Patent FR-2950891-A1 (FR)
Title: New pyrrolo-dipyridine azacarboline derivatives are protein kinase inhibitors useful for treating cancer
Inventor: BABIN DIDIER
IPC: A61K31/437
Filed: 2009-10-06
Abstract: Pyrrolo-dipyridine azacarboline derivatives (I) and their isomeric forms, racemates, enantiomers, diastereoisomers, addition salts with organic or mineral acids or bases, are new. Pyrrolo-dipyridine azacarboline derivatives of formula (I) and their isomeric forms, racemates, enantiomers, diastereoisomers, addition salts with organic or mineral acids or bases, are new. Z 2>-Z 4> : CH, CR1a, CR1s or N; R 3> : (hetero)aryl, C(O)Oalkyl or 1-10C alkyl optionally comprising heteroatom (all optionally mono, di or tri substituted), H, halo (F, Cl, Br, I), CF 3, CHF 2, OH, NH 2, CONH(alkyl), CON(alkyl) 2, alkoxy, NH(alkyl), or N(alkyl) 2(in which all the alkyl part is in CONH(alkyl), CON(alkyl) 2, alkoxy, NH(alkyl), or N(alkyl) 2are optionally mono, di or tri substituted); R 6> : heteroaryl (5 or 6 membered ring with 1-4 heteroatoms of N, S or O) connected to azacarboline unit, C or N of R 6>, where R 6>is optionally mono or polysubstituted; either R1a : CON(alkyl) 2, CONHalkyl, CONHcycloalkyl, CONH(alkyl)heterocycloalkyl, CONHheterocycloalkyl or CON(alkyl)(heterocycloalkyl) (all optionally mono, di or tri substituted), CONHN(alkyl) 2(in which alkyl part is optionally mono, di or tri substituted) or CONH 2; and R1s : O-1-10C alkyl, N(1-10C alkyl or 3-7C cycloalkyl) 2(all optionally mono or polysubstituted), H, Cl, Br, I, OH, NH 2, NHCOR3a, N-1-10C alkylCOR3a, NHSO 2R3a, N-1-10C alkylSO 2R3a, CO 2R3a, SR3a, SOR3a or SO 2R3a; or R1aR1s : 4-7 membered ring optionally substituted by oxo, comprising at least one nitrogen atom and optionally another heteroatom such as N, O and S and optionally substituted by one or more oxo, F, Cl, Br, I, CF 3, CHF 2, alkyl, OH, Oalkyl, NO 2, NH 2, NHAlk or N(Alk) 2; and R3a : F, Cl, Br, I, CF 3, 1-10C alkyl, 3-7C cycloalkyl, 2-6C alkenyl, 2-6C alkynyl, OH, linear, branched or cyclic -O-1-10C alkyl or -O-3-7C alkyl, 3-7C heterocycloalkyl, NH 2, NH-(1-10C alkyl or 3-7C cycloalkyl), NH-(1-10C alkyl or 3-7C cycloalkyl) 2or NH-(1-10C alkyl or 3-7C heterocycloalkyl) 2. Independent claims are included for: (1) intermediates comprising 3-chloro-pyridine compound of formula (A1), 3'-chloro-[3,4']bipyridinyl-2-ylamine compound of formula (B1) and 9H-dipyrido[2,3-b;4',3'-d]pyrrole compound of formula (C1); and (2) the preparation of (I). Q : M or X; Q 1> : H or GP; X : Br or I; M : Sn(CH 3) 3, B(OH) 2or 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane; R : Cl, OCH 3, OH, or -OSO 2CF 3; R 4> : H, I, OCH 3, -OH, -OSO 2CF 3, (4-methoxycarbonylphenyl) or (4-carboxyphenyl); and GP : protecting group comprising tosyl, [beta -(trimethylsilyl)ethoxy]methyl, pivaloyl or acetyl. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Protein kinase inhibitor. The ability of (I) to inhibit Proto-oncogene serine/threonine-protein 2 (Pim 2) kinase was tested using time resolved-fluorescence resonance energy transfer assays. The result showed that N-cyclopropyl-4-[3-fluoro-6-(pyridin-3-yl)-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzamide exhibited an IC 5 0value of 1-5 mu M.