Macrocyclic inhibitors of flaviviridae viruses

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is O, S, or NR 1 ;

each R 1 is independently H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl or optionally substituted (C 2 -C 4 )alkynyl;

each R 2 or R 3 is independently H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl, optionally substituted (C 2 -C 4 )alkynyl, halogen, cyano, C(O)R 1 , C(O)OR 1 or CON(R 1 ) 2 ; or R 2 and R 3 when taken together with the carbon to which they are both attached form —C(═O)—, —C(═S)— or —C(═NR 1 )—;

A is O, S(O) n , NR 4 or optionally substituted (C 1 -C 2 )alkylene;

each n is independently 0, 1 or 2;

each R 4 is independently H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl, optionally substituted (C 2 -C 4 )alkynyl, cyano, C(O)R 7 , C(O)OR 7 , CON(R 7 ) 2 , S(O)R 16 , S(O) 2 R 16 , S(O) 2 OR 7 or S(O) 2 N(R 7 ) 2 ;

R 5 is optionally substituted aryl(C 0 -C 4 )alkyl, optionally substituted heterocyclyl(C 0 -C 4 )alkyl, optionally substituted cycloalkyl(C 0 -C 4 )alkyl or optionally substituted (C 1 -C 8 )alkyl wherein each optionally substituted aryl(C 0 -C 4 )alkyl, optionally substituted cycloalkyl(C 0 -C 4 )alkyl or optionally substituted (C 1 -C 8 )alkyl is substituted with one or more R 6 ;

each R 6 is independently halo, CF 3 , OR 4 , CH 2 OR 4 , SR 4 , S(O)R 16 , S(O) 2 R 16 , N(R 1 ) 2 , NHCOR 1 , NHC(O)OR 1 , NHC(O)N(R 1 ) 2 , NHC(NR 1 )R 1 , NHC(NR 1 )N(R 1 ) 2 , C(O)R 1 , C(O)N(R 1 ) 2 , CO 2 R 1 , S(O) 2 OR 1 , S(O) 2 N(R 1 ) 2 , NHS(O) 2 OR 1 , NHS(O) 2 R 16 , NHS(O) 2 N(R 1 ) 2 , P(O)(OR 1 ) 2 , P(O)(OR 1 )(N(R 1 ) 2 ), P(O)(R 7 )(OR 1 ), OP(O)(OR 1 ) 2 , OP(O)(OR 1 )(N(R 1 ) 2 ), NHP(O)(OR 1 ) 2 or NHP(O)(OR 1 )(N(R 1 ) 2 );

each R 7 is H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl, optionally substituted (C 2 -C 8 )alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C 1 -C 4 )alkyl, optionally substituted cycloalkyl(C 1 -C 4 )alkyl or optionally substituted heterocyclyl(C 1 -C 4 )alkyl;

each R 16 is optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl, optionally substituted (C 2 -C 8 )alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C 1 -C 4 )alkyl, optionally substituted cycloalkyl(C 1 -C 4 )alkyl or optionally substituted heterocyclyl(C 1 -C 4 )alkyl;

each R 8 , R 8b , R 9 or R 9b is independently H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl, optionally substituted (C 2 -C 8 )alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C 1 -C 4 )alkyl, optionally substituted cycloalkyl(C 1 -C 4 )alkyl, optionally substituted heterocyclyl(C 1 -C 4 )alkyl, OR 4 , SR 4 , S(O)R 16 , S(O) 2 R 16 or N(R 4 ) 2 ;

provided that each R 8 , R 8b , R 9 and R 9b is not H; and

provided that when R 9 is OH and each R 8b and R 9b are H, then R 8 is not

A 1 is optionally substituted (C 2 -C 5 )alkylene, optionally substituted (C 2 -C 5 )alkenylene or optionally substituted (C 2 -C 5 )alkynylene, wherein a sp 3 carbon atom of said optionally substituted (C 2 -C 5 )alkylene, optionally substituted (C 2 -C 5 )alkenylene, or optionally substituted (C 2 -C 5 )alkynylene, is optionally replaced by O, S(O) n or NR 4 , and A 2 is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted heterocyclene or optionally substituted cycloalkylene, or

A 1 is optionally substituted aryl(C 0 -C 2 )alkylene, optionally substituted cycloalkyl(C 0 -C 2 )alkylene or optionally substituted heterocyclyl(C 0 -C 2 )alkylene, wherein a sp 3 carbon atom of said optionally substituted aryl(C 0 -C 2 )alkylene, optionally substituted cycloalkyl(C 0 -C 2 )alkylene or optionally substituted heterocyclyl(C 0 -C 2 )alkylene is optionally replaced by O, S(O) n or NR 4 , and A 2 is optionally substituted (C 1 -C 3 )alkylene, optionally substituted (C 2 -C 3 )alkenylene or optionally substituted (C 2 -C 3 )alkynylene;

