 ; wherein the —C 1-4 alkyl and the —C 3-6 monocyclic cycloalkyl are optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, hydroxy, —C 1-4 alkoxy, —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 , —NHC(═O)R Z3 , —NHC(═O)N(R Z1 )R Z3 and —N(R Z1 )S(═O) 2 N(R Z2 )R Z3 ; and
wherein R Z5 is hydrogen, —C 1-4 alkyl, —C 1-4 haloalkyl and —C 3-6 cycloalkyl;
R 3a , R 3b , R 3c , R 3d , R 3f and R 3g are independently selected from the group consisting of hydrogen and halogen;
R 3d and R 3h 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 4a1 is selected from the group consisting of amino, —NR p1 R q1 , —(C 3-6 monocyclic cycloalkyl)N(R p2 )R q2 , -R y1 and —(C 1-4 alkyl)R y1 ;
R p1 and R p2 are independently 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 y2 ; wherein the monocyclic heteroaryl, the bicyclic heteroaryl the monocyclic heterocyclyl and the bicyclic heterocyclyl contain at least one heteroatom independently selected from the group consisting of O, S, C(═O), S(═O), S(═O) 2 and N; wherein the —C 1-4 alkyl is optionally substituted with one or two or three substituents independently selected from the group consisting of halogen, cyano, -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 ; wherein the C 3-6 monocyclic cycloalkyl, the C 3-6 monocyclic cycloalkyl(C 1-4 alkyl), the 5- or 6-membered monocyclic heteroaryl, the 4-7 membered monocyclic heterocyclyl, the 8-11 membered fused-heteroaryl, the 8-11 membered fused-heterocyclyl and the 4-7 membered monocyclic heterocyclyl(CH 2 ) are optionally substituted with one or two or three substituents independently selected from the group consisting of 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 ; and R p1 and R q2 are independently hydrogen, —C 1-4 alkyl, —C 1-4 halolkyl or C 3-6 monocyclic cycloalkyl(CH 2 );
R x1 is selected from the group consisting of:
wherein R x1 is optionally substituted with one or two substituents independently selected from the group consisting of halogen, cyano, —C 1-4 alkyl, hydroxy, —C 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 the group consisting of 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:
R 5a1 and R 5b1 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl, —C 1-4 haloalkyl, —C 1-4 alkoxy and —C 1-4 haloalkoxy; or
R 5a1 and R 5b1 are taken together along with the atom to which R 5a1 and R 5b1 are attached to form monocyclic —C 3-6 cycloalkyl or 4-6 monocyclic heterocyclyl, wherein the —C 3-6 cycloalkyl or the 4-6 monocyclic heterocyclyl can be optionally further substituted;
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;
R X3 is 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 ;
R Y3 is selected from the group consisting of hydrogen, halogen, —C 1-4 alkyl, —C 1-4 haloalkyl, —C(═O)R Z3 , —C(═O)OR Z3 , —S(═O) 2 R W3 , —C(═O)N(R W1 )R W2 and —S(═O)N(R W1 )R W2 ;
R Z1 , R Z2 , R W1 and R W2 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl, and —C 1-4 haloalkyl; and
R Z3 and R W3 are independently selected from the group consisting of hydrogen, —C 1-4 alkyl and —C 1-4 haloalkyl.
2. The compound of claim 1 ; wherein R 4a1 is -R y1 ; and R 5a1 and R 5b1 are each hydrogen.
3. The compound of claim 2 , wherein -R y1 is selected from the group consisting of:
4. The compound of claim 1 , wherein Ring A is a monocyclic C 5-7 cycloalkyl substituted with R 2a1 .
5. The compound of claim 4 , wherein R 2a1 is -R x1 , wherein -R x1 is selected from the group consisting of:
or wherein R 2a1 is selected from the group consisting of:
6. The compound of claim 5 , wherein R 4a1 is -R y1 ; and R 5a1 and R 5b1 are each hydrogen.
7. The compound of claim 6 , wherein -R y1 is selected from the group consisting of:
8. The compound of claim 7 , wherein -R y1 is
9. The compound of claim 8 , wherein -R x1 is
10. The compound of claim 9 , wherein -R y1 is
11. The compound of claim 7 , wherein n 1 , n 2 , n 3 and n 4 are each 1.
12. The compound of claim 9 , wherein m 1 , m 2 and m 3 are each 1.
13. The compound of claim 1 , wherein Ring A is 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 2a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 2a4 or R 2a5 , and wherein when R 2a5 is present, R 2a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is selected from the group consisting of:
wherein asterisks indicate the position of the fused bond, and R 2a4 and R 2a5 are each optionally present; or wherein Ring A is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 2a7 or R 2a8 ; wherein R 2a8 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 is selected from the group consisting of:
wherein asterisks indicate the position of the fused bond, and R 3a7 or R 3a8 is present.
14. The compound of claim 13 , wherein Ring A is
wherein asterisks indicate the position of the fused bond; and R 2a3 can be selected from the group consisting of —(CH 2 ) 1-2 —C(═O)OR Z1 , —(CH 2 ) 1-2 —OH and —(CH 2 ) 1-2 —C 1-4 alkoxy; or Ring A is
wherein asterisks indicate the position of the fused bond.
15. The compound of claim 6 , wherein R 2a7 is -R x1 , wherein -R x1 is selected from the group consisting of:
or R 2a7 is selected from the group consisting of:
16. The compound of claim 1 , wherein R 1 is —C 1-4 alkyl.
17. The compound of claim 1 , wherein R 3a , R 3b , R 3c , R 3d , R 3f and R 3g are each hydrogen; and R 3d and R 3h are each halogen; or wherein R 3a , R 3b , R 3c , R 3d , R 3f and R 3g are each hydrogen; and R 3d is halogen; and R 3h is —CH 3 .
18. The compound of claim 1 , wherein Y 1 is N.
19. The compound of claim 1 , wherein Y 1 is —CH or CH 3 .
20. The compound of claim 4 , wherein Ring A is
wherein asterisks indicate the position of the fused bond.
21. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
22. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
23. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and excipient.
24. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
25. A method for treating hepatitis B comprising administering to a subject suffering from hepatitis B an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
26. A method for treating hepatocellular carcinoma (HCC) in a subject comprising administering to a subject suffering from hepatocellular carcinoma (HCC) an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.