Compounds as S-Nitrosoglutathione Reductase Inhibitors
The present invention is directed to compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
1 . What is claimed is:
A method of inhibiting GSNOR in a patient in need thereof by administering an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
HO-Cy 1 -linker-Cy 2 -acidic moiety Formula 1
wherein
Cy 1 is selected from the group consisting of substituted and unsubstituted monocyclic aryl, substituted and unsubstituted bicyclic aryl, substituted and unsubstituted monocyclic heterocycle, substituted and unsubstituted bicyclic heterocycle, substituted and unsubstituted monocyclic heteroaryl, substituted and unsubstituted bicyclic heteroaryl, substituted and unsubstituted monocyclic cycloalkyl, and substituted and unsubstituted bicyclic cycloalkyl;
linker is selected from the group consisting of a direct bond, O, S, SO, SO 2 , C═O, CR 5 R 6 , NR 7 , substituted and unsubstituted (C 2 -C 3 ) alkyl, substituted and unsubstituted (C 2 -C 3 ) heteroalkyl, substituted and unsubstituted (C 2 -C 3 ) alkene, substituted and unsubstituted 5 or 6 membered aryl, substituted and unsubstituted 5 or 6 membered heteroaryl, substituted and unsubstituted 3-6 membered cycloalkyl, and substituted and unsubstituted 3-6 membered saturated heterocyclyl; wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) heteroalkyl, halogen, (C 1 -C 6 ) haloalkyl, cyano, and hydroxyl; R 7 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 ) haloalkyl, and (C 1 -C 6 ) heteroalkyl; substitutions for the (C 2 -C 3 ) alkyl, (C 2 -C 3 ) heteroalkyl, and (C 2 -C 3 ) alkene are selected from the group consisting of ═O, halogen, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) heteroalkyl, cyano, and hydroxyl, and wherein when the heteroalkyl group contains nitrogen or sulfur, the N and S atoms may be optionally oxidized; substitutions for aryl, heteroaryl, cycloalkyl and saturated heterocyclyl are selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 ) haloalkyl, and (C 1 -C 8 )heteroalkyl; and
Cy 2 is selected from the group consisting of substituted and unsubstituted monocyclic aryl, substituted and unsubstituted monocyclic saturated heterocycle, substituted and unsubstituted monocyclic heteroaryl, and substituted and unsubstituted monocyclic cycloalkyl.
2 . The method of claim 1 wherein,
linker is selected from the group consisting of a direct bond, O, S, SO, SO 2 , C═O, CH 2 , NH, NMe, substituted and unsubstituted (C 2 -C 3 ) alkyl, substituted and unsubstituted (C 2 -C 3 ) heteroalkyl, a 5 or 6 membered aryl, and a 5 or 6 membered heteroaryl group; wherein substitutions for the (C 2 -C 3 ) alkyl and (C 2 -C 3 ) heteroalkyl are selected from the group consisting of ═O, halogen, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, and hydroxyl, and wherein if the heteroalkyl group contains nitrogen or sulfur, they may be optionally oxidized.
3 . The method of claim 1 wherein Cy 2 -Acidic moiety is selected from the group consisting of
wherein
* represents the position on Cy 2 that is connected to the linker;
A is an acidic moiety, and is selected from the group consisting of
R 4 is selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, cyano, and NR 8 R 8′ where R 8 and R 8′ are independently selected from the group consisting of (C 1 -C 3 ) alkyl, or R 8 when taken together with R 8′ form a ring with 3 to 6 members;
and p is selected from the group consisting of 0, 1, 2, 3, and 4.
4 . The method of claim 1 wherein,
linker is selected from a group consisting of a direct bond, O, S, SO, SO 2 , C═O, CR 5 R 6 , NR 7 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) heteroalkyl, halogen, (C 1 -C 6 ) haloalkyl, cyano, and hydroxyl; R 7 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 ) haloalkyl, and (C 1 -C 6 ) heteroalkyl; and
Cy 1 is selected from the group consisting of substituted and unsubstituted bicyclic aryl, substituted and unsubstituted bicyclic heterocycle, substituted and unsubstituted bicyclic heteroaryl, and substituted and unsubstituted bicyclic cycloalkyl.
5 . The method of claim 4 wherein HO-Cy 1 is selected from the group consisting of
Wherein
* represents the position on Cy 1 that is connected to the linker;
R 1 is selected from the group consisting of halogen, methoxy, and cyano;
R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, unsubstituted aryl(C 1 -C 4 )alkyl, substituted aryl(C 1 -C 6 )alkyl, (C 1 -C 6 )heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 3 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, SMe, and N(CH 3 ) 2 ;
n is selected from the group consisting of 0, 1, 2, and 3; and
m is selected from the group consisting of 0, 1, and 2.
