Deuterium-Substituted Pyridin- And Pyrimidin-2-yl-Methylamine Compounds

Abstract

Described are deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds of structural Formula (I), which are agonists of 5-hydroxytryptamine receptors. Also described are pharmaceutical compositions comprising the deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds, and methods of use thereof.

What is claimed is: 
     
         1 . A method of treating or preventing an 5-HT 1A  receptor-mediated disorder, the method comprising administering, to a patient in need thereof a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, prodrug, co-crystal, or solvate thereof, wherein:
 X is N or C—R 21 ; 
 R 1 -R 21  are, independently, hydrogen or deuterium; 
 at least one of R 1 -R 21  is deuterium; and 
 at least one of R 1 -R 21  has deuterium enrichment of at least about 1%. 
 
     
     
         2 . The method of  claim 1 , wherein R 1 -R 3  are deuterium. 
     
     
         3 . The method of  claim 1 , wherein R 4  and/or R 5  is deuterium. 
     
     
         4 . The method of  claim 1 , wherein R 6  and/or R 7  is deuterium. 
     
     
         5 . The method of  claim 1 , wherein R 4 -R 7  are deuterium. 
     
     
         6 . The method of  claim 1 , wherein at least one of R 8 -R 15  is deuterium. 
     
     
         7 . The method of  claim 1 , wherein at least one of R 16 -R 20  is deuterium. 
     
     
         8 . The method of  claim 1 , wherein X is N. 
     
     
         9 . The method of  claim 1 , wherein X is C—R 21 . 
     
     
         10 . The method of  claim 9 , wherein R 21  is deuterium. 
     
     
         11 . The method of  claim 1 , wherein at least one of R 1 -R 21  has deuterium enrichment of at least about 90%. 
     
     
         12 . The method of  claim 1 , wherein at least one of R 1 -R 21  has deuterium enrichment of at least about 95%. 
     
     
         13 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 1 , wherein the compound is a pharmaceutically acceptable salt that is a hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, propionate, succinate, fumarate, citrate, tartrate, glutamate, benzoate, salicylate, stearate, lactate, mesylate, tosylate, besylate, phosphate, or maleate salt. 
     
     
         18 . The method of  claim 1 , wherein the 5-HT 1A  receptor-mediated disorder is anxiety, depression, bipolar disorder, an obsessive-compulsive disorder, a panic attack, aggression, impulsivity, alcohol abuse, a sexual disorder, a sleeping disorder, pain, acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain hypertension, nausea, dizziness, vomiting, regulation of gastric secretion, obesity, regulation of food intake, an immune disease, migraine, dyskinesia, akinesia, chorea, ballismus, dystonia, myoclonus, athetosis, akathisia, ataxia, synkinesia, tics, bradykinesia, tremor, a movement disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, tardive dyskinesia, muscle spasm, muscle hypertonia, schizophrenia, drug-seeking behavior, opioid-induced respiratory syndrome, restless leg syndrome, or L-DOPA-induced dyskinesia. 
     
     
         19 . The method of  claim 18 , wherein the 5-HT 1A  receptor-mediated disorder is anxiety, depression, bipolar disorder, an obsessive-compulsive disorder, a panic attack, aggression, impulsivity, alcohol abuse, a sexual disorder, a sleeping disorder, pain, acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain hypertension, nausea, dizziness, vomiting, regulation of gastric secretion, obesity, regulation of food intake, an immune disease, migraine, dyskinesia, akinesia, chorea, ballismus, dystonia, myoclonus, athetosis, akathisia, ataxia, synkinesia, tics, bradykinesia, tremor, a movement disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, tardive dyskinesia, muscle spasms, muscle hypertonia, schizophrenia, drug-seeking behavior, opioid-induced respiratory syndrome, restless leg syndrome, or L-DOPA-induced dyskinesia. 
     
     
         20 . The method of  claim 1 , further comprising administering an additional therapeutic agent in combination with the compound.