Nicotinamide mononucleotide derivatives and their uses

1. A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula I:

wherein V is selected from hydrogen, phenyl and monocyclic heteroaryl, wherein (i) each said monocyclic heteroaryl contains five or six ring atoms of which 1 or 2 ring atoms are heteroatoms selected from N, S, and O, and the remainder of the ring atoms are carbon, and (ii) each said phenyl or monocyclic heteroaryl is unsubstituted or is substituted by one or two groups independently selected from halogen, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and cyano.

2. The compound of claim 1 , or a stereoisomer or salt thereof, wherein V is selected from the following substituents:

3. The compound of claim 1 , or a stereoisomer or salt thereof, wherein the compound is selected from

4. A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula II:

(a) each R 1 is independently hydrogen; n-alkyl; branched alkyl; cycloalkyl; or aryl, where aryl is optionally substituted with at least one of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, F, Cl, Br, I, nitro, cyano, C 1-6 haloalkyl, —N(R 1′ ) 2 , C 1-6 acylamino, —NHSO 2 C 1-6 alkyl, —SO 2 N(R 1′ )2, COR 1″ , and —SO 2 C 1-6 alkyl;

each R 1′ is independently hydrogen or C 1-20 alkyl, and

R 1″ is —OR 1′ or —N(R 1′ ) 2 ;

(b) R 2

is hydrogen, C 1-10 alkyl, or C(O)CR 3a R 3b N HR1 ; or

R 2 and either R 3a or R 3b together are (CH 2 ) n , forming a ring that includes the intervening N and C atoms, where n is from 2 to 4;

(c) each R 3a and R 3b are

(i) independently selected from hydrogen, C 1-10 alkyl, cycloalkyl, —(CH 2 ) c (NR 3′ ) 2 , C 1-6 hydroxyalkyl, —CH 2 SH, —(CH 2 ) 2 S(O) d Me, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH 2 ) e COR 3 , aryl and aryl C 1-3 alkyl, said aryl groups are optionally substituted with a group selected from hydroxyl, C 1-10 alkyl, C 1-6 alkoxy, halogen, nitro and cyano; or

(ii) R 3a and R 3b both are C 1-6 alkyl; or

(iii) R 3a and R 3b together are (CH 2 ) f so as to form a spiro ring; or

(iv) R 3a is hydrogen and R 3b and R 2 together are (CH 2 ) n forming a ring that includes the adjoining N and C atoms; or

(v) R 3b is hydrogen and R 3a and R 2 together are (CH 2 ) n forming a ring that includes the adjoining N and C atoms; or

(vi) R 3a is H and R 3b is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or C 3-7 cycloalkyl; or

(vii) R 3a is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 Ph, CH 2 -indol-3-yl, —CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C(O)NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C(O)NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(NH)NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH(OH)CH 3 , CH 2 ((4′-OH)-Ph), CH 2 SH, or C 3-7 cycloalkyl and R 3b 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) R 4 is hydrogen; C 1-10 alkyl optionally substituted with alkoxy, di(C 1-6 - alkyl)-amino, or halogen; C 1-10 haloalkyl; C 3-10 cycloalkyl; cycloalkyl alkyl; cycloheteroalkyl; aminoacyl; aryl; heteroaryl; substituted aryl; or substituted heteroaryl.

5. The compound of claim 4 , or a stereoisomer or salt thereof, wherein R 1 is optionally substituted phenyl or naphthyl.

6. The compound of claim 4 , or a stereoisomer or salt thereof, wherein R 1′ is C 1-10 alkyl.

7. A compound, or a stereoisomer or salt thereof, selected from

8. A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein each W 1 and W 2 is independently

(i) each R c and R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl; or

(ii) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl; or

(iii) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl wherein the chirality of the carbon to which said R c and R d is attached is S; or

(iv) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl wherein the chirality of the carbon to which said R c and R d is attached is R; or

(v) each R c is H and each R d is independently (C 1 -C 8 )alkyl; or

(vi) each R c is H and each R d is independently (C 1 -C 8 )alkyl wherein the chirality of the carbon to which said R c and R d is attached is S; or

(vii) each R c is H and each R d is independently (C 1 -C 8 )alkyl wherein the chirality of the carbon to which said R c and R d is attached is R; and

each R 6 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl or (C 4 -C 8 )carbocyclylalkyl.

9. The compound, or a stereoisomer or salt thereof, of claim 8 , wherein each

comprises a nitrogen-linked naturally occurring a-amino acid ester.

10. The compound, or a stereoisomer or salt thereof, of claim 8 , wherein each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl.

11. The compound, or a stereoisomer or salt thereof, of claim 8 , wherein each R c is H and each R d is independently (C 1 -C 8 )alkyl.

