Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections

1. A compound of Formula I:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, thereof; wherein:

R A is (i) hydrogen or halogen; or (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and

R B is a moiety (Ia) or (Ib):

wherein:

each Z is independently CR 1 or N;

R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 are each independently (i) hydrogen, halo, cyano, trifluoromethyl, or nitro; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —P(O)R 1a R 1d , —P(O)(OR 1a )R 1d , —P(O)(OR 1a )(OR 1d ), —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and

each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently (a) oxo, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four, substituents Q a ; or (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —P(O)R a R d , —P(O)(OR a )R d , —P(O)(OR a )(OR d ), —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , or —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one, two, three, or four, substituents Q a ;

wherein each Q a is independently (a) oxo, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g ,

—C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —P(O)R e R h , —P(O)(OR e )R h , —P(O)(OR e )(OR h ), —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , or —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1 , having the structure of Formula IA:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compound of claim 1 , wherein Z is CR 1 .

4. The compound of claim 3 , wherein Z is CH.

5. The compound of claim 1 , wherein Z is N.

6. The compound of claim 1 , wherein R 5 is hydrogen.

7. The compound of claim 1 , wherein R 6 is hydrogen.

8. The compound of claim 1 , wherein R 7 is —OR 1a .

9. The compound of claim 8 , wherein R 7 is C 1-6 alkoxy, optionally substituted with one or more substituents Q.

10. The compound of claim 8 , wherein R 7 is methoxy.

11. The compound of claim 1 , wherein R 8 is C 1-6 alkyl, optionally substituted with one or more substituents Q.

12. The compound of claim 11 , wherein R 8 is methyl.

13. The compound of claim 1 , having the structure of Formula IB:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. The compound of claim 13 , wherein Z is CR 1 .

15. The compound of claim 13 , wherein Z is CH.

16. The compound of claim 13 , wherein Z is N.

17. The compound of claim 13 , wherein R 2 is heteroaryl, optionally substituted with one or more substituents Q.

18. The compound of claim 17 , wherein R 2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.

19. The compound of claim 17 , wherein R 2 is 5-membered heteroaryl, optionally substituted with one or more substituents Q.

20. The compound of claim 17 , wherein R 2 is furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, optionally substituted with one or two substituents Q.

21. The compound of claim 17 , wherein R 2 is thiazol-2-yl, optionally substituted with one or two substituents Q, and each Q is independently selected from cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, ethynyl, phenyl, benzyl, pyrrolidinyl, and methoxy.

22. The compound of claim 17 , wherein R 2 is thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 4-isopropyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 2,4-dimethylthiazol-5-yl, 4,5-dimethylthiazol-2-yl, 4-ethynyl-thiazol-2-yl, 2-methoxy-thiazol-4-yl, or 2-pyrrolidin-1-yl-thiazol-4-yl.

23. The compound of claim 13 , wherein R 5 is hydrogen.

24. The compound of claim 13 , wherein R 6 is hydrogen.

25. The compound of claim 13 , wherein R 7 is —OR 1a .

26. The compound of claim 25 , wherein R 7 is C 1-6 alkoxy, optionally substituted with one or more substituents Q.

27. The compound of claim 25 , wherein R 7 is methoxy.

28. The compound of claim 1 selected from:

and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

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

30. The pharmaceutical composition of claim 29 , further comprising a second antiviral agent.

31. The pharmaceutical composition of claim 30 , wherein the second antiviral agent is 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, or a ribozyme.

32. The pharmaceutical composition of claim 30 , wherein the second antiviral agent is an interferon.

33. The pharmaceutical composition of claim 32 , wherein the interferon is pegylated interferon alpha 2a, interferon alfahcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, or interferon gamma-1b.

34. The pharmaceutical composition of claim 29 , wherein the composition is formulated for single dose administration.

35. The pharmaceutical composition of claim 29 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

36. The pharmaceutical composition of claim 35 , wherein the oral dosage form is a tablet or capsule.

37. The pharmaceutical composition of claim 29 , wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.