6 . The method of claim 5 wherein HO-Cy 1 is selected from the group consisting of
7 . The method of claim 6 wherein Cy 2 -Acidic moiety is selected from the group consisting of
wherein
* represents the position on Cy 2 that is connected to the linker;
A is the acidic moiety, and is selected from the group consisting of
R 4 is selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, cyano, and NR 8 R 8′ where R 8 and R 8′ are independently selected from the group consisting of (C 1 -C 3 ) alkyl, or R 8 when taken together with R 8′ form a ring with 3 to 6 members;
and p is selected from the group consisting of 0, 1, 2, 3, and 4.
8 . The method of claim 1 wherein
linker is selected from the group consisting of substituted and unsubstituted (C 2 -C 3 ) alkyl, substituted and unsubstituted (C 2 -C 3 ) heteroalkyl, and substituted and unsubstituted (C 2 -C 3 ) alkene, wherein substitutions for (C 2 -C 3 ) alkyl, (C 2 -C 3 ) heteroalkyl, and (C 2 -C 3 ) alkene are selected from the group consisting of ═O, halogen, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) heteroalkyl, cyano, and hydroxyl, and wherein when the heteroalkyl group contains nitrogen or sulfur, the N and S atoms may be optionally oxidized; and
Cy 1 is selected from the group consisting of substituted and unsubstituted monocyclic aryl, substituted and unsubstituted monocyclic heterocycle, substituted and unsubstituted monocyclic heteroaryl, and substituted and unsubstituted monocyclic cycloalkyl.
9 . The method of claim 8 wherein HO-Cy 1 is
wherein R 1 is selected from the group consisting of halogen, methoxy, and cyano;
n is selected from the group consisting of 0, 1, 2, and 3;
Cy 2 -Acidic moiety is selected from the group consisting of
* represents the positions on Cy 1 and Cy 2 that are connected to the linker;
A is the acidic moiety, and is selected from the group consisting of
R 4 is selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, cyano, and NR 8 R 8′ where R 8 and R 8′ are independently selected from the group consisting of (C 1 -C 3 ) alkyl, or R 8 when taken together with R 8′ form a ring with 3 to 6 members;
and p is selected from the group consisting of 0, 1, 2, 3, and 4.
10 . The method of claim 9 wherein linker is selected from the group consisting of substituted and unsubstituted C 2 alkyl, and substituted and unsubstituted C 2 heteroalkyl; wherein heteroalkyl consists of one heteroatom selected from the group consisting of O, S, SO, SO 2 , NH, NMe, and wherein substitutions for C 2 alkyl and C 2 heteroalkyl are selected from the group consisting of ═O, R 5 and R 6 .
11 . The method of claim 10 wherein the GSNOR inhibitor has the structure shown in Formula 2
wherein Y is selected from the group consisting of CH 2 , O, S, SO, SO 2 , and NR 7 ; and
--- indicates the bond can be saturated or unsaturated.
12 . The method of claim 10 wherein the GSNOR inhibitor has the structure shown in Formula 3
wherein Y is selected from the group consisting of CH 2 and NH
--- indicates the bond can be saturated or unsaturated.
13 . A method of claim 1 , wherein
linker is selected from the group consisting of substituted and unsubstituted 5 or 6 membered aryl, substituted and unsubstituted 5 or 6 membered heteroaryl; substitutions for aryl and heteroaryl are selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 ) haloalkyl, and (C 1 -C 8 )heteroalkyl; and
Cy 1 is selected from the group consisting of a substituted or unsubstituted monocyclic aryl group, and a substituted or unsubstituted monocyclic heteroaryl group.
14 . A method of claim 13 wherein the GSNOR inhibitor has the structure shown in Formula 4
wherein
Z 1 , Z 2 , Z 3 , and Z 4 are independently selected from the group consisting of CH and N;
Cy 2 -Acidic moiety is selected from the group consisting of
wherein
* represents the positions on Cy 1 and Cy 2 that are connected to the linker;
A is the acidic moiety, and is selected from the group consisting of
R 4 is selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, cyano, and NR 8 R 8′ where R 8 and R 8′ are independently selected from the group consisting of (C 1 -C 3 ) alkyl, or R 8 when taken together with R 8′ form a ring with 3 to 6 members;
and p is selected from the group consisting of 0, 1, 2, 3, and 4.
