Compositions comprising prodrugs of hydroxamate-based compounds and methods of making and using same

A compound of Formula (IV):

• or a stereo-isomer, an enantiomer, a polymorph, a pharmaceutically acceptable salt, an ester or a derivative thereof, wherein
• n is an integer selected from 0, 1, 2, 3, or 4;
• R11 is —C≡C—R33, C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R18, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R18, or heterocyclyl optionally substituted with R18;
• wherein R33 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R19, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R19, a C3-C7 cyclyl or heterocyclyl optionally substituted with R19;
• R12 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R13 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R14 is C1-C6 haloalkyl;
• R15 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R16 is hydrogen or C1-C6 alkyl;
• each R17 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R18 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-(C1-C6 alkoxy), —C1-C6 alkyl-NH2, —C1-C6alkyl-NH—C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, —C1-C6 alkyl-NH(SO2 C1-C6 alkyl), —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —NH(SO2 C1-C6 alkyl), —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C1-C6 alkyl-CONH2, —C1-C6 alkyl-CONH(C1-C6 alkyl), —C1-C6 alkyl- CON(C1-C6 alkyl)2, —C1-C6 alkyl-CONH—OH, —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl- CO2H, and —C1-C6 alkyl-CO2(C1-C6 alkyl);
• or two R18 groups when attached to the same carbon atom form ═O;
• each R19 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —C1-C6 alkyl-OH, —C1-C6 alkyl-(C1-C6 alkoxy), —C1-C6 alkyl-NH2, —C1-C6 alkyl-NH—C1-C6 alkyl), —C1-C6 alkyl-N(C1-C6 alkyl)2, —C1-C6 alkyl-NH(SO2 C1-C6 alkyl), —CONH2, —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —NH(SO2 C1-C6 alkyl), —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C1-C6 alkyl-CONH2, —C1-C6 alkyl-CON(C1-C6 alkyl), —C1-C6 alkyl-CON(C1-C6 alkyl)2, —C1-C6 alkyl-CONH—OH, —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, and —C1-C6 alkyl-CO2(C1-C6 alkyl);
• or two R19 groups when attached to the same carbon atom form ═O;
• and
• each R21 is independently selected from Formula (IIa), Formula (IIb), or Formula (IIc):
• wherein each AM is independently selected from Na, Li, K, Rb, or C1-C6 alkyl.

A compound of Formula (VI):

• or a stereo-isomer, an enantiomer, a polymorph, a pharmaceutically acceptable salt, an ester, or a derivative thereof, wherein
• L represents a linker, wherein L is absent or is selected from the group consisting of —C≡C—C≡C—, or —C≡C—R32, wherein R32 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R29, (C3-C8 cycloalkyl)-C1-C6 alkyl- optionally substituted with R29, C3-C7 cyclyl, and heterocyclyl optionally substituted with R29;
• Y1 represents aryl optionally substituted with R28, heteroaryl optionally substituted with R28, cycloalkyl, or heterocyclyl optionally substituted with R28;
• n is an integer selected from 0, 1, 2, 3, or 4;
• R30 is hydrogen, C1-C6 alkyl optionally substituted with R29, aryl optionally substituted with R29, heteroaryl optionally substituted with R29, or heterocyclyl optionally substituted with R29;
• R22 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), -hydroxy(C1-C6 alkyl), -alkoxy(C1-C6 alkyl), or -amino(C1-C6 alkyl);
• R23 is halogen, —C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R24 is C1-C6 haloalkyl;
• R25 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R26 is hydrogen or C1-C6 alkyl;
• each R27 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R29 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups when attached to the same carbon atom form ═O;
• each R29 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R9 groups when attached to the same carbon atom form ═O;
• and
• each R31 is independently selected from Formula (IIa), Formula (IIb), or Formula (IIc):
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl.

A method of synthesizing a compound of Formula (I), the method comprising:

• (a) contacting a compound of Formula (I′)
• with a phosphate salt of the formula
• in the presence of a base catalyst to form a reaction mixture;
• and
• (b) contacting the reaction mixture with an alkali metal hydroxide to form a compound of Formula (I):
• wherein
• X is a halogen;
• Y represents aryl optionally substituted with R8, heteroaryl optionally substituted with R8, cycloalkyl or heterocyclyl optionally substituted with R8;
• n is an integer 0, 1, 2, 3, or 4;
• R1 is hydrogen, C1-C6 alkyl optionally substituted with R9, aryl optionally substituted with R9, heteroaryl optionally substituted with R9, or heterocyclyl optionally substituted with R9;
• R2 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R20, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R2′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R3 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R20, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R3′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R4 is C1-C6 haloalkyl;
• R5 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R5′ is —C1-C6 alkyl, —C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CON(C1-C6 alkyl)-OH, —CONH2, —OCO(C1-C6 alkyl), —O—CH(C1-C6 alkyl)2, —CONH—NH2, —CO2H, or —CO2(C1-C6 alkyl);
• R6 is hydrogen or C1-C6 alkyl;
• each R7 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R8 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups when attached to the same carbon atom form ═O;
• each R9 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R9 groups when attached to the same carbon atom form ═O;
• and
• each R20 is independently of Formula (IIa):
• wherein each AM is independently selected from Na, Li, K, Rb, or C1-C6 alkyl.

