Imidazo[1,2-B]pyridazine and pyrazolo[1 .5-A]pyrimidine derivatives and their use as protein kinase inhibitors
View Patent ↗The present invention provides protein kinase inhibitors comprising imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine compounds of the following structure (I) and (II): or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer and other Pim kinase-associated conditions are also disclosed.
1. A compound having a structure according to structure (I) below:
including stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, where:
X is NH, S, O, SO or SO 2 ;
R is H, —OH, halo, alkyl, haloalkyl, alkoxy or haloalkoxy;
R 1 has the following structure:
where R 1 ′ is —CF 3 and m is 1, 2, 3, 4 or 5; and
R 2 is —(CH 2 ) n -cyclopropyl, —(CH 2 ) n -cyclopentyl or —(CH 2 ) n -cyclohexyl, where n is 0, 1, 2, 3 or 4, and wherein the —(CH 2 ) n -cyclopropyl, —(CH 2 ) n -cyclopentyl and —(CH 2 ) n -cyclohexyl moieties are each optionally substituted with one or more substituents selected from hydroxyalkyl.
2. The compound of claim 1 , wherein X is NH or O.
3. The compound of claim 1 , wherein R is H.
4. The compound of claim 1 , wherein R 2 is —(CH 2 ) n -cyclohexyl optionally substituted with one or more hydroxyalkyl.
5. The compound of claim 1 , wherein R 1 is:
where R 1 ′ is CF 3 .
6. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.
7. The compound of claim 1 , wherein n is 0.
8. The compound of claim 1 , wherein X is NH.
9. The compound of claim 1 , wherein the —(CH 2 ) n -cyclopropyl, —(CH 2 ) n -cyclopentyl or —(CH 2 ) n -cyclohexyl moiety is substituted with one or more hydroxyalkyl.
10. The compound of claim 5 , wherein R 2 is —(CH 2 ) n -cyclohexyl optionally substituted with one or more hydroxyalkyl.
11. The compound of claim 7 , wherein R 2 is —(CH 2 ) n -cyclohexyl optionally substituted with one or more hydroxyalkyl.
12. The compound of claim 8 , wherein R 2 is —(CH 2 ) n -cyclohexyl optionally substituted with one or more hydroxyalkyl.
13. The compound of claim 4 , wherein R 2 is substituted with hydroxyalkyl.
14. The compound of claim 10 , wherein R 2 is substituted with hydroxyalkyl.
15. The compound of claim 11 , wherein R 2 is substituted with hydroxyalkyl.
16. The compound of claim 12 , wherein R 2 is substituted with hydroxyalkyl.