Trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors

Abstract

is administered to the subject or is contacted with the cancer cell. Compounds of formula (I) have substituents R1, R2 and R3 which have the meanings given in the specification, and pharmaceutically acceptable salts thereof.

1 - 17 . (canceled) 
     
     
         18 . A method of treating an autoimmune disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 the dotted lines [. . . . ] in the ring represent an optional bond which may be present in any stable combination; 
 R 1  is selected from hydrogen and alkyl; 
 R 2  is -A-R 4 . 
 A is arylene or tetrasubstituted arylene where the substituent is halogen. 
 R 3  is selected from hydroxy and amino; 
 R 4  is selected from an optionally substituted aryl and an optionally substituted heteroaryl; 
 wherein the optional substituent for the aryl and the heteroaryl selected from one or more R 5 ; 
 R 5  is selected from alkyl and —(CH 2 ) n N(R a )R b ; 
 R a  and R b  are each independently selected from hydrogen, alkyl and —C(O)alkyl; 
 alternatively R a  and R b  can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N; wherein the optional substituent for the 4-6 membered heterocyclyl is alkyl; and 
 ‘n’ is an integer selected from 0 and 1. 
 
     
     
         19 . The method according to  claim 18 , wherein the autoimmune disease is selected from systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. 
     
     
         20 . The method according to  claim 18 , wherein the autoimmune disease is responsive to inhibition of dihydroorotate dehydrogenase. 
     
     
         21 . The method according to  claim 18 , wherein R 1  is methyl. 
     
     
         22 . The method according to  claim 18 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method according to  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.