Inhibitors of phosphoinositide dependent kinase 1 (PDK1)
View Patent ↗The instant invention provides for compounds of formula A that inhibit PDK1 activity: The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting PDK1 activity by administering the compound to a patient in need of treatment of cancer.
1. A compound of the Formula A:
wherein:
n is 0, 1, 2, 3, 4 or 5;
W is C, Y is N, Z is C;
X is O, CH 2 or NH;
Ring K is aryl or heteroaryl;
L 1 is C 0 -C 6 alkyl, C 2 -C 6 alkenyl or heteroaryl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl or phenyl, wherein said phenyl is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, halo and OH;
L 2 is C 0 -C 6 alkyl, C 2 -C 6 alkenyl or heteroaryl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl or phenyl;
R 1 is heterocyclyl which is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, NH(C═O)C 1 -C 6 alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH, oxo and NR 8 R 9 ;
R 2 is independently selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH and NR 8 R 9 ;
R 3 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl, O(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH and NR 8 R 9 when W is C;
R 5 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH and NR 8 R 9 ;
R 6 and R 7 are independently selected from: H and C 1 -C 6 alkyl; and
R 8 and R 9 are independently selected from: H and C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
2. The compound according to claim 1 of the Formula B:
wherein:
n is 1, 2 or 3;
W is C and Y is N;
X is O, CH 2 or NH;
L 2 is C 0 -C 6 alkyl, C 2 -C 6 alkenyl or heteroaryl, wherein said alkyl is optionally substituted with C 1 -C 6 alkyl or phenyl;
R 1 is heterocyclyl which is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, NH(C═O)C 1 -C 6 alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH, oxo and NR 8 R 9 ;
R 2 is halo;
R 3 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH and NR 8 R 9 when W is C;
R 5 is selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, O(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, CO 2 H, halo, OH and NR 8 R 9 ;
R 6 and R 7 are independently selected from: H and C 1 -C 6 alkyl; and
R 8 and R 9 are independently selected from: H and C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
3. The compound according to claim 2 of the following formula:
wherein:
X is O or NH; and
R 2 is halo;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
4. A compound according to claim 1 which is:
1-(3,4-difluorobenzyl)-6-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,6-dihydropyrimidine-5-carboxamide;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
5. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .