Embodiments of the present invention include nucleoside 5′-monophosphate derivative compounds, their preparation and their uses. In some embodiments, nucleoside 5′-monophosphate derivative compounds are useful to treat viral infections.
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1. A compound of Formula I: or a pharmaceutically acceptable salt thereof,wherein:R1 is an optionally substituted phenyl;R2 is R2A is selected from the group consisting of H, a C1-C6 alkyl, a C1-C6 heteroalkyl, and a C1-C6 acyl;R2B is selected from the group consisting of H, a C1-C6 alkyl, a C1-C6 h
1. A compound of Formula I: or a pharmaceutically acceptable salt thereof,wherein:R1 is an optionally substituted phenyl;R2 is R2A is selected from the group consisting of H, a C1-C6 alkyl, a C1-C6 heteroalkyl, and a C1-C6 acyl;R2B is selected from the group consisting of H, a C1-C6 alkyl, a C1-C6 heteroalkyl, and a C1-C6 acyl;R3 and R4 are each independently selected from the group consisting of H, acyl, and heteroacyl; or R3 and R4 can be optionally linked to form a carbonyl; andX is O, S, or NH. 2. The compound of claim 1, wherein R1 is selected from the group consisting of: 3. The compound of claim 2, wherein R2 is 4. The compound of claim 3, wherein X is O. 5. The compound of claim 4, wherein R2A is selected from the group consisting of H and C1-C6 alkyl. 6. The compound of claim 5, wherein R3 and R4 are each H, or R3 and R4 can be optionally linked to form a carbonyl. 7. The compound of claim 2, wherein R2 is 8. The compound of claim 7, wherein X is O. 9. The compound of claim 8, wherein R2A is of H. 10. The compound of claim 9, wherein R2B is C1-C6 alkyl. 11. The compound of claim 10, wherein R3 and R4 are each independently selected from the group consisting of H, acyl, and heteroacyl. 12. The compound of claim 1 selected from the group consisting of 2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinanyloxymethyl)-3R,4R-dihydroxytetrahydrofuran,2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4R-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinanyloxymethyl)-3R,4R-dihydroxytetrahydrofuran,2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-dihydroxytetrahydrofuran,2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-4R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-7-oxo-3,6,8-trioxa-cis-bicyclo[3.3.0]octane,2R-(3-Aminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran,2R-(3-(1-Ethoxy-1-iminomethyl)-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran,2R-(3-Ethylaminocarbonyl-1H-1,2,4-triazole)-5R-(4S-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2R-yloxymethyl)-3R,4R-diacetyloxytetrahydrofuran, and(2R,3R,4R,5R)-2-(3-Carbamoyl-1H-1,2,4-triazol-1-yl)-5-((((2R,4S)-4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy)methyl)tetrahydrofuran-3,4-diyl dipropionate, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, wherein R1 is phenyl substituted with halogen. 14. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier. 15. A method of treating a viral infection comprising administering an effective amount of a compound claim 1 to a subject in need thereof. 16. The method of claim 15, further comprising administering an effective amount of a second therapeutic agent in combination with the compound claim 1 to the subject in need thereof, wherein the second therapeutic agent is selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, interferon-α, and pegylated interferon-α. 17. The method of claim 15, wherein the viral infection is an infection of the liver. 18. The method of claim 15, wherein the viral infection is HCV. 19. A method of inhibiting viral replication in a cell comprising contacting the cell with the compound of claim 1. 20. The method of claim 19, wherein the viral replication is HCV replication. 21. The method of claim 19, further comprising contacting the cell with a second antiviral agent selected from the group consisting of thymosin alpha-1, interferon-λ, an inhibitor of HCV protease, an inhibitor of HCV NS5A replication complex, an inhibitor of HCV NS5B polymerase, an inhibitor of HCV helicase, a cyclophilin inhibitor, an inhibitor of inosine monophosphate dehydrogenase, interferon-α, and pegylated interferon-α. 22. The method of claim 19, wherein the cell is a hepatocyte.
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