Novel macrocyclic inhibitors of hepatitis C virus replication

• US 20070054842A1
• Filed: 07/21/2006
• Published: 03/08/2007
• Est. Priority Date: 07/25/2005
• Status: Active Grant

• Current Assignee: Array Biopharma Incorporated (Pfizer Inc.), Intermune Incorporated (Roche Holding AG)
• Original Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Wang, Bin, Liu, Weidong, Lyon, Michael, Seiwert, Scott, Jiang, Yutong, Martin, Pierre, Kennedy, April, Kaus, Robert, Sammakia, Tarek, Nichols, Paul, Schumacher, Andreas, Kercher, Timothy, Barnett, Bradley, Andrews, Steven, Blatt, Lawrence, Eary, C.
• Granted Patent: US 7,829,665 B2
• Time in Patent Office: Days
• US Class Current: 424/85.400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 38/2292 Thymosin; Related peptides
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/0804 and aliphatic
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The embodiments provide compounds of the general Formulae I through general Formula VIII, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Claims

1. A compound of the general formula (Ia) or (Ib)

3. The compound of claim 1 or 2, wherein R¹ is H.

4. The compound of claim 1 or 2, wherein R¹ is:

5. The compound of claim 4, wherein R¹ is:

8. The compound of claim 1 or 6, wherein R² is NHR⁵.

9. The compound of claim 8, wherein R⁵ is SO₂R⁸.

10. The compound of claim 9, wherein R⁸ is NR¹¹R¹².

11. The compound of claim 9, wherein R⁸ is

12. The compound of claim 1 or 6, wherein R³ is CO₂R⁷.

13. The compound of claim 1 or 6, wherein R³ is CH₂R⁶.

14. The compound of claim 1 or 6, wherein R³ is H.

15. The compound of claim 1 or 6, wherein R³ is a substituted thiazole of the general structure:

85. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1, 2, 6, 16, 18, 19, 25, 37, 52, 65, 66, 68, 69, 71, 75, or 84.

86. A method of inhibiting NS3/NS4 protease activity, comprising contacting a NS3/NS4 protease with a compound of any one of claims 1, 6, 16, 37, 52, 75, or 84.

87. The method of claim 86 in which the contacting is conducted in vivo.

88. The method of claim 86, further comprising identifying a subject suffering from a hepatitis C infection and administering the compound or composition to the subject in an amount effective to treat the infection.

89. The method of claim 86 in which the contacting is conducted ex vivo.

90. A method of treating an individual, the method comprising administering to the individual an amount of a composition comprising a compound of any one of claims 1, 6, 16, 37, 52, 75, or 84 that is effective to treat a least one condition selected from the group consisting of a hepatitis C virus infection, liver fibrosis, and impaired liver function.

91. The method of claim 90, wherein a sustained viral response is achieved.

92. The method of claim 90, wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.

93. The method of claim 92, wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.

94. The method of claim 90, wherein the method further comprises administering to the individual pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.

95. The method of claim 90, wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.

96. The method of claim 90, wherein the method further comprises administering to the individual an effective amount of a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab.

97. The method of claim 90, wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ

).

98. The method of claim 97, wherein the IFN-γ

is administered subcutaneously in an amount of from about 10 μ

g to about 300 μ

g.

99. The method of claim 90, wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α

).

100. The method of claim 99, wherein the IFN-α

is monoPEG (30 kD, linear)-ylate consensus IFN-α

administered at a dosing interval of every 8 days to every 14 days.

101. The method of claim 99, wherein the IFN-α

is monoPEG (30 kD, linear)-ylated consensus IFN-α

administered at a dosing interval of once every 7 days.

102. The method of claim 99, wherein the IFN-α

is INFERGEN consensus IFN-α

.

103. The method of claim 99, wherein the IFN-α

is PEGASYS®

PEGylated IFN-α

2a or PEG-INTRON®

PEGylated IFN-α

2b.

104. The method of claim 90, further comprising administering an effective amount of an agent selected from 3′

-azidothymidine, 2′

,3′

-dideoxyinosine, 2′

,3′

-dideoxycytidine, 2-,3-didehydro-2′

,3′

-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, ritonavir, and an inosine monophosphate dehydrogenase inhibitor.

105. The method of claim 90, further comprising administering interferon, another NS3 protease inhibitor, a NS5b polymerase inhibitor, or a NS3 helicase inhibitor.

