Substituted fused bicyclic macrocyclic compounds and related methods of treatment

A compound of Formula II-A or a pharmaceutically acceptable salt thereof:

• wherein:
• fused ring A is a C4-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
• is a single bond or double bond;
• J and L are each, independently, C or N;
• M is N or CR19;
• Q is N or CR20;
• G is C(═O) or S(═O)2;
• n is 1, 2, or 3;
• E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
• T is CR1R2 or O;
• W is CR4R5 or O;
• U is CR6R7;
• X is CR8R9;
• V is CR3 or N;
• Y is NR10, O or absent;
• Z is (CR12R13)m;
• Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
• m is 1, 2, 3, or 4;
• and further wherein:
• R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
• R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
• or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
• each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen;
• and
• R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• and
• R19 and R20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium.

A compound of Formula III-A or a pharmaceutically acceptable salt thereof:

• wherein:
• fused ring A is a C4-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
• is a single bond or double bond;
• J and L are each, independently, C or N;
• M is N or CR19;
• Q is N or CR20;
• G is C(═O) or S(═O)2;
• n is 1, 2, or 3;
• E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
• T is CR1R2 or O;
• W is CR4R5 or O;
• U is CR6R7;
• X is CR8R9;
• V is CR3 or N;
• Y is NR10, O or absent;
• Z is (CR12R13)m;
• Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
• m is 1, 2, 3, or 4;
• and further wherein:
• R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
• R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
• or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
• each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen;
• and
• R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• and
• R19 and R20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium.

A compound of Formula IV-A or a pharmaceutically acceptable salt thereof:

• wherein:
• fused ring A is a C4-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
• is a single bond or double bond;
• J and L are each, independently, C or N;
• M is N or CR19;
• Q is N or CR20;
• G is C(═O) or S(═O)2;
• n is 1, 2, or 3;
• E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
• T is CR1R2 or O;
• W is CR4R5 or O;
• U is CR6R7;
• X is CR8R9;
• V is CR3 or N;
• Y is NR10, O or absent;
• Z is (CR12R13)m;
• Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
• m is 2, 3, 4, or 5 when Y is absent;
• or
• m is 1, 2, 3, or 4 when Y is NR10 or O;
• and further wherein:
• R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
• R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
• or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
• each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen;
• and
• R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• and
• R19 and R20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium.

A compound of Formula V-A or a pharmaceutically acceptable salt thereof:

• wherein:
• fused ring A is a C4-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
• is a single bond or double bond;
• J and L are each, independently, C or N;
• M is N or CR19;
• Q is N or CR20;
• G is C(═O) or S(═O)2;
• n is 1, 2, or 3;
• E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
• T is CR1R2 or O;
• W is CR4R5 or O;
• U is CR6R7;
• X is CR8R9;
• V is CR3 or N;
• Y is NR10, O or absent;
• Z is (CR12R13)m;
• Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
• m is 2, 3, 4, or 5 when Y is absent;
• or
• m is 1, 2, 3, or 4 when Y is NR10 or O;
• and further wherein:
• R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
• R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
• or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
• each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen;
• and
• R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• and
• R19 and R20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium.

A compound of Formula VI-A or a pharmaceutically acceptable salt thereof:

• wherein:
• fused ring A is a C4-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C4-C8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
• is a single bond or double bond;
• J and L are each, independently, C or N;
• M is N or CR19;
• Q is N or CR20;
• G is C(═O) or S(═O)2;
• n is 1, 2, or 3;
• E is selected from the group consisting of H, hydroxyl, NRaRb, C(═O)NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
• T is CR1R2 or O;
• W is CR4R5 or O;
• U is CR6R7;
• X is CR8R9;
• V is CR3 or N;
• Y is NR10, O or absent;
• Z is (CR12R13)m;
• Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
• m is 2, 3, 4, or 5 when Y is absent;
• or
• m is 1, 2, 3, or 4 when Y is NR10 or O;
• and further wherein:
• R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
• R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
• or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
• R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
• R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
• each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen;
• and
• R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
• and
• R19 and R20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium.