Pyrimidinone compounds and methods for treating influenza

1. A compound of the formula:

wherein R 1 is an optionally substituted heteroaryl;

wherein R 3 is optionally substituted and selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —CONR 4 R 5 , and —COR 6 ;

wherein R 4 and R 5 are each optionally substituted and independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein at least one of R 4 or R 5 is not hydrogen, and provided that when R 1 is a heteroaryl group having 6 or more ring members, then neither R 3 nor R 4 is hydrogen; or wherein —NR 4 R 5 together form an optionally substituted ring selected from piperidinyl, morpholinyl, and piperazinyl; and

wherein R 6 is optionally substituted and selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl,

or a pharmaceutically acceptable salt thereof.

2. A method for treating influenza in a subject, the method comprising: administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, thereby treating the influenza.

3. The method of claim 2 , wherein the compound is an endonuclease inhibitor.

4. The method of claim 2 , wherein the compound is a RNA dependent RNA polymerase inhibitor.

5. The method of claim 2 , wherein the influenza is Influenza A.

6. The method of claim 2 , wherein the influenza is Influenza B.

7. The method of claim 2 , wherein the influenza is H1N1, H2N2, H3N2, H5N1, or any combination of H1N1, H2N2, H3N2, and H5N1.

8. The method of claim 2 , wherein the influenza is drug resistant.

9. A therapeutic method comprising co-administration of one or more treatments selected from Oseltamavir, Zanamivir, Amantadine, Rimantadine, Arbidol, Laninamivir, Peramivir, Vitamin D, and an interferon, with one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the one or more treatments and the one or more compounds are administered simultaneously.

11. The method of claim 9 , wherein the one or more treatments and the one or more compounds are administered in a single pharmaceutical composition.

12. The compound of claim 1 , wherein R 3 is a five-membered heterocycle selected from:

wherein Y is selected from O, S, and N—R 8 ;

wherein Z 1 is selected from N and C—R 9 ; and

wherein Z 2 is selected from N and C—R 9 ,

wherein each R 8 is independently selected from hydrogen, methyl, ethyl, propyl, and butyl; and

wherein each R 9 is independently selected from hydrogen, cyano, acyl, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyl, acetoxyl, methoxyl, ethoxyl, propoxyl, and butoxyl.

13. The compound of claim 1 , wherein R 3 is a six-membered heterocycle selected from:

wherein n is an integer from 0-2; and

wherein each R 10 is independently selected from hydrogen, cyano, acyl, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyl, acetoxyl, methoxyl, ethoxyl, propoxyl, and butoxyl.

14. The method of claim 2 , wherein the compound is an influenza endonuclease inhibitor.

15. The method of claim 9 , wherein the compound is an endonuclease inhibitor.

16. The method of claim 9 , wherein the compound is an influenza endonuclease inhibitor.

17. The compound of claim 1 , wherein the compound is an endonuclease inhibitor.

18. The compound of claim 1 , wherein the compound is an influenza endonuclease inhibitor.

19. A compound of the formula:

wherein X is selected from hydroxyl, fluoro, chloro, bromo, —OR 7 , —NR 11 R 12 , —NR 11 COR 12 , —NR 11 CO 2 R 12 , and —NR 11 CONR 12 R 13 ;

wherein R 1 is optionally substituted heteroaryl;

wherein R 2 is optionally substituted and selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or wherein R 1 and R 2 together form an optionally substituted ring with the carbon and nitrogen to which they are attached, selected from pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, 1,3,5-triazinanyl, and piperidinyl;

wherein R 3 is optionally substituted and selected from cycloalkyl; heterocycloalkyl; aryl or heteroaryl, provided that R 1 and R 2 do not form a ring together with the carbon and nitrogen to which they are attached; —CONR 4 R 5 , and —COR 6 ;

wherein R 4 and R 5 are each optionally substituted and independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein at least one of R 4 or R 5 is not hydrogen, and provided that when R 1 is an aryl or heteroaryl group having 6 or more ring members, then neither R 3 nor R 4 is hydrogen; or wherein —NR 4 R 5 together form an optionally substituted ring selected from piperidinyl, morpholinyl, and piperazinyl;

wherein R 6 is optionally substituted and selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl;

wherein R 7 is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and

wherein each of R 11 , R 12 , and R 13 , when present, is independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

or a pharmaceutically acceptable salt thereof,

wherein the compound is an endonuclease inhibitor.

20. The compound of claim 19 , wherein X is hydroxyl.

21. The compound of claim 19 , wherein R 2 is hydrogen.

22. A method for treating influenza in a subject, the method comprising: administering to the subject an effective amount of the compound of claim 19 , or a pharmaceutically acceptable salt thereof, thereby treating influenza.

23. A therapeutic method comprising co-administration of one or more treatments selected from Oseltamavir, Zanamivir, Amantadine, Rimantadine, Arbidol, Laninamivir, Peramivir, Vitamin D, and an interferon, with one or more compounds of the formula:

wherein X is selected from hydroxyl, fluoro, chloro, bromo, —OR 7 , —NR 11 R 12 , —NR 11 COR 12 , —NR 11 CO 2 R 12 , and —NR 11 CONR 12 R 13 ;

wherein R 1 is optionally substituted and selected from heteroaryl, aryl-substituted alkyl, heteroaryl-substituted alkyl, —NR 11 R 12 , —NR 11 COR 12 , —NR 11 CO 2 R 12 , —NR 11 CONR 12 R 13 , —COR 11 , —CONR 12 R 13 , and —OR 7 ;

wherein R 2 is optionally substituted and selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or wherein R 1 and R 2 together form an optionally substituted ring with the carbon and nitrogen to which they are attached, selected from pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, 1,3,5-triazinanyl, and piperidinyl;

wherein R 3 is optionally substituted and selected from cycloalkyl; heterocycloalkyl; aryl or heteroaryl, provided that R 1 and R 2 do not form a ring together with the carbon and nitrogen to which they are attached; —CONR 4 R 5 , and —COR 6 ;

wherein R 4 and R 5 are each optionally substituted and independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein at least one of R 4 or R 5 is not hydrogen, and provided that when R 1 is an aryl or heteroaryl group having 6 or more ring members, then neither R 3 nor R 4 is hydrogen; or wherein —NR 4 R 5 together form an optionally substituted ring selected from piperidinyl, morpholinyl, and piperazinyl;

wherein R 6 is optionally substituted and selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, thienyl, isoxazolyl, thiazolyl, and oxazolyl;

wherein R 7 is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and

wherein each of R 11 , R 12 , and R 13 , when present, is independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

or a pharmaceutically acceptable salt thereof,

wherein the compound is an endonuclease inhibitor.

24. The method of claim 19 , wherein R 1 is selected from 2-pyridinyl and 1-methyl-1H-imidazole.

25. The method of claim 23 , wherein R 1 is heteroaryl.

26. The method of claim 23 , wherein R 1 is selected from 2-pyridinyl and 1-methyl-1H-imidazole.