Vmat inhibitory compounds

Abstract

Disclosed herein are compounds that bind to the vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions comprising those compounds, and methods of treatment using said compounds and pharmaceutical compositions.

1 - 48 . (canceled) 
     
     
         49 . A compound with the formula: 
       
         
           
           
               
               
           
         
         wherein X is a substituted or unsubstituted 5- or 6-membered aryl or substituted or unsubstituted 5- or 6-membered heteroaryl, 
         Z is N or CH, 
         m is 1, 2, or 3, 
         Ar is a substituted or unsubstituted 5- or 6-membered aryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, 
         R is H, ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted or unsubstituted 5-membered heteroaryl, 
         Y is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers, crystal form, or isotopomer thereof. 
       
     
     
         50 . The compound of  claim 49 , wherein R is ethyl ester or —C(O)-alkyl. 
     
     
         51 . The compound of  claim 49 , wherein Ar is phenyl, substituted phenyl, pyrrolyl, substituted pyrrolyl, pyridinyl, substituted pyridinyl, thiophene-yl, substituted thiophene-yl, or [1,4]-dioxinyl. 
     
     
         52 . The compound of  claim 49 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2 , A 3 , and A 4 , are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy, ester, keto, hydroxyl, amino, substituted amino, amido, nitro, methyl, ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl, amino, dimethylamino, methylamido, azo, benzyl, 2-phenyl ethyl, pyrrolyl, ethyl ester, 1-hydroxyethyl, methoxy, trifluoromethoxy, or tert-butoxycarbonylamino. 
       
     
     
         53 . The compound of  claim 52 , wherein A 1  and A 2  are H, and A 3  and A 4  are independently H, fluoro, or trifluoromethyl. 
     
     
         54 . The compound of  claim 49 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
       
       and
 wherein A 3  is halo or fluoro, and m is 2 or 3. 
 
     
     
         55 . The compound of  claim 49 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein Y 1  is H, methyl, ethyl, or 2-benzylethyl, 
         wherein Y 2  is H or halo, and 
         wherein A 3  and A 4  are independently H or halo. 
       
     
     
         56 . The compound of  claim 49 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2 , A 3 , and A 4  are independently H, halo, or haloalkyl, and wherein Y is H or alkyl. 
       
     
     
         57 . The compound of  claim 56 , wherein Y is H, A 1  and A 2  are H, and A 3  and A 4  are independently H, fluoro, or trifluoromethyl. 
     
     
         58 . A compound of the Formula I: 
       
         
           
           
               
               
           
         
         wherein X is a substituted or unsubstituted 5- or 6-membered aryl or substituted or unsubstituted 5- or 6-membered heteroaryl, 
         Z is N or CH, 
         m is 1, 2, or 3, 
         Ar is a substituted or unsubstituted 5- or 6-membered aryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, 
         R is ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted or unsubstituted 5-membered heteroaryl, 
         Y is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         wherein the bond between the carbon atoms bearing Ar and R is a single or double bond, 
         or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers, crystal form, or isotopomer thereof. 
       
     
     
         59 . The compound of  claim 58 , wherein R is ethyl ester or —C(O)-alkyl. 
     
     
         60 . The compound of  claim 58 , wherein Ar is phenyl, substituted phenyl, pyrrolyl, substituted pyrrolyl, pyridinyl, substituted pyridinyl, thiophene-yl, substituted thiophene-yl, or [1,4]-dioxinyl. 
     
     
         61 . The compound of  claim 58 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2 , A 3 , and A 4 , are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy, ester, keto, hydroxyl, amino, substituted amino, amido, nitro, methyl, ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl, amino, dimethylamino, methylamido, azo, benzyl, 2-phenyl ethyl, pyrrolyl, ethyl ester, 1-hydroxyethyl, methoxy, trifluoromethoxy, or tert-butoxycarbonylamino. 
       
     
     
         62 . The compound of  claim 61 , wherein A 1  and A 2  are H, and A 3  and A 4  are independently H, fluoro, or trifluoromethyl. 
     
     
         63 . The compound of  claim 58 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein A 3  is halo or fluoro, and m is 2 or 3. 
       
     
     
         64 . The compound of  claim 58 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein Y 1  is H, methyl, ethyl, or 2-benzylethyl, 
         wherein Y 2  is H or halo, and 
         wherein A 3  and A 4  are independently H or halo. 
       
     
     
         65 . The compound of  claim 58 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2 , A 3 , and A 4  are independently H, halo, or haloalkyl, and 
         wherein Y is H or alkyl. 
       
     
     
         66 . The compound of  claim 65 , wherein Y is H, A 1  and A 2  are H, and A 3  and A 4  are independently H, fluoro, or trifluoromethyl. 
     
     
         67 . The compound of  claim 58 , wherein the structure of the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         68 . A method for treating a subject having a methamphetamine (MA) addiction, comprising:
 Administering to the subject a therapeutically effective amount of a pharamaceutical composition comprising compound with the formula:   
       
         
           
           
               
               
           
         
         
           wherein X is a substituted or unsubstituted 5- or 6-membered aryl or substituted or unsubstituted 5- or 6-membered heteroaryl, 
           Z is N or CH, 
           m is 1, 2, or 3, 
           Ar is a substituted or unsubstituted 5- or 6-membered aryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, 
           R is ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted or unsubstituted 5-membered heteroaryl, 
           Y is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
           wherein the bond between the carbon atoms bearing Ar and R is a single or double bond, 
           or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers, crystal form, or isotopomer thereof.