Nicotinate and nicotinamide riboside-based compounds and derivatives thereof

A nicotinate/nicotinamide riboside compound or derivative of formula (V), or a salt, hydrate, or solvate thereof:

• wherein:
• Q is absent,
• or H;
• R1 is HPO4, H2PO4, —OH, or —OC(O)R4;
• R2 and R3 are independently —OH, —C(O)R4, —C(O)OR4, —C(O)NHR4 or halogen;
• R4 is —H, C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• X is O, NH, NR7, or S;
• L is a bond, C1-20 alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or —R1—S—S—R11—, wherein the C1-20 alkyl is optionally substituted with one or more groups selected from an amino acid side chain, —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Rb, —CO2Rb, —O—C(O)Rb, —NHC(O)Rb, —NRbC(O)Rb, —NO2, —CN, and —SO2Rb, and the aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy, are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Rb, —CO2Rb, —O—C(O)Rb, —NHC(O)Rb, —NRbC(O)Rb, —NO2, —CN, and —SO2Rb, wherein each Rb is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• Y is —C(O)NH2, —C(O)OH, —R5, —P(R7)3, —NH2, —NHR5,
• —SH, or —OH;
• R5 is —C(O)R4,
• R7 is individually selected at each occurrence from the group consisting of substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
• R8 is HPO4, H2PO4, —OH or —OC(O)R4;
• R9 and R10 are independently —H, —C(O)R4, —C(O)OR4, —C(O)NHR4 or halogen;
• R11 is C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• G is an anion (e.g., a pharmaceutically acceptable anion);
• and
• Z is H, or C1-20 alkyl;
• or Z and R1 are optionally taken together as a bond, forming a macrocycle,
• with the proviso that if X is O, NH, or NR7, and L is C1-20 alkyl, aryl, heteroaryl, or alkoxy, then Y is not —C(O)NH2, —C(O)OH, —R5, —NH2, —NHR5, —SH, or —OH.

A compound or derivative of formula (IV), or a salt, hydrate, or solvate thereof:

• wherein:
• R1 is HPO4, H2PO4, —OH, or —OC(O)R4;
• R2 and R3 are independently —OH, —C(O)R4, —C(O)OR4, —C(O)NHR4 or a halogen;
• R4 is —H, C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• R5, R6, R7, R8 are independently a lone pair, H, a C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10 alkyl and C3-10 cycloalkyl are optionally substituted with -alkyl, —O-alkyl, —N(R9)2;
• R9 is —H, or a C1-10 alkyl;
• and
• G is an anion (e.g., a pharmaceutically acceptable anion).

A nicotinate/nicotinamide riboside compound or derivative of formula (V), or a salt, hydrate, or solvate thereof:

• wherein:
• Q is absent,
• or H;
• R1 is HPO4, H2PO4, —OH, or —OC(O)R4;
• R2 and R3 are independently —OH, —C(O)R4, —C(O)OR4, —C(O)NHR4 or halogen;
• R4 is —H, C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• X is O, NH, NR7, or S;
• L is a bond, C1-20 alkyl, aryl, heteroaryl, arylalkylaryl, arylalkyl, alkoxy, or —R11—S—S—R11—, wherein the C1-20 alkyl is optionally substituted with one or more groups selected from an amino acid side chain, —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Rb, —CO2Rb, —O—C(O)Rb, —NHC(O)Rb, —NRbC(O)Rb, —NO2, —CN, and —SO2Rb, and the aryl, heteroaryl, arylalkylaryl, arylalkyl, and alkoxy, are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Rb, —CO2Rb, —O—C(O)Rb, —NHC(O)Rb, —NRbC(O)Rb, —NO2, —CN, and —SO2Rb, wherein each Rb is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• Y is —C(O)NH2, —C(O)OH, —R5, —P(R7)3, —NH2, —NHR5,
• —SH, or —OH;
• R5 is —C(O)R4,
• R7 is individually selected at each occurrence from the group consisting of substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl;
• R8 is HPO4, H2PO4, —OH or —OC(O)R4;
• R9 and R10 are independently —H, —C(O)R4, —C(O)OR4, —C(O)NHR4 or halogen;
• R11 is C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• and
• Z is H, or C1-20 alkyl;
• or Z and R1 are optionally taken together as a bond, forming a macrocycle,
• with the proviso that if X is O, NH, or NR7, and L is C1-20 alkyl, aryl, heteroaryl, or alkoxy, then Y is not —C(O)NH2, —C(O)OH, —R5, —NH2, —NHR5, —SH, or —OH.

A compound or derivative of formula (IV), or a salt, hydrate, or solvate thereof:

• wherein:
• R1 is HPO4, H2PO4, —OH, or —OC(O)R4;
• R2 and R3 are independently —OH, —C(O)R4, —C(O)OR4, —C(O)NHR4 or a halogen;
• R4 is —H, C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-20 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups selected from —OH, halogen, -alkyl, —O-alkyl, —N-alkyl, -alkenyl, -alkynyl, —O-aryl, —O-heteroaryl, —N-aryl, —N-heteroaryl, -aryl, —C(O)Ra, —CO2Ra, —O—C(O)Ra, —NHC(O)Ra, —NRaC(O)Ra, —NO2, —CN, and —SO2Ra, wherein each Ra is independently Ar, C1-6 alkyl, or CH2Ar;
• and Ar is an aryl or heteroaryl;
• R5, R6, R7, R8 are independently a lone pair, H, a C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-10alkyl and C3-10 cycloalkyl are optionally substituted with -alkyl, —O-alkyl, —N(R9)2;
• and
• R9 is —H, or a C1-10 alkyl.

A method of making Compound 1, wherein the method is performed as depicted in Scheme I:

• wherein
• R50 is alkyl;
• G1 is an anion;
• and
• G2 is a cation.

A method of making Compound 1, wherein the method is performed as depicted in Scheme II:

• wherein
• R51 is alkyl or aralkyl;
• and
• G3 is an anion.