Primary amine diazeniumdiolate heterocyclic derivatives

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

X is O or NR 7 ;

is attached to any ring carbon atom other than the carbon to which R 1 and R 2 are attached;

R 1 is hydrogen, —C(O)OC 1-6 alkyl, or —C(O)OH, or together with R 2 , forms ═O;

R 2 is hydrogen, or together with R 1 , forms ═O;

R 4 is

—C 1-6 alkyl,

—CD 2 C 1-5 alkyl,

—C 2-5 alkylene-OH,

—C 2-5 alkylene-O—C(O)C 1-6 alkyl,

—C 1-6 alkylene-aryl, or

—CH 2 CH═CH 2 ;

R 5 and R 6 , which are attached to any available carbon ring atom, are independently

hydrogen,

deuterium,

—C 1-6 alkyl,

—C(O)OC 1-6 alkyl,

—C(O)OH,

aryl,

or R 5 and R 6 , when they are attached to the same carbon atom, together form ═O;

R 7 is

hydrogen,

—C 1-6 alkyl,

—C 1-6 alkylene-aryl,

—C 1-6 alkyleneC(O)O—C 1-6 alkyl,

—C 1-6 alkylene-CR 8 R 9 R 10 ,

—CN,

—C(O)O—C 1-6 alkyl,

—C(O)O—C 1-6 alkylene CR 8 R 9 R 10 ,

—C(O)C 1-6 alkyl,

—C(O)OC 3-6 carbocycle,

—C(O)CHF 2 ,

—C(O)CF 3 ,

—C(O)CH 2 OH,

—C(O)aryl,

—C(O)heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring containing 1-4 heteroatoms selected from N, O and S,

—C(O)C 1-6 alkyleneOH,

—C(O)C 3-6 carbocycle,

—C(O)NH 2 ,

—C(O)NHC 1-6 alkyl,

—C(O)NH-adamantyl,

—C(O)heterocycle, wherein heterocycle is a saturated monocyclic 5- to 8-membered ring containing 1-4 heteroatoms selected from N, O and S, or a 7- to 12-membered saturated bicyclic ring system containing 1-6 heteroatoms selected from N, O and S,

—C(O)NHC 3-6 carbocycle,

—C(O)N(C 1-6 alkyl)Cl 1-6 alkyl,

—C(O)NHSO 2 aryl,

—SOC 1-6 alkyl,

—SO 2 C 1-6 alkyl,

—SO 2 NH(C 1-6 alkyl),

—SO 2 N(C 1-6 alkyl)(C 1-6 alkyl),

—SO 2 CF 3 ,

—SO 2 aryl,

—SO 2 heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring containing 1-4 heteroatoms selected from N, O and S,

aryl,

an unsaturated 5- or 6-membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S, or

—C 3-6 carbocycle;

wherein aryl, alkyl, alkylene, carbocycle, heteroaryl, and heterocycle are unsubstituted or substituted with 1-4 groups independently selected from —CN, halogen, —CF 3 , —OCF 3 , —C(O)NH 2 , —C 1-6 alkyl, —C 3-6 carbocycle, ═O, —C(O)OC 1-6 alkyl,

—COOH, —C(CH 3 ) 2 OH,

—SO 2 (C 1-6 alkyl), aryl, an unsaturated 5-membered heteroaryl ring containing 1-3 nitrogen atoms, or —OC 1-6 alkyl,

wherein R 8 and R 9 , together with the carbon to which they are attached, form a C 3-6 carbocycle or 4-8-membered heterocycle, and

wherein R 10 is C 1-6 alkyl.

2. A compound of claim 1 , of formula

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 , of formula

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 , of formula

or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 , wherein X is —NR 7 and

R 7 is

—C 1-6 alkyl,

—C 1-6 alkylene-CR 8 R 9 R 10 ,

—C(O)O—C 1-6 alkyl,

—C(O)O—C 1-6 alkylene CR 8 R 9 R 10 ,

—C(O)C 1-6 alkyl,

—C(O)OC 3-6 carbocycle,

—C(O)CF 3 ,

—C(O)aryl,

—C(O)heteroaryl, wherein heteroaryl is an unsaturated 6-membered ring containing 1-2 nitrogen atoms,

