Macrocyclic hepatitis C serine protease inhibitors

1. A compound of Formula I:

wherein

A is H, —(C═O)—O—R 1 , —(C═O)—R 1 , —(C═O)—N(R 1 R 2 ), —S(O) 2 —R 1 , or —S(O) 2 —N(R 1 R 2 ),

each R 1 is independently selected from the group consisting of:

(i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl;

(ii) heterocycloalkyl or substituted heterocycloalkyl; and

(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

each R 2 is independently selected from the group consisting of:

(i) hydrogen;

(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;

(iii) heterocycloalkyl or substituted heterocycloalkyl; and

(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3

heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

G is —NHS(O) 2 —R 3 ;

each R 3 is independently selected from:

(i) C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, aryl; substituted aryl; heteroaryl; substituted heteroaryl;

(ii) heterocycloalkyl or substituted heterocycloalkyl; and

(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; and

L is a C 2 -C 5 saturated or unsaturated chain, optionally containing one to three heteroatoms independently selected from O, N and S(O) n , wherein L is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, group is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl and cyano;

Z is

(i) —C 1 -C 8 alkyl containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N and optionally substituted with one or more halo; or

(ii) thienyl or substituted thienyl;

j=0, 1, 2, 3, or 4;

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, or 2;

denotes a carbon-carbon single or double bond (i.e.,

means

R 6 is H or halo;

R 7 is H or halo;

R 8 is H or halo;

R 9 is H or halo;

wherein if each of R 6 , R 7 , R 8 and R 9 is H, then Z is —C 1 -C 8 alkyl substituted with one or more halo and containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; and

salts, solvates and hydrates thereof.

2. The compound of claim 1 , wherein R 3 is independently cyclopropyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, —C(O)OH, —C(O)NH 2 , or —C(O)O—C 1 -C 6 alkyl.

3. The compound of claim 1 , wherein A is —(C═O)—O—R 1 .

4. The compound of claim 1 , wherein A is —(C═O)—R 1 .

5. The compound of claim 4 , wherein R 1 is optionally substituted aryl.

6. The compound of claim 4 , wherein R 1 is optionally substituted heteroaryl.

7. The compound of claim 5 or 6 , wherein Z is —C 1 -C 8 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N and substituted with one or more halo.

8. The compound of claim 7 wherein each of R 6 , R 7 , R 8 and R 9 is H.

9. The compound of claim 7 wherein one of R 6 , R 7 , R 8 and R 9 is halo.

10. The compound of claim 7 wherein two of R 6 , R 7 , R 8 and R 9 are halo.

11. The compound of claim 7 wherein one of R 7 or R 8 is halo.

12. The compound of claim 7 wherein R 7 is fluoro.

13. The compound of claim 7 wherein R 8 is fluoro.

14. The compound of claim 7 wherein R 9 is fluoro.

15. The compound of claim 13 wherein G is —NHS(O) 2 —R 3 and R 3 is independently cyclopropyl optionally substituted with alkyl.

16. The compound of claim 14 wherein G is —NHS(O) 2 —R 3 and R 3 is independently cyclopropyl optionally substituted with alkyl.

17. The compound of claim 1 wherein,

G is —NHS(O) 2 —R 3 ;

R 3 is independently cyclopropyl optionally substituted with alkyl;

A is —(C═O)—R 2 ;

R 2 is independently heteroaryl, or substituted heteroaryl;

Z is C 1 -C 8 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N and optionally substituted with one or more halo; and

R 7 or R 8 is fluoro.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.

19. A method of treating an HCV infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A method of producing a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of Formula (II) with a compound of Formula (III) to provide a compound of Formula (I):

wherein for Formulae (I), (II) and (III):

A is —(C═O)—R 1 ,

each R 1 is independently selected from the group consisting of:

(i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl;

(ii) heterocycloalkyl or substituted heterocycloalkyl; and

(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;

G is —NHS(O) 2 —R 3 ;

each R 3 is independently selected from:

(i) C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, aryl; substituted aryl; heteroaryl; substituted heteroaryl;

(ii) heterocycloalkyl or substituted heterocycloalkyl; and

(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl or substituted —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; and

L is a C 2 -C 5 saturated or unsaturated chain, optionally containing one to three heteroatoms independently selected from O, N and S(O) n , wherein L is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, group is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl and cyano;

Z is (i) —C 1 -C 8 alkyl containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N and optionally substituted with one or more halo; or

(ii) thienyl or substituted thienyl;

j=0, 1, 2, 3, or 4;

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, or 2;

denotes a carbon-carbon single or double bond (i.e.,

means

R 6 is H or halo;

R 7 is H or halo;

R 8 is H or halo; and

R 9 is H or halo;

wherein if each of R 6 , R 7 , R 8 and R 9 is H, then Z is —C 1 -C 8 alkyl substituted with one or more halo and containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N.