Substituted nucleosides, nucleotides and analogs thereof

1. A compound selected from Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

B 1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;

R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid,

the dashed line (------) is absent;

R 2A is selected from the group consisting of an unsubstituted C 1-6 alkyl, a halogen substituted C 1-6 alkyl, a hydroxy substituted C 1-6 alkyl, an alkoxy substituted C 1-6 alkyl, a sulfenyl substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted —O—C 1-6 alkyl, an optionally substituted —O—C 3-6 alkenyl, an optionally substituted —O—C 3-6 alkynyl and cyano;

R 3A is selected from the group consisting of OH, —OC(═O)R″ A and an optionally substituted O-linked amino acid;

R 4A is fluoro or chloro;

R 5A is hydrogen or halogen;

R 6A , R 7A and R 8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C 1-6 alkyl), an optionally substituted *—(CR 15A R 16A ) p —O—C 1-24 alkyl, an optionally substituted *—(CR 17A R 18A ) q —O—C 1-24 alkenyl,

or

R 6A is

and R 7A is absent or hydrogen; or

R 6A and R 7A are taken together to form a moiety selected from the group consisting of an optionally substituted

and an optionally substituted

wherein the oxygens connected to R 6A and R 7A , the phosphorus and the moiety form a six-membered to ten-membered ring system;

R 9A is independently selected from the group consisting of an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, NR 30A R 31A , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;

R 10A and R 11A are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative;

R 12A , R 13A and R 14A are independently absent or hydrogen;

each R 15A , each R 16A , each R 17A and each R 18A are independently hydrogen, an optionally substituted C 1-24 alkyl or alkoxy;

R 19A , R 20A , R 22A and R 23A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;

R 21A and R 24A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl and an optionally substituted —O-aryl;

R 25A and R 29A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;

R 26A and R 27A are independently —C≡N or an optionally substituted substituent selected from the group consisting of C 2-8 organylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 organylaminocarbonyl;

R 28A is selected from the group consisting of hydrogen, an optionally substituted C 1-24 -alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl;

R 30A and R 31A are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 -alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl;

R″ A is an optionally substituted C 1-24 -alkyl;

m is 0 or 1;

p and q are independently selected from the group consisting of 1, 2 and 3;

r is 1 or 2;

Z 1A , Z 2A , Z 3A and Z 4A are independently O or S; and

provided that when R 1A is

wherein R 8A is an unsubstituted C 1-4 alkyl or phenyl optionally para-substituted with a halogen or methyl and R 9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline; R 3A is OH; R 4A is fluoro; R 5A is fluoro or hydrogen; and B 1A is an unsubstituted uracil; then R 2A cannot be —OCH 3 ;

provided that when R 1A is H; R 3A is OH; R 4A is fluoro; R 5A is fluoro; and B 1A is an unsubstituted cytosine; then R 2A cannot be allenyl; and

provided that when R 1A is H; R 3A is OH; R 4A is fluoro; R 5A is fluoro; and B 1A is an unsubstituted cytosine; then R 2A cannot be ethynyl.

2. The compound of claim 1 , wherein R 1A is

is

; and R 7A is absent or hydrogen.

3. The compound of claim 1 , wherein R 1A is an optionally substituted acyl.

4. The compound of claim 1 , wherein R 1A is H.

5. The compound of claim 1 , wherein R 1A is an optionally substituted O-linked amino acid.

6. The compound of claim 1 , wherein R 1A is

7. The compound of claim 6 , wherein both R 6A and R 7A are independently selected from the group consisting of an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C 1-6 alkyl).

8. The compound of claim 6 , wherein both R 6A and R 7A are independently selected from the group consisting of

9. The compound of claim 6 , wherein R 6A and R 7A are both

*—(CR 15A R 16A ) p —O—C 1-24 alkyl or *—(CR 17A R 18A ) q —O—C 2-24 alkenyl; or wherein R 6A and R 7A can be taken together to form a moiety selected from the group consisting of an optionally substituted

and an optionally substituted

wherein the oxygens connected to R 6A and R 7A , the phosphorus and the moiety form a six-membered to ten-membered ring system.

10. The compound of claim 6 , wherein R 8A is selected from the group consisting of absent, hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl; and R 9A is independently selected from the group consisting of an optionally substituted C 1-24 alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted C 3-6 cycloalkenyl and NR 30A R 31A .

11. The compound of claim 6 , wherein R 8A is an optionally substituted aryl; and R 9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

12. The compound of claim 6 , wherein R 1A is

and, R 10A and R 11A are both independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

13. The compound of claim 1 , wherein B 1A is selected from the group consisting of:

wherein:

R A2 is selected from the group consisting of hydrogen, halogen and NHR J2 , wherein R J2 is selected from the group consisting of hydrogen, —C(═O)R K2 and —C(═O)OR L2 ;

R B2 is halogen or NHR W2 , wherein R W2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl, an optionally substituted C 3-8 cycloalkyl, —C(═O)R M2 and —C(═O)OR N2 ;

R C2 is hydrogen or NHR O2 , wherein R O2 is selected from the group consisting of hydrogen, —C(═O)R P2 and —C(═O)OR Q2 ;

R D2 is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl and an optionally substituted C 2-6 alkynyl;

R E2 is selected from the group consisting of hydrogen, hydroxy, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-8 cycloalkyl, —C(═O)R R2 and —C(═O)OR S2 ;

R F2 is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl and an optionally substituted C 2-6 alkynyl;

Y 2 and Y 3 are independently N or CR 12 , wherein R 12 is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 2-6 -alkenyl and an optionally substituted C 1-6 -alkynyl;

R G2 is an optionally substituted C 1-6 alkyl;

R H2 is hydrogen or NHR T2 , wherein R T2 is independently selected from the group consisting of hydrogen, —C(═O)R U2 and —C(═O)OR V2 ; and

R K2 , R L2 , R M2 , R N2 , R P2 , R Q2 , R R2 , R S2 , R U2 and R V2 are independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6 alkyl), heteroaryl(C 1-6 alkyl) and heteroalicyclyl(C 1-6 alkyl).

14. The compound of claim 1 , wherein R 2A is a halogen substituted C 1-6 alkyl or a sulfenyl substituted C 1-6 alkyl, and R 3A is OH or —OC(═O)R″ A .

15. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

17. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.

18. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptance salt of the foregoing.

19. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

20. A method for ameliorating or treating a viral infection comprising contacting a cell infected with the virus in a subject identified as suffering from the viral infection with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and wherein the viral infection is selected from a paramyxovirus viral infection and an orthomyxovirus viral infection.

21. A method for ameliorating or treating a viral infection in combination with one or more agents comprising administering to or contacting a cell in a subject identified as suffering from the viral infection with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and wherein the viral infection is selected from a paramyxovirus viral infection and an orthomyxovirus viral infection.

22. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , wherein the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

37. The method of claim 20 , wherein the viral infection is a paramyxovirus viral infection.

38. The method of claim 37 , wherein the paramyxovirus viral infection is human respiratory syncytial virus infection.

39. The method of claim 21 , wherein the viral infection is a paramyxovirus viral infection.

40. The method of claim 39 , wherein the paramyxovirus viral infection is human respiratory syncytial virus infection.