Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

8- Substituted 2- morpholin- 4- yl- quinolin- 4- ones and 9- substituted 2- morpholin- 4- ylpyrido[ 1,2- a] pyrimidin- 4- ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA- dependent protein kinase. A multiple- parallel approach, employing Suzuki cross- coupling methodology, was utilised in the preparation of 8- substituted 2- morpholin- 4- yl- quinolin- 4- ones. For this purpose 8- bromo- 2- morpholin- 4- yl- quinolin- 4- one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of ( 2- bromoanilino)- morpholin- 4- yl- 5- methylene- 2,2- dimethyl[ 1,3] dioxane4,6- dione afforded 8- bromo- 2- morpholin- 4- yl- quinolin- 4- one. A multiple- parallel approach, employing Suzuki cross- coupling methodology, was also utilised to prepare 9- substituted 2- morpholin- 4- ylpyrido[ 1,2- a] pyrimidin- 4- ones using 9- hydroxy- 2- morpholin- 4- yl- pyrido[ 1,2- a] pyrimidin- 4- one O- trifluoromethanesulfonate as an intermediate. 8- Substituted 2- morpholin- 4- yl- quinolin- 4- ones and 9- substituted 2- morpholin- 4- yl- pyrido[ 1,2- a] pyrimidin- 4- ones were both inhibitors of DNA- dependent protein kinase. When the substituent was dibenzothiophen- 4- yl, dibenzofuran- 4- yl or biphen- 3- yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8- substituted 2- morpholin- 4yl- chromen- 4- ones previously reported ( I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El- Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Grif. n, J. Med. Chem., 2005, 48, 7829 - 7846).