R 12 is H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl or optionally substituted (C 2 -C 4 )alkynyl;

each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocyclyl, aryl(C 1 -C 8 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 8 )alkyl and

wherein when R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 8b , R 9b , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , A, A 1 or A 2 is substituted, the substitutent is, independently, one or more substituents selected from the group consisting of halo, CN, CF 3 , N 3 , N(R a ) 2 , SR a , OR a , R a , NHCOR a , NHC(O)OR a , NHC(O)N(R a ) 2 , NHC(NR a )R a , NHC(NR a )N(R a ) 2 , C(O)R a , C(O)N(R a ) 2 , CO 2 R a , S(O) 2 OR a , S(O) 2 N(R a ) 2 , NHS(O) 2 OR a , NHS(O) 2 N(R a ) 2 , OP(O)(OR a ) 2 , OP(O)(OR a )(N(R a ) 2 ), NHP(O)(OR a ) 2 and NHP(O)(OR a )(N(R a ) 2 ).

2. The compound of claim 1 represented by Formula II

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein each R 8b and R 9b is H.

4. The compound of claim 3 wherein R 8 is methyl.

5. The compound of claim 2 wherein A 1 is optionally substituted (C 4 )alkylene or optionally substituted (C 4 )alkenylene.

6. The compound of claim 5 wherein A 1 is

wherein each R 13 , R 14 or R 15 is independently H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl, optionally substituted (C 2 -C 8 )alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C 1 -C 4 )alkyl, optionally substituted cycloalkyl(C 1 -C 4 )alkyl, optionally substituted heterocyclyl(C 1 -C 4 )alkyl, OR 4 , SR 4 , S(O)R 16 , S(O) 2 R 16 , or N(R 4 ) 2 .

7. The compound of claim 6 wherein R 15 is H.

8. The compound of claim 2 wherein A 2 is optionally substituted arylene.

9. The compound of claim 8 wherein A 2 is

10. The compound of claim 2 wherein A 2 is

wherein:

each R 10 or R 11 , independently, is H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl, optionally substituted (C 2 -C 4 )alkynyl, halogen, cyano, C(O)R 1 , C(O)OR 1 or CON(R 1 ) 2 , or R 11 and R 10 taken together with the atoms to which they are attached form an optionally substituted (C 5 -C 7 )cycloalkenylene ring wherein a sp 3 carbon atom of said optionally substituted (C 5 -C 7 )cycloalkenylene ring is optionally replaced by O, S(O) n or NR 4 .

11. The compound of claim 10 wherein each R 10 or R 11 is independently H, optionally substituted (C 1 -C 4 )alkyl or halogen.

12. The compound of claim 11 wherein each R 10 and R 11 is H.

13. The compound of claim 2 wherein R 7 is optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl, or optionally substituted aryl(C 1 -C 4 )alkyl.

14. The compound of claim 13 wherein R 7 is optionally substituted (C 1 -C 8 )alkyl.

15. The compound of claim 2 wherein R 5 is optionally substituted aryl(C 0 -C 4 )alkyl.

16. The compound of claim 15 wherein R 5 is optionally substituted benzyl.

17. The compound of claim 16 wherein R 5 is optionally substituted

18. The compound of claim 17 wherein R 6 is OR 4 , CH 2 OR 4 , N(R 1 ) 2 , NHCOR 1 , NHC(O)OR 1 , NHC(O)N(R 1 ) 2 , NHC(NR 1 )R 1 , NHC(NR 1 )N(R 1 ) 2 , C(O)N(R 1 ) 2 , S(O) 2 N(R 1 ) 2 , NHS(O) 2 OR 1 , NHS(O) 2 R 16 or NHS(O) 2 N(R 1 ) 2 .