—C(O)NHC 1-6 alkyl,

—C(O)NH-adamantyl,

—SO 2 C 1-6 alkyl,

aryl, or

heteroaryl, wherein heteroaryl is an unsaturated 6-membered ring containing 1-2 nitrogen atoms,

wherein aryl, alkyl, alkylene, carbocycle, and heteroaryl are unsubstituted or substituted with 1-4 groups independently selected from —CN, —CF 3 , Cl, —OCF 3 , —C(O)NH 2 , —C 1-6 alkyl, —C 3-6 carbocycle, ═O, —C(O)OC 1-6 alkyl, aryl, an unsaturated 5-membered heteroaryl ring containing 3 nitrogen atoms or —OC 1-6 alkyl,

wherein R 8 and R 9 , together with the carbon to which they are attached, form a C 3-6 carbocycle or 4-8-membered heterocycle, and

wherein R 10 is C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 5 , wherein R 7 is —C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2-CF 3 , or a pharmaceutically acceptable salt thereof.

7. A compound of claim 5 , wherein

R 7 is —C(O)O—C 1-6 alkyl, —C(O)C 1-6 alkyl, —C(O)O—C 1-6 alkylene CR 8 R 9 R 10 , —C(O)OC 3-6 carbocycle, —C(O)CF 3 , —C(O)aryl, —C(O)pyridyl, —C(O)NHC 1-6 alkyl, or —C(O)NH-adamantyl,

wherein alkyl is unsubstituted or substituted with aryl or —CF 3 ,

wherein R 8 and R 9 , together with the carbon to which they are attached, form a C 3-6 carbocycle or 4-8-membered heterocycle, and

wherein R 10 is C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

8. A compound of claim 5 , wherein R 7 is —SO 2 C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

9. A compound of claim 5 , wherein R 7 is aryl, wherein aryl is unsubstituted or substituted with 1-2 groups independently selected from —CN, —CF 3 , —OCF 3 , —CH 3 or an unsaturated 5-membered heteroaryl ring having 3 nitrogen atoms,

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 5 , wherein R 7 is an unsaturated heteroaryl 6-membered ring containing 1-2 nitrogen atoms, wherein heteroaryl is unsubstituted or substituted with 1-4 groups independently selected from Cl, an unsaturated 5-membered heteroaryl ring containing 3 nitrogen atoms, —CN, —CF 3 , and —C(O)NH 2 , or a pharmaceutically acceptable salt thereof.

11. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 7 is

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5 and R 6 are hydrogen.

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the atom to which they are attached, form ═O, and R 5 and R 6 are hydrogen.

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —C 1-6 alkyl.

15. A compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —C(CH 3 ) 3 .

16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —NR 7 and R 7 is

—C 1-6 alkyl,

—C 1-6 alkylene-aryl,

—C 1-6 alkyleneC(O)O—C 1-6 alkyl,

—C 1-6 alkylene-CR 8 R 9 R 10 ,

—CN,

—C(O)O—C 1-6 alkyl,

—C(O)O—C 1-6 alkylene CR 8 R 9 R 10 ,

—C(O)C 1-6 alkyl,

—C(O)OC 3-6 -carbocycle,

—C(O)CHF 2 ,

—C(O)CF 3 ,

—C(O)CH 2 OH,

—C(O)aryl,

—C(O)heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring containing 1-4 heteroatoms selected from N, O and S,

—C(O)C 1-6 alkyleneOH,

—C(O)C 3-6 -carbocycle,

—C(O)NH 2 ,

—C(O)NHC 1-6 alkyl,

—C(O)NH-adamantyl,

—C(O)heterocycle, wherein heterocycle is a saturated monocyclic 5- to 8-membered ring containing 1-4 heteroatoms selected from N, O and S, or a 7- to 12-membered saturated bicyclic ring system containing 1-6 heteroatoms selected from N, O and S,

—C(O)NHC 3-6 carbocycle,

—C(O)N(C 1-6 alkyl)C 1-6 alkyl,

—C(O)NHSO 2 aryl,

—SOC 1-6 alkyl,

—SO 2 C 1-6 alkyl,

—SO 2 NH(C 1-6 alkyl),

—SO 2 N(C 1-6 alkyl)(C 1-6 alkyl),

—SO 2 CF 3 ,

—SO 2 aryl,

—SO 2 heteroaryl, wherein heteroaryl is an unsaturated 5- or 6-membered ring containing 1-4 heteroatoms selected from N, O and S,

aryl,

an unsaturated 5- or 6-membered heteroaryl ring containing 1-4 heteroatoms selected from N, O and S, or

