Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators

Abstract

wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds. Methods and intermediates useful for making the compounds, and methods of using the compounds and compositions thereof are also provided.

1 . A method of treating and/or preventing a disease or a disorder associated with inflammation or oxidative stress in a patient in need thereof, comprising administering to the patient a pharmaceutically effect amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 the atoms labeled 1 and 2 are connected either by a double bond or an epoxidized double bond; 
 n is 1 or 2; 
 m is 0 or 1; 
 X is —CN, —CF 3 , or —C(O)R a , wherein R a  is —OH, alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or —NHS(O) 2 -alkyl (C1-4) ; 
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkoxydiyl (C≤12) , alkylaminodiyl (C≤12) , or a substituted version of any of these groups; 
 R 3  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; or R 3  is taken together with R 4  as provided below; provided that R 3  is absent when and only when the atom to which it is bound forms part of a double bond; 
 R 4  is hydrogen, hydroxy, amino, halo, cyano, or oxo; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or R 4  is taken together with either R 3  or R 5  as provided below; 
 R 5  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; or R 5  is taken together with R 4  as provided below; provided that R 5  is absent when and only when the atom to which it is bound forms part of a double bond; and 
 R 6  is hydrogen, hydroxy, amino, halo, cyano, or oxo; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 provided that when R 3  and R 4  are taken together, the compound is further defined by formula Ia: 
 
       
       
         
           
           
               
               
           
         
         
           wherein R 7  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
           provided that when R 4  and R 5  are taken together, the compound is further defined by formula Ib: 
         
       
       
         
           
           
               
               
           
         
         
           wherein R 8  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
         
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is further defined by the formula: 
       
         
           
           
               
               
           
         
         wherein:
 n is 1 or 2; 
 X is —CN, —CF 3 , or —C(O)R a , wherein R a  is —OH, alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or —NHS(O) 2 -alkyl (C1-4) ; 
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkoxydiyl (C≤12) , alkylaminodiyl (C≤12) , or a substituted version of any of these groups; 
 R 3  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; provided that R 3  is absent when and only when the atom to which it is bound forms part of a double bond; 
 R 5  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; provided that R 5  is absent when and only when the atom to which it is bound forms part of a double bond; and 
 R 6  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the compound is further defined by the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkoxydiyl (C≤12) , alkylaminodiyl (C≤12) , or a substituted version of any of these groups; 
 R 3  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; provided that R 3  is absent when and only when the atom to which it is bound forms part of a double bond; 
 R 5  is absent, hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; provided that R 5  is absent when and only when the atom to which it is bound forms part of a double bond; and 
 R 6  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the compound is further defined by the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 R 3  is hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; and 
 R 6  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         5 . The method of  claim 3 , wherein the compound is further defined by the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , alkoxydiyl (C≤12) , alkylaminodiyl (C≤12) , or a substituted version of any of these groups; 
 R 5  is hydrogen; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; and 
 R 6  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently hydrogen, hydroxy, halo, or amino; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 R 4  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 R 6  is hydrogen, hydroxy, amino, halo, or cyano; or alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkyl-amino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         7 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein R 1  and R 2  are each methyl. 
     
     
         19 - 103 . (canceled) 
     
     
         104 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         105 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         106 - 107 . (canceled) 
     
     
         108 . A method of treating and/or preventing a disease or a disorder associated with inflammation or oxidative stress in a patient in need thereof, comprising administering to the patient a pharmaceutically effect amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently:
 hydrogen, hydroxy or amino; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , hetero-aryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , arenediyl (C≤12) , alkoxydiyl (C≤12) , alkenyloxydiyl (C≤12) , alkylamino-diyl (C≤12) , alkenylaminodiyl (C≤12) , or a substituted version of any of these groups; 
 
 R 3  is:
 hydrogen, hydroxy or amino, or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , hetero-aryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; and 
 
 R 4  is:
 hydrogen; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , hetero-aryl (C≤12) , acyl (C≤12)  or a substituted version of any of these groups; 
 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         109 - 123 . (canceled) 
     
     
         124 . A method of treating and/or preventing a disease or a disorder associated with inflammation or oxidative stress in a patient in need thereof, comprising administering to the patient a pharmaceutically effect amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  and R 2  are each independently:
 hydrogen, hydroxy or amino; or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , hetero-aryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or 
 R 1  and R 2  are taken together and are alkanediyl (C≤12) , alkenediyl (C≤12) , arenediyl (C≤12) , alkoxydiyl (C≤12) , alkenyloxydiyl (C≤12) , alkylamino-diyl (C≤12) , alkenylaminodiyl (C≤12) , or a substituted version of any of these groups; and 
 
 R 3 , R 4 , R 5  and R 6  are each independently:
 hydrogen, hydroxy or amino, or 
 alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , hetero-aryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroaryl-amino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; and 
 
 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         125 - 142 . (canceled) 
     
     
         143 . The method of  claim 1 , wherein the compound is administered to the patient in the form of a pharmaceutical composition comprising the compound and an excipient. 
     
     
         144 . The method of  claim 1 , wherein the disease or disorder is cancer. 
     
     
         145 . The method of  claim 1 , wherein the disease or disorder is a cardiovascular disease. 
     
     
         146 . The method of  claim 145 , wherein the cardiovascular disease is atherosclerosis. 
     
     
         147 . The method of  claim 1 , wherein the disease or disorder is an autoimmune disease. 
     
     
         148 . The method of  claim 147 , wherein the autoimmune disease is Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. 
     
     
         149 . The method of  claim 1 , wherein the disease or disorder is a neurodegenerative disease. 
     
     
         150 . The method of  claim 149 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease. 
     
     
         151 . The method of  claim 1 , wherein the disease or disorder is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury, influenza osteoarthritis, osteoporosis, pancreatitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, multiple sclerosis, myocardial infarction, stroke, muscular dystrophy, cachexia, or graft-versus-host disease. 
     
     
         152 . The method of  claim 1 , wherein the disease or disorder is an eye disease. 
     
     
         153 . The method of  claim 152 , wherein the eye disease is uveitis, glaucoma, macular degeneration, or retinopathy. 
     
     
         154 . The method of  claim 1 , wherein the disease or disorder is psychiatric or neuropsychiatric. 
     
     
         155 . The method of  claim 154 , wherein the psychiatric or neuropsychiatric disease or disorder is psychosis, schizophrenia, depression, bipolar disorder, a seizure disorder, migraine, neuropathic pain, tinnitus, post-traumatic stress disorder, attention deficit disorder, autism, or anorexia nervosa. 
     
     
         156 . The method of  claim 155 , wherein the seizure disorder is epilepsy. 
     
     
         157 . The method of  claim 1 , wherein the disease or disorder is mitochondrial dysfunction.