Novel Pyrrole Inhibitors of S-Nitrosoglutathione Reductase as Therapeutic Agents

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof:

• wherein
• Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• X1-X4 is independently selected from the group consisting of C and N;
• R5 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, carboxyl, C1-C6 alkylhydroxy, sulfamoyl, C1-C6 alkylsulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
• R6 is selected from the group consisting of halogen, hydroxyl, carbamoyl, substituted carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, amino, CF3, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, 1H-imidazol-1-yl, and 2-methyl-1H-imidazol-1-yl;
• or alternatively R5 and R6 together form a substituted or unsubstituted 5 or 6 membered heterocyclic ring containing up to 2 heteroatoms chosen from O, N or S;
• R7 is selected from the group consisting of hydrogen, hydroxyl, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, carbamoyl, C1-C6 alkylcarbamoyl, sulfamoyl, C1-C6 alkylsulfamoyl, amino, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxyl, and C3-C6 cycloalkoxyl;
• n is 0-3;
• wherein R5 can be hydrogen only when at least one of X1-X4 is N;
• and further wherein, X1 and X3 must be CH or N unless R5 and R6 together form a 5 or 6 membered heterocyclic ring or at least one of X1-X4 is N;
• and wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;
• with the following provisos:
• proviso IIa:
• when all X are C and one of R5, R6, or R7 are carboxyl, methylsulfonamido, or sulfamoyl, then Ar cannot be phenyl, substituted or unsubstituted phenyl-(C1-C3)-alkyl, or phenyl-(C2-C6)-alkenyl;
• and
• proviso IIb:
• when all X are C and one of R5, R6, or R7 are independently selected from the group consisting of halogen or methyl, then Ar cannot be 4-hydroxyphenyl or 4-C1-C6 acyl-oxy-phenyl;
• and
• proviso IIc:
• when all X are C and R5 is methyl, Cl, hydroxyl, trifluoromethyl and R6 is methyl, methyoxy, carboxyethyl, Cl, or carboxypropyl, and n is 1, then Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl;
• and
• proviso IId:
• when all X are C and R5 and R6 together form a heterocyclic ring and the resulting bicyclic ring system is benzo[d]thiazol substituted at the 2 position with C1-C3 alkyl, then Ar cannot be phenyl, 4-F-phenyl, 4-methoxy-phenyl, or thiophen-yl.

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof:

• Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• X5-X8 are independently selected from the group consisting of N, C and S, wherein at least one X must be N or S;
• R8 and R9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl, C1-C6 alkyl, C3-C6 cycloalkyl, cyano, nitro, amino, CF3, carboxyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, heteroarylamino, C1-C6 alkoxyl, C3-C6 cycloalkoxyl, aryl, aryloxyl, substituted aryl, heteroaryl, substituted heteroaryl, and null if X5-X8 are all N;
• n is 0-3;
• wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl.

A method of treatment of pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of a compound of formula IV or a pharmaceutically acceptable salt thereof:

• Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R10 is hydroxyl, carbamoyl, ureido, sulfamoylamino, 2-amino-2-oxoethyl, hydroxyethyl, pyridin-3-ylamino, piridin-4-ylamino, 1-methylpyrrolidin-3-yloxy, trifluoroacetyl, imidazol-1-yl, acetamido, methylsulfamido, 2-oxooxazolidin-3-yl, 2-hydroxyethylamino, and methylcarbamoyl;
• n is 0-3;
• wherein Ar excludes substituted or unsubstituted indazol-3-yl and substituted or unsubstituted 1H-pyrazolo[3,4-b]pyridyl;
• with the following proviso:
• proviso IVa:
• when R10 is hydroxyl or carbamoyl, Ar cannot be phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-halo-phenyl, or thiophen-yl when n is 0 or 1.