Imidazo[1,2-beta]pyridazine and pyrazolo[1,5-alpha]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:
or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein:
X is NH;
R is H, —OH, halo, alkyl, haloalkyl, alkoxy or haloalkoxy;
R 1 is phenyl or substituted phenyl; and
R 2 is —(CH 2 ) 1,2 -piperid-4-yl, substituted —(CH 2 ) 1,2 -piperid-4-yl, —(CH 2 ) 1,2 -piperazin-1-yl, or substituted —(CH 2 ) 1,2 -piperazin-1-yl.
2. The compound of claim 1 wherein R is hydrogen.
3. The compound of claim 1 wherein R is methyl.
4. The compound of claim 1 wherein R 1 is substituted phenyl having at least one p, o or m substituent selected from —OCF 3 , —OCHF 2 , —CF 3 , —OCH 3 , and —OH.
5. The compound of claim 1 wherein R 1 is selected from:
6. The compound of claim 1 wherein R 2 is substituted —(CH 2 ) 1,2 -piperid-4-yl or substituted —(CH 2 ) 1,2 -piperazin-1-yl having one or two substituents selected from alkyl.
7. The compound of claim 6 wherein R 2 is selected from:
8. The compound of claim 1 , wherein the compound is:
N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-29);
N-(2-(4-methylpiperazin-1-yl)butyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-31);
7-methyl-N-((1-methylpiperidin-4-yl)methyl)-3-(3-trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-37); or
N-((1-ethylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-39).
9. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.