Pyrimidine derivatives as kinase inhibitors
The invention provides novel pyrimidine derivatives of formula I and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of insulin-like growth factor (IGF-IR) or analplastic lymphoma kinase (ALK).
1. A compound of Formula (3):
a pharmaceutically acceptable salt thereof, or a tautomer thereof;
wherein ring E may optionally contain a double bond;
Z 1 and Z 2 are CH 2 ;
Z 3 is NR 6 or N(R 6 ) + —O − ;
R 1 is halo or an optionally halogenated C 1-6 alkyl;
R 3 and R 4 are each H;
R 5b is H; and R 5a and R 5c are independently halo, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, cyano or C(O)O 0-1 R 8 ;
R 6 is a radical selected from formula (a), (b), (c) or (d):
L is (CR 2 ) 1-4 or a bond; wherein R is independently H or C 1-6 alkyl;
R 10 is O, S, NR 17 wherein R 17 is H, C 1-6 alkyl, SO 2 R 8a or CO 2 R 8a and R 8a is C 1-6 alkyl;
R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently selected from H; C 1-6 alkoxy; C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino or hydroxyl groups; or R 11 and R 12 , R 12 and R 15 , R 15 and R 16 , R 13 and R 14 , or R 13 and R 15 together with the atoms to which they are attached may form a 3-7 membered saturated, unsaturated or partially unsaturated ring containing 1-3 heteroatoms selected from N, O and S, and optionally substituted with oxo and 1-3 R 5 groups;
wherein R 5 is halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkoxy, cyano or C(O)O 0-1 R 8 ; and
R 8 is C 1-6 alkyl.
2. The compound of claim 1 , wherein R 5a is halo and R 5c is C 1-6 alkyl.
3. The compound of claim 1 , wherein R 6 is a radical of formula (a) or (c); and R 10 is O.
4. The compound of claim 1 , wherein R 1 is halo.
5. A compound selected from the group
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
7. The compound of claim 1 , wherein said compound is 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(1,1-dioxido-3-thietanyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein said compound is 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 7 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.