Claims for Patent: 9,187,489

Summary for Patent: 9,187,489

Title:	Imidazo[1,2-b]pyridazine derivatives as kinase inhibitors
Abstract:	The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
Inventor(s):	Yasuyuki Takeda, Kenji Yoshikawa, Yoshiko Kagoshima, Yuko Yamamoto, Ryoichi Tanaka, Yuichi Tominaga, Masaki Kiga, Yoshito Hamada
Assignee:	Daiichi Sankyo Co Ltd
Application Number:	US14/378,318
Patent Claims:	1. A compound selected from the following group or a pharmacologically acceptable salt thereof: N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine, N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[2-(methylamino)ethoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine, 3-[4-[[(2S)-azetidin-2-yl]methoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine, 3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine, 3-[4-[(2S)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine, (4S)-4-amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one, (4S)-4-amino-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one, (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one, and (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]-3-methoxyphenyl]pyrrolidin-2-one. 2. N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine. 3. 3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine. 4. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one. 5. (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one. 6. N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine maleate. 7. N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine adipate. 8. 3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine methanesulfonate. 9. 3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate. 10. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one benzenesulfonate. 11. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one hydrochloride. 12. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one adipate. 13. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one lactate. 14. (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one benzoate. 15. (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one benzenesulfonate. 16. (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one adipate. 17. (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one camphorate. 18. A pharmaceutical composition comprising a compound according to claim 9 as an active ingredient. 19. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of ROS1 gene, comprising administering a compound according to claim 9 as an active ingredient. 20. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of NTRK gene, comprising a compound according to claim 9 as an active ingredient. 21. A method for inhibiting proliferation of a cancer cell having a detectable expression of ROS1 fusion gene, comprising administering a compound according to claim 9. 22. A method for inhibiting proliferation of a cancer cell having a detectable expression of NTRK fusion gene, comprising administering a compound according to claim 9. 23. A method for inhibiting proliferation of a cancer cell by the inhibition of ROS1 kinase enzyme activity, comprising administering a compound according to claim 9. 24. A method for inhibiting proliferation of a cancer cell by the inhibition of NTRK kinase enzyme activity, comprising a compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 25. A method for inhibiting ROS1 kinase enzyme activity in a subject, comprising administering a compound according to claim 9. 26. A method for inhibiting NTRK kinase enzyme activity in a subject, comprising administering a compound according to claim 9. 27. A pharmaceutical composition comprising a compound according to claim 3 or a pharmacologically acceptable salt thereof as an active ingredient. 28. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of ROS1 gene, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof as an active ingredient. 29. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of NTRK gene, comprising a compound according to claim 3 or a pharmacologically acceptable salt thereof as an active ingredient. 30. A method for inhibiting proliferation of a cancer cell having a detectable expression of ROS1 fusion gene, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof. 31. A method for inhibiting proliferation of a cancer cell having a detectable expression of NTRK fusion gene, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof. 32. A method for inhibiting proliferation of a cancer cell by the inhibition of ROS1 kinase enzyme activity, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof. 33. A method for inhibiting proliferation of a cancer cell by the inhibition of NTRK kinase enzyme activity, comprising a compound according to claim 3 or a pharmacologically acceptable salt thereof as an active ingredient. 34. A method for inhibiting ROS1 kinase enzyme activity in a subject, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof. 35. A method for inhibiting NTRK kinase enzyme activity in a subject, comprising administering a compound according to claim 3 or a pharmacologically acceptable salt thereof.