Novel stat3 pathway inhibitors and cancer stem cell inhibitors

Abstract

The present invention relates to a novel naphtho class of compounds as Stat3 pathway inhibitors and as cancer stem cell inhibitors; to methods of using such compounds to treat cancer; to methods of using such compounds to treat disorders in a mammal related to aberrant Stat3 pathway activity; to pharmaceutical compositions containing such compounds.

1 . A compound of formula IV, 
       
         
           
           
               
               
           
         
         or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the symbols have the following meanings and are, for each occurrence, independently selected: 
         X is O or S; 
         R 1  is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , or SR a ; 
         R 7  is hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR a , or SR a ; 
         R 8  is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, alkylaryl or substituted alkylaryl; 
         R 9  and R 10  are each independently hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, alkylaryl or substituted alkylaryl, alkylheteroaryl or substituted alkylheteroaryl; or R 9  and R 10  together with the carbon to which they are bonded optionally form cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle; 
         R a  is hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl; and 
         n is 1-4. 
       
     
     
         2 . The compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition comprising a compound or a pharmaceutically-acceptable salt thereof as claimed in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically-acceptable excipient, carrier, or diluent. 
     
     
         4 . A method of treating a cancer in a subject, the method comprising administering the subject a therapeutically effective amount of a compound as claimed in  claim 1 , or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. 
     
     
         5 . The method of  claim 4 , wherein the cancer is selected from the group consisting of breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, multiple myeloma, colorectal carcinoma, prostate cancer, melanoma, kaposi sarcoma, ewing's sarcoma, liver cancer, gastric cancer, medulloblastoma, brain tumors, and leukemia. 
     
     
         6 . A method of inhibiting a cancer stem cell survival and/or self-renewal, the method comprising administering to a cancer stem cell with an effective amount of a compound as claimed in  claim 1 , or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. 
     
     
         7 . The method of  claim 6 , wherein the cancer is selected from the group consisting of breast cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, multiple myeloma, colorectal carcinoma, prostate cancer, melanoma, kaposi sarcoma, ewing's sarcoma, liver cancer, gastric cancer, medulloblastoma, brain tumors, leukemia. 
     
     
         8 . The method of  claim 6 , wherein the cancer is metastatic. 
     
     
         9 . The method of  claim 6 , wherein the cancer is refractory to a chemotherapy or radiotherapy. 
     
     
         10 . The method of  claim 6 , wherein the cancer is inherently resistant to chemotherapy.