Substituted bicyclic aromatic compounds as S-nitrosoglutathione reductase inhibitors
The present invention is directed to novel substituted bicyclic aromatic compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
1. A method of treatment of a disorder which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) wherein the disorder is selected from the group consisting of pulmonary disorders associated with hypoxemia and/or smooth muscle constriction in the lungs and airways and/or lung infection and/or lung inflammation and/or lung injury, inflammatory diseases and functional bowel disorders:
wherein
Z 1 is selected from the group consisting of CR 2a and N;
Z 2 is selected from the group consisting of CR 2b and N;
Z 3 is selected from the group consisting of CR 2c and N;
wherein if Z 1 is N, then one or both of Z 2 or Z 3 is also N with the proviso that at least 1 of Z 1 , Z 2 , or Z 3 must be N;
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2a , R 2b , and R 2c , are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
2. The method of claim 1 wherein when Z 1 and Z 2 are both N, and Z 3 is CR 2c , then R 2c is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, and cyano.
3. The method of claim 1 wherein
m is selected from the group consisting of 0 and 1;
R 2a , R 2b , and R 2c , are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 ;
n is selected from the group consisting of 0 and 1; and
R 3 is independently selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, cyano, methoxy, and NR 4 R 4′ where R 4 and R 4′ are methyl, or alternatively together with the said N form the ring aziridin-1-yl or morpholino.
4. The method of claim 3 wherein X is
5. The method of claim 4 wherein A is COOH.
6. The method of claim 1 , wherein the compound is a compound of Formula II
wherein
Z 2 is selected from the group consisting of CR 2b and N;
Z 3 is selected from the group consisting of CR 2c and N;
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2b and R 2c are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
n is selected from 0, 1, and 2;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
7. The method of claim 6 wherein when Z 2 is N, and Z 3 is CR 2c , then R 2c is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, and cyano.
8. The method of claim 6 wherein
m is selected from the group consisting of 0 and 1;
R 2a , R 2b , and R 2c , are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 ;
n is selected from the group consisting of 0 and 1; and
R 3 is independently selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl, cyano, methoxy, and NR 4 R 4′ where R 4 and R 4′ are methyl, or alternatively together with the said N form the ring aziridin-1-yl or morpholino.
9. The method of claim 1 , wherein the compound is a compound of Formula III
wherein
Z 2 is selected from the group consisting of CR 2b and N;
Z 3 is selected from the group consisting of CR 2c and N;
with the proviso that at least 1 of Z 2 or Z 3 must be N;
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2a , R 2b , and R 2c , are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
n is selected from 0, 1, and 2;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
10. The method of claim 1 wherein the compound is a compound of Formula V:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2c is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
11. The method of claim 10 wherein R 2c is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, and cyano.
12. The method of claim 10 wherein the compound is selected from the group consisting of
4-(6-hydroxyquinazolin-2-yl)benzoic acid;
4-(6-hydroxy-4-methylquinazolin-2-yl)benzoic acid;
3-chloro-4-(6-hydroxyquinazolin-2-yl)benzoic acid;
4-(6-hydroxyquinazolin-2-yl)-3-methylbenzoic acid;
4-(6-hydroxyquinazolin-2-yl)-3-methoxybenzoic acid;
3-fluoro-4-(6-hydroxyquinazolin-2-yl)benzoic acid; and
1-(6-hydroxyquinazolin-2-yl)piperidine-4-carboxylic acid.
13. The method of claim 1 wherein the compound is a compound of Formula VI:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2b is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
14. The method of claim 13 wherein the compound is selected from the group consisting of
4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid;
2-(4-(2H-tetrazol-5-yl)phenyl)-3-(trifluoromethyl)quinoxalin-6-ol;
1-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)piperidine-4-carboxylic acid;
4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)cyclohex-3-enecarboxylic acid;
3-chloro-4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid;
4-(6-hydroxyquinoxalin-2-yl)benzoic acid;
3-fluoro-4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid;
(1r,4r)-4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)cyclohexanecarboxylic acid; and
(1s,4s)-4-(6-hydroxy-3-(trifluoromethyl)quinoxalin-2-yl)cyclohexanecarboxylic acid.
15. The method of claim 1 wherein the compound is a compound of Formula VII:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
16. The method of claim 15 wherein the compound is selected from the group consisting of
3-(4-carboxyphenyl)-7-hydroxybenzo[e][1,2,4]triazine 1-oxide;
4-(7-hydroxybenzo[e][1,2,4]triazin-3-yl)benzoic acid;
3-(4-carboxy-2-fluorophenyl)-7-hydroxybenzo[e][1,2,4]triazine 1-oxide; and
3-fluoro-4-(7-hydroxybenzo[e][1,2,4]triazin-3-yl)benzoic acid.
17. The method of claim 1 wherein the compound is a compound of Formula VIII:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2a and R 2c are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
18. The method of claim 17 wherein the compound is selected from the group consisting of
4-(7-hydroxyisoquinolin-3-yl)benzoic acid;
3-fluoro-4-(7-hydroxyisoquinolin-3-yl)benzoic acid; and
4-(7-hydroxy-4-methylisoquinolin-3-yl)benzoic acid.
19. The method of claim 1 wherein the compound is a compound of Formula IX:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2a and R 2b are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
20. The method of claim 19 wherein the compound is selected from the group consisting of
4-(7-hydroxyquinolin-3-yl)benzoic acid; and
3-(4-carboxyphenyl)-7-hydroxyquinoline 1-oxide.
21. The method of claim 1 wherein the compound is a compound of Formula X:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;
R 2a is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;
X is selected from the group consisting of
n is selected from 0, 1, and 2;
R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.
22. The method of claim 1 wherein the pulmonary disorder is selected from the group consisting of cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD).
23. The method of claim 1 wherein the inflammatory disease is inflammatory bowel disease (IBD).