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Last Updated: March 29, 2024

Claims for Patent: 7,932,240


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Summary for Patent: 7,932,240
Title:Phosphadiazine HCV polymerase inhibitors IV
Abstract: Provided herein are phosphadiazine polymerase inhibitor, for example, of any of Formulas IV, IV\', I\'\', II\'\', or IVa, 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 in need thereof.
Inventor(s): Dousson; Cyril (Canet, FR), Surleraux; Dominique (Wauthier-Braine, BE), Paparin; Jean-Laurent (Vendemian, FR), Pierra; Claire (Montarnaud, FR), Roland; Arlene (Marsillargues, FR)
Assignee: Idenix Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:12/198,895
Patent Claims:1. A compound of Formula IV': ##STR00356## or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein: R.sup.1 is H, alkyl, arylalkyl, heteroarylalkyl, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, aryl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl; R.sup.4 is H, alkyl, aryl-CH.sub.2--, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; R.sup.4' is H, alkyl, aryl-CH.sub.2--, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl or heteroaryl; R.sup.5 is H, halogen, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl, or R.sup.4 and R.sup.5 together form a part of a 3-8 membered heterocycloalkyl ring; R.sup.6 is H, halogen, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl, or R.sup.5 and R.sup.6 together form a part of a 3-8 membered cycloalkyl or heterocycloalkyl ring; R.sup.5' is H, halogen, cyano, nitro, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, heteroaryl, --NR.sup.8R.sup.10, alkenyl, or alkynl; R.sup.6' is H, halogen, cyano, nitro, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl, or R.sup.5' and R.sup.6' together form a part of a 3-8 membered, aryl ring; R.sup.12 is F, --OR.sup.8, --SR.sup.8, --NR.sup.8R.sup.9, alkyl, or aryl; each R.sup.8 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, heterocyclyl, C.sub.1-6 alkyl-C.sub.3-7 cycloalkylene, or C.sub.1-10 alkyl-siloxyl; each R.sup.9 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl; or R.sup.8 and R.sup.9 together with the N atom to which they are attached form heterocyclyl; each R.sup.10 is independently H, alkyl, aryl, sulfonyl, C(O)R.sup.8, C(O)OR.sup.8 or C(O)NR.sup.8R.sup.9; and each Y is independently O or S, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.

2. The compound of claim 1, wherein each pair of R.sup.5' and R.sup.6' together independently forms a benzo ring having formula (A): ##STR00357## where each * is a bond; each R.sup.14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, C(O)NR.sup.8R.sup.9, --OCH.sub.2C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, --O--(C.sub.1-C.sub.6 hydroxyalkyl), --O--(C.sub.1-C.sub.6 alkoxy), --O--(C.sub.1-C.sub.6 alkylene)-cyano, --O--(C.sub.1-C.sub.6 alkylene)-C(O)R.sup.9', --OCHR.sup.9'C(O)O--R.sup.8, --OCHR.sup.9'C(O)NHOH, --O--(C.sub.1-C.sub.6 alkyl)-C(O)NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)R.sup.8, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)OR.sup.8, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)NR.sup.8R.sup.9, --OCHR.sup.9'C(O)NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-S(O)R.sup.9', --O--(C.sub.1-C.sub.6 alkyl)-S(O).sub.2R.sup.9', --O--(C.sub.1-C.sub.6 alkylene)-S(O).sub.2NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2R.sup.8--O--(C.sub.1-C.sub.6 alkylene)-S(O).sub.2R.sup.9'--O--(C.sub.1-C.sub.6 alkylene)-NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-S(O).sub.2R.sup.8, --(C.sub.1-C.sub.6 alkylene)-S(O).sub.2NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-S(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-C(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-C(O)NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2R.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9C(O)OR.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-C(O)OR.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.8R.sup.9, --NR.sup.8C(O)R.sup.9, --NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --NR.sup.9'S(O).sub.2NR.sup.8R.sup.10, --S(O)R.sup.9', --S(O).sub.2R.sup.9', or --S(O).sub.2NR.sup.8R.sup.9; each R.sup.9' is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl; and n is an integer from 1 to 4.

3. The compound of claim 1, wherein each pair of R.sup.5 and R.sup.6 together independently forms a part of a 3-8 membered cycloalkyl, aryl, heterocycloalkyl or heteroaryl ring.

