Methods and compositions for targeting PD-L1

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

• wherein:
• R1a is selected from the group consisting of:
• Ring A1a, Ring A3a and Ring A4a are independently selected from the group consisting of:
• a monocyclic C5-7 cycloalkyl substituted with R3a1;
• a bicyclic C6-12 cycloalkyl substituted with R3a2;
• a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R3a3, wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R3a4 or R3a5, and wherein when R3a5 is present, R3a5 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 R3a6;
• wherein a carbon of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R3a7 or R3a8, and wherein R3a8 is present, R3a8 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 R3a9 or R3a10;
• wherein R3a10 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 A1a, Ring A2a, Ring A3a and Ring A4a is optionally further substituted;
• wherein when R1a is
• and Ring A1a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3a3 is present;
• wherein when R1a is
• and Ring A3a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3a3 is present;
• wherein when R1a is
• then Ring A4a cannot be a monocyclic C5-7 cycloalkyl substituted with R3a1 or a bicyclic C6-12 cycloalkyl substituted with R3a2;
• and
• wherein when R1a is
• and Ring A4a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3a3 is present;
• X1a, X2a and X3a are independently N or CR4a1;
• X5a, X6a and X7a are independently N or CR4a3;
• R1b is selected from the group consisting of:
• Ring A1b, Ring A3b and Ring A4b are independently selected from the group consisting of:
• a monocyclic C5-7 cycloalkyl substituted with R3b1;
• a bicyclic C6-12 cycloalkyl substituted with R3b2;
• a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R3b3, wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R3b4 or R3b5, and wherein when R3b5 is present, R3b5 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 R3b6;
• wherein a carbon of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R3b7 or R3b8, and wherein R3b8 is present, R3b8 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 R3b9 or R3b10;
• wherein R3b10 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 A1b, Ring A2b, Ring A3b and Ring A4b is optionally further substituted;
• wherein when R1b is
• and Ring A1b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3b3 is present;
• wherein when R1b is
• and Ring A3b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3b3 is present;
• wherein when R1b is
• then Ring A4b cannot be a monocyclic C5-7 cycloalkyl substituted with R3b1 or a bicyclic C6-12 cycloalkyl substituted with R3b2;
• and
• wherein when R1b is
• and Ring A4b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, then R3b3 is optional;
• X1b, X2b and X3b are independently N or CR4b1;
• X5b, X6b and X7b are independently N or CR4b3;
• R3a1, R3a2, R3a9, R3b1, R3b2 and R3b9 are independently selected from the group consisting of —OH, —N(Rm)Rn, —C1-4 alkyl-N(Rm)Rn, —OC2-4 alkyl-N(Rm)Rn,
• R3a3, R3b3, R3a6 and R3b6 are independently selected from the group consisting of —Rx1, C1-4 alkyl, C3-7 cycloalkyl, —C(═O)C1-4 alkyl and -Heta1, wherein the —C3-7 cycloalkyl, the —C(═O)C1-4 alkyl and the -Heta1 is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —C1-4 alkyl, —OH, —N(Rm)Rn, —C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —NHC(═O)C1-4 alkyl and —C(═O)N(Rm)Rn, wherein the —C1-4 alkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, —N(Rm)Rn, C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —NHC(═O)C alkyl and —C(═O)N(Rm)Rn;
