New thiazol-2-yl-morpholine compounds are akt phosphorylation inhibitors useful for treating glioblastomas, thyroid cancer, bladder cancer, breast cancer, melanoma, sarcomas, cancer of bone and pancreas, and hamartomas

摘要

Thiazol-2-yl-morpholine compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Thiazol-2-yl-morpholine compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. R1a, R1b : H, halo or alkyl (optionally substituted by one or more halo atoms); R1c : NH 2, OH, or alkoxy; R1 : aryl or heteroaryl (both optionally substituted by halo, OH, CN, nitro, -COOH, -COOalk, -NR1xR1y, -CONR1xR1y, NR1xCOR1y-, -COR1y, NR1xCO 2R1z, alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, O-cycloalkyl, heterocycloalkyl, aryl or heteroaryl), where heterocycloalkyl and heteroaryl optionally contain one or more oxo, and the alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl or heteroaryl are optionally substituted by halo, OH, alkoxy or NR1vR1w, and the aryl and heteroaryl are optionally substituted alkyl or alkoxy optionally substituted by halo; either R : H; or RR1 : optionally and partially saturated 5 or 6-membered aryl or heteroaryl ring (optionally containing one or more other heteroatoms comprising O, S, N, NH or Nalk), or bicyclic radical (optionally substituted by halo, OH, alkyl, or alkoxy), (hetero)aryl or NR1xR1y, where the alkyl, alkoxy, aryl and heteroaryl are optionally substituted by halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, NR1vR1w or SO 2Alk; or two substituents on the same carbon atom of the ring formed by R with R1 may form together with the carbon atom (CRR1) : a 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, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; or two adjacent substituents of the ring formed by R with R1 may optionally form, together with the carbon atoms to which they are attached (CRR1) : 3-10 membered ring (spirocycloalkyl) optionally containing one or more heteroatoms (spiroheterocycloalkyl (tetrahydropyran or oxetane)) of O, S, NH or N-alkyl, where the ring is optionally substituted by one or more halo, alkyl, hydroxyl , oxo, alkoxy, 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 containing 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 containing 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 R1z : cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl, where all the alkyl (alk), alkoxy and alkylthio are linear or branched and contains 1-6C. Independent claims are included for: (1) the preparation of (I); and (2) intermediates comprising (5-bromo-2-morpholin-4-yl-thiazol-4-yl)-acetic acid ethyl ester (C), (5-cyano-2-morpholin-4-yl-thiazol-4-yl)-acetic acid ethyl ester (D), 2-(5-cyano-2-morpholin-4-yl-thiazol-4-yl)-acetamide compound of formula (E), (5-carbamoyl-2-morpholin-4-yl-thiazol-4-yl)-sodium acetate (F), (5-carbamoyl-2-morpholin-4-yl-thiazol-4-yl)-acetic acid ethyl ester (G), 4-ethoxycarbonylmethyl-2-morpholin-4-yl-thiazole-5-carboxylic acid ethyl ester (J), 4-carboxymethyl-2-morpholin-4-yl-thiazole-5-carboxylic acid (K), 2-morpholin-4-yl-7H-pyrano[4,3-d]thiazole-4,6-dione (L), and substituted 2,3-dihydro-1H-indole compound of formula (N). R2 : H or F; R3 : H, alkoxy, F, Cl or Br; R4 : alkyl or alkoxy (both optionally substituted by at least 1 halo, OH heterocycloalkyl or NR1vR1w), heteroaryl or aryl (both optionally substituted by at least 1 halo, OH, alkyl heterocycloalkyl, alkoxy, NH 2, NHalkyl, N(alkyl) 2or SO 2-alkyl), H, F, Cl, Br, NR1xR1y or OH; R5, R5a : H or alkyl, or CR5R5a : 3-7 membered ring optionally including at least 1 O, S or NH (optionally substituted by at least 1 halo, alkyl, OH, oxo, alkoxy, NH 2, NHalkyl or N(alkyl) 2), and R6 : alkyl or cycloalkyl (both optionally substituted by at least 1 halo (F), D, OH or alkoxy) or H, or CR5 + CR6 : 3-1 membered cycloalkyl optionally including at least 1 O, S or NH (optionally substituted by at least 1 halo, alkyl, OH, oxo, NH 2, NHalkyl or N(alkyl) 2). [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 (-)-4-{2-[4-bromo-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide exhibited an IC 5 0value of 3 nM.