PIM kinase inhibitors and methods of their use
New compounds, compositions and methods of inhibition of kinase activity associated with tumorigenesis in a human or animal subject are provided. In certain embodiments, the compounds and compositions are effective to inhibit the activity of at least one serine/threonine kinase or receptor tyrosine kinase. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a serine/threonine kinase- or receptor tyrosine kinase-mediated disorder, such as cancer.
1. A compound of Formula III, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
wherein,
Z 3 is CR 2 ;
R 1 is selected from the group consisting of hydrogen, halo, alkyl, and —NHR 3 ;
each R 2 is independently selected from the group consisting of hydrogen, halo, hydroxyl, and substituted or unsubstituted alkyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and hetero cycloalkyl; and
R 3 is hydrogen.
2. A compound of claim 1 wherein R 1 is hydrogen.
3. A compound of claim 1 wherein each R 2 is independently selected from the group consisting of hydrogen, halo, hydroxyl, amino, and substituted or unsubstituted alkyl and phenyl.
4. A compound of claim 1 having the following Formula IV, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
wherein,
R 1 is selected from the group consisting of hydrogen, halo, and —NHR 3 ;
each R 2 is independently selected from the group consisting of hydrogen, halo, hydroxyl, and substituted or unsubstituted alkyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, hetero cycloalkyl; and
R 3 is hydrogen.
5. A composition comprising a therapeutically effective amount of compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
6. The compound of claim 2 , where Z 1 is CR 2 wherein R 2 is substituted or unsubstituted phenyl.
7. The compound of claim 1 , wherein R 1 is amino.
8. A compound selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
9. A composition comprising a therapeutically effective amount of compound of claim 8 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.