12. The compound, or a stereoisomer or salt thereof, of claim 8 , wherein each R 6 is independently (C 1 -C 8 )alkyl.

13. A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein one of W 1 and W 2 is OR 5

R 5 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl; and

the other of W 1 and W 2 is

(i) each R c and R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl; or

(ii) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl; or

(iii) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl wherein the chirality of the carbon to which said R c and R d is attached is S; or

(iv) each R c is H and each R d is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl wherein the chirality of the carbon to which said R c and R d is attached is R; or

(v) each R c is H and each R d is independently (C 1 -C 8 )alkyl; or

(vi) each R c is H and each R d is independently (C 1 -C 8 )alkyl wherein the chirality of the carbon to which said R c and R d is attached is S; or

(vii) each R c is H and each R d is independently (C 1 -C 8 )alkyl wherein the chirality of the carbon to which said R c and R d is attached is R; and

each R 6 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl or (C 4 -C 8 )carbocyclylalkyl.

14. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 5 is (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl.

15. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 5 is unsubstituted phenyl.

16. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 5 is pyridyl.

17. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein one of R c or R d is H and the other of R c or R d is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl.

18. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein one of R c or R d is H and the other of R c or R d is (C 1 -C 8 )alkyl.

19. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 5 is unsubstituted phenyl, one of R c or R d is H and the other of R c or R d is methyl.

20. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 6 is (C 1 -C 8 )alkyl.

21. The compound, or a stereoisomer or salt thereof, of claim 13 , wherein R 5 is unsubstituted phenyl and R 6 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, or (C 4 -C 8 )carbocyclylalkyl.

22. A compound, or a stereoisomer or salt thereof, wherein the compound has a structure represented by formula III:

wherein W 1 and W 2 are independently selected from the substituents in Table 1, and

each R 21 is independently H or (C 1 -C 8 )alkyl;

each R 22 is independently H, R 21 , R 23 or R 24 , wherein each R 24 is independently substituted with 0 to 3 R 23 ;

each R 23 is independently R 23a , R 23b , R 23c or R 23d , provided that when R 23 is bound to a heteroatom, then R 23 is R 23c or R 23d ;

each R 23a is independently F, Cl, Br, I, —CN, —N 3 or —NO 2 ;

each R 23b is independently Y 21 ;

each R 23c is independently —R 2x , —OR 2x , —N(R 2x )(R 2x ), —SR 2x , —S(O)R 2x ; —S(O) 2 R 2x , —S(O)(OR 2x ), —S(O) 2 (OR 2x ), —OC(═Y 21 )R 2x , —OC(═Y 21 )OR 2x , —OC(═Y 21 )(N(R 2x )(R 2x )); —SC(═Y 21 )R 2x ; —SC(═Y 21 )OR 2x , —SC(═Y 21 )(N(R 2x )(R 2x )), —N(R 2x )C(═Y 21 )R 2x , —N(R 2x )C(═Y 21 )OR 2x , or —N(R 2x )C(═Y 21 )(N(R 2x )(R 2x ));

each R 23d is independently —C(═Y 21 )R 2x ; —C(═Y 21 )OR 2x or —C(═Y 21 )(N(R 2x )(R 2x ));

each R 2x is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heteroaryl; or two R 2x taken together with a nitrogen or oxygen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR 21 —; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR 21 —;

each R 24 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;

each R 25 is independently R 24 , wherein each R 24 is substituted with 0 to 3 R 23 groups;

each R 25a is independently (C 1 -C 8 )alkylene, (C 2 -C 8 )alkenylene, or (C 2 -C 8 )alkynylene, any one of which said (C 1 -C 8 )alkylene, (C 2 -C 8 )alkenylene, or (C 2 -C 8 )alkynylene is substituted with 0-3 R 23 groups;

each W 23 is independently W 24 or W 25 ;

each W 24 is independently R 25 , —C(═Y 21 )R 25 , —C(═Y 21 )W 25 , —SO 2 R 25 , or —SO 2 W 25 ;

each W 25 is independently carbocycle or heterocycle, wherein W 25 is independently substituted with 0 to 3 R 22 groups; and

each Y 21 is independently O or S.

23. The compound of claim 8 , or a stereoisomer or salt thereof, wherein R d and R c are selected such that

represents an ester of a naturally occurring α-amino acid.

24. The compound of claim 1 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

25. The compound of claim 4 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

26. The compound of claim 7 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

27. The compound of claim 8 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

28. The compound of claim 13 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

29. The compound of claim 22 , or a salt thereof, wherein the salt is formed with an anion selected from acetate, triflate, halide, trifluoroacetate, and formate.

30. The compound of claim 1 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4 − , HPO 4 − , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .

31. The compound of claim 4 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4 − , HPO 4 2− , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .

32. The compound of claim 7 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4− , HPO 4 2− , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .

33. The compound of claim 8 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4 − , HPO 4 2− , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .

34. The compound of claim 13 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4 − , HPO 4 2− , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .

35. The compound of claim 22 , or a salt thereof, wherein the salt is formed with an anion selected from OH − , H 2 PO 4 − , HPO 4 2− , HSO 4 − , SO 4 2− , NO 3 − , HCO 3 − , and CO 3 2− .