A method of synthesizing a compound of Formula (IV), the method comprising:

• (a) contacting a compound of Formula (IV′)
• with a phosphate salt of the formula
• in the presence of a base catalyst to form a reaction mixture;
• and
• (b) contacting the reaction mixture with an alkali metal hydroxide to form a compound of Formula (IV):
• wherein
• X is a halogen;
• n is an integer 0, 1, 2, 3, or 4;
• R11 is —C≡C—R33, C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R18, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R18, or heterocyclyl optionally substituted with R18;
• wherein R33 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R19, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R19, a C3-C7 cyclyl or heterocyclyl optionally substituted with R19;
• R12 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R12′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R13 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R13′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R14 is C1-C6 haloalkyl;
• R15 is independently selected from the group consisting of —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, and —CO2(C1-C6 alkyl)-;
• R15′ is independently selected from the group consisting of —C1-C6 alkyl, —C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CON(C1-C6 alkyl)-OH, —CONH2, —OCO(C1-C6 alkyl), —O—CH(C1-C6 alkyl)2, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• R16 is hydrogen or C1-C6 alkyl;
• each R17 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R18 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups when attached to the same carbon atom form ═O;
• each R19 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R19 groups when attached to the same carbon atom form ═O;
• and
• each R21 is independently of Formula (IIa):
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl.

A method of synthesizing a compound of Formula (VI), the method comprising:

• (a) contacting a compound of Formula (VI′)
• with a phosphate salt of the formula
• in the presence of abase catalyst to form a reaction mixture;
• and
• (b) contacting the reaction mixture with an alkali metal hydroxide to form a compound of Formula (VI):
• wherein
• X is a halogen;
• L represents a linker, wherein L is absent or is selected from the group consisting of —C≡C—C≡C—, or —C≡C—R32, wherein R32 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R29, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R29, a C3-C7 cyclyl and heterocyclyl optionally substituted with R29;
• Y1 represents aryl optionally substituted with R28, heteroaryl optionally substituted with R28, cycloalkyl or heterocyclyl optionally substituted with R28;
• n is an integer 0, 1, 2, 3, or 4;
• R30 is hydrogen, C1-C6 alkyl optionally substituted with R29, aryl optionally substituted with R29, heteroaryl optionally substituted with R29, or heterocyclyl optionally substituted with R29;
• R22 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R22′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), and amino(C1-C6 alkyl);
• R23 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R23′ is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), and —NHCO(C1-C6 alkoxy);
• R24 is C1-C6 haloalkyl;
• R25 is independently selected from the group consisting of —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, and —CO2(C1-C6 alkyl)-;
• R25′ is independently selected from the group consisting of —C1-C6 alkyl, —C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH(C1-C6 alkyl)-OH, —CONH2, —OCO(C1-C6 alkyl), —O—CH(C1-C6 alkyl)2, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• R26 is hydrogen or C1-C6 alkyl;
• each R27 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R28 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups when attached to the same carbon atom form ═O;
• each R29 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R9 groups when attached to the same carbon atom form ═O;
• and
• each R31 is independently a compound of Formula (IIa):
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl.

A method of synthesizing a compound of Formula (I), comprising contacting a compound of Formula (I″)

• with a) a monophosphate kinase, b) a mixture of H3PO4 and P4O10, c) P4O10 alone, or d) a mixture of p-toluenesulfonyl chloride (TsCl) and pyridine to form a compound of Formula (I)
• wherein Y represents aryl optionally substituted with R8, heteroaryl optionally substituted with R8, cycloalkyl, or heterocyclyl optionally substituted with R8;
• X is a halogen;
• n is an integer selected from 0, 1, 2, 3, or 4;
• R1 is hydrogen, C1-C6 alkyl optionally substituted with R9, aryl optionally substituted with R9, heteroaryl optionally substituted with R9, or heterocyclyl optionally substituted with R9;
• R2 is halogen, C1-C6 alkyl, C1-C6haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R2′ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R3′ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R4 is C1-C6 haloalkyl;
• R5 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R50′ is H or Formula (IIa)
• R6 is hydrogen or C1-C6 alkyl;
• each R7 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R8 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups that when attached to the same carbon atom form ═O;
• each R9 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R9 groups that when attached to the same carbon atom form ═O;
• and
• R20 is of Formula (IIb):
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl.