4. The compound of claim 2, wherein the compound of Formula IV' has formula I'': ##STR00358## wherein each A is independently CR.sup.18; R.sup.18 is a bond, H, halogen, --NR.sup.10SO.sub.2R.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.10, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl; and Z has the following structure: ##STR00359##

5. A compound of Formula IV: ##STR00360## or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein R.sup.1 is H, alkyl, arylalkyl, heteroarylalkyl, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, aryl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl; R.sup.5 is H, halogen, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl; R.sup.6 is H, halogen, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, --C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, alkyl, aryl, or heteroaryl, or R.sup.5 and R.sup.6 together form a part of a 3-8 membered cycloalkyl or heterocycloalkyl ring; R.sup.12 is -OR.sup.8, --SR.sup.8, --NR.sup.8R.sup.9, alkyl, or aryl; each R.sup.14 is independently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano, nitro, OH, --NR.sup.10SO.sub.2R.sup.8, --OR.sup.8, --NR.sup.8R.sup.9, --C(O)R.sup.8, C(O)NR.sup.8R.sup.9, --OCH.sub.2C(O)NR.sup.8R.sup.9, --C(O)OR.sup.8, --O--(C.sub.1-C.sub.6 hydroxyalkyl), --O--(C.sub.1-C.sub.6 alkoxy), --O--(C.sub.1-C.sub.6 alkylene)-cyano, --O--(C.sub.1-C.sub.6 alkylene)-C(O)R.sup.9', --OCHR.sup.9'C(O)O--R.sup.8, --OCHR.sup.9'C(O)NHOH, --O--(C.sub.1-C.sub.6 alkyl)-C(O)NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)R.sup.8, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)OR.sup.8, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)NR.sup.8R.sup.9, --OCHR.sup.9'C(O)NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-S(O)R.sup.9', --O--(C.sub.1-C.sub.6 alkyl)-S(O).sub.2R.sup.9', --O--(C.sub.1-C.sub.6 alkylene)-S(O).sub.2NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --O--(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2R.sup.8--O--(C.sub.1-C.sub.6 alkylene)-S(O).sub.2R.sup.9'--O--(C.sub.1-C.sub.6 alkylene)-NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-S(O).sub.2R.sup.8, --(C.sub.1-C.sub.6 alkylene)-S(O).sub.2NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-S(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-C(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-C(O)NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)R.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2R.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9C(O)OR.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'C(O)NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --(C.sub.1-C.sub.6 alkylene)-C(O)OR.sup.8, --(C.sub.1-C.sub.6 alkylene)-NR.sup.8R.sup.9, --NR.sup.8C(O)R.sup.9, --NR.sup.9'S(O).sub.2NR.sup.8R.sup.9, --NR.sup.9'S(O).sub.2NR.sup.8R.sup.10, --S(O)R.sup.9', --S(O).sub.2R.sup.9', or --S(O).sub.2NR.sup.8R.sup.9; n is an integer from 1 to 4; each R.sup.8 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, heterocyclyl, C.sub.1-6 alkyl-C.sub.3-7 cycloalkylene, or C.sub.1-10 alkyl-siloxyl; each R.sup.9 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl; or R.sup.8 and R.sup.9 together with the N atom to which they are attached form heterocyclyl; each R.sup.9' is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, heteroaryl, or heterocyclyl; or R.sup.8 and R.sup.9 together with the N atom to which they are attached form heterocyclyl; and each R.sup.10 is independently H, alkyl, aryl, sulfonyl, C(O)R.sup.8, C(O)OR.sup.8 or C(O)NR.sup.8R.sup.9, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionally substituted.

6. The compound of claim 5 according to Formula IVa: ##STR00361## or a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, or any tautomeric form thereof; or a pharmaceutically acceptable salt or prodrug thereof.

