Macrocyclic hepatitis C serine protease inhibitors

1. A compound of formula I or I′:

or a pharmaceutically acceptable salt thereof,

wherein:

J is absent, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, —C(O)—, —O—C(O)—, —N(R 3 )—C(O)—, —C(S)—, —C(═NR 4 )—, —S(O)—, —S(O 2 )—, or —N(R 3 )—;

A is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted arylalkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, or optionally substituted carbocyclic;

Each R 1 is independently selected from

(i) halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , —N(R 3 )S(O) 2 —R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—OR 4 , —C(O)R 4 , —C(O)NR 3 R 4 , or —N(R 3 )C(O)R 4 ;

(ii) optionally substituted aryl;

(iii) optionally substituted heteroaryl;

(iv) optionally substituted heterocyclic;

(v) optionally substituted carbocyclic; or

(vi) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

G is -E-R 5 ;

wherein E is absent; optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; or —O—, —S—, —N(R 3 )—, —N(R 3 )S(O p )—, —N(R 3 )C(O)—, —N(R 3 ) C(O)S(O p )—, —OS(O p )—, —C(O)S(O p )—, or —C(O)N(R 3 )S(O p )—;

p is 0, 1, or 2;

R 5 is H; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;

R 3 and R 4 are each independently selected at each occurrence from the following: optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;

L is absent or is selected from optionally substituted alkylene, optionally substituted alkenylene or optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

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

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, 2, 3, or 4; and

denotes a carbon-carbon single or double bond,

Y is —C(R″)—, R′ and R″ taken together with the carbon atoms to which they are attached form an aryl or heteroaryl ring, each said ring is optionally substituted.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein k=3, j=1 and L is absent.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or halogen; E is —NHS(O)— or —NHS(O 2 )—, and R 5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or imidazolyl, each of which is optionally substituted.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein J is —C(O)— and A is optionally substituted —C 1 -C 8 alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted heteroaryl, optionally substituted —C 3 -C 12 cycloalkyl, or optionally substituted —C 3 -C 12 heterocycloalkyl.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R′ and R″ together form an optionally substituted aryl.

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R′ and R″, and the atoms to which each is attached, form an aryl which is substituted by (R 2 ) x , wherein

each R 2 is independently selected from

(i) halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , —NHS(O 2 )—R 4 , —NHS(O 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)OR 4 , —C(O)R 4 , —C(O)NR 3 R 4 , or —N(R 3 )C(O)R 4 ;

(ii) optionally substituted aryl;

(iii) optionally substituted heteroaryl;

(iv) optionally substituted heterocyclic;

(v) optionally substituted carbocyclic; or

(iv) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

and x is 0, 1, 2, 3, or 4.

7. 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.

8. A method of treating a hepatitis C viral 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.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is —N(R 3 )S(O p )—, R 3 is H, p is 2, and R 5 is optionally substituted carbocyclic.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is optionally substituted cyclopropyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E is —N(R 3 )S(O p )—, R 3 is H, p is 2, and R 5 is optionally substituted heteroaryl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is —C(O)— and A is optionally substituted heteroaryl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein A is substituted heteroaryl.

14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein A is pyrazinyl.

15. The method of claim 8 , wherein:

k=3;

j=1;

L is absent;

R′ and R″, and the atoms to which each is attached, form an aryl which is substituted by (R 2 ) x ;

each R 2 is independently selected from

(i) halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , —NHS(O 2 )—R 4 , —NHS(O 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)OR 4 , —C(O)R 4 , —C(O)NR 3 R 4 , or —N(R 3 )C(O)R 4 ;

(ii) optionally substituted aryl;

(iii) optionally substituted heteroaryl;

(iv) optionally substituted heterocyclic;

(v) optionally substituted carbocyclic; or

(iv) optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

and x is 0, 1, 2, 3, or 4.

16. The method of claim 8 , wherein E is —N(R 3 )S(O p )—, R 3 is H, p is 2, and R 5 is optionally substituted carbocyclic.

17. The method of claim 8 , wherein E is —N(R 3 )S(O p )—, R 3 is H, p is 2, and R 5 is optionally substituted heteroaryl.

18. The method of claim 8 , wherein J is —C(O)— and A is optionally substituted heteroaryl.

19. The method of claim 18 , wherein A is substituted heteroaryl.

20. The method of claim 18 , wherein A is pyrazinyl.