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. The compound of Formula I:
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 2 and 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 compound 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.
3. The compound of claim 2 wherein X is
4. The compound of claim 3 wherein A is COOH.
5. The compound 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.
6. The compound of claim 5 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.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically accepted carrier or excipient.
8. A method of making a pharmaceutical composition according to claim 7 comprising combining a compound of Formula I as defined in claim 1 with a pharmaceutically accepted carrier or excipient.
9. 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
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;
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 with3 to 6 members;
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof;
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.
10. The method of claim 9 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.
11. The method of claim 10 wherein X is
12. The method of claim 11 wherein A is COOH.
13. The method of claim 9 , 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.
14. The method of claim 13 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.
15. The method of claim 9 wherein the disorder is selected from asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis.