COMBINATION OF A IMIDAZOPYRIDAZINE DERIVATIVE AND A MITOTIC AGENT FOR THE TREATMENT OF CANCERThe present invention relates to a combination comprising an Mps-1 kinase inhibitor and a mitotic inhibitor. The present invention also relates to the use of said combination for the treatment of cancer, in particular of pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer and/or gastric cancer.A combination comprising: a compound A which is selected from:N-cyclopropyl-4-{6-[1-(3-fluoro-4-methoxyphenyl)ethenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[difluoro(3-fluoro-4-methoxyphenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(RS)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(R)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(S)—N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(RS)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(R)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(S)—N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(RS)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(R)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,(S)—N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[difluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(3-methoxybenzoyl)-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(3-methoxyphenyl)vinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(4-methoxyphenyl)vinyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1, 2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[(2, 5-difluorophenyl)(hydroxy)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(2, 5-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(3-fluoro-4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(2,3-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[difluoro(4-methoxyphenyl)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[(2,3-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(2, 5-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(2, 5-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[(2,5-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)ethenyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(3-fluoro-4-methoxyphenoxy)-8-[(oxetan-3-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide,N-cyclopropyl-4-{6-(2,3-difluoro-4-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, andN-cyclopropyl-4-{6-(2,3-difluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H-pyran-4-ylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, or an N-oxide, a hydrate, a solvate, or a salt thereof; ando ne or more mitotic inhibitors.
암의 치료를 위한 이미다조피리다진 유도체 및 유사분열제의 조합본 발명은 Mps-1 키나제 억제제 그리고 유사분열 억제제를 포함하는 조합물에 관한 것이다. 본 발명은 또한 암, 특히 췌장암, 교모세포종, 난소암, 비소세포 폐 암종, 유방암 및/또는 위암의 치료를 위한 상기 조합물의 용도에 관한 것이다.N-시클로프로필-4-{6-[1-(3-플루오로-4-메톡시페닐)에테닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[디플루오로(3-플루오로-4-메톡시페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(RS)-N-시클로프로필-4-{6-[(3-플루오로-2-히드록시페닐)(히드록시)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(R)-N-시클로프로필-4-{6-[(3-플루오로-2-히드록시페닐)(히드록시)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(S)-N-시클로프로필-4-{6-[(3-플루오로-2-히드록시페닐)(히드록시)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(RS)-N-시클로프로필-4-{6-[1-(3-플루오로-2-히드록시페닐)-1-히드록시에틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(R)-N-시클로프로필-4-{6-[1-(3-플루오로-2-히드록시페닐)-1-히드록시에틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(S)-N-시클로프로필-4-{6-[1-(3-플루오로-2-히드록시페닐)-1-히드록시에틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(RS)-N-시클로프로필-4-{6-[플루오로(3-플루오로페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(R)-N-시클로프로필-4-{6-[플루오로(3-플루오로페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,(S)-N-시클로프로필-4-{6-[플루오로(3-플루오로페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[디플루오로(3-플루오로페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(3-메톡시벤조일)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(3-메톡시페닐)비닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(4-메톡시벤조일)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(4-메톡시페닐)비닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[(2,5-디플루오로페닐)(히드록시)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(2,5-디플루오로벤조일)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(3-플루오로-4-메톡시벤조일)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(2,3-디플루오로벤조일)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(2,3-디플루오로페닐)비닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[디플루오로(4-메톡시페닐)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(2,3-디플루오로페닐)시클로프로필]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[(2,3-디플루오로페닐)(디플루오로)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(2,5-디플루오로페닐)비닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(2,5-디플루오로페닐)시클로프로필]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[(2,5-디플루오로페닐)(디플루오로)메틸]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(5-플루오로-2-히드록시페닐)에테닐]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-[1-(5-플루오로-2-히드록시페닐)시클로프로필]-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(3-플루오로-4-메톡시페녹시)-8-[(옥세탄-3-일메틸)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드,N-시클로프로필-4-{6-(2,3-디플루오로-4-메톡시페녹시)-8-[(3,3,3-트리플루오로프로필)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드, 및N-시클로프로필-4-{6-(2,3-디플루오로-4-메톡시페녹시)-8-[(테트라히드로-2H-피란-4-일메틸)아미노]이미다조[1,2-b]피리다진-3-일}-2-메틸벤즈아미드로부터 선택된 화합물 A, 또는 그의 N-옥시드, 수화물, 용매화물 또는 염 및 하나 이상의 유사분열 억제제를 포함하는 조합물.