15 . A method of claim 14 wherein
HO-Cy 1 is
wherein R 1 is selected from the group consisting of halogen, methoxy, and cyano;
n is selected from the group consisting of 0, 1, 2, and 3.
16 . The method of claim 15 wherein acidic moiety is a carboxylic acid.
17 . A method of claim 13 , wherein the GSNOR inhibitor has the structure shown in Formula 5
wherein
X 1 , X 3 , and X 4 are independently selected from the group consisting of N, NR 9 , CR 10 , S, and O;
X 2 and X 5 are independently selected from the group consisting of C, CH, and N;
R 9 and R 10 are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 ) haloalkyl, and (C 1 -C 8 )heteroalkyl;
HO-Cy 1 is
wherein R 1 is selected from the group consisting of halogen, methoxy, and cyano;
n is selected from the group consisting of 0, 1, 2, and 3;
Cy 2 -Acidic moiety is selected from the group consisting of
wherein
* represents the positions on Cy 1 and Cy 2 that are connected to the linker;
A is the acidic moiety, and is selected from the group consisting of
R 4 is selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, cyano, and NR 8 R 8′ where R 8 and R 8′ are independently selected from the group consisting of (C 1 -C 3 ) alkyl, or R 8 when taken together with R 8′ form a ring with 3 to 6 members;
and p is selected from the group consisting of 0, 1, 2, 3, and 4.
18 . The method of claim 17 wherein the GSNOR inhibitor has the structure shown in Formula 6
wherein
X 1 , X 3 , and X 4 are independently selected from the group consisting of N, NR 9 , CR 10 , S, and O.
19 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 7
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2, and
* represents the position on Cy 2 that is connected to the compound of Formula 7.
20 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 8
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2, and
* represents the position on Cy 2 that is connected to the compound of Formula 8.
21 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 9
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2;
* represents the position on Cy 2 that is connected to the compound of formula 9; and
R 9 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 ) haloalkyl, and (C 1 -C 8 ) heteroalkyl.
22 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 10
wherein
X is selected from CH and N,
Y is selected from CH and N, and wherein when X is CH, then Y is N, and when X is N, then Y is CH;
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2;
* represents the position on Cy 2 that is connected to the compound of formula 10.
23 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 11
wherein
X is selected from CH and N,
Y is selected from CH and N, and wherein when X is CH, Y is N, and when X is N, then Y is CH;
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2; and
n+p is greater than 0.
24 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 12
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2;
* represents the position on Cy 2 that is connected to the compound of formula 12.
25 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 13
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2;
* represents the position on Cy 2 that is connected to the compound of formula 13.
26 . The method of claim 18 wherein the GSNOR inhibitor has the structure shown in Formula 14
wherein
R 1 is selected from the group consisting of F, Cl, Br, OMe, and CN;
n is selected from the group consisting of 0 and 1;
Cy 2 -COOH is selected from the group consisting of
R 4 is selected from the group consisting of F, Cl, Br, CN, Me, OMe, N(Me) 2 ;
p is selected from the group consisting of 0, 1, and 2;
* represents the position on Cy 2 that is connected to the compound of formula 14.
27 . The method of claim 1 wherein the patient has one or more of the following diseases, disorders, or conditions: 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; cardiovascular disease and heart disease; diseases characterized by angiogenesis; disorders where there is risk of thrombosis occurring; disorders where there is risk of restenosis occurring; inflammatory diseases; functional bowel disorders; diseases where there is risk of apoptosis occurring; impotence; sleep apnea; diabetic wound healing; cutaneous infections; treatment of psoriasis; obesity caused by eating in response to craving for food; stroke; reperfusion injury; and disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial, central nervous system (CNS) disorders; and infections caused by bacteria.
28 . The method of claim 27 wherein the disease or condition is selected from one or more of the following, pulmonary hypertension, ARDS, asthma, pneumonia, pulmonary fibrosis/interstitial lung diseases, cystic fibrosis, COPD, hypertension, ischemic coronary syndromes, atherosclerosis, heart failure, glaucoma, coronary artery disease, AIDS related dementia, inflammatory bowel disease (IBD), Crohn's disease, colitis, and psoriasis, irritable bowel syndrome (IBS), heart failure, atherosclerosis, degenerative neurologic disorders, arthritis, and liver injury (drug induced, ischemic, alcoholic), traumatic muscle injury in heart or lung or crush injury, anxiety, depression, psychosis, and schizophrenia, tuberculosis, and C. difficile infections.