Imidazopyridazine inhibitors of PI3 kinase for cancer treatment
The present invention relates to imidazopyridazine compounds of Formula I, such as representative structure A, or a pharmaceutically acceptable salt thereof, that inhibit phosphoinositide 3-kinase; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
Q is —NR 1 R 1 , or —NR 1 C(═O)R 1 ;
each R 1 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
L is
X 1 , X 3 , X 4 and X 5 are CR or N;
X 2 is CR 2 ;
R 2 is —NR 1 [S(═O) 2 R 1 ];
A 1 and A 4 are N;
A 2 , A 3 and A 5 are CR;
A 6 is C; and
each R is independently halogen, hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.
2. A compound in accordance with claim 1 wherein Q is NH 2 , or —NHC(═O)CH 3 .
3. A compound in accordance with claim 1 wherein A 2 and A 3 are CH and A 5 is CR.
4. A compound in accordance with claim 1 wherein A 2 and A 3 are CH; A 5 is CR; and R is heteroaryl or substituted heteroaryl.
5. A compound in accordance with claim 1 wherein L is
X 1 , X 3 and X 5 are CR;
and X 4 is N.
6. A compound in accordance with claim 1 wherein L is
X 1 , X 3 and X 5 are CR;
X 4 is N;
X 2 is CR 2 ;
R 2 is —NH[S(═O) 2 R 1 ]; and
R 1 is aryl or substituted aryl.
7. A compound in accordance with claim 1 wherein L is
X 1 , X 3 and X 5 are CR;
X 4 is N;
X 2 is CR 2 ;
R 2 is —NH[S(═O) 2 R 1 ]; and
R 1 is difluoromethoxyphenyl.
8. The compound:
N-(6-(6-Chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-acetamide;
N-(5-(2-amino-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl) -3-(difluoromethoxy)benzenesulfonamide;
N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide;
N-(5-(2-amino-3-(2-methylpyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide;
N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide;
N-(5-(2-amino-3-(pyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide; or
N-(5-(2-amino-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising:
A) a compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
Q is —NR 1 R 1 , or —NR 1 C(═O)R 1 ;
each R 1 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
L is
X 1 , X 3 , X 4 and X 5 are CR or N;
X 2 is CR 2 ;
R 2 is —NR 1 [S(═O) 2 R 1 ];
A 1 and A 4 are N;
A 2 , A 3 and A 5 are CR;
A 6 is C; and
each R is independently halogen, hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted C 3 -C 8 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; and
B) a pharmaceutically acceptable excipient.