IMIDAZO[1,2-beta]PYRIDAZINE AND PYRAZOLO[1,5-alpha]PYRIMIDINE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS
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 - 28 . (canceled)
29 . A method for treating a protein kinase-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to structure (I) below:
(I)
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.
30 - 34 . (canceled)
35 . The method of claim 29 wherein R is hydrogen.
36 . The method of claim 29 wherein R is methyl.
37 . The method of claim 29 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.
38 . The method of claim 29 wherein R 1 is selected from:
39 . The method of claim 29 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.
40 . The method of claim 39 wherein R 2 is selected from:
41 . The method of claim 29 , 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).
42 . The method of claim 29 wherein the compound is administered to the subject in the form of a composition comprising the compound in combination with a pharmaceutically acceptable excipient.
43 . The method of any one of claims 29 and 41 , wherein the protein-kinase mediated disease is a cancer.
44 . The method of claim 43 wherein the cancer is colon cancer.
45 . The method of claim 43 wherein the cancer is breast cancer.
46 . The method of claim 43 wherein the cancer is stomach cancer.
47 . The method of claim 43 wherein the cancer is prostate cancer.
48 . The method of claim 43 wherein the cancer is pancreatic cancer.
49 . The method of claim 43 wherein the cancer is ovarian cancer.