106. The method of claim 105, wherein the another NS3 protease inhibitor is selected from

1-1. 1

2. A compound of the formula (Ic) or (Id):

6. A compound of the general formula (II):

7. The compound of claim 6 having the structure:

16. A compound having the Formula III:

17. The compound of claim 16, wherein:

W is selected from hydrogen, OCH₃, SR³, NHR³, CH(R³)₂, or

R³ is H or C_1-3alkyl;

R⁴ and R⁵ are each independently substituted or unsubstituted groups selected from H, C_1-6 alkyl, C(O)R⁸, C(O)OR⁸, C_3-7 cycloalkyl, alkyl-C_4-10 cycloalkyl, phenyl, or benzyl;

R⁸ is a substituted or unsubstituted group selected from C_1-6 alkyl, C_3-7 cycloalkyl, alkyl-C_3-7 cycloalkyl, C_{6 or 10} aryl, or alkyl-C_{6 or 10} aryl; and

R^1a and R^1b are each independently substituted or unsubstituted groups selected from H, CN, CF₃, C_1-6 alkyl, C_1-6 alkenyl, C_1-6 alkynyl, C_3-7 cycloalkyl, alkyl-C_3-10 cycloalkyl, C_{6 or 10} aryl, alkyl-C_{6 or 10} aryl, alkenyl-C_{6 or 10} aryl, heterocycle, or alkyl-heterocycle,

or NR^1aR^1b form a substituted or unsubstituted three- to seven-membered ring.

18. A compound having the Formula IV:

19. A compound having the Formula V:

20. The compound of claim 19, wherein R¹ is phenyl substituted with halo, C_1-3 alkyl, substituted C_1-3 alkyl substituted with up to 3 fluoro, C_1-3 alkoxy, substituted C_1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH₂, NHR₂, or NR₂R₃.

21. The compound of claim 19, wherein R¹ is benzyloxy substituted with halo, C_1-3 alkyl, substituted C_1-3 alkyl with up to 3 fluoro, C_1-3 alkoxy, substituted C_1-3 alkoxy substituted with up to 3 fluoro, cyano, hydroxy, nitro, NH₂, NHR₂, or NR₂R₃.

22. The compound of claim 19, wherein R² is phenyl substituted with halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, C_1-6 alkoxy, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

23. The compound of claim 19, wherein R⁵ and R⁶ are each individually phenyl substituted with halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, C_1-6 alkoxy, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

24. The compound of claim 19, wherein R⁴ is C₆ aryl substituted with up to three halo.

25. A compound having the Formula VI:

26. The compound of claim 25, wherein R¹⁵ is substituted with up to three halogens or alkyl groups.

27. The compound of claim 25, wherein at least one of the phenyl and benzyl groups in the definitions of R⁴ and R⁵ are substituted with up to three halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

28. The compound of claim 25, wherein R⁸ is substituted with halo, cyano, nitro, hydroxy, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, C_1-6 alkoxy, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

29. The compound of claim 25, wherein R⁸ is a tetrahydrofuran ring linked through the C₃ or C₄ position of the tetrahydrofuran ring, or R⁸ is a tetrapyranyl ring linked through the C₄ position of the tetrapyranyl ring.

30. The compound of claim 25, wherein R⁹ is substituted with alkyl, trifluoromethyl, halo, cyano, nitro, hydroxy, C_1-6 alkoxy, carboxylic acid, carboxylic ester, carboxyamide, phenyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hydroxyalkyl, substituted C_1-6 alkyl with up to 5 fluoro, or substituted C_1-6 alkoxy with up to 5 fluoro.

31. The compound of claim 25, wherein R²¹ is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkoxy, C_1-6 alkyl optionally substituted with up to 5 fluoro, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

32. The compound of claim 25, wherein R²² is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkyl optionally substituted with up to 5 fluoro or phenyl.

33. The compound of claim 25 having the structure of the Formula VIa:

34. The compound of claim 33, wherein Y is an amide of the formula —

C(O)NHR⁹, wherein R⁹ is selected from the group consisting CH₂—

C_3-6cycloalkyl, CH(CH₃)C_6-10cycloalkyl, CH₂C_6-10aryl, CH(CH₃)C_6-10aryl CH₂C_6-10heteroaryl, CH(CH₃)C_6-10 heteroaryl which are all optionally substituted from one to two times with alkyl, triflouromethyl, halo, cyano or C_1-3 alkoxy.

