Substituted [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compounds as pde2 inhibitors

Abstract

The invention provides a chemical entity of Formula (I):, wherein R1, R2, 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.