Orally-bioavailable nucleoside analogs

1. A compound of Formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

X is hydrogen or —CN;

G is

R 12 is —C(═O)R 22 , —C(═O)OR 22 , or C 1 -C 6 alkyl optionally substituted with one or more R 12a ;

each R 12a is independently halogen, —CN, —OH, —OR a , —NR c R d , cycloalkyl, or heterocycloalkyl;

or two R 12a on the same atom are taken together to form an oxo;

R 22 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 22a ;

each R 22a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R 22a on the same atom are taken together to form an oxo;

or two R 22a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;

R 13 is hydrogen or C 1 -C 6 alkyl;

R 14 is —OH or fluoro;

R 15 is hydrogen, —C(═O)R 25 , —C(═O)OR 25 , —CH 2 —O—C(═O)R 25 , or —CH 2 —O—C(═O)OR 25 ;

R 25 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 25a;

each R 25a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R 25a on the same atom are taken together to form an oxo;

or two R 25a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;

R 16 is —C(═O)R 26 , —C(═O)OR 26 , —CH 2 —O—C(═O)R 26 , —CH 2 —O—C(═O)OR 26 , or C 1 -C 6 alkyl optionally substituted with one or more R 16a ;

each R 16a is independently halogen, —CN, —OH, —OR a , —NR c R d , cycloalkyl, or heterocycloalkyl;

or two R 16a on the same atom are taken together to form an oxo;

R 26 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 26a ;

each R 26a is independently halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R;

or two R 26a on the same atom are taken together to form an oxo;

or two R 26a are taken together to form a cycloalkyl or heterocycloalkyl; each optionally and independently substituted with one or more R;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and

each R is independently halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, and C 1 -C 6 heteroalkyl;

or two R on the same atom are taken together to form an oxo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is —CN; R 13 is hydrogen; and R 14 is —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 is —C(═O)R 22 or —C(═O)OR 22 .

4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 22 is C 1 -C 6 alkyl optionally and independently substituted with one or more R 22a .

5. The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 22a is independently halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 15 is hydrogen, —C(═O)R 25 , or —C(═O)OR 25 .

7. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 25 is C 1 -C 6 alkyl or C 1 -C 6 aminoalkyl; wherein the alkyl is optionally and independently substituted with one or more R 25a .

8. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 25 is C 1 -C 6 alkylene(cycloalkyl) or C 1 -C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R 25a .

9. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 25a is independently halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 16 is —C(═O)R 26 or —C(═O)OR 26 .

11. The compound of claim 10 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 26 is alkyl optionally and independently substituted with one or more R 26a .

12. The compound of claim 10 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 26 is C 1 -C 6 alkylene(cycloalkyl) or C 1 -C 6 alkylene(aryl); wherein the alkylene, cycloalkyl, and aryl is optionally and independently substituted with one or more R 26a .

13. The compound of claim 10 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 26a is independently halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

14. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

16. A method of treating a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

17. The method of claim 16 , further comprising administering at least one antiviral agent.

18. The method of claim 16 , wherein the viral infection is caused by a virus selected from the group consisting of coronavirus disease 2019 (SARS-COV-2), Yellow Fever, Eastern Equine Encephalitis virus, Human Immunodeficiency virus (HIV), “African Swine Fever Viruses,” Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Astroviridae, Baculoviridae, Bimaviridae, Bimaviridae, Bunyaviridae, Caliciviridae, Caulimoviridae, Circoviridae, Coronaviridae, Cystoviridae, Ebolavirus, Deltaviridae, Filviridae, Filoviridae, Flaviviridae, Iridoviridae, Mononegavirus, Myoviridae, Papiloma virus, Papovaviridae, Paramyxoviridae, Prions, Parvoviridae, Phycodnaviridae, Poxviridae, Potyviridae, Reoviridae, Retroviridae, Rhabdoviridae, Tectiviridae, Togaviridae, pox, papilloma, corona, influenza, sendai virus (SeV), sindbis virus (SINV), vaccinia viruses, West Nile, Hanta, viruses which cause the common cold, and any combination thereof.

19. The method of claim 16 , wherein the viral infection is caused by coronavirus disease 2019 (SARS-COV-2) or an Ebolavirus.