Compounds and compositions as kinase inhibitors
The present invention provides a compound of Formula I: wherein X, Y, Z, R 1 and R 2 are as described herein, and salts thereof and therapeutic uses of these compounds for treatment of disorders associated with RAF kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.
1. A compound of formula I:
in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
X and Y are independently selected from N and C—OCH 2 CHR 3 R 4 ; wherein R 3 is selected from hydrogen and OH; and R 4 is selected from 2-(phosphonooxy)methyl and phosphonooxy; with the proviso that if X is N, Y is C—OCH 2 CHR 3 R 4 ; and if Y is N, X is C—OCH 2 CHR 3 R 4 ; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of formula Ia:
in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
R 3 is selected from hydrogen and OH;
R 4 is selected from 2-(phosphonooxy)methyl and phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, selected from:
4. The compound of claim 1 of formula Ib:
in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
R 3 is selected from hydrogen and OH;
R 4 selected from 2-(phosphonooxy)methyl and phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, selected from:
6. A compound, or a pharmaceutically acceptable salt thereof, of formula:
7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
8. A combination comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.