Stat3 pathway inhibitors and cancer stem cell inhibitors
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 aberrent Stat3 pathway activity; to pharmaceutical compositions containing such compounds.
1. A compound selected from the group consisting of:
or a tautomer, or pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of formula IV,
or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt 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, 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, 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;
and a pharmaceutically-acceptable excipient, carrier, or diluent.
3. A method of treating a cancer in a subject, the method comprising administering the subject a therapeutically effective amount of a compound of formula IV,
or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt 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, 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, 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; and
wherein the cancer is selected from the group consisting of breast cancer, lung cancer, cervical cancer, colon cancer, prostate cancer, liver cancer, head and neck cancer, and pancreatic cancer.