Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection

• US 8,071,568 B2
• Filed: 12/28/2007
• Issued: 12/06/2011
• Est. Priority Date: 01/05/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Istituto Di Ricerche Di Biologia Molecolare P Angeletti SPA, Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Narjes, Frank, Gardelli, Cristina, Donghi, Monica, Attenni, Barbara, Durette, Philippe L.
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US12/520,738
• Publication Number:
  US 20100035835A1
• Time in Patent Office: 1,439 Days
• Field of Search: None
• US Class Current: 514/51
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention provides nucleoside aryl phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as precursors to inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors to inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside aryl phosphoramidates alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside aryl phosphoramidates of the present invention. (I)

Claims

1. A compound of the structural formula I:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-A:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B1:

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein

R³ is selected from the group consisting of hydrogen, C_1-16 alkylcarbonyl, C_2-18 alkenylcarbonyl, C_1-10 alkyloxycarbonyl, C_3-6 cycloalkylcarbonyl, C_3-6 cycloalkyloxycarbonyl, and an amino acyl residue of structural formula:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl or fluoromethyl, R² is hydroxy, and R³ is hydrogen.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl or fluoromethyl, R² is fluoro, and R³ is hydrogen.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a bond.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, cyano, nitro, amino, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4 alkylamino, di(C_1-4 alkyl)amino, C_1-4 alkylcarbonyl, C_1-4 alkylcarbonyloxy, and C_1-4 alkyloxycarbonyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein Ar is unsubstituted phenyl.

12. The Compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is indolyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Ar is 1H-indol-5-yl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵, R¹¹, and R¹² are each hydrogen, and R⁴ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, 2-methyl-1-propyl, hydroxymethyl, fluoromethyl, mercaptomethyl, carboxymethyl, carbamoylmethyl, 1-hydroxyethyl, 2-carboxyethyl, 2-carbamoylethyl, 2-methylthioethyl, 4-amino-1-butyl, 3-amino-1-propyl, 3-guanidino-1-propyl, 1H-imidazol-4-ylmethyl, phenyl, benzyl, 4-hydroxybenzyl, and 1H-indol-3-ylmethyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R⁴ is methyl or benzyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a bond, and R⁶ is C_1-8 alkyl, cyclohexyl, or cyclopentyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R⁶ is C_1-4 alkyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X a bond, Ar is phenyl, R⁴ is methyl or benzyl, R⁶ is C_1-4 alkyl, and R⁵, R¹¹, and R¹² are each hydrogen.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, R² is hydroxy, and R³ is hydrogen.

20. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II-A:

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula II-B:

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III:

23. A compound of claim 1 which is selected from the group consisting of:

5′

-O-[{(1S)-2-[(2,2-Dimethylpropanoyl)-oxy]-1-methylethyl}-amino)-(phenoxy)-phosphoryl]-2′

-C-methylcytidine;

5′

-O-[{[(1S)-2-(Butyryloxy)-1-methylethyl]-amino}-(phenoxy)-phosphoryl]-2′

-C-methylcytidine;

5′

-O-[[[2-(2,2-Dimethyl-1-oxopropoxy)-ethyl]-amino]-(phenoxy)-phosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[2-(2,2-Methyl-1-oxopropoxy)-ethyl]-amino]-(phenoxy)-phosphinyl]-2′

-C-methylcytidine;

5′

-O-[{[(1S)-1-Methyl-2-(2-methyl-1-oxopropoxy)ethyl]-amino}-(phenoxy)-phosphinyl]-2′

-C-methylcytidine;

5′

-O-[{[(1S,2S)-1-[(2,2-Dimethyl-1-oxopropoxy)methyl]-2-methylbutyl]amino}-(phenoxy)-phosphoryl]-2′

-C-methylcytidine;

5′

-O-[[[(1S)-1-[(2,2-dimethyl-1-oxopropoxy)methyl]pentyl]amino]-(phenoxy)-phosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(1S)-2-[(2,2-dimethyl-1-oxopropoxy)-1-(phenylmethyl)]-ethyl]amino]-(phenoxy)-phosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[2-[(1-oxo-2-propylpentyl)oxy]ethyl]amino]phenoxyphosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(1S)-2-(1H-indol-3-yl)-1-(2-methyl-1-oxopropoxy)methyl]ethyl]amino]phenoxyphosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(1S)-2-(2-methyl-1-oxopropoxy)-1-(phenylmethyl)]ethyl]amino]phenoxyphosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(2S)-2-(2-methyl-1-oxopropoxy)propyl]amino]phenoxyphosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(2R)-2-(2-methyl-1-oxopropoxy)propyl]amino]phenoxyphosphinyl]-2′

-C-methylcytidine;

5′

-O-[[[(1S)-2-(2,2-dimethyl-1-oxopropoxy)-1-(phenylmethyl)ethyl]amino]henoxyphosphinyl]-2′

-C-methyl-2′

,3′

-O-(1-methylethylidene)-cytidine;

5′

-O-[[[(1S)-1-[(2,2-dimethyl-1-oxopropoxy)methyl]pentyl]amino]phenoxyphosphinyl]-2′

-C-methyl-2′

,3′

-O-(1-methylethylidene)-cytidine;

5′

-O-[[[2-(benzoyloxy)ethyl]amino]phenoxyphosphinyl]-2′

-C-methyl-cytidine;

5′

-O—

[({(1S)-1-benzyl-2-[(2,2-dimethylpropanoyl)oxy]ethyl}amino) (phenoxy)phosphoryl]-2′

-C-methylcytidine;

5′

-O-[{[2-(acetyloxy)ethyl]amino}(phenoxy)phosphoryl]-2′

-C-methylcytidine;

2′

-C-methyl-5′

-O-[[methyl[2-(2-methyl-1-oxopropoxy)ethyl]amino]phenoxyphosphinyl]-cytidine;

5′

-O—

[({2-[(2-ethylbutanoyl)oxy]ethyl}amino)(phenoxy)phosphoryl]-2′

-C-methylcytidine;

5′

-O—

[({2-[(cyclohepytlcarbonyl)oxy]ethyl}amino)(phenoxy)phosphoryl]-2′

-C-methylcytidine; and

2′

-C-methyl-5′

-O-[[(3R)-3-(2-methyl-1-oxopropoxy)-1-pyrrolidinyl]phenoxyphosphinyl]-cytidine,

and pharmaceutically acceptable, salts thereof.

24. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A method for the treatment of hepatitis C virus infection in a mammal in need thereof, which comprises administering a compound of claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.