New fused-ring diazepinone compounds, useful for treatment and prevention of e.g. cancers and arteriosclerosis, are inhibitors of serine-threonine kinase

摘要

Fused-ring diazepinone compounds (I) and their salts, derivatives, solvates and stereoisomers (including mixtures in all proportions) are new. Fused-ring diazepinone compounds of formula (I) and their salts, derivatives, solvates and stereoisomers (including mixtures in all proportions) are new. R 1>', R 1>'', R 1>''', R 1>'''', R 3>, R 4>, R 5>', R 5>'' and R 5>''' : hydrogen, A, R 6>, Ar, OR 6>, SR 6>, OAr, SAr, NR 6> 2, NHAr, hal, nitro, cyano, (CH 2) mCOOR 6>, (CH 2) mCOOAr, (CH 2) mCONR 6> 2, (CH 2) mCONAAr, COA, COR 6>, COAr, S(O) mA, S(O) mAr, NACOA, NACOAr, NASO 2A, NASO 2Ar, SO 2NR 6> 2, SO 2NAAr, M(CH 2) nNR 6> 2, M(CH 2)NAR 6>, M(CH 2) nNA 2, M(CH 2) n(R 6>) n, M(CH 2) n-oxopiperazine, -oxomorpholine or -oxopyrrolidine, M(CH 2) nC(CH 3) n(CH 2) nNR 6> 2, M(CH 2) nMR 6> nSO mA, M(CH 2) nMR 6> 2S(O) mMR 6> 2, M(CH 2) nMR 6> 2S(O) mAr, (CH 2) nM(R 6>) nSO mA, (CH 2) nM(R 6>) nSO mMR 6> 2, (CH 2) nM(R 6>) nSO mAr, M(CH 2) nSO mA, M(CH 2) nSO mNR 6> nA, M(CH 2) nSO mAr, (CH 2) nSO mA, (CH 2) nSO mMR 6> n or (CH 2) nSO mAr, where two adjacent R 1> may together form a saturated or unsaturated 5-6 membered carbo- or hetero-cycle, optionally substituted by 1 or 2 M; R 2>' and R 2>'' : R 6>; R 6> : hydrogen, hal, cyano, amino, nitro, SO 2(sic), 1-4C alkyl (optionally with one CH 2 replaced by O or S atom and/or by NH, NA, CONH, NHCO or CH=CH and/or 1-4 H can be replaced by hal and one Me can be replaced by NH 2, NHR 7>, NR 7> 2, nitro or SO 2; R 7> : Me or Et; n : 0-5; m : 0-2; A : 1-14C linear, branched or cyclic alkyl, optionally with one or two CH 2 replaced by O or S and/or by NH, CONH, NHCO, CO or CH=CH and/or 1-7 H can be replaced by hal and 1 or 2 Me replaced by R 6>; Ar : mono- or di-nuclear homo- or hetero-cycle with 1-4 N, O and/or S and 5-10 basic atoms, optionally substituted 1-3 times by carbonyl, hal, A, hydroxy, OA, NH 2, NHA, NA 2, nitro, cyano, OCN, SCN, COOH, COOA, CONH 2, CONHA, CONA 2, NHCOA, NHCONH 2, NHSO 2A, CHO, COA, SO 2NH 2 and/or S(O) mA; hal : fluoro, chloro, bromo or iodo; X : CR 1>, CHR 5>, N, NR 1>, O or S and at least one is CR 1> or CHR 1> and O or S can not be directly linked to N, NR 1>, O or S; Y : NR 4>, O or S; Z : CR 1>, CHR 5>, N, NR 5>, O or S, at least one must be CR 5> or CHR 5> and O or S can not be linked directly to N, NR 5>, O or S; Q : CR 5>, CHR 5> or bond; M : NH, O or S, and ? : indicates a single or double bond. Independent claims are included for the following: (1) method for preparing (I) and (2) kit comprising, in separate packages, (I) and another pharmaceutical. [Image] ACTIVITY : Cytostatic; Antiarteriosclerotic; Antidiabetic; Ophthalmological; Antiinflammatory. MECHANISM OF ACTION : Inhibition of kinases, specifically the serine-threonine kinase PDK1. The compound 3-methyl(1-methylpiperidin-4-yl)amino)-5,10-dihydro-2,4,5,10-tetra-aza-dibenzo[a,d]cyclohepta-11-one has IC50 against PDK1 of 2.3 mu M.