35. A compound of claim 33, wherein Y is an acyl sulfonamide of the formula —

C(O)NHS(O)₂R⁹ or an acyl sulfonimide of the formula —

C(O)NHS(O)R⁹, wherein R⁹ is C_1-6 alkyl, C_3-7 cycloalkyl, or C_4-10 cycloalkyl-alkyl, C_5-10 arylalkyl which are all optionally substituted from one to two times with alkyl, halo, cyano, nitro, hydroxy, or C_1-6 alkoxy, or R⁹ is C_{6 or 10} aryl which is optionally substituted by up to two times by alkyl;

halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, or C_1-6 alkyl optionally substituted with up to 5 fluoro, C_1-6 alkoxy optionally substituted with up to 3 fluoro.

36. The compound of claim 33, wherein Y is a sulfonimide of the formula —

C(O)NHS(O)₂NR^1aR^1b wherein R^1a and R^1b are each independently H, C_1-6 alkyl, C_3-7 cycloalkyl, or C_4-10 cycloalkyl-alkyl, which are all optionally substituted from one to two times with halo, cyano, nitro, C_1-6 alkoxy, amido, or phenyl, or R^1a and R^1b are each independently H and C_{6 or 10} aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

37. A compound having the Formula VII:

38. The compound of claim 37, wherein the core ring is substituted with H, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl, C_1-6 alkoxy, substituted C_1-6 alkoxy, C_{6 or 10} aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.

39. The compound of claim 37, wherein R¹ or R² is substituted with NR⁶R⁷, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

40. The compound of claim 37, wherein phenyl or benzyl groups are substituted with up to three halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

41. The compound of claim 37, wherein R⁸ is substituted with halo, cyano, nitro, hydroxy, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl with up to 5 fluoro, C_1-6 alkoxy, or substituted C_1-6 alkoxy with up to 5 fluoro.

42. The compound of claim 37, wherein R⁸ is a tetrahydrofuran ring linked through the C₃ or C₄ position of the tetrahydrofuran ring;

or R⁸ is a tetrapyranyl ring linked through the C₄ position of the tetrapyranyl ring.

43. The compound of claim 37, wherein R⁹ is substituted with alkyl, trifluoromethyl, halo, cyano, nitro, hydroxy, C_1-6 alkoxy, carboxylic acid, carboxylic ester, carboxyamide, phenyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hydroxyalkyl, substituted C_1-6 alkyl with up to 5 fluoro, substituted C_1-6 alkoxy with up to 5 fluoro.

44. The compound of claim 37, wherein R²¹ is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkoxy, C_1-6 alkyl optionally substituted with up to 5 fluoro, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

45. The compound of claim 37, wherein R²² is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.

46. The compound of claim 37, wherein when V is O or S, W is selected from O, NH, or CH₂.

47. The compound of claim 37, wherein when V is NH, W is selected from NH or CH₂.

48. The compound of claim 37 having the structure of the Formula VIIa:

49. A compound of claim 48, wherein Y is an amide of the formula —

C(O)NHR⁹, where R⁹ is selected from the group consisting CH₂—

C_3-6cycloalkyl, CH(CH₃)C_6-10cycloalkyl, CH₂C_6-10aryl, CH(CH₃)C_6-10aryl CH₂C_6-10heteroaryl, CH(CH₃)C_6-10 heteroaryl which are all optionally substituted from one to two times with alkyl, triflouromethyl, halo, cyano or C_1-3 alkoxy.

50. A compound of claim 48, wherein Y is an acyl sulfoxide of the formula —

C(O)NHS(O)R⁹, where R⁹ is C_1-6 alkyl, C_3-7 cycloalkyl, or C_4-10 cycloalkyl-alkyl, C_5-10 arylalkyl which are all optionally substituted from one to two times with alkyl, halo, cyano, nitro, hydroxy, or C_1-6 alkoxy, or R⁹ is C_{6 or 10} aryl which is optionally substituted by up to two times by alkyl, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, or C_1-6 alkyl optionally substituted with up to 5 fluoro, C_1-6 alkoxy optionally substituted with up to 3 fluoro.

