Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2c (5-ht2c)

Abstract

Disclosed are novel small molecules, methods of synthesis of the small molecules, and uses of the small molecules for modulating activity of the human serotonin receptor 2C (5-HT2c), preferably selectively. The small molecules have a substituted beta-carboline core structure, which optionally may be saturated at one or more bonds to provide a dihydro-beta-carboline core or a tetrahydro-beta-carboline core. The small molecules may be administered to treat and/or prevent diseases, disorders, and/or conditions associated with human serotonin receptor 2C (5-HT2c) including psychiatric, mental, and/or neurological diseases, disorders, and conditions such as cognitive impairment, addiction, and obsessive compulsive disorder. The disclosed small molecules also may be administered to treat and/or prevent obesity, for example, via appetite suppression.

1 .- 20 . (canceled) 
     
     
         21 . A compound or a salt or solvate thereof having a Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         n is 0-3; 
         X is CH 2 , NH, or O; 
         R 1  is selected from hydrogen, hydroxyl, alkyl, alkoxy, halo, haloalkyl, amino, and cyano; 
         R 2  is hydrogen, or alkyl, or a 3-7 membered carbocycle or heterocycle which is saturated or unsaturated at one or more bonds and which heterocycle includes one or more heteroatoms selected from N, O, and S, optionally which carbocycle or heterocycle is substituted to include one or more non-hydrogen substituents, which non-hydrogen substituents optionally are selected from hydroxyl, alkyl, halo, haloalkyl, phenyl, amino, and carbonyl. 
         R 3  is present or absent, and when R 3  is present, R 3  is selected from selected from hydrogen, alkyl, alkenyl, and alkyl-alkoxy. 
       
     
     
         22 . The compound of  claim 21 , wherein R 2  is selected from phenyl, cyclohexyl, pyridine-2-yl, pyridine-3-yl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl. 
     
     
         23 . The compound of  claim 21 , wherein —(X) n —R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 21 , wherein —(X) n —R 2  is selected from phenyl and cyclohexyl. 
     
     
         25 . The compound of  claim 21 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 21  having formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 26 , wherein R 2  is selected from phenyl, cyclohexyl, pyridin-2-yl, pyridin-3-yl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl. 
     
     
         28 . The compound of  claim 26 , wherein —(X) n —R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 21 , wherein R 1  is selected from hydroxyl, halo, methyl, and hydrogen. 
     
     
         30 . The compound of  claim 29 , wherein R 2  is selected from phenyl, cyclohexyl, pyridinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl. 
     
     
         31 . The compound of  claim 29 , wherein —(X) n —R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 29  having formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 32 , wherein R 2  is selected from phenyl, cyclohexyl, pyridinyl, imidazolyl, 1-methylimidazolyl; piperidinyl, 1-methyl-piperidinyl, piperazinyl, 1-methyl-piperazinyl, tetrahydropyranyl, and morpholinyl. 
     
     
         34 . The compound of  claim 32 , wherein —(X) n —R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 32 , wherein R 1  is hydroxyl. 
     
     
         36 . A pharmaceutical composition comprising the compound of  claim 21  and a pharmaceutical carrier. 
     
     
         37 . A method for treating and/or preventing a disease, disorder, or condition that is associated with 5-HT 2c  receptor activity in a subject in need thereof, the method comprising administering to the subject the compound of  claim 21 . 
     
     
         38 . The method of  claim 37 , wherein the disease or disorder is a psychiatric, mental, or neurological disease, disorder, or condition. 
     
     
         39 . The method of  claim 37 , wherein the disease, disorder, or condition is cognitive impairment, addiction, and/or obsessive compulsive disorder. 
     
     
         40 . The method of  claim 37 , wherein the disease, disorder, or condition is obesity and the method results in suppressing the appetite of the subject.