Azepinoindole derivatives are PARP inhibitors and are useful for the treatment of neurodegenerative diseases, ischemia, tumor, septic shock, inflammation, rheumatic diseases, ARDS and diabetes mellitus

摘要

Azepinoindole derivatives are new. The azepinoindole derivatives of formula (I) and their tautomers, enantiomers, diastereomers, salts and prodrugs are new: A = 1-3C chain optionally substituted on each C by 1 or 2 1-4C alkyl, OH, 1-4C alkoxy, COOH, COO-1-4C alkyl or phenyl or optionally substituted with 1 oxo; X1 = S, O, or NH; X2 = C optionally carrying a 1-4C chain; or N; X3 = N, or CR2; R2 = H, 1-6C alkyl, phenyl-1-4C alkyl, or phenyl; R1 = H, Cl, Br, I, 1-6C alkyl, OH, NO2, CF3, CN; NR11R12, NHCOR13, or 1-4C alkoxy; R11, R12 = H or 1-4C alkyl; R13 = H, 1-4C alkyl, phenyl-1-4C alkyl, or phenyl; B = an unsaturated, saturated or partly unsaturated mono-, bi- or tricyclic ring with up to 15C which (a) optionally contains up to 5 N atoms or 1 or 2 O or S atoms when it has up to 14C, (b) is substituted with 1 R4 and up to 3 R5; and (c) is optionally substituted with =O on 1 or 2 C or S atoms; R4 = -(D)p-(E)s-(F1)q-G1-(F2)r-(G2)-G3; G1 = a bond or an unsaturated, saturated or partly unsaturated mono-, bi- or tricyclic ring with up to 15C which (a) optionally contains up to 5 N atoms or 1 or 2 O or S atoms when it has up to 14C, (b) is substituted with up to 3 R5; and (c) is optionally substituted with =O on 1 or 2 C or S atoms; G2 = NR41R42, a bond; or pyrrolidin-1-yl, piperidin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 4-R9-piperazin-1-yl, 4-R9-1,4-diazepin-1-yl, azepin-1-yl or morpholin-1-yl (each ring-substituted with R7); G3 = H; or an unsaturated, saturated or partly unsaturated mono-, bi- or tricyclic ring with up to 15C which (a) optionally contains up to 5 N atoms or 1 or 2 O or S atoms when it has up to 14C, (b) is substituted with up to 3 R5; and (c) is optionally substituted with =O on 1 or 2 C or S atoms; D = S, NR43, or O; E = phenyl, -C(O)-, -SO2-, -SO2NH-, -NHCO-, -CONH-, -NHSO2-, or -NHCOCH2X4-; X4 = S, O, or NH; F1, F2 = saturated or unsaturated 1-8C chain; p, q, r and s = 0 or 1; R41 = H, 1-6C alkyl optionally substituted on each C with 1 or 2R6, phenyl optionally substituted with 1 or 2 R 6, or (CH2)t-K; R42 = H, 1-6C alkyl, COR8, CO2R8, SO2NH2, SO2R8, -(C=N)-R8, or -(C=N)-NHR8; R43 = H or 1-4C alkyl; t = 1-4; K = NR11R12, NR11-(1-4C alkyl)-phenyl, pyrrolidinyl, piperidinyl, 1,2,5,6-tetrahydropyridinyl, morpholinyl, homopiperidinyl, or piperazