Disubstituted phthalazine hedgehog pathway antagonists
The present invention provides novel 1,4-disubstituted phthalazine hedgehog pathway antagonists useful in the treatment of cancer.
1. A compound of the formula
wherein:
R 1 is hydrogen or methyl;
R 2 is hydrogen or methyl; and
R 3 , R 4 , R 5 , R 6 , or R 7 are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 1 is methyl, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 wherein R 2 is methyl, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 wherein R 3 , R 4 , R 5 , R 6 and R 7 are independently hydrogen, fluoro, chloro, trifluoromethyl, or methylsulfonyl, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 wherein R 3 , R 4 , R 5 , R 6 and R 7 are independently hydrogen, fluoro, or trifluoromethyl, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 wherein R 4 , R 6 and R 7 are hydrogen, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride.
9. The compound according to claim 1 which is N-(1-(4-(1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 which is N-(1-(4-(1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-4-fluoro-N-methyl-2-(trifluoromethyl)benzamide hydrochloride.
11. The compound according to claim 1 which is 4-fluoro-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 which is 4-fluoro-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide hydrochloride.
13. A pharmaceutical composition comprising a compound of the formula
wherein:
R 1 is hydrogen or methyl;
R 2 is hydrogen or methyl; and
R 3 , R 4 , R 5 , R 6 , or R 7 are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen;
or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient.
14. The pharmaceutical composition according to claim 13 comprising the compound of the formula
wherein:
R 1 is methyl;
R 2 is methyl; and
R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, fluoro, chloro, trifluoromethyl, or methylsulfonyl, or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition according to claim 14 comprising the compound which is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.