Nicotinamide mononucleotide derivatives and their uses

A composition comprising a compound of formula II:

• or a pharmaceutically acceptable salt thereof, wherein:
• (a) R1 is hydrogen;
• n-alkyl;
• branched alkyl;
• cycloalkyl;
• or aryl, where aryl is optionally substituted with at least one of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C1-6 haloalkyl, —N(R1′)2, C1-6 acylamino, —NHSO2C1-6 alkyl, —SO2N(R1′)2, COR1″, and —SO2C1-6 alkyl;
• R1′ is independently hydrogen or alkyl selected from C1-20 alkyl, C1-10 alkyl, or C1-6 alkyl, and
• R1″ is —OR′ or —N(R1′)2;
• (b) R2 is hydrogen, C1-10 alkyl;
• or C(O)CR3aR3bNHR1, where n is 2 to 4;
• or
• R3a or R3b and R2 together are (CH2)n forming a cyclic ring that includes the adjoining N and C atoms;
• (c) R3a and R3b are:
• (i) independently selected from hydrogen, C1-10 alkyl, cycloalkyl, —(CH2)c(NR3′)2, C1-6 hydroxyalkyl, —CH2SH, —(CH2)2S(O)dMe, —(CH2)3NHC(═NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH2)eCOR3″, aryl and aryl C1-3 alkyl, said aryl groups are optionally substituted with a group selected from hydroxyl, C1-10 alkyl, C1-6 alkoxy, halogen, nitro and cyano;
• or
• (ii) R3a and R3b both are C1-6 alkyl;
• or
• (iii) R3a and R3b together are (CH2)f so as to form a spiro ring;
• or
• (iv) R3a is hydrogen and R3b and R2 together are (CH2)n forming a ring that includes the adjoining N and C atoms;
• or
• (v) R3b is hydrogen and R3a and R2 together are (CH2)n forming a ring that includes the adjoining N and C atoms;
• or
• (vi) R3a is H and R3b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl;
• or
• (vii) R3a is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-indol-3-yl, —CH2CH2SCH3, CH2CO2H, CH2C(O)NH2, CH2CH2COOH, CH2CH2C(O)NH2, CH2CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4′-OH)-Ph), CH2SH, or lower cycloalkyl and R3b is H;
• c is from 1 to 6,
• d is from 0 to 2,
• e is from 0 to 3,
• f is from 2 to 5,
• n is from 2 to 4;
• and
• (d) R4 is hydrogen;
• C1-10 alkyl optionally substituted with lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen;
• C1-10 haloalkyl;
• C3-10 cycloalkyl;
• cycloalkyl alkyl;
• cycloheteroalkyl;
• aminoacyl;
• aryl;
• heteroaryl;
• substituted aryl;
• or substituted heteroaryl;
• and a pharmaceutically acceptable carrier, diluent,
• stabilizer or excipient.

A method of making the compound of formula III:

• wherein W1 and W2 are each independently O− or OR5, and R5 is hydrogen or alkyl;
• provided that when W1 is O−, and W2 is OR5′ then R5 is not hydrogen, methyl or butyl;
• the method comprising:
• reacting a compound having the structure:
• with a compound having the structure:
• in the presence of tetrazole and acetonitrile to afford compound (iii):
• and converting compound (iii) to the compound of formula III.

A method of preparing a crystalline solid form of the compound of formula III:

• wherein W1 and W2 are each independently O− or OR5, and R5 is hydrogen or alkyl;
• provided that when W1 is O−, and W2 is OR5′ then R5 is not hydrogen, methyl or butyl;
• wherein the method comprises:
• a) dissolving the compound of formula III in a solvent to form a solution;
• and
• b) crystallizing the compound of formula III from the solution to form the crystalline solid, wherein the solvent comprises ethyl acetate and methanol.