SUBSTITUTED [1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL COMPOUNDS AS PDE2 INHIBITORS
The invention provides a chemical entity of Formula (I): , wherein R 1 , R 2 , X, Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods as disclosed herein, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive treatments; modulating and treating disorders mediated by PDE2 activity; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including hematological, cardiovascular, gastroenterological, and dermatological disorders.
1 - 20 . (canceled)
21 . A method of treating a cardiovascular disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I):
, or a pharmaceutically acceptable salt thereof, wherein
X is —CH 2 — or —O—;
Y is —CH 2 — or —CF 2 —;
Z is —CH 2 — or —C(═O)—;
R 1 is a member selected from the group consisting of:
(a) phenyl unsubstituted or substituted with one, two, three, four, or five R a members;
where R a is each independently selected from the group consisting of: -halo, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -CN, -N(C 1-6 alkyl) 2 , -SF 5 , -C 3-6 cycloalkyl, -pyrrolidine, -morpholine, -piperidine, -pyrazole, -furan, -imidazole, -thiophene, -thiazole, -pyridine, and -phenyl, wherein phenyl is unsubstituted or substituted with one, two, three, four, or five R b members;
where R b is each independently selected from the group consisting of: -Cl and -F; or optionally two adjacent R a members come together to form a cyclopentyl, cyclohexyl, phenyl, pyridine, furan, tetrahydrofuran, tetrahydropyran, thiazole, thiophene, pyrrole, indole, 1,4-dioane, or 1,3-dioxolane ring, each optionally unsubstituted or substituted with one or more members independently selected from the group consisting of: -halo, -C 1-6 alkyl, or -C 1-6 alkoxy;
(b) monocyclic or bicyclic heteroaromatic ring having from 3 to 12 ring atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur, each unsubstituted or substituted with one, two, three, or four R c members;
where R c is each independently selected from the group consisting of: -halo, -C 1-6 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -N(C 1-6 alkyl) 2 , -(C 1-6 alkyl)cycloalkyl, -cyclopropyl, -morpholine, -pyrrolidine, -4-chlorophenoxy, and -phenyl optionally unsubstituted or substituted with -halo, -C 1-6 alkyl, or -C 1-4 alkoxy;
(c) heterocycloalkyl ring being partially saturated and having from 3 to 12 ring atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur, unsubstituted or substituted with one or more —F, or-OCH 3 ; and
(d) 2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl; and
R 2 is -C 1-6 alkyl.
22 . The method of claim 21 , wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
(2S)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl} morpholine;
(2R)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl} morpholine;
(2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{ 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl } morpholine;
(2R)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine; and
(2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-15-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl} morpholine.
23 . The method of claim 21 , wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
(3R)-1-[(3R)-3,4-Dihydro-2H-1-benzopyran-3-carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine;
1-[(2,3-Dihydro-1-benzofuran-5-yl)carbonyl]-3-{ 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine; and
1-[(3,4-Dihydro-2H-1-benzopyran-6-yl)carbonyl]-3-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine.
24 . The method of claim 21 , wherein the compound, or pharmaceutically acceptable salt thereof, is selected from the group consisting of:
4-[(3-Iodophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl} morpholine;
2-{5-Methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-4-[(naphthalen-2-yl)carbonyl]morpholine; and
3,3-Difluoro-1-[(3-iodophenyl)carbonyl]-5-{ 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine.
25 . The method of claim 21 , wherein the compound is (2S)-4-[(3,5-Dichlorophenyl)carbonyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
26 . The method of claim 21 , wherein the compound is (2S)-4-[3-Bromo-4-(trifluoromethyl)benzoyl]-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
27 . The method of claim 21 , wherein the compound is (2S)-4-(3-Bromo-4,5-difluorobenzoyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}morpholine, or a pharmaceutically acceptable salt thereof.
28 . The method of claim 21 , wherein the cardiovascular disease is selected from the group consisting of: a congestive heart failure, a myocardial infarction, an ischemic disease, an atrial arrhythmia, a ventricular arrhythmia, a hypertensive vascular disease, and atherosclerosis.
29 . The method of claim 28 , wherein the cardiovascular disease is a congestive heart failure.
30 . The method of claim 28 , wherein the cardiovascular disease is an atrial arrhythmia.
31 . The method of claim 28 , wherein the cardiovascular disease is a ventricular arrhythmia.
32 . The method of claim 25 , wherein the cardiovascular disease is selected from the group consisting of: a congestive heart failure, a myocardial infarction, an ischemic disease, an atrial arrhythmia, a ventricular arrhythmia, a hypertensive vascular disease, and atherosclerosis.
33 . The method of claim 32 , wherein the cardiovascular disease is an atrial arrhythmia.
34 . The method of claim 32 , wherein the cardiovascular disease is a ventricular arrhythmia.
35 . The method of claim 26 , wherein the cardiovascular disease is selected from the group consisting of: a congestive heart failure, a myocardial infarction, an ischemic disease, an atrial arrhythmia, a ventricular arrhythmia, a hypertensive vascular disease, and atherosclerosis.
36 . The method of claim 35 , wherein the cardiovascular disease is an atrial arrhythmia.
37 . The method of claim 35 , wherein the cardiovascular disease is a ventricular arrhythmia.
38 . The method of claim 27 wherein the cardiovascular disease is selected from the group consisting of: a congestive heart failure, a myocardial infarction, an ischemic disease, an atrial arrhythmia, a ventricular arrhythmia, a hypertensive vascular disease, and atherosclerosis.
39 . The method of claim 38 , wherein the cardiovascular disease is an atrial arrhythmia.
40 . The method of claim 38 , wherein the cardiovascular disease is a ventricular arrhythmia.