Methods for treating arenaviridae and coronaviridae virus infections

1. A method for treating an Arenaviridae infection in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or ester, thereof;

wherein:

each R 1 is H or halogen;

each R 2 , R 3 , R 4 and R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl;

or any two R 2 , R 3 , R 4 and R 5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;

R 6 is OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )substituted alkynyl, or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl;

R 7 is selected from the group consisting of

a) H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ,

wherein:

R c is selected from phenyl, 1-naphthyl, 2-naphthyl,

R d is H or CH 3 ;

R e1 and R e2 are each independently H, (C 1 -C 6 )alkyl or benzyl;

R f is selected from H, (C 1 -C 8 )alkyl, benzyl, (C 3 -C 6 )cycloalkyl, and —CH 2 —(C 3 -C 6 )cycloalkyl;

R g is selected from (C 1 -C 8 )alkyl, —O—(C 1 -C 8 )alkyl, benzyl, —O-benzyl, —CH 2 —(C 3 -C 6 )cycloalkyl, —O—CH 2 —(C 3 -C 6 )cycloalkyl, and CF 3 ; and

n′ is selected from 1, 2, 3, and 4; and

d) a group of formula:

wherein:

Q is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;

Z 1 and Z 2 , when taken together, are -Q 1 (C(R y ) 2 ) 3 Q 1 -;

wherein

 each Q 1 is independently O, S, or NR; and

 each R y is independently H, F, Cl, Br, I, OH, R, —C(=Q 2 )R, —C(=Q 2 )OR, —C(=Q 2 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(=Q 1 )R, —OC(=Q 2 )OR, —OC(=Q 2 )(N(R) 2 ), —SC(=Q 2 )R, —SC(=Q 2 )OR, —SC(=Q 2 )(N(R) 2 ), —N(R)C(=Q 2 )R, —N(R)C(=Q 2 )OR, —N(R)C(=Q 2 )N(R) 2 , —SO 2 NR 2 , —C N, —N 3 , —NO 2 , —OR, or Z 3 ; or when taken together, two R y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

 each Q 2 is independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ; or

Z 1 and Z 2 are each, independently, a group of Formula Ia:

wherein:

 each Q 3 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;

 M2 is 0, 1 or 2;

 each R x is independently R y or a formula:

 wherein:

 each M1a, M1c, and M1d is independently 0 or 1;

 M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

 Z 3 is Z 4 or Z 5 ;

 Z 4 is R, —C(Q 2 )R y , —C(Q 2 )Z 5 , —SO 2 R y , or —SO 2 Z 5 ; and

 Z 5 is a carbocycle or a heterocycle wherein Z 5 is independently substituted with 0 to 3 R y groups;

R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 N 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 )optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, OR 11 or SR 11 ;

each R 9 and R 10 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S) NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11 or SR 11 ;

each R 11 and R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 )optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —;

each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR 2 , —C(═O)SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), or —SO 2 NR 2 ; wherein

each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, (C 6 -C 20 )aryl, (C 6 -C 20 )substituted aryl, (C 2 -C 20 )heterocyclyl, (C 2 -C 20 )substituted heterocyclyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl or substituted (C 6 -C 20 )aryl(C 1 -C 8 )alkyl;

each n is independently 0, 1, or 2; and

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl of each R 2 , R 3 , R 5 , R 6 , R 11 and R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —.

2. The method of claim 1 wherein the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt or ester, thereof.

3. The method of claim 1 wherein R 7 is H.

4. The method of claim 1 wherein R 7 is selected from the group consisting of

a) H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 ,

wherein:

R c is selected from phenyl, 1-naphthyl, 2-naphthyl,

R d is H or CH 3 ;

R e1 and R e2 are each independently H or C 1 -C 6 alkyl;

R f is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl;

R g is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, —O—CH 2 —C 3 -C 6 cycloalkyl, and CF 3 ; and

n′ is selected from 1, 2, 3, and 4.

5. The method of claim 1 wherein R 7 is

wherein Z 1 and Z 2 are each, independently, a group of structure:

and Z 3 is Z 5 .

6. The method of claim 1 wherein R 7 is

wherein Z 1 and Z 2 are each, independently, a group having the structure:

and Z 3 is Z 5 .

7. The method of claim 1 wherein R 7 is

wherein each Q 3b is, independently, O or N(R).

8. The method of claim 7 wherein each Q 3b is O and each R x is independently:

wherein M12c is 1, 2 or 3 and each Q 3 is independently a bond, O, CR 2 , or S.

9. The method of claim 1 wherein R 7 is

10. The method of claim 1 wherein R 7 is

11. The method of claim 1 wherein R 7 is

12. The method of claim 11 wherein R f is C 1 -C 8 alkyl.

13. The method of claim 1 wherein R 7 is

14. The method of claim 1 wherein R 7 is

15. The method of claim 14 wherein R f is C 1 -C 8 alkyl.

16. The method of claim 14 wherein R f is C 1 -C 6 alkyl.

17. The method of claim 1 wherein R 7 is:

18. The method of claim 17 wherein R g is C 1 -C 8 alkyl.

19. The method of claim 18 wherein R g is C 1 -C 6 alkyl.

20. The method of claim 1 wherein R 7 is selected from the group consisting of:

21. The method of claim 1 wherein R 7 is

22. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt or ester thereof.

23. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt or ester thereof.

24. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt or ester thereof.

25. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt or ester thereof.

26. The method of claim 1 further comprising administering a pharmaceutically acceptable carrier or excipient.

27. The method of claim 1 further comprising administering a therapeutically effective amount of at least one other therapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating Arenaviridae virus infections; or mixtures thereof.

28. The method of claim 27 wherein the at least one other therapeutic agent is selected from the group consisting of ribavirin, favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, ST-193, and mixtures thereof.

29. The method of claim 1 wherein the Arenaviridae infection is caused by an Arenaviridae virus.

30. The method of claim 1 wherein the Arenaviridae infection is caused by a Lassa virus.

31. The method of claim 1 wherein the Arenaviridae infection is caused by a Junin virus.

32. The method of claim 1 wherein the Arenaviridae infection is caused by a Lassa virus strain selected from the group consisting of Josiah, NL, z148, Macenta, AV, and CSF.

33. The method of claim 1 wherein an Arenaviridae polymerase is inhibited.

34. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

35. The method of claim 1 wherein the compound is:

36. The method of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

37. The method of claim 1 wherein the compound is:

38. A method for treating an Arenaviridae infection in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of structure:

or a pharmaceutically acceptable salt thereof.

39. The method of claim 38 wherein the compound is:

40. The method of claim 38 wherein the Arenaviridae infection is caused by an Arenaviridae virus.

41. The method of claim 38 wherein the Arenaviridae infection is caused by a Lassa virus.

42. The method of claim 38 wherein the Arenaviridae infection is caused by a Junin virus.

43. The method of claim 38 wherein the Arenaviridae infection is caused by a Lassa virus strain selected from the group consisting of Josiah, NL, z148, Macenta, AV, and CSF.