Modulators of p97 aaa atpase activity

A method of treating cancer or a neurodegenerative disease susceptible to treatment by p97 inhibition and/or modulation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one pharmaceutically acceptable excipient and a compound selected from the group consisting of:

• (a) a compound having a structure of Formula (I):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• Y′ is alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclyl, or a bond;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (b) a compound having a structure of Formula (Ia):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, NR, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (c) a compound of Formula (IIa):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• and
• R8 is selected from the group consisting of H,
• wherein indicates a point of attachment to O;
• (d) a compound having a structure of Formula (Ib):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or NR;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R6 is independently selected from the group consisting of alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• p is 0, 1, or 2;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (e) a compound having a structure of Formula (IIb):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• and
• R8 is selected from the group consisting of H,
• wherein indicates a point of attachment to O;
• (f) a compound having a structure of Formula (Ic):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or NR;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is independently selected from the group consisting of NO2, optionally substituted alkynyl, optionally substituted alkenyl, C1-6 alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• R6 is independently selected from the group consisting of NO2, optionally substituted alkynyl, optionally substituted alkenyl, alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• p is 0, 1, or 2;
• q is 0, 1, 2, 3, 4, or 5;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R)2;
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• (g) a compound of Formula (III):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, NR, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• Y′ is alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclyl, or a bond;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• k is 1, 2, 3, 4, or 5;
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —CO—, —CO(NR)—, —SO0-2—, —SO0-2NR—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R9 is H, nitrile, halogen, —C(O)(optionally substituted alkyl), optionally substituted heterocycle, optionally substituted cyclic ring, or optionally substituted alkyl;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• and
• (h) a compound selected from the group consisting of:
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

A method of treating antibacterial and/or antiviral infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a compound selected from the group consisting of:

• (a) a compound having a structure of Formula (I):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• Y′ is alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclyl, or a bond;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (b) a compound having a structure of Formula (Ia):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, NR, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (c) a compound of Formula (IIa):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• and
• R8 is selected from the group consisting of H,
• wherein indicates a point of attachment to O;
• (d) a compound having a structure of Formula (Ib):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or NR;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R6 is independently selected from the group consisting of alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• p is 0, 1, or 2;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• (e) a compound having a structure of Formula (IIb):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• and
• R8 is selected from the group consisting of H,
• wherein indicates a point of attachment to O;
• (f) a compound having a structure of Formula (Ic):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, or NR;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is independently selected from the group consisting of NO2, optionally substituted alkynyl, optionally substituted alkenyl, C1-6 alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• R6 is independently selected from the group consisting of NO2, optionally substituted alkynyl, optionally substituted alkenyl, alkyl, —CF3, —OR, —CN, —CO2R, halogen, —SR, —SOR, —SO2R, —SF5, and —NR2;
• p is 0, 1, or 2;
• q is 0, 1, 2, 3, 4, or 5;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R)2;
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• (g) a compound of Formula (III):
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
• X is O, SO0-2, NR, or C(R7)2;
• Y is optionally substituted aryl, optionally substituted alkenyl, alkynyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocyclyl;
• Y′ is alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclyl, or a bond;
• R2 and R3 are independently H, optionally substituted C1-6 alkyl, optionally substituted C1-9 cyclic, optionally substituted C3-9 heterocyclyl, or halogen, or R2 and R3 together form an optionally substituted C3-9 cyclic or optionally substituted 3- to 9-membered heterocyclyl ring;
• Z is O, SO0-2, NR, C(R7)2, alkenyl or alkynyl;
• R1 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted non-aromatic heterocyclic;
• R4 is H, C(R7)2, aryl, or heteroaryl;
• R5 is H, nitrile, an optionally substituted aryl, an optionally substituted heterocycle, optionally substituted C1-C6 alkyl, optionally substituted C3-C9 cycloalkyl, or
• where
• k is 1, 2, 3, 4, or 5;
• R′ and R″ are each independently selected from the group consisting of H, optionally substituted alkyl, —OR, halogen, —N(R)2, optionally substituted cycloalkyl, and optionally substituted heterocyclyl;
• or R′ and R″ may together form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 6-membered non-aromatic heterocycle;
• D′ is selected from the group consisting of —O—, —NR—, —OCONR—, —OCO—, —CO—, —CO(NR)—, —SO0-2—, —SO0-2NR—, —NRSO2—, —NRCO—, —NRSO2NR—, —NRCOO—, —NRCONR—, and —NRC(NR)NR—;
• E′ is selected from the group consisting of a bond, an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted cycloalkyl;
• and
• F′ is selected from the group consisting of H, an optionally substituted cycloalkyl, an optionally substituted non-aromatic heterocycle, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted cycloalkyl;
• R7 is independently selected from the group consisting of H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, —OR, and —N(R);
• and
• A is H, halogen, nitrile, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclyl, —COR, —CON(R)2, or —COOR;
• R9 is H, nitrile, halogen, —C(O)(optionally substituted alkyl), optionally substituted heterocycle, optionally substituted cyclic ring, or optionally substituted alkyl;
• provided that the compound is not 3-(4-((2-(cyclohex-2-en-1-ylthio)-1-(pyridin-3-yl)-1H-imidazol-5-yl)methoxy)-2-methylphenyl)prop-2-yn-1-yl (2-(4-isopropylpiperazin-1-yl)ethyl)carbamate;
• and
• (h) a compound selected from the group consisting of:
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.