51. The compound of claim 48, wherein Q is a core ring selected from:

52. A compound having the structure of Formula VIII:

53. The compound of claim 52, wherein the core ring is substituted with H, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl, C_1-6 alkoxy, substituted C_1-6 alkoxy, C_{6 or 10} aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.

54. The compound of claim 52, wherein R¹ or R² is substituted with NR⁶R⁷, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

55. The compound of claim 52, wherein phenyl or benzyl groups are substituted with up to three halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro.

56. The compound of claim 52, wherein R⁸ is substituted with halo, cyano, nitro, hydroxy, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, C_1-6 alkyl, substituted C_1-6 alkyl with up to 5 fluoro, C_1-6 alkoxy, or substituted C_1-6 alkoxy with up to 5 fluoro.

57. The compound of claim 52, wherein R⁸ is a tetrahydrofuran ring linked through the C₃ or C₄ position of the tetrahydrofuran ring;

or R⁸ is a tetrapyranyl ring linked through the C₄ position of the tetrapyranyl ring.

58. The compound of claim 52, wherein R⁹ is substituted with alkyl, trifluoromethyl, halo, cyano, nitro, hydroxy, C_1-6 alkoxy, carboxylic acid, carboxylic ester, carboxyamide, phenyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hydroxyalkyl, substituted C_1-6 alkyl substituted with up to 5 fluoro, or substituted C_1-6 alkoxy substituted with up to 5 fluoro.

59. The compound of claim 52, wherein R²¹ is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkoxy, C_1-6 alkyl optionally substituted with up to 5 fluoro, phenyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, substituted C_1-6 alkyl with up to 5 fluoro, or substituted C_1-6 alkoxy with up to 5 fluoro.

60. The compound of claim 52, wherein R²² is substituted with halo, cyano, nitro, hydroxy, C_1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.

61. The compound of claim 52, wherein when V is O or S, W is selected from O, NH, or CH₂.

62. The compound of claim 52, wherein when V is NH, W is selected from NH or CH₂.

63. The compound of claim 52, wherein R^1a or R^1b is substituted with halo, cyano, nitro, C_1-6 alkoxy, amido, phenyl, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, substituted C_1-6 alkyl with up to 5 fluoro, or substituted C_1-6 alkoxy with up to 5 fluoro.

64. The compound of claim 52, wherein NR^1aR^1b is a three- to six-membered alkyl cyclic secondary amine substituted with halo, cyano, nitro, C_1-6 alkoxy, amido, or phenyl.

65. A compound having the general Formula VIIIa:

66. A compound having the general Formula VIIIb:

67. The compound of claim 66, wherein

Z is a chain selected from:

and the dashed line represents an optional double bond.

68. A compound having the Formula VIIIc:

69. A compound having the Formula VIIId:

70. The compound of claim 69, wherein

Z is a chain selected from:

and the dashed line represents an optional double bond.

71. A compound having the Formula VIIIe

72. The compound of claim 71, wherein

R¹ is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each optionally substituted with up to 1-2 NR⁵R⁶, halo, cyano, nitro, hydroxy, C_1-2 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R² is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole, or pyrazole, each optionally substituted with up to 1-2 NR⁵R⁶, halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R³ is H;

R⁴ is C_1-6 alkyl, C(O)NR⁵R⁶, C(S)NR⁵R⁶, C(O)R⁷, C(O)OR⁷, or S(O)₂R⁷;

R⁵ and R⁶ are each independently H, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, or C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

or R⁵ and R⁶ are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R⁷ is C_1-6 alkyl, C_3-7 cycloalkyl, or C_4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C_1-6 alkoxy, or phenyl;

or R⁷ is C_{6 or 10} aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R⁸ is C_1-3 alkyl, C_3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C_1-3 alkyl, or C_1-3 alkoxy; and

the dashed line represents an optional double bond.

