3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-diones as MEK inhibitors
The invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are as defined herein. The invention further relates to pharmaceutical compositions comprising such compounds and salts, and to methods and uses of such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject in need thereof. The invention further relates to solid forms of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.
1. A compound
or a pharmaceutically acceptable salt thereof.
2. A compound
3. A crystalline form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, wherein the crystalline form is a monohydrate or anhydrous.
4. The crystalline form according to claim 3 , which is anhydrous and has a PXRD pattern comprising peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8, and 20.5 degrees 2-theta (±0.2 degrees 2-theta).
5. The crystalline form according to claim 3 , which is anhydrous and has a PXRD pattern comprising peaks at 7.1, 9.4, 12.4, 12.8, 14.3, 15.6, 16.4, 17.4, 18.5, 18.9, 19.5, 19.9, 21.1, 21.4, 23.2, 23.7, 24.8, 25.6, 27.6, 30.3, 33.2, 33.5, and 37.5 degrees 2-theta (±0.2 degrees 2-theta).
6. The crystalline form according to claim 3 , which is a monohydrate and has a PXRD pattern comprising peaks at 13.7, 18.0, and 18.3 degrees 2-theta (±0.2 degrees 2-theta).
7. An amorphous form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.
8. A pharmaceutical composition, comprising:
the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and
at least one pharmaceutically acceptable excipient.
9. A pharmaceutical composition, comprising:
the compound according to claim 2 ; and
at least one pharmaceutically acceptable excipient.
10. A pharmaceutical composition, comprising:
the crystalline form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione according to claim 3 ; and
at least one pharmaceutically acceptable excipient.
11. A pharmaceutical composition, comprising:
the amorphous form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione according to claim 7 ; and
at least one pharmaceutically acceptable excipient.