7. The compound of claim 6, wherein the compound has the structure of Formula IVa.

8. The compound of claim 5, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.

9. The compound of claim 5, wherein R.sup.1 is C.sub.1-6 alkyl.

10. The compound of claim 9, wherein R.sup.1 is 3,3-dimethylbutyl.

11. The compound of claim 5 wherein R.sup.6 is hydrogen or halogen.

12. The compound of claim 5, wherein R.sup.6 is tert-butyl.

13. The compound of claim 5, wherein R.sup.12 is C.sub.1-6 alkoxy.

14. The compound of claim 13, wherein R.sup.12 is methoxy.

15. The compound of claim 13, wherein R.sup.12 is ethoxy.

16. The compound of claim 5, wherein R.sup.12 is NH.sub.2.

17. The compound of claim 5, wherein R.sup.12 is OH.

18. The compound of claim 5, wherein R.sup.14 is hydrogen.

19. The compound of claim 5, wherein R.sup.14 is --NHSO.sub.2R.sup.8.

20. The compound of claim 19, wherein R.sup.8 is C.sub.1-6 alkyl.

21. The compound of claim 20, wherein R.sup.8 is methyl.

22. The compound of claim 5, wherein R.sup.1 is 3,3-dimethylbutyl; R.sup.6 is tert-butyl; R.sup.12 is methoxy, ethoxy, fluoro, NH.sub.2 or OH; and R.sup.14 is hydrogen or --NHSO.sub.2Me.

23. The compound of claim 5 according to the following formula: ##STR00362##

24. The compound of claim 23 according to the following formula: ##STR00363##

25. The compound of claim 23 according to the following formula: ##STR00364##

26. The compound of claim 23 according to the following formula: ##STR00365##

27. The compound of claim 23 according to the following formula: ##STR00366##

28. The compound of claim 5 according to the following formula: ##STR00367##

29. The compound of claim 5 according to the following formula: ##STR00368##

30. The compound of claim 5 according to the following formula: ##STR00369##

31. The compound of claim 5 according to the following formula: ##STR00370##

32. The compound of claim 5 according to the following formula: ##STR00371##

33. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.

34. The pharmaceutical composition of claim 33, further comprising a second antiviral agent.

35. The pharmaceutical composition of claim 34, 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 nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

36. The pharmaceutical composition of claim 35, wherein the second antiviral agent is an interferon.

37. The pharmaceutical composition of claim 36, 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, and interferon gamma-1b.

38. The pharmaceutical composition of claim 33, wherein the composition is formulated for single dose administration.

39. The pharmaceutical composition of claim 33, wherein the composition is formulated as an oral, parenteral, or intravenous dosage form.

40. The pharmaceutical composition of claim 39, wherein the oral dosage form is a tablet or capsule.

41. The pharmaceutical composition of claim 33, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.

42. A method for treating an HCV infection, which comprises administering the compound of claim 1.

43. A method for treating an HCV infection, which comprises administering the pharmaceutical composition of claim 33.

44. The method of claim 42, wherein the method comprises administering a second antiviral agent, in combination or alternation.

45. The method of claim 43, wherein the method comprises administering a second antiviral agent, in combination or alternation.

46. The method of claim 44, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate ologodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

47. The method of claim 45, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin, acerulenin, an antisense phosphorothioate ologodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.

48. The method of claim 44, wherein the second antiviral agent is an interferon.

49. The method of claim 45, wherein the second antiviral agent is an interferon.

50. The method of claim 48, 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, and interferon gamma-1b.

51. The method of claim 49, 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, and interferon gamma-1b.

52. A method for inhibiting replication of a virus in a host, which comprises contacting the host with the compound of claim 1.

53. A method for inhibiting replication of a virus in a host, which comprises contacting the host with the pharmaceutical composition of claim 33.

54. The method of claim 52, wherein the host is a human.

55. The method of claim 53, wherein the host is a human.

56. A method for inhibiting replication of a virus, which comprises contacting the virus with the compound of claim 1.

57. A method for inhibiting replication of a virus, which comprises contacting the virus with the pharmaceutical composition of claim 33.

58. A method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with the compound of claim 1.

59. A method for inhibiting the activity of a polymerase, which comprises contacting the polymerase with the pharmaceutical composition of claim 33.

60. The method of claim 58, wherein the polymerase is an HCV NS5B polymerase.

61. The method of claim 59, wherein the polymerase is an HCV NS5B polymerase.

Details for Patent 7,932,240

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Biogen Inc. AVONEX interferon beta-1a For Injection 103628 05/17/1996 ⤷  Try a Trial 2027-08-31
Biogen Inc. AVONEX interferon beta-1a Injection 103628 05/28/2003 ⤷  Try a Trial 2027-08-31
Biogen Inc. AVONEX interferon beta-1a Injection 103628 02/27/2012 ⤷  Try a Trial 2027-08-31
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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