Substituted Quinazoline and Pyrido-Pyrimidine Derivatives
The present application provides novel substituted quinazoline and pyrido-pyrimidine compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating PI3K and/or mTOR activity by administering a therapeutically effective amount of one or more of the compounds to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the PI3K/AKT/mTOR pathway. Advantageously, these compounds perform as dual PI3K/mTOR inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.
1 . A compound of formula (I):
wherein:
R 1 is H, F, Cl, or OCH 3 ;
R 2 is H, optionally substituted aryl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted heterocycle-amino, optionally substituted alkylcarbonylamino, optionally substituted alkylsulfonylamino, optionally substituted alkylthio, optionally substituted alkylsulfonyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycle-oxy, optionally substituted alkylaminocarbonyl, optionally substituted arylaminocarbonyl, optionally substituted heteroarylaminocarbonyl, optionally substituted heterocycle-aminocarbonyl, or C(O)-(optionally substituted heterocycle) and R 3 is H, halogen, CN, OH, NH 2 , NHCH 3 , or OCH 3 ; or
R 2 is H, halogen, CN, OH, NH 2 , NHCH 3 , or OCH 3 and R 3 is H, optionally substituted aryl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted heterocycle-amino, optionally substituted alkylcarbonylamino, optionally substituted alkylsulfonylamino, optionally substituted alkylthio, optionally substituted alkylsulfonyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycle-oxy, optionally substituted alkylaminocarbonyl, optionally substituted arylaminocarbonyl, optionally substituted heteroarylaminocarbonyl, optionally substituted heterocycle-aminocarbonyl, or C(O)-(optionally substituted heterocycle);
R 4 is optionally substituted morpholine or thiomorpholine;
R 5 is H, F, or Cl;
R 6 is H, F or Cl;
M is selected from the group consisting of:
R 7 and R 8 are, independently, H, or optionally substituted alkyl; or
R 7 and R 8 are joined to form an optionally-substituted heterocycle containing 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, 0 or 1 sulfur atom, 0 or 1 S(O) fragment, 0 or 1 S(O) 2 fragment, and 3 to 6 carbon atoms;
R 9 is H or alkyl;
R 10 is H or alkyl optionally substituted with OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , halogen, alkoxy, CF 3 , OCF 3 , or CN; or
R 9 and R 10 are joined to form an optionally-substituted heterocycle wherein the fragment —R 9 -R 10 — is optionally substituted —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 CH 2 —;
A is CH or C—F;
X is N, CH, C—F or C—Cl;
Y is N, CH, C—F or C—Cl; and
Z is N, CH, C—F, or C—Cl;
or a pharmaceutically acceptable salt or solvate thereof.