Amino pyrimidine anticancer compounds
Compounds of Formula 1, as shown below and defined herein: and pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by FAK.
1. A pharmaceutical composition comprising a compound having the Formula 1 a:
wherein:
X 1 and X 2 are independently a bond or methylene and X 1 is meta or para to the position of nitrogen attachment;
R1 is Br, CI, or —CF 3 ;
R2 is —P(O)R 9 R 10 ;
R4 is C 4-6 cycloalkyl which is optionally substituted by hydroxy, piperazinyl that is optionally N-methyl substituted, —C(O)O—C 0-3 alkyl, or C 1-3 alkyl optionally substituted by 1-2 hydroxy groups;
R5 is methyl;
R6 is H or methoxy;
R 9 and R 10 are independently C 0-3 alkoxy; or a pharmaceutically acceptable salt thereof;
which is formulated with at least one pharmaceutically acceptable carrier.
2. A pharmaceutical composition comprising diethyl (3-methoxy-4-{[4-({2-methyl-7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising diethyl (4-{[4-{[7-(trans-4-hydroxycyclohexyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl) phosphonate hydrochloride and at least one pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising a compound having the formula:
wherein R6 is H or methoxy; and
R9 and R10 are independently C 0-3 alkoxy; or a pharmaceutically acceptable salt thereof;
which is formulated with at least one pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising diethyl (3-methoxy-4-{[4-{[2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising 2-{2-[3-(dimethylphosphinoylmethyl)phenylamino]-5-trifluoromethylpyrimidin-4-ylamino}-N-methylbenzamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising 2-{[2-{[4-(dimethylphosphoryl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.