A method of synthesizing a compound of Formula (IV) comprising contacting a compound of Formula (IV″)

• with a) a monophosphate kinase, b) a mixture of H3PO4 and P4O10, c) P4O10 alone, or d) a mixture of p-toluenesulfonyl chloride (TsCl) and pyridine to form a compound of Formula (IV)
• wherein n is an integer selected from 0, 1, 2, 3, or 4;
• R11 is —C≡C—R33, C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R18, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R18, or heterocyclyl optionally substituted with R18;
• R33 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R19, (C3-C8 cycloalkyl) C1-C6 alkyl-optionally substituted with R19, a C3-C7 cyclyl or heterocyclyl optionally substituted with R19;
• R12 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R12′ is halogen, C1-C6 alkyl, C1-C6haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R13 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R21, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R13′ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R14 is C1-C6 haloalkyl;
• R51′ is H or Formula (IIa)
• R15 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—1—OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R16 is hydrogen or C1-C6 alkyl;
• each R17 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R18 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups that when attached to the same carbon atom form ═O;
• each R19 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R19 groups that when attached to the same carbon atom form ═O;
• and
• R21 is Formula (IIb):
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl. In an exemplary embodiment, each AM is independently Na or methyl.

A method of synthesizing a compound of Formula (VI) comprising contacting a compound of Formula (VI″)

• with a) a monophosphate kinase, b) a mixture of H3PO4 and P4O10, c) P4O10 alone, or d) a mixture of p-toluenesulfonyl chloride (TsCl) and pyridine to form a compound of Formula (VI)
• wherein
• L represents a linker, wherein L is absent or is selected from the group consisting of —C≡C—C≡C—, or —C≡C—R32, wherein R32 is C1-C6 alkyl, C1-C6 haloalkyl, —CO(C1-C6 alkyl), —C1-C6 alkyl-CO(C1-C6 alkyl), —C1-C6 alkyl-CO2H, C3-C8 cycloalkyl optionally substituted with R29, (C3-C8 cycloalkyl) C1-C6 alkyl- optionally substituted with R29, a C3-C7 cyclyl and heterocyclyl optionally substituted with R29;
• Y1 represents aryl optionally substituted with R28, heteroaryl optionally substituted with R29, cycloalkyl, or heterocyclyl optionally substituted with R28;
• n is an integer selected from 0, 1, 2, 3, or 4;
• R30 is hydrogen, C1-C6 alkyl optionally substituted with R29, aryl optionally substituted with R29, heteroaryl optionally substituted with R29, or heterocyclyl optionally substituted with R29;
• R22 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R22′ is halogen, C1-C6 alkyl, C1-C6haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), or amino(C1-C6 alkyl);
• R23 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —O—R31, C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R23′ is halogen, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, —C1-C6 alkoxy, C1-C6 haloalkoxy, —SH, —S(C1-C6 alkyl), hydroxy(C1-C6 alkyl), alkoxy(C1-C6 alkyl), amino(C1-C6 alkyl), —NHCO(C1-C6 alkyl), —NHCONH2, —NHCONH(C1-C6 alkyl), —OCO(C1-C6 alkyl), or —NHCO(C1-C6 alkoxy);
• R24 is C1-C6 haloalkyl;
• R25 is —C1-C6 alkyl-, —C1-C6 haloalkyl-, —NH—, —NH(C1-C6 alkyl)-, —N(C1-C6 alkyl)-, —N(C1-C6 alkyl)2-, —O—, —C1-C6 alkoxy-, —C1-C6 haloalkoxy-, —CONH—, —CONH(C1-C6 alkyl)-, —CON(C1-C6 alkyl)-, —CON(C1-C6 alkyl)2-, —CONH—O—, —CON(C1-C6 alkyl)-O—, —CONH—, —OCO(C1-C6 alkyl)-, —O—C(C1-C6 alkyl)2-, —CONH—NH—, —CO2—, or —CO2(C1-C6 alkyl)-;
• R52′ is H or Formula (IIa)
• R26 is hydrogen or C1-C6 alkyl;
• each R27 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• each R28 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, d-C6 haloalkoxy, —CONH2, —CONH(C1-C6 alkyl), —CON(C1-C6 alkyl)2, —CONH—OH, —CONH—OCO(C1-C6 alkyl), —C(NH)NH—OH, —CONH—NH2, —CO2H, and —CO2(C1-C6 alkyl);
• or two R8 groups when attached to the same carbon atom form ═O;
• each R29 is independently selected from the group consisting of halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• or two R9 groups when attached to the same carbon atom form ═O;
• and
• each R31 is Formula (IIb);
• R20 is of Formula (IIb);
• wherein each AM is independently selected from Na, Li, K, Rb, or a C1-C6 alkyl.