Chemical compounds
The invention is directed to pyrido[4,3-d]pyrimidin-5(6H)-one derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R 1 , R 2 , R 3 , and R 4 are defined below. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
1. A compound according to Formula I:
wherein:
R 1 is aryl, —CH 2 -aryl, or heteroaryl each of which is optionally substituted with one to three R5;
R 2 is H, C 1 -C 6 alkyl optionally substituted with one or two R 6 , C 3 -C 6 cycloalkyl optionally substituted with one to three R 7 , or heterocycloalkyl optionally substituted with one to three R 7 ; and R3 is H, C 1 -C 6 alkyl, or phenyl;
or
R 2 and R 3 are joined together with the nitrogen atom to which they are attached forming a saturated 4-7 membered heterocycloalkyl which may contain one additional N, S, or O atom and being optionally substituted with one to three C 1 -C 3 alkyl groups optionally substituted with one OH, oxo, aryl, or —NR a R b ;
R 4 is H, halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, cyano, C 1 -C 3 alkoxy, NR a R b , aryl optionally substituted with one to three R 5 , or heteroaryl optionally substituted with one to three R 6 ;
each R 5 is independently selected from the group consisting of halo, CN, C 1 -C 3 alkoxy, heteroaryl, —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R a , —NR b C(O)R a , —C(O)NR a R b , —NR b C(O)NR a R b , and C 1 -C 3 alkyl optionally substituted by —NR a R b ;
each R 6 is independently selected from the group consisting of OH, —NR a R b , —NR b C(O)R a , 1,1-cyclopropanedicarboxamide, heteroaryl, heterocycloalkyl, and aryl optionally substituted by S(O) 2 NH 2 ;
each R 7 is independently selected from the group consisting of OH, C 1 -C 3 alkoxy, —NR a R b , and C 1 -C 3 alkyl optionally substituted by —NR a R b ;
each R a is independently selected from the group consisting of H, heterocycloalkyl, and C 1 -C 3 alkyl optionally substituted with one —NH 2 or NHCH 3 ; and
each R b is independently H or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R 2 is H, C 1 -C 6 alkyl optionally substituted with one or two R 6 , C 3 -C 6 cycloalkyl optionally substituted with one to three R 7 , or heterocycloalkyl optionally substituted with one to three R 7 ; and R 3 is H, C 1 -C 6 alkyl, or phenyl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 wherein R 1 is phenyl optionally substituted with one to three R 5 ; or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 2 wherein R 1 is —CH 2 -phenyl optionally substituted with one to three R 5 ; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 2 wherein R 1 is pyrazolyl or indazolyl optionally substituted with one to three R 5 ; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 2 wherein R 2 is C 1 -C 6 alkyl optionally substituted with —NR a R b and R 3 is H; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 2 wherein R 2 is pyrrolidinyl, piperidinyl, cyclohexyl, or cyclopropyl each of which is optionally substituted with one to three R 7 ; and R 3 is H, C 1 -C 6 alkyl, or phenyl; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 6 wherein R 4 is H, methyl, or bromo; or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable excipients.