Methods of Use for Trisubstituted Benzotriazole Derivatives as Dihydroorotate Oxygenase Inhibitors

Abstract

The present invention provides methods for treating a cancer in a subject and for inhibiting tumor growth, metastasis or a dihydrorotate oxygenase enzyme activity of a tumor or cancer cell. At least one trisubstituted benzotriazole derivative with the formula (I) is administered to the subject or is contacted with the cancer cell. Compounds of formula (I) have substituents R 1 , R 2 and R 3 which have the meanings given in the specification, and pharmaceutically acceptable salts thereof.

1 . A method of treating a cancer selected from acute myeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lung cancer, breast cancer, triple negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, cancer of the head or neck, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, lymphocytic lymphoma cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancer, and a PTEN mutant cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 the dotted lines [ . . . ] in the ring represent an optional bond which is 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; wherein the substituent is halogen; 
 R 3  is selected from hydroxy and amino; 
 R 4  is selected from an aryl and a heteroaryl that is optionally substituted with 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 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 a 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N and is optionally substituted with alkyl; and 
 n is an integer selected from 0 and 1. 
 
     
     
         2 . The method according to  claim 1 , wherein the cancer is selected from acute myeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, triple negative breast cancer, melanoma, prostate cancer, and cancer of the esophagus. 
     
     
         3 . The method according to  claim 1 , wherein the cancer is acute myeloid leukemia. 
     
     
         4 . The method according to  claim 1 , wherein the cancer is multiple myeloma. 
     
     
         5 . The method according to  claim 1 , wherein the cancer is B-prolymphocytic leukemia. 
     
     
         6 . The method according to  claim 1 , wherein the cancer is non-Hodgkin's lymphoma. 
     
     
         7 . The method according to  claim 1 , wherein the cancer is diffuse large B cell lymphoma. 
     
     
         8 . The method according to  claim 1 , wherein the cancer is anaplastic large cell lymphoma. 
     
     
         9 . The method according to  claim 1 , wherein the cancer is mantle cell lymphoma. 
     
     
         10 . The method according to  claim 1 , wherein the cancer is triple negative breast cancer. 
     
     
         11 . The method according to  claim 1 , wherein the cancer is melanoma. 
     
     
         12 . The method according to  claim 1 , wherein the cancer is prostate cancer. 
     
     
         13 . The method according to  claim 1 , wherein the cancer is cancer of the esophagus. 
     
     
         14 . The method according to  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.