19. The compound of claim 18 wherein R 6 is OH.

20. The compound of claim 2 wherein R 7 is isopropyl and R 5 is

21. The compound of claim 20 wherein R 9 is O(C 1 -C 4 )alkyl.

22. The compound of claim 21 wherein R 8 is (C 1 -C 4 )alkyl.

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

wherein:

X 1 is O or NR 1 ;

each R 1 is independently H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl or optionally substituted (C 2 -C 4 )alkynyl;

each R 4 is independently H, optionally substituted (C 1 -C 4 )alkyl, optionally substituted (C 2 -C 4 )alkenyl, optionally substituted (C 2 -C 4 )alkynyl, cyano, C(O)R 7 , C(O)OR 7 , CON(R 7 ) 2 , S(O)R 16 , S(O) 2 R 16 , S(O) 2 OR 7 or S(O) 2 N(R 7 ) 2 ;

R 5 is aryl(C 0 -C 4 )alkyl, optionally substituted with one or more R 6 ;

each R 6 is independently halo, CF 3 , OR 4 , CH 2 OR 4 , SR 4 , S(O)R 16 , S(O) 2 R 16 , N(R 1 ) 2 , NHCOR 1 , NHC(O)OR 1 , NHC(O)N(R 1 ) 2 , NHC(NR 1 )R 1 , NHC(NR 1 )N(R 1 ) 2 , C(O)R 1 , C(O)N(R 1 ) 2 , CO 2 R 1 , S(O) 2 OR 1 , S(O) 2 N(R 1 ) 2 , NHS(O) 2 OR 1 , NHS(O) 2 R 16 , NHS(O) 2 N(R 1 ) 2 , P(O)(OR 1 ) 2 , P(O)(OR 1 )(N(R 1 ) 2 ), P(O)(R 7 )(OR 1 ), OP(O)(OR 1 ) 2 , OP(O)(OR 1 )(N(R 1 ) 2 ), NHP(O)(OR 1 ) 2 or NHP(O)(OR 1 )(N(R 1 ) 2 );

each R 16 is optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl, optionally substituted (C 2 -C 8 )alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryl(C 1 -C 4 )alkyl, optionally substituted cycloalkyl(C 1 -C 4 )alkyl or optionally substituted heterocyclyl(C 1 -C 4 )alkyl;

each R 7 is optionally substituted (C 1 -C 8 )alkyl or optionally substituted aryl(C 1 -C 4 )alkyl;

each R 8 , R 8b , R 9 or R 9b is independently H, optionally substituted (C 1 -C 8 )alkyl, or OR 4 ;

A 1 is optionally substituted (C 2 -C 5 )alkylene or optionally substituted (C 2 -C 5 )alkenylene, and A 2 is optionally substituted arylene or optionally substituted heteroarylene, or A 1 is aryl(C 0 -C 2 )alkylene and A 2 is optionally substituted (C 1 -C 3 )alkylene or optionally substituted (C 2 -C 3 )alkenylene;

R 12 is H or optionally substituted (C 1 -C 4 )alkyl;

each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heterocyclyl, aryl(C 1 -C 8 )alkyl, cycloalkyl or cycloalkyl(C 1 -C 8 )alkyl; and

wherein when R 1 , R 4 , R 7 , R 8 , R 9 , R 8b , R 9b , R 12 , R 16 , A 1 or A 2 is substituted, the substitutent is, independently, one or more substituents selected from the group consisting of halo, CN, CF 3 , N 3 , N(R a ) 2 , SR a , OR a , R a , NHCOR a , NHC(O)OR a , NHC(O)N(R a ) 2 , NHC(NR a )R a , NHC(NR a )N(R a ) 2 , C(O)R a , C(O)N(R a ) 2 , CO 2 R a , S(O) 2 OR a , S(O) 2 N(R a ) 2 , NHS(O) 2 OR a , NHS(O) 2 N(R a ) 2 , OP(O)(OR a ) 2 , OP(O)(OR a )(N(R a ) 2 ), NHP(O)(OR a ) 2 and NHP(O)(OR a )(N(R a ) 2 ).

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

wherein:

X 1 is O or NH;

R 5 is

R 7 is (C 1 -C 4 )alkyl or

each R 8 , R 8b , R 9 or R 9b is independently H, (C 1 -C 4 )alkyl, OH or O(C 1 -C 4 )alkyl;

A 1 is (C 2 -C 5 )alkylene or (C 2 -C 5 )alkenylene, wherein the alkylene or alkenylene groups are each optionally substituted with OH or O(C 1 -C 4 )alkyl and A 2 is phenylene, pyridinylene or thienylene; or

A 1 is phenylene and A 2 is (C 1 -C 3 )alkylene or (C 2 -C 3 )alkenylene; and

R 12 is H or (C 1 -C 4 )alkyl.

25. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1 or 25 and a pharmaceutically acceptable carrier or excipient.

27. The pharmaceutical composition of claim 26 , further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists; or mixtures thereof.