N-ACYLOXYSULFONAMIDE AND N-HYDROXY-N-ACYLSULFONAMIDE DERIVATIVES

1 . A compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof wherein:

L is a bond, —SO 2 — or —O—;

Y is W, alkyl or aryl, wherein said alkyl and aryl are unsubstituted or substituted with one or more substituents independently selected from W;

W is halo, —OH, —CN, —NO 2 , —COR 1 , —COOR 1 , —CONR 1 R 2 , —CH(C(O)R 1 ) 2 , —SO 2 R 1 , or —COX, wherein X is halo and R 1 and R 2 are independently alkyl or aryl, or R 1 and R 2 are taken together to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more substituents;

R is hydrogen, alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy, benzyloxy, —NR 3 R 4 or —N(OR 3 )R 4 , wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy and benzyloxy are unsubstituted or substituted with one or more substituents; and

R 3 and R 4 are independently alkyl, heterocycloalkyl or aryl, wherein said alkyl, heterocycloalkyl and aryl are unsubstituted or substituted with one or more substituents;

provided that when L is —SO 2 — and R is methyl, then Y is not phenyl; and

provided that when Y is W and W is —OH, then L is a bond.

2 . The compound of claim 1 , wherein L is —SO 2 —.

3 . The compound of claim 1 , wherein Y is aryl and said aryl is unsubstituted or substituted with one or more substituents independently selected from W.

4 . The compound of claim 1 , wherein Y is aryl and said aryl is unsubstituted or substituted with one or two substituents independently selected from W.

5 . The compound of claim 1 , wherein Y is phenyl and said phenyl is unsubstituted or substituted with one or more substituents independently selected from W.

6 . The compound of claim 1 , wherein W is halo or —SO 2 .

7 . The compound of claim 1 , wherein W is chloro, bromo or —SO 2 .

8 . The compound of claim, wherein R is alkyl or phenyl, wherein said alkyl and phenyl are unsubstituted or substituted with one or more halos.

9 . The compound of claim 2 , wherein Y is alkyl and said alkyl is unsubstituted or substituted with one or more substituents independently selected from W.

10 . The compound of claim 2 , wherein Y is alkyl and said alkyl is unsubstituted or substituted with one or more halos.

11 . The compound of claim 9 , wherein R is alkyl or phenyl, wherein said alkyl and phenyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, alkylsulfonyl and trihalomethyl.

12 . The compound of claim 1 , wherein the compound is selected from:

N-acetyloxy-2-bromobenzenesulfonamide;

N-acetyloxy-2,6-dichlorobenzenesulfonamide;

N-acetyloxy-2,6-dibromobenzenesulfonamide;

N-benzoyloxy-benzenesulfonamide;

N-trifluoroacetyloxy)-benzenesulfonamide;

N-(trifluoroacetyloxy)-2,6-dichlorobenzenesulfonamide;

N-(trimethylacetyloxy)-2,6-dichlorobenzenesulfonamide;

N-(trimethylacetyloxy)-2-bromobenzenesulfonamide;

N-(acetyloxy)-2-(methylsulfonyl)benzenesulfonamide;

2-(methylsulfonyl)-N-(propanoyloxy)benzenesulfonamide;

N-[(2-methylpropanoyl)oxy]-2-(methylsulfonyl)benzenesulfonamide;

N-[(2,2-dimethylpropanoyl)oxy]-2-(methylsulfonyl)benzenesulfonamide;

2-(methylsulfonyl)-N-[(phenylcarbonyl)oxy]benzenesulfonamide;

N-hydroxy-N-benzoyl-benzenesulfonamide;

N-hydroxy-N-trimethylacetyl-2,6-dichlorobenzenesulfonamide;

N-[(2-bromophenyl)sulfonyl]-N-hydroxymorpholine-4-carboxamide;

(2-methanesulfonylbenzene)-sulfonamido-oxan-4-yl carbonate;

(2-bromobenzene)sulfonamido-oxan-4-yl carbonate;

(1-acetylpiperidiN-4-yl)(2-methanesulfonylbenzene)-sulfonamido carbonate;

2-methanesulfonyl-N-[(methoxycarbonyl)oxy]benzene-1-sulfonamide;

2-methanesulfonyl-N-{[(2-methoxyethoxy)carbonyl]oxy}-benzene-1-sulfonamide;

2-methanesulfonyl-N-({[2-(2-methoxyethoxy) ethoxy]carbonyl}-oxy)benzene-1-sulfonamide;

(4S)-4-[({[(2-methanesulfonyl-benzene)sulfonamidooxy]carbonyl}oxy)methyl]-2,2-dimethyl-1,3-dioxolane;

