Substituted pyridazine carboxamide compounds as kinase inhibitor compounds
The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against c-Met and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
1. A compound of formula I:
or a salt thereof; wherein:
R 1 , R 2 , R 3 , and R 4 each are independently H, alkyl, or Z 1 ;
R 6 is an unsaturated heterocyclyl, wherein R 6 is optionally substituted by 1- 3 groups independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, and Z 1 ;
Each Z 1 is halogen, CN, NO 2 , OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 , C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 ,S(O) 2 NR 15 R 16 , R 17 ,C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , oxo, C(O)R 16 , C(O)(CH 2 ) n OH, (CH 2 ) n OR 15 , (CH 2 ) n C(O)NR 15 R 16 ,NR 15 S(O) 2 R 17 , where each n is independently 0-6;
Each R 15 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
Each R 16 is independently hydrogen, alkenyl, alkynyl,C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl; and
Each R 17 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
2. A compound of formula II:
or a salt thereof; wherein
R 1 , R 2 , R 3 , R 4 , R 7 and R 5 each are independently H, alkyl or Z 1 ;
Each Z 1 is halogen, CN, NO 2 , OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 , C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy,1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 , S(O) 2 NR 15 R 16 , R 17 , C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , oxo, C(O)R 16 ,C(O)(CH 2 ) n OH, (CH 2 ) n OR 15 , (CH 2 ) n C(O)NR 15 R 16 ,NR 15 S(O) 2 R 17 , where each n is independently 0-6;
Each R 15 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
Each R 16 is independently hydrogen, alkenyl, alkynyl, C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl; and
Each R 17 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
3. A compound of formula III:
or a salt thereof; wherein
R 7 and R 8 each are independently H, alkyl or Z 1 ;
Each Z 1 is halogen, CN, NO 2 , OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 ,C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy,1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 ,
S(O) 2 NR 15 R 16 , R 17 , C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , oxo, C(O)R 16 , C(O)(CH 2 )nOH,(CH 2 )nOR 15 , (CH 2 )nC(O)NR 15 R 16 , NR 15 S(O) 2 R 17 , where each n is independently 0-6;
Each R 15 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
Each R 16 is independently hydrogen, alkenyl, alkynyl, C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 ,-C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl; and
Each R 17 is independently C 3 -C 6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 ,-C 4 alkyl or C 1 , -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl.
4. The compound of claim 3 , wherein R 8 is hydrogen and R 7 is C 1 -C 3 alkyl.
5. The compound of claim 3 , wherein each Z 1 is independently halogen.
6. The compound of claim 1 , wherein the compound is {5-[(1R)-1-(2,6-dichloro-3-fluoropheny)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxarnide.
7. The compound of claim 1 , wherein the compound is selected from the following:
{6-amino-5[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;
{5-[(1S)-1-(2,6dichloro-3-fluoropheny)ethoxy]-6-aminopyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide;
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6oxo- 1,6-dihydro-pyridin-3-yl]carboxamide;
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)carboxamide.