—C 3-6 carbocycle;

wherein aryl, alkyl, alkylene, carbocycle, heteroaryl, and heterocycle are unsubstituted or substituted with 1-4 groups independently selected from —CN, halogen, —CF 3 , —OCF 3 , —C(O)NH 2 , —C 1-6 alkyl, —C 3-6 carbocycle, ═O, —C(O)OC 1-6 alkyl,

—COOH, —C(CH 3 ) 2 OH,

—SO 2 (C 1-6 alkyl), aryl, an unsaturated 5-membered heteroaryl ring containing 1-3 nitrogen atoms, or —OC 1-6 alkyl,

wherein R 8 and R 9 , together with the carbon to which they are attached, form a C 3-6 carbocycle or 4-8-membered heterocycle, and

wherein R 10 is C 1-6 alkyl.

17. A compound of claim 1 , which is

O 2 -[1-(tert-butoxycarbonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[(cyclohexyloxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-dioate,

O 2 -{(3R)-1-[(propan-2-yloxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[(2,2-dimethylpropoxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2diolate,

O 2 -{(3R)-1-[(cyclopropylmethoxy)carbonyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2diolate,

O 2 -[(3R)-1-{[(3-methyloxetan-3-yl)methoxy]carbonyl}pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(tert-butylcarbamoyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(tricyclo[3.3.1.13,7]dec-1-ylcarbamoyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[(2-phenylpropan-2-yl)carbamoyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

(±)—O 2 -[1-(tert-butylcarbamoyl)azepan-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -(1-acetylpiperidin-4-yl)1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(2,2-dimethylpropanoyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{1-[(4-cyanophenyl)carbonyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{1-[(2-methylphenyl)carbonyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

(±)—O 2 -[1-(pyridin-4-ylcarbonyl)azepan-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(methylsulfonyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(methylsulfonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(tert-butylsulfonyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(4-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(3-cyanophenyl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(5-cyanopyrazin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(3-cyanophenyl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[2-(trifluoromethyl)pyridin-3-yl}pyrrolidin-3-yl) 1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(6-cyanopyridin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(5-chloropyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(5-carbamoylpyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[3-(1H-1,2,3-triazol-1-yl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{1-[3-(1H-1,2,4-triazol-1-yl)phenyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{1-[3-(1H-1,2,3-triazol-1-yl)phenyl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{1-[5-(1H-1,2,3-triazol-1-yl)pyridin-2-yl]piperidin-4-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -(tetrahydro-2H-pyran-4-yl)1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(3-methylphenyl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-2-oxo-1-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(5-chloropyridin-3-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(5-cyanopyridin-2-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate, or

O 2 -{(3R)-2-oxo-1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

or a pharmaceutically acceptable salt thereof.

18. A compound of claim 17 , which is

O 2 -[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(4-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-1-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(6-cyanopyridin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(5-chloropyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[1-(5-carbamoylpyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(5-chloropyridin-3-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -[(3R)-1-(5-cyanopyridin-2-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

O 2 -{(3R)-2-oxo-1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate,

or pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a compound of claim 17 , a diuretic, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a compound of claim 17 , an angiotensin II receptor antagonist, and a pharmaceutically acceptable carrier.

23. A method for treating hypertension in a patient which comprises administering to the patient a therapeutically effective amount of the composition of claim 20 .

24. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[1-(5-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

25. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[1-(4-cyanopyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

26. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -{(3R)-1-[2-(trifluoromethyl)pyridin-3-yl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

27. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[(3R)-1-(6-cyanopyridin-2-yl)pyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

28. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[1-(5-chloropyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

29. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[1-(5-carbamoylpyridin-2-yl)piperidin-4-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

30. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[(3R)-1-(5-chloropyridin-3-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

31. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -[(3R)-1-(5-cyanopyridin-2-yl)-2-oxopyrrolidin-3-yl]1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.

32. A compound of claim 18 , or a pharmaceutically acceptable salt thereof, which is O 2 -{(3R)-2-oxo-1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}1-(N-tert-butylamino)diazen-1-ium-1,2-diolate.