Radiolabeled pde10a ligands

Abstract

Compounds of formula (I) are disclosed Compounds of formula (I) are useful in treating conditions and disorders prevented by or ameliorated by PDE10A ligands. Radiolabeled compounds of formula (I) are also useful as diagnostic tools as PDE10A positron emission tomography ligands. Also disclosed are pharmaceutical compositions comprising compound of formula (I), methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, amide, prodrug, or radiolabeled form thereof, wherein 
         R is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, and C 3 -C 8  cycloalkyl; 
         HetAr is a heteroaryl group selected from the group consisting of formula (i) and formula (ii); 
       
       
         
           
           
               
               
           
         
         --- is absent or a bond; 
         Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 8 , Z 9 , Z 10 , Z 11 , and Z 12  are each independently selected from the group consisting of N and CR 2 ; 
         Z 6  and Z 7  are each independently selected from the group consisting of N, NR 1 , CR 2 , CHR 3 , SO 2 , and C═O; 
         Z 13  is selected from the group consisting of NR 1 , CHR 3 , and O; and 
         R 1 , R 2 , and R 3  are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, and C 3 -C 8  cycloalkyl; 
         provided that at least two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7  are heteroatoms; and 
         provided that the following non-radiolabeled compounds are excluded: 
         2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazoline; and 
         1-methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1H-benzo[d]imidazole. 
       
     
     
         2 . The compound of  claim 1 , wherein said compound comprises a radiolabel. 
     
     
         3 . The compound of  claim 1 , wherein R comprises a radiolabel. 
     
     
         4 . The compound of  claim 1 , wherein HetAr comprises a radiolabel. 
     
     
         5 . The compound of  claim 1 , wherein HetAr is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 8 , Z 13 , and R 1  are as defined in  claim 1 . 
       
     
     
         6 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein R is C 1 -C 6  alkyl. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein R is C 1 -C 6  alkyl. 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein R is C 1 -C 6  alkyl. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 15 , wherein R is C 1 -C 6  alkyl. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 18 , wherein R is C 1 -C 6  alkyl. 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 21 , wherein
 Z 1  is CH;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         23 . The compound of  claim 21 , wherein
 Z 1  is N;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         24 . (canceled) 
     
     
         25 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 25 , wherein
 Z 1  is CH;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         27 . The compound of  claim 25 , wherein
 Z 1  is N;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         28 . (canceled) 
     
     
         29 . The compound of  claim 5 , wherein HetAr is 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 29 , wherein
 Z 8  is CH;   Z 13  is O; and   R is C 1 -C 6  alkyl.   
     
     
         31 . The compound of  claim 29 , wherein
 Z 8  is N;   Z 13  is O; and   R is C 1 -C 6  alkyl.   
     
     
         32 . The compound of  claim 29 , wherein
 Z 8  is CH;   Z 13  is NR 1 ;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         33 . The compound of  claim 29 , wherein
 Z 8  is N;   Z 13  is NR 3 ;   R 1  is C 1 -C 6  alkyl; and   R is C 1 -C 6  alkyl.   
     
     
         34 . (canceled) 
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt, ester, amide, prodrug, or radiolabeled form thereof, in combination with a pharmaceutically acceptable carrier. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . A method for imaging PDE10A in a mammal comprising administering to a subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt, ester, amide, prodrug, or radiolabeled form thereof. 
     
     
         40 . A method of treating or preventing a condition or disorder selected from the group consisting of schizophrenia, cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive-compulsive disorder, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention-deficit/hyperactivity disorder (ADHD), attentional disorders, diabetes, obesity, inflammatory disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, cancer, renal cell carcinoma, and breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt, ester, amide, prodrug, or radiolabeled form thereof. 
     
     
         41 . The method of  claim 39 , wherein the compound is selected from the group consisting of:
 2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine;   6-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine;   6-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazoline;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylquinazolin-4(3H)-one;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylpyrido[3,2-d]pyrimidin-4 (3H)-one;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   1,1-dioxo-2-methyl-3-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-methyl-3-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-[ 11 C]methyl-3-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-(2-[ 18 F]fluoroethyl)-3-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole;   1-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1H-benzo[d]imidazole;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)oxazolo[5,4-b]pyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)oxazolo[5,4-b]pyridine;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3H-imidazo[4,5-b]pyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methyl-3H-imidazo[4,5-b]pyridine;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3H-imidazo[4,5-b]pyridine;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3H-imidazo[4,5-b]pyridine; and   2-((4-(1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-5-[ 3 H]benzo[d]oxazole.   
     
     
         42 . The method of  claim 41 , wherein the compound is selected from the group consisting of:
 2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine; and   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole.   
     
     
         43 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,5-naphthyridine;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1,6-naphthyridine;   6-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine;   6-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-c]pyridazine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazoline;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidine;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylquinazolin-4(3H)-one;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinazolin-4(3H)-one;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methylpyrido[3,2-d]pyrimidin-4 (3H)-one;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)pyrido[3,2-d]pyrimidin-4(3H)-one;   1,1-dioxo-2-methyl-3-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-methyl-3-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-[ 11 C]methyl-3-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   1,1-dioxo-2-(2-[ 18 F]fluoroethyl)-3-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-2H-benzo[e][1,2,4]thiadiazine;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)benzo[d]oxazole;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole;   1-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-1H-benzo[d]imidazole;   2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl) phenoxy)methyl) oxazolo[5,4-b]pyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl) phenoxy)methyl) oxazolo[5,4-b]pyridine;   3-methyl-2-((4-(1-[ 11 C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl) phenoxy)methyl)-3H-imidazo[4,5-b]pyridine;   2-((4-(1-(2-[ 18 F]fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3-methyl-3H-imidazo[4,5-b]pyridine;   3-[ 11 C]methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl) phenoxy)methyl)-3H-imidazo[4,5-b]pyridine;   3-(2-[ 18 F]fluoroethyl)-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-3H-imidazo[4,5-b]pyridine; and   2-((4-(1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-5-[ 3 H]-benzo[d]oxazole.