New (6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide derivatives are akt phosphorylation inhibitors useful for treating e.g. gastric cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, sarcoma and hamartoma

摘要

(6-Oxo-1,6-dihydro-pyrimidin-2-yl)-amide derivatives of formula (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. (6-Oxo-1,6-dihydro-pyrimidin-2-yl)-amide derivatives of formula (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. R 1> : aryl or heteroaryl group (both optionally substituted by one or more groups of alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocycloalkyl (all optionally substituted by one or more halo, OH, alkoxy, NR1vR1w, heterocycloalkyl or heteroaryl), halo, OH, CN, nitro, -COOH, cycloalkyl, -O-cycloalkyl, -COOalk, NR1xR1y-, -CONR1xR1y, NR1xCOR1y-, -NR1xCO2R1z, or -COR1y, where aryl and heteroaryl is optionally substituted by one or more alkyl or alkoxy (both optionally substituted by one or more halo and the heterocycloalkyl and heteroaryl are optionally contains one or more oxo)); either R : H; or RR 1> : 5 or 6 membered ring (saturated or partially or completely unsaturated fused with aryl or heteroaryl and optionally containing one or more other heteroatoms of O, S, N, NH or N-alk), bicyclic group optionally substituted by one or more halo, CO-NH 2, OH, alkyl (optionally substituted by OH, alkoxy, NH 2, NH-Alk or N(alk) 2) or alkoxy; R 2>, R 3> : H, halo or alkyl optionally substituted by one or more halo; R 4> : H; R 5> : H or alkyl optionally substituted by one or more halo; either R1x : H or alkyl; and R1y : H, cycloalkyl, or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl); or NR1xR1y : 3-10 membered cyclic group optionally containing one or more other heteroatoms of O, S, NH or N-alkyl and optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; either R1v : H or alkyl; and R1w : H, cycloalkyl, CO 2alk or alkyl (optionally substituted by one or more OH, alkoxy, or heterocycloalkyl); or NR1vR1w : 3-10 membered cyclic group optionally containing heteroatoms of O, S, NH or N-alkyl and optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; alk : alkyl; and R1z : cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl), where all the alk, alkoxy and alkylthio are linear or branched 1-6C alkyl, 1-6C alkoxy and 1-6C alkylthio. Independent claims are included for: (1) 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)-sodium acetate (D1), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-lithium acetate (D2), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-potassium acetate (D3), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (E) and (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-metal acetate compound of formula (F). Y1 +> : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt Phosphorylation inhibitor; Protein kinase B (PKB) inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma cells using western blotting technique. The result showed that N-(3-bromophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide exhibited an IC 5 0value of 23 nM.