Substituted nucleosides, nucleotides and analogs thereof

1. A method for ameliorating or treating a norovirus infection comprising contacting a cell infected with the norovirus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) is:

wherein:

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

R aa1 and R aa2 are independently hydrogen or deuterium;

R A is hydrogen, deuterium, an unsubstituted C 1-3 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-3 alkynyl or cyano;

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

R 2A is selected from the group consisting of halogen, azido, an optionally 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 halogen, OH, —OC(═O)R″ A and an optionally substituted O-linked amino acid;

R 4A is selected from the group consisting of hydrogen, halogen, OR 1D , an optionally substituted O-linked amino acid, azido and NR 2D R 3D ;

R 1D is hydrogen or —C(═O)R ″D ;

R 2D and R 3D are independently hydrogen or an optionally substituted C 1-6 alkyl;

R 5A 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 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 and the asterisks indicate the points og attachment in the R 1A moiety defined to include variables R 6A and R 7A ;

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, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic heterocyclyl and

R 25A1 , R 25A2 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 alkylcarbonyl, C 2-8 alkoxycarbonyl and C 2-8 alkylaminocarbonyl;

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 and R ″D are independently an optionally substituted C 1-24 -alkyl;

h is 1 or 2;

w1 is 0 or 1;

w2 is 3, 4 or 5;

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; and

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

2. The method of claim 1 , wherein R 1A is an optionally substituted acyl, an optionally substituted O-linked amino acid,

3. The method of claim 2 , wherein R 6A and R 7A are independently selected from the group consisting of hydrogen, absent, 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 aryl(C 1-6 alkyl), *—(CR 15A R 16A ) p —O—C 1-24 alkyl, *—(CR 17A R 18A ) q —O—C 2-24 alkenyl,

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.

4. The method of claim 2 , 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 , wherein 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.

5. The method of claim 2 , wherein R 8A is absent, hydrogen, an optionally substituted aryl, an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; and R 9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative.

6. The method of claim 1 , wherein R 1A is H or

7. The method 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, deuterium, 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 I2 , wherein R I2 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;

W 1 is NH or —NCH 2 —OC(═O)CH(NH 2 )—CH(CH 3 ) 2 ;

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 hydrogen, 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).

8. The method of claim 1 , wherein R 2A is halogen, azido or cyano.

9. The method of claim 1 , wherein R 2A is an optionally 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 or an optionally substituted —O—C 3-6 alkynyl.

10. The method of claim 1 , wherein R 3A is halogen.

11. The method of claim 1 wherein R 3A is OH, —OC(═O)R ″A or O-linked amino acid.

12. The method of claim 1 , wherein R 5A is hydrogen or halogen.

13. The method of claim 1 , wherein R 5A is an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.

14. The method of claim 1 , wherein R 4A is hydrogen, halogen, azido, NR 2D R 3D or cyano.

15. The method of claim 1 , wherein R 4A is OR 1D , —OC(═O)R ″D or an optionally substituted O-linked amino acid.

16. The method of claim 1 , wherein R A is an unsubstituted C 1-3 alkyl, an unsubstituted C 2-4 alkenyl or an unsubstituted C 2-3 alkynyl.

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

or a pharmaceutically acceptable salt of the foregoing.