73. The compound of claim 71, wherein

R¹ is phenyl, benzothiazole, or benzothiophene each optionally substituted with up to 1-2 halo, hydroxy, C_1-2 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R² is H or phenyl optionally substituted with up to 1-2 halo, hydroxy, C_1-3 alkyl, alkyl, or C_1-3 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R³ is H;

R⁴ is C_1-6 alkyl, C(O)NR⁵R⁶, C(O)R⁷, or C(O)OR⁷;

R⁵ is H and R⁶ is H, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, hydroxy-C_1-6 alkyl, C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro;

R⁷ is C_1-6 alkyl or C_3-7 cycloalkyl, which are all optionally substituted from one to three times with halo or phenyl;

or R⁷ is C_{6 or 10} aryl which is optionally substituted by up to one halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_3-7 cycloalkyl, C_4-10 cycloalkyl-alkyl, C_2-6 alkenyl, C_1-6 alkoxy, hydroxy-C_1-6 alkyl, or C_1-6 alkyl optionally substituted with up to 5 fluoro, or C_1-6 alkoxy optionally substituted with up to 5 fluoro; and

R⁸ is C_1-3 alkyl, C_3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C_1-3 alkyl, or C_1-3 alkoxy; and

the dashed line represents an optional double bond.

74. The compound of claim 71, wherein

Z is a chain selected from:

and the dashed line represents an optional double bond.

75. A compound of the formula (IX):

76. The compound of claim 75 having the formula

77. The compound of claim 75 having the formula

78. The compound of claim 75 in which L consists of from 2 to 5 atoms.

79. The compound of claim 75 in which L comprises a —

W—

C(═

V)—

group, where V and W are each individually selected from O, S or NH.

80. The compound of claim 75 in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide.

81. The compound of claim 75 in which P2 is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Val78, Asp79, Gln80 and Asp81.

82. The compound of claim 75 in which P2 is

83. The compound of claim 75, wherein Y is a chain selected from:

84. A compound having a formula selected from the group consisting of the compounds in Tables 1 through 8 as described in the specification and compounds numbered 100, 701-706, 801, 922, 927, 2001-2011, 2101-2154, 2201-2252, 2301-2322, 2401-2404, 2501-2502, and 2601-2604.

107. A compound having the formula (1):

108. A method of making the compound of claim 107, comprising intermixing compound (1a) with TBTU and DIEBA:

109. A method of making a compound of formula (3), comprising intermixing a compound of (2) with sodium methanolate and water:

110. The method of claim 109, wherein approximately 12 equivalents of water are used.

111. A method of making a compound of formula (7), comprising intermixing a compound formula (4) with a compound of formula (5) and a compound of formula (6):

112. A method of making a compound of formula (7), comprising intermixing a compound of formula (6) with a compound of formula (5) and a compound of formula (8):

113. A method of purifying a compound of formula (7), comprising intermixing a compound of formula (7) with a compound of formula (8) and a compound of formula (9) and treating the product thereof with hydrochloric acid:

114. A method of making a compound of formula (11):

115. A method of making a compound of formula (14), comprising intermixing a compound of formula (11), a compound of formula (12), a compound of formula (13), and methanol:

116. A method of making a compound of formula (15), comprising intermixing a compound of formula (14), N,N-dimethylpyridin-4-amine, and boc anhydride:

117. A method for making a compound of formula (15), comprising:

converting an amide of formula (11) to a carbamate of formula (14);

adding a boc functionality to the carbamate (14) to obtain a compound of formula (15);

118. A method of making a compound of formula (19), comprising intermixing a dihalobutene and a compound of formula (18):

119. The method of claim 118, wherein the dihalobutene is 1,4-dichloro-2-butene.

120. A method of making a compound of formula (20), comprising intermixing lithium hexamethyldisilazide and compound (19):

121. A method of making a compound of formula (21):

122. A method of making a compound of formula (22), comprising intermixing a compound of formula (21) and iodoethane and a base:

123. A method of making a compound of formula (22), comprising:

intermixing a dihalobutene and a compound of formula (18) to form a compound of formula (19);

intermixing lithium hexamethyldisilazide and the compound of formula (19) to form a compound of formula (20);

intermixing the compound of formula (20) and an acid and treating the resulting product with boc anhydride and to form a compound of formula (21);

intermixing the compound of formula (21) and iodoethane and a base to form the compound of formula (22);

wherein X is a halogen.

124. A method of making a compound of formula (23), comprising intermixing a 7-Bromo-1-heptene and a compound of formula (18):

125. A method of making a compound of formula (24), comprising intermixing an acid and a compound of formula (23), and treating the resulting product with boc anhydride:

126. A method of making a compound of formula (24), comprising:

intermixing a 7-Bromo-1-heptene and a compound of formula (18) to form a compound of formula (23);

intermixing an acid and the compound of formula (23), and treating the resulting product with boc anhydride to form the compound of formula (24);