Phosphothiophene and phosphothiazole HCV polymerase inhibitors
Provided herein are phosphothiophene and phosphothiazole compounds, for example, of any of Formulae I, IA, IIA, IIIA, IVA, VA, VIA, VIIA, IB, IIB, IIIB, IVB, VB, VIB and VIIB disclosed herein, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host infected with HCV.
1. A compound of Formula I:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt or an isotopically enriched form thereof;
wherein each of R 1 and R 2 is independently —OR 6 , alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl or heteroaryl;
R 3 is —C(O)R 7 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(═NR 11 )R 12 , —P(O)(OR 6 ) 2 or —C(O)NHSO 2 R 21 ;
X is CR 4 ;
each of R 4 and R 5 is independently H, halogen, cyano, azido, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(═NR 11 )R 12 , —NHSO 2 R 13 , —NR 14 R 15 , —SO 3 R 17 or —SO 2 R 18 , or R 4 and R 5 together with the two carbon atoms to which they are attached form a ring;
L is NR 16 ; and
each of R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkyl-cycloalkylene or cycloalkyl-alkylene,
wherein each alkyl, aryl, arylalkyl, alkaryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or alkyl-cycloalkyl is optionally substituted.
2. The compound of claim 1 according to Formula IIA, IIIA, VA, or VIA:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof;
wherein each of R 1 and R 2 is independently —OR 6 , alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl or heteroaryl;
each R 3 is —C(O)R 7 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(═NR 11 )R 12 , —P(O)(OR 6 ) 2 or —C(O)NHSO 2 R 21 ;
each of R 4 and R 5 is independently H, halogen, cyano, azido, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 8 , —C(O)NR 9 R 10 , —C(═NR 11 )R 12 , —NHSO 2 R 13 , —NR 14 R 15 , —SO 3 R 17 or —SO 2 R 18 , or R 4 and R 5 together with the two carbon atoms to which they are attached form a ring;
each L is NR 16 ; and
each of R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkyl-cycloalkylene or cycloalkyl-alkylene,
wherein each alkyl, aryl, arylalkyl, alkaryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is optionally substituted.
3. The compound of claim 2 having Formula IIA.
4. The compound of claim 2 having Formula IIIA.
5. The compound of claim 2 having Formula VA.
6. The compound of claim 2 having Formula VIA.
7. The compound of claim 1 , wherein each alkyl, aryl, arylalkyl, alkaryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.
8. The compound of claim 1 , wherein each R 1 is alkyl, alkoxy, hydroxy or aryl.
9. The compound of claim 1 , wherein each R 1 is methyl, ethyl, methoxy, ethoxy or hydroxy.
10. The compound of claim 1 , wherein each R 2 is cycloalkyl, aryl or heteroaryl and wherein each cycloalkyl, aryl or heteroaryl is optionally substituted.
11. The compound of claim 1 , wherein each R 3 is —C(O)OH or —C(O)OCH 3 .
12. The compound of claim 1 , wherein each R 4 is H, alkenyl, alkynyl, halogen, aryl, heteroaryl.
13. The compound of claim 1 , wherein each R 5 is alkyl, alkenyl, alkynyl, aryl, heteroaryl.
14. The compound of claim 1 , wherein each R 6 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.
15. The compound of claim 1 , wherein each R 8 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.
16. The compound of claim 1 , wherein each R 16 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cycloalkyl or heterocyclyl.
17. The compound of claim 1 according to the following structure:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 according to the following structure:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 according to the following structure:
or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is isotopically enriched.
21. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable diluents, excipents, or carriers.
22. The pharmaceutical composition of claim 21 , further comprising a second antiviral agent.
23. The pharmaceutical composition of claim 22 , wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, a ribozyme and combinations thereof.
24. The pharmaceutical composition of claim 22 , wherein the second antiviral agent is an interferon.
25. The pharmaceutical composition of claim 24 , wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alphcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, interferon gamma-1 b and combinations thereof.
26. The pharmaceutical composition of claim 21 , wherein the composition is formulated for single dose administration.
27. The pharmaceutical composition of claim 21 , wherein the composition is formulated as an oral, parenteral, or intravenous dosage form.
28. The pharmaceutical composition of claim 27 , wherein the oral dosage form is a tablet or capsule.
29. The pharmaceutical composition of claim 21 , wherein the compound is administered in a dose from about 0.5 milligram to about 1,000 milligram daily.