Methods for treating arenaviridae and coronaviridae virus infections

1. A method for treating a Coronaviridae infection in a human in need thereof, comprising administering a therapeutically effective amount of a compound of Formula IV:

or a pharmaceutically acceptable salt thereof;

wherein:

R 7 is selected from the group consisting of

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 ), and —SO 2 NR 11 R 12 ,

wherein

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, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or 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 is optionally 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, 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, arylalkyl or substituted arylalkyl; and

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each 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 is optionally replaced with —O—, —S— or —NR a —,

wherein:

R c is selected from the group consisting of 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; and

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

and

d) a group of the 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 2 )R, —OC(=Q 2 )OR, —OC(=Q 2 )(N(R) 2 ), —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 , —CN, —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 the 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(O), or S(O) 2 ;

M2 is 0, 1 or 2;

each R x is independently R y or the 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.

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

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 ), and —SO 2 NR 11 R 12 ,

wherein:

R c is selected from the group consisting of 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; and

R f is selected from the group consisting of H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.

3. 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 .

4. The method of claim 1 wherein R 7 is

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

5. The method of claim 4 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, or CR 2 .

6. The method of claim 1 wherein R 7 is

7. The method of claim 1 wherein R 7 is

8. The method of claim 1 wherein R 7 is

wherein

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

R g is selected from the group consisting of —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 .

9. The method of claim 1 wherein R 7 is

wherein

R f is selected from the group consisting of H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.

10. The method of claim 9 wherein R f is C 1 -C 8 alkyl.

11. The method of claim 9 wherein R f is C 1 -C 6 alkyl.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 wherein the compound of formula IV is:

or a pharmaceutically acceptable salt thereof.

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

17. 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 a Coronaviridae virus infection; or mixtures thereof.

18. The method of claim 1 wherein the Coronaviridae infection is caused by a Coronaviridae virus.

19. The method of claim 1 wherein the Coronaviridae infection is caused by a Coronaviridae virus selected from SARS, MERS, 229E, NL63, OC43, and HKU1.

20. The method of claim 1 , wherein the compound of Formula IV is

or a pharmaceutically acceptable salt thereof.