N-substituted hydroxamic acids with carbon-based leaving groups as efficient HNO donors and uses thereof

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R and R 1 are selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )perhaloalkyl, (C 6 -C 10 )aryl, (C 1 -C 6 )heteroalkyl, (C 5 -C 7 )heterocycloalkyl, (5- or 6-membered)heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and (C 3 -C 6 )cycloalkyl;

R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —C(═O)R 4 , —C(═S)R 4 , C(═NR 4 )R 5 , —C(═NOR 4 )R 5 , (5- or 6-membered)heteroaryl and (C 6 -C 10 )aryl;

R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, and —NR 6 R 7 ;

R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, phenyl and benzyl;

wherein said alkyl, aryl, phenyl, benzyl, heteroalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )perhaloalkoxy, —C(═O)OH, —C(═O)O(C 1 -C 6 )alkyl, —C(═O)NR 4 R 5 , —C(═O)—(C 5 -C 7 )heterocycloalkyl, (C 5 -C 7 )heterocycloalkyl, (C 1 -C 6 )alkylsulfanyl, (C 1 -C 4 )haloalkylsulfanyl, (C 1 -C 4 )perhaloalkylsulfanyl, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkylsulfonyl, (C 1 -C 4 )haloalkylsulfinyl, (C 1 -C 4 )haloalkylsulfonyl, (C 1 -C 4 )perhaloalkylsulfinyl, (C 1 -C 4 )perhaloalkylsulfonyl, —S(O) 2 —NH 2 , —S(O) 2 —NR 6 R 7 , —S(O) 2 -phenyl, —S(O) 2 —(C 5 -C 7 )heterocycloalkyl, —S(═O)(═NR 8 )(C 1 -C 6 )alkyl, —NR 4 R 5 , N—(C 1 -C 6 )alkylaminosulfonyl, and N,N-di(C 1 -C 6 )alkylaminosulfonyl.

2. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl and (5- or 6-membered)heteroaryl, wherein said alkyl, heteroaryl and aryl are unsubstituted or substituted with 1, 2 or 3 substituents.

3. The compound of claim 1 , wherein R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 4 )perhaloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, (5- or 6-membered)heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and (C 3 -C 6 )cycloalkyl, wherein said alkyl, perhaloalkyl, alkoxy, aryl, heteroaryl, phenylsulfanyl, phenylsulfonyl, phenylsulfinyl and cycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents.

4. The compound of claim 1 , wherein R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, —C(═O)R 4 , —C(═S)R 4 , C(═NR 4 )R 5 , —C(═NOR 4 )R 5 , (5- or 6-membered)heteroaryl and (C 6 -C 10 )aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 substituents.

5. The compound of claim 1 , wherein R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, phenyl, and —NR 6 R 7 , wherein R 6 and R 7 are independently selected from hydrogen and (C 1 -C 6 )alkyl.

6. The compound of claim 1 , wherein the compound of formula (I) is:

7. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

N-hydroxy-N-(4-(1-(methoxyimino)ethyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)acetamide;

N-hydroxy-N-(4-(1-(methoxyimino)ethyl)-1,3-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)acetamide;

1-hydroxy-1-(4-(1-(methoxyimino)ethyl)-3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-3,3-dimethylurea;

1-hydroxy-1-(4-(1-(methoxyimino)ethyl)-1,3-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-3,3-dimethylurea;

1-(3,4-dimethyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-1-hydroxy-3,3-dimethylurea;

1-hydroxy-3,3-dimethyl-1-(1,3,4-trimethyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)urea;

N-hydroxy-N-(3,4-dimethyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-acetamide;

N-hydroxy-N-(3-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrazol-4-yl)acetamide;

N-(1,3-dimethyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-N-hydroxyacetamide;

N-hydroxy-N-(3-methyl-5-oxo-1,4-diphenyl-4,5-dihydro-1H-pyrazol-4-yl)acetamide;

N-hydroxy-N-(3-methyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrazol-4-yl)benzamide;

N-(1,3-dimethyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-N-hydroxybenzamide;

N-hydroxy-N-(3-methyl-5-oxo-1,4-diphenyl-4,5-dihydro-1H-pyrazol-4-yl)benzamide;

1-(1,3-dimethyl-5-oxo-4-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-1-hydroxy-3,3-dimethylurea;

1-hydroxy-3,3-dimethyl-1-(3-methyl-5-oxo-1,4-diphenyl-4,5-dihydro-1H-pyrazol-4-yl)urea;

N-(1,4-dimethyl-3-(4-(methylsulfonyl)phenyl)-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-N-hydroxyacetamide; and

1-(1,4-dimethyl-3-(4-(methylsulfonyl)phenyl)-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-1-hydroxy-3,3-dimethylurea.

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

9. A method for modulating in vivo nitroxyl levels, the method comprising administering a compound of claim 1 , or a pharmaceutical composition of claim 8 , to a subject in need thereof.

10. A method for inhibiting or reducing the severity of a disease or condition responsive to nitroxyl therapy, the method comprising administering to a subject in need of treatment, a compound of claim 1 , or a pharmaceutical composition of claim 8 , in an amount effective to inhibit or reduce the severity of the disease or condition.

11. A method for inhibiting or reducing the severity of a cardiovascular disease, the method comprising administering to a subject in need of treatment, a compound of claim 1 , or a pharmaceutical composition of claim 8 , in an amount effective to inhibit or reduce the severity of the cardiovascular disease.

12. A kit for inhibiting or reducing the severity of a disease or condition responsive to nitroxyl therapy, comprising a compound of claim 1 , or a pharmaceutical composition of claim 8 ; and instructions for use of the kit.