• R3a4, R3a7, R3b4 and R3b7 are independently selected from the group consisting of -halogen, —C1-4 alkyl, —C3-7 cycloalkyl, —OH, —OC1-4 alkyl, —N(Rm)Rn, —C1-4 alkyl(Rm)Rn, —C(═O)OH, —C1-4 alkyl-C(═O)OH, —C(═O)OC1-4 alkyl and —C1-4 alkyl-C(═O)OC1-4 alkyl;
• wherein the —C1-4 alkyl, is optionally substituted with one or two substituents selected from the group consisting of -halogen, —OH, —C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —NHC(═O)C1-4 alkyl and C(═O)N(Rm)Rn, and wherein the —C3-7 cycloalkyl and the —OC1-4 alkyl is optionally substituted with one or two substituents selected from the group consisting of -halogen, —OH, —C1-4 alkyl, —C1-4 alkoxy, C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —NHC(═O)C1-4 alkyl and —C(═O)N(Rm)Rn,
• R3a5, R3a8, R3b5 and R3b8 are independently selected from the group consisting of —C(═O)OH, —C1-4 alkyl and —C3-7 cycloalkyl;
• wherein the —C1-4 alkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —N(Rm)C(═O)C1-4 alkyl, —C(═O) N(Rm)Rn and —N(Rm)Rn, and wherein the —C3-7 cycloalkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, —C1-4 alkyl, —C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl, —N(Rm)C(═O)C1-4 alkyl, —C(═O) N(Rm)Rn and —N(Rm)Rn;
• R3a10 and R3b10 are independently selected from the group consisting of —C1-4 alkyl, —C3-7 cycloalkyl and —(C1-4 alkyl)N(Rm)Rn, wherein the —C1-4 alkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, OH, —C1-4 alkoxy, —C(═O)OH, —(C═O)NHS(═O)2(C1-4 alkyl) and —NHC(═O)C1-4 alkyl, and wherein the —C3-7 cycloalkyl and the —(C1-4 alkyl)N(Rm)Rn is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, —C1-4 alkyl, —C1-4 alkoxy, —C(═O)OH, —C(═O)OC1-4 alkyl, —(C═O)NHS(═O)2(C1-4 alkyl) and —NHC(═O)C1-4 alkyl;
• each Rm and each Rn are independently selected from the group consisting of hydrogen, —Rx2, —C1-4 alkyl, C3-7 cycloalkyl, —C(═O)C1-4 alkyl and -Heta1, wherein the —C1-4 alkyl, the —C3-7 cycloalkyl and the —C(═O)C1-4 alkyl is optionally substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, -NH2—C1-4 alkyl, —OC1-4 alkyl, C(═O)OH, —C(═O)OC1-4 alkyl, —C(═O)NHS(═O)2C1-4 alkyl and —NHC(═O)C1-4 alkyl;
• or
• Rm and Rn are taken together along with the atom to which Rm and Rn are attached to form an optionally substituted 4-7 monocyclic heterocyclic ring or an optionally substituted 7-10 bicyclic heterocyclic ring;
• Rx1 and Rx2 are independently selected from the group consisting of:
• RW, RW1, RW2, RW3 and RW4 are independently selected from the group consisting of an unsubstituted —C1-4 alkyl and a substituted —C1-4 alkyl substituted with one or two or three substituents selected from the group consisting of -halogen, —OH, —OC1-4 alkyl, —C(═O)OH and —C(═O)OC1-4 alkyl;
• Heta1 is an optionally substituted 5-, 6- or 7-membered monocyclic heteroaryl, an optionally substituted 4-, 5-, 6- or 7-membered monocyclic heterocyclyl, an optionally substituted fused 8-, 9-, 10- or 11-membered bicyclic heteroaryl or an optionally substituted fused 8-, 9-, 10- or 11-membered heterocyclyl, wherein each heteroaryl and each heterocyclyl contains at least one heteroatom independently selected from the group consisting of O, S, S(═O), S(═O)2 and N;
• n1, n2, n3, n4, n5, n6, n7 and n8 are independently 1 or 2;
• m1, m2, m3 and m4 are independently 1 or 2;
• R2d and R2f are independently selected from the group consisting of hydrogen, halogen, cyano, —CH3, —CH2CH3, —CH2OH, —OCH3 and —SCH3;
• R2a, R2b, R2c, R2e, R2g, R2h are independently selected from the group consisting of hydrogen and halogen;
• R4a1, R4a3, R4b1 and R4b3 are selected from the group consisting of hydrogen, halogen, cyano, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkoxy.