Patent FR-2969614-A1 (FR)
Title: New pyrimidinone compounds are akt phosphorylation inhibitors useful for treating e.g. gastric cancer, glioblastomas, thyroid cancer, bladder cancer, breast cancer, melanoma, lymphoid or myeloid hematopoietic tumors, and sarcomas
Inventor: CARRY JEAN CHRISTOPHE
IPC: A61K31/5377
Filed: 2010-12-28
Abstract: Pyrimidinone compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Pyrimidinone compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. R1 : H or methyl; R2 : H or F; R3 : H or halo, preferably F; R4 : alkyl, alkoxy, heterocycloalkyl, aryl or heteroaryl (all optionally substituted by halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, NR1vR1w or SO 2Alk), NR1xR1y, H, halo, or hydroxyl; either R5, R5a : H or an alkyl; or CR5R5a : 3-10-membered cyclic group (spirocycloalkyl) optionally containing one or more heteroatoms (preferably spiroheterocycloalkyl) of O, S, or NH, where the cyclic group is optionally substituted by one or more halo, alkyl, cycloalkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; either R6 : H, alkyl (optionally substituted by halo, deuterium, OH or alkoxy), cycloalkyl or phenyl (optionally substituted by halo or alkoxy); or CR5R6 : 3-10 membered cyclic group (cycloalkyl) optionally containing one or more heteroatoms (heterocycloalkyl) of O, S, or NH (where the cyclic groups are optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy or NH 2), NHalk or N(alk) 2; either R1x : H or alkyl group; and R1y : H, cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl; or NR1xR1y : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by one or more halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, -NR1vR1w or SO 2Alk; either R1v : H or alkyl group; and R1w : H, cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, or heterocycloalkyl; or NR1vR1w : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by one or more halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, or NH 2, NHalk, N(alk) 2or SO 2alk; and R : H, alkyl, cycloalkyl, or (hetero)aryl. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester (C), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (E), or (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt of formula (D) or (F) and 2,3-dihydro-1H-indole compound of formula (L). Y0 : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt phosphorylation inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma (PC3) cell line using multi-spot biomarker detection of meso scale technique. The result showed that 2-[2-((+)-2-fluoromethyl-2,3-dihydro-indol-1-yl)2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one exhibited an IC 50value of 2 nM.