Compositions and methods for inhibiting influenza RNA polymerase PA endonuclease

1. A compound having the formula:

wherein,

Y is O, S, or NH;

W 1 is —CH(R 1 )—, or —N(R 1 )—;

R 1 is hydrogen;

W 2 is —C(R 2 )═;

R 2 is hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —OCX 2 3 , —OCH 2 X 2 , —OCHX 2 2 , —CN, —SO n2 R 2D , —SO v2 NR 2A R 2B , —NHC(O)NR 2A R 2B , —N(O) m2 , —NR 2A R 2B , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A C(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 4 is halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —OCX 4 3 , —OCH 2 X 4 , —OCHX 4 2 , —CN, —SO n4 R 4D , —SO v4 NR 4A R 4B , —NHC(O)NR 4A R 4B , —N(O) m4 , —NR 4A R 4B , —C(O)R 4C , —C(O)—OR 4C , —C(O)NR 4A R 4B , —OR 4D , —NR 4A SO 2 R 4D , —NR 4A C(O)R 4C , —NR 4A C(O)OR 4C , —NR 4A OR 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R 2A , R 2B , R 2C , R 2D , R 4A , R 4B , and R 4D are independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 , —CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 4A and R 4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

R 1D is hydrogen;

R 4C is hydrogen;

each X, X 2 , and X 4 is independently —F, —Cl, —Br, or —I;

n2 and n4 are independently an integer from 0 to 4; and

m2, m4, v2 and v4 are independently an integer from 1 to 2.

2. The compound of claim 1 , wherein Y is S or O.

3. The compound of claim 1 , wherein W 1 is —N(R 1 )—.

4. The compound of claim 1 , wherein W 2 is —C(R 2 )═.

5. The compound of claim 4 , wherein R 2 is hydrogen, —OR 2D , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

6. The compound of claim 1 , wherein R 3 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

7. The compound of claim 1 , wherein R 4 is halogen, —C(O)R 4c , —C(O)—OR 4c , —C(O)NR 4A R 4B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

9. A method of inhibiting RNA-dependent RNA polymerase PA subunit endonuclease protein activity, said method comprising contacting the RNA-dependent RNA polymerase PA subunit endonuclease protein with an effective amount of a compound of claim 1 , wherein the RNA-dependent RNA polymerase PA subunit endonuclease protein is an influenza virus protein.

10. A method of treating a viral infection, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , wherein the viral infection is an influenza virus infection.

11. The method of claim 10 , wherein the viral infection is an influenza virus A infection.

12. The compound of claim 1 having the formula:

13. The compound of claim 1 , wherein R 3 is R 30 -substituted or unsubstituted aryl;

wherein,

R 30 is independently oxo, halogen, —CX 30 3 , —CHX 30 2 , —CH 2 X 30 , —OCX 30 3 , —OCH 2 X 30 , —OCHX 30 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OR 31 , —NHR 31 , —N(CH 3 )R 31 , —COOR 31 , —CONHR 31 , —SR 31 , —SO 2 NHR 31 , —SO 2 R 31 , R 31 -substituted or unsubstituted alkyl, R 31 -substituted or unsubstituted heteroalkyl, R 31 -substituted or unsubstituted cycloalkyl, R 31 -substituted or unsubstituted heterocycloalkyl, R 31 -substituted or unsubstituted aryl, or R 31 -substituted or unsubstituted heteroaryl;

X 30 is independently —F, —Cl, —Br, or —I;

R 31 is independently oxo, halogen, —CX 31 3 , —CHX 31 2 , —CH 2 X 31 , —OCX 31 3 , —OCH 2 X 31 , —OCHX 31 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O) NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OR 32 , —NHR 32 , —N(CH 3 )R 32 , —COOR 32 , —CONHR 32 , —SR 32 , R 32 -substituted or unsubstituted alkyl, R 32 -substituted or unsubstituted heteroalkyl, R 32 -substituted or unsubstituted cycloalkyl, R 32 -substituted or unsubstituted heterocycloalkyl, R 32 -substituted or unsubstituted aryl, or R 32 -substituted or unsubstituted heteroaryl;

X 31 is independently —F, —Cl, —Br, or —I;

R 32 is independently oxo, halogen, —CX 32 3 , —CHX 32 2 , —CH 2 X 32 , —OCX 32 3 , —OCH 2 X 32 , —OCHX 32 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and

X 32 is independently —F, —Cl, —Br, or —I.

14. The compound of claim 13 , wherein R 3 is R 30 -substituted or unsubstituted —CH 2 N(CH 3 )Ph, or R 30 -substituted or unsubstituted phenyl.

15. The compound of claim 1 , wherein R 4 is —C(O)R 4C , —C(O)—OR 4C , —C(O)NR 4A R 4B , or substituted or unsubstituted heteroaryl.

16. The compound of claim 15 , wherein R 4 is —C(O)OH, —C(O)NHCH 3 , or unsubstituted tetrazolyl.