Phenanthridine macrocyclic hepatitis C serine protease inhibitors

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

J is absent, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, —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;

wherein at least one of R 1 is halogen or —OR 4 ;

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)—, —OS(O p )—, —C(O)S(O p )—, or —C(O)N(R 3 )S(O p )—;

each p is independently 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 1, 2, 3, or 4; and

denotes a carbon-carbon single bond

 or double bond

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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.

3. The compound of claim 1 , 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.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —SR 4 , —SOR 4 , —SO 2 R 4 , —N(R 3 )S(O 2 )—R 4 , —N(R 3 ) S(O 2 )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 ; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; wherein at least one R 1 is halogen or —OR 4 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently halogen or —OR 4 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the following:

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

8. The compound of claim 1 , of formula II,

or a pharmaceutically acceptable salt thereof,

wherein:

J is absent, —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, —OR 4 , —N(R 3 )S(O) 2 —R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—O—R 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;

wherein at least one of R 1 is halogen or —OR 4 —;

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;

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

denotes a carbon-carbon single bond

 or double bond

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein 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.

10. The compound of claim 8 , 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.

11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein A is selected from Me, Et, Pr, i-Pr, Bu, s-Bu, t-Bu,

12. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein A is

wherein:

J′ is —NHC(O)—, —NHC(O)O—, —C(O)—, —O—C(O)—, —C(S)—, —S(O)—, —S(O 2 )—;

A′ is optionally substituted —C 1 -C 8 alkyl, containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted —C 1 -C 8 haloalkyl, 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 heterocyclyl;

R′ is H, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted C 3 -C 12 heterocyclyl;

R″ is H, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted C 3 —C 12 heterocyclyl; and

t is 0 or 1.

13. The compound of claim 12 , wherein J′ is —NHC(O)—, or —NHC(O)O—; 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, or optionally substituted heteroaryl; R′ is H, optionally substituted —C 1 -C 8 alkyl or optionally substituted —C 3 -C 12 cycloalkyl; R″ is H, and t is 0 or 1.

14. The compound of claim 13 , wherein A′ is Me, Et, Pr, i-Pr, Bu, s-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl,

each of which is optionally substituted.

15. The compound of claim 8 , wherein A is

wherein,

J′ is —NC(O)—, —NC(O)O—, —C(O)—, —O—C(O)—, —C(S)—, —C(═NR 4 )—, —S(O)—, —S(O 2 )—; 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 —C 1 -C 8 haloalkyl, 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 heterocyclyl.

16. The compound of claim 8 , wherein A is —CHR Z (OH)—, wherein R Z is cyclohexyl, i-Pr, i-Bu, t-Bu, or CF 3 .

17. The compound of claim 8 , wherein, A is CHF 2 —R Y , wherein R Y is Ph or Et.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt prodrug 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 claim 1 , or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula X:

wherein,

J is absent, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, —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;

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)—, —N(R 3 )C(O)—, —N(R 3 ) C(O)S(O)—, —OS(O)—, —C(O)S(O)—, or —C(O)N(R 3 )S(O)—;

each p is independently 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;

denotes a carbon-carbon single bond

 or double bond

 and

LG is a leaving group;

with a compound of formula XI:

wherein:

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 )(O 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—O_R 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;

wherein at least one of R 1 is halogen or —OR 4 —; and

n is 1, 2, 3, or 4;

to thereby produce a compound of formula I.