N-({[(1,3-diethoxypropaN-2 yl)oxy]carbonyl}oxy)-2-methane sulfonylbenzene-1-sulfonamide;

3-({[(2-methanesulfonylbenzene)-sulfonamidooxy]carbonyl}oxy)propane-1,2-diol;

4-({[(2-methanesulfonylbenzene)-sulfonamidooxy]carbonyl}oxy)-butan-1-ol;

2-({[(2-methanesulfonylbenzene)sulfonamidooxy]carbonyl}oxy)ethan-1-ol;

(2-methanesulfonylbenzene)-sulfonamido N,N-dimethylcarbamate;

(2-bromobenzene)sulfonamido N, N-dimethylcarbamate;

(2-methanesulfonylbenzene)-sulfonamido morpholine-4-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido 4-acetylpiperazine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido N-cyclohexyl-N-methylcarbamate;

(2-methanesulfonylbenzene)-sulfonamido piperazine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido N-(2-methoxyethyl)-N-methylcarbamate;

(2-methanesulfonylbenzene)-sulfonamido 4-(pyridiN-4-yl)piperazine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido 4-(morpholin-4-yl)piperidine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido N,N-diethylcarbamate;

(2-methanesulfonylbenzene)-sulfonamido 4-(piperidiN-1-yl)piperidine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido N-methoxy-N-methylcarbamate;

(2-methanesulfonylbenzene)-sulfonamido pyrrolidine-1-carboxylate;

2-[(carboxymethyl)({[(2-methanesulfonyl benzene)sulfonamidooxy]carbonyl}) amino]acetic acid;

(2-methanesulfonylbenzene)-sulfonamido 4-carbamoylpiperidine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido N-methyl-N-(pyridiN-3-ylmethyl)carbamate;

2-({[(2-methanesulfonylbenzene)sulfonamidooxy]carbonyl}(methyl)-amino) acetic acid;

(2-methanesulfonylbenzene)-sulfonamido N-methyl-N-(1-methylpiperidiN-4-yl)carbamate;

2-[(carboxymethyl)({[(2-methanesulfonylbenzene)sulfonamidooxy]carbonyl})amino]acetic acid;

(2-methanesulfonylbenzene)-sulfonamido 2-oxoimidazolidine-1-carboxylate;

(2-methanesulfonylbenzene)-sulfonamido 3-oxopiperazine-1-carboxylate;

[2-Chloro-5-(dimethylcarbamoyl)benzene]-sulfonamido-2,2-dimethylpropanoate;

(2-methanesulfonylbenzene)sulfonamido 2-(acetyloxy)benzoate;

(2-methanesulfonylbenzene)sulfonamido 2-[4-(2-methylpropyl)phenyl]propanoate;

(2-bromobenzene)sulfonamido benzoate;

(2-bromobenzene)sulfonamido 2-methylpropanoate;

(2-chlorobenzene)sulfonamido 2,2-dimethylpropanoate;

[2-chloro-5-(dimethylcarbamoyl)benzene]-sulfonamido acetate;

[2-chloro-5-(dimethylcarbamoyl)benzene]-sulfonamido 2-(acetyloxy)benzoate;

(2-chlorobenzene)sulfonamido 2-methylpropanoate;

(2-bromobenzene)sulfonamido 2-phenylacetate;

(2-bromobenzene)sulfonamido 2-phenylbutanoate;

(2-methanesulfonylbenzene)-sulfonamido 2-phenylbutanoate;

(2-methanesulfonylbenzene)sulfonamido (2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3-methylbutanoate;

(2-bromobenzene)sulfonamido (2S)-2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3-methylbutanoate;

(2-bromobenzene)sulfonamido 2-methyl-2-phenylpropanoate;

(2-bromobenzene)sulfonamido 1-phenylcyclopentane-1-carboxylate;

(2-bromobenzene)sulfonamido 1-acetylpyrrolidine-2-carboxylate;

(2-bromobenzene)sulfonamido (2S)-2-phenylpropanoate;

(2-bromobenzene)sulfonamido (2R)-2-phenylpropanoate;

(3-methanesulfonylbenzene)sulfonamido 2,2-dimethylpropanoate;

(3-methanesulfonylbenzene)sulfonamido 2-methylpropanoate;

(2-methanesulfonylbenzene)sulfonamido 2-(N-methylacetamido)acetate;

(2-methanesulfonylbenzene)sulfonamido (2S)-4-methyl-2-(methylamino)pentanoate;

(2-methanesulfonylbenzene)sulfonamido (2R)-2-(methylamino) propanoate;

(2-methanesulfonylbenzene)sulfonamido (2S)-2-(methylamino) propanoate;

(2-methanesulfonylbenzene)-sulfonamido 2-(methylamino)acetate;

(2-methanesulfonylbenzene)-sulfonamido (2S)-3-methyl-2-(methylamino)butanoate;

methanesulfonamido 2,2-dimethylpropanoate;

[(4-chlorophenyl)methane]-sulfonamido 2,2-dimethylpropanoate; and

pharmaceutically acceptable salts, hydrates and solvates thereof

13 . A compound of formula (II)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof wherein:

L is a bond, —SO 2 — or —O—;

Y is W, alkyl or aryl, wherein said alkyl and aryl are unsubstituted or substituted with one or more substituents independently selected from W;

W is halo, —OH, —CN, —NO 2 , —COR 1 , —COOR 1 , —CONR 1 R 2 , —CH(C(O)R 1 ) 2 , —SO 2 R 1 or —COX, wherein X is halo, and R 1 and R 2 are independently alkyl or aryl, or R 1 and R 2 are taken together to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more substituents;

R is hydrogen, alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy, benzyloxy or —NR 3 R 4 , wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy and benzyloxy are unsubstituted or substituted with one or more substituents; and

R 3 and R 4 are independently alkyl or aryl;

provided that when Y is W and W is —OH, then L is a bond.

14 . a compound of formula (Ia)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof wherein:

L is a bond, —SO 2 — or —O—;

Y is a heteroaryl, wherein said heteroaryl is unsubstituted or substituted with one or more substituents independently selected from W;

W is halo, —OH, —CN, —NO 2 , —COR 1 , —COOR 1 , —CONR 1 R 2 , —CH(C(O)R 1 ) 2 , —SO 2 R 1 , or —COX, wherein X is halo, and R 1 and R 2 are independently alkyl or aryl, or R 1 and R 2 are taken together to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more substituents;

R is hydrogen, alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy, benzyloxy or —NR 3 R 4 , wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy, and benzyloxy are unsubstituted or substituted with one or more substituents; and

R 3 and R 4 are independently alkyl or aryl.

15 . a compound of formula (IIa)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof wherein:

L is a bond, —SO 2 — or —O—;

Y is a heteroaryl, wherein said heteroaryl is unsubstituted or substituted with one or more substituents independently selected from W;

W is halo, —OH, —CN, —NO 2 , —COR 1 , —COOR 1 , —CONR 1 R 2 , —CH(C(O)R 1 ) 2 , —SO 2 R 1 or —COX, wherein X is halo, and R 1 and R 2 are independently alkyl or aryl, or R 1 and R 2 are taken together to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more substituents;

R is hydrogen, alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy, benzyloxy or —NR 3 R 4 , wherein said alkyl, heterocycloalkyl, aryl, benzyl, alkoxy, heterocycloalkoxy, aryloxy and benzyloxy are unsubstituted or substituted with one or more substituents; and

R 3 and R 4 are independently alkyl or aryl.

16 . A pharmaceutical composition comprising:

a compound of claims 1 ; and

a pharmaceutically acceptable excipient.

17 . A method of treating a disease or condition selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy, comprising administering a compound of any one of claims 1 to 24 to a subject in need thereof.

18 . The method of claim 17 , wherein the disease or condition is a cardiovascular disease.

19 . The method of claim 18 , wherein the cardiovascular disease is heart failure.

20 . The method of claim 19 , wherein the heart failure is congestive heart failure.

21 . The method of claim 19 , wherein the heart failure is acute congestive heart failure.

22 . The method of claim 19 , wherein the heart failure is acute decompensated heart failure.

23 . The method of claim 17 , wherein the disease or condition is ischemia or reperfusion injury.

24 . The method of claim 17 , wherein the disease or condition is a cancerous disease.

25 . The method of claim 24 , wherein the cancerous disease is breast cancer, pancreatic cancer, prostate cancer or colorectal cancer.

26 . The method of claim 17 , wherein the disease or condition is pulmonary hypertension.

27 . The method of claim 26 , wherein the pulmonary hypertension is pulmonary arterial hypertension.

28 . The method of claim 26 , wherein the pulmonary hypertension is pulmonary hypertension owing to left heart disease.

29 . The method of claim 28 , wherein the left heart disease is left heart failure.

30 . The method of claim 29 , wherein the left heart failure is systolic heart failure.

31 . The method of claim 29 , wherein the left heart failure is diastolic heart failure.

32 . The method of claim 29 , wherein the left heart failure is chronic or acutely decompensated.

33 . The method of claim 26 , wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

34 . A method of modulating in vivo nitroxyl levels, comprising administering a compound of claim 1 to a subject in need thereof.

35 . A kit comprising:

a compound of claim 1 ; and

instructions for treating a disease or condition selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.