Substituted pyridazine carboxamide compounds as kinase inhibitor compounds
Pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases 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 is arylalkyl or heteroarylalkyl, each optionally substituted with 1-4 independent Z 1 ;
R 3 is hydrogen, hydroxyl, alkoxy, or alkylamino;
R 6 is pyridonyl optionally substituted by 1-3 groups, independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, —C(O)NR 7 R 8 , and Z 1 ;
R 7 and R 8 are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7 and R 8 together with nitrogen form a heterocyclyl or heteroaryl;
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 n is independently 0-6 inclusive;
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. The compound of claim 1 , wherein R 1 is arylalkyl optionally substituted with 1-4 independent Z 1 .
3. The compound of claim 2 , wherein each Z 1 is independently halogen.
4. The compound of claim 1 , wherein R 3 is H.
5. The compound of claim 1 , of formula II:
or a salt thereof; wherein:
R 6 is pyridonyl optionally substituted by alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, or —C(O)NR 7 R 8 ; and
R 7 and R 8 are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7 and R 8 together with nitrogen form a heterocyclyl or heteroaryl.
6. 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 (19);
6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydropyridin-3-yl))carboxamide (21);
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6-oxo-1,6-dihydro-pyridin-3-yl)]carboxamide (27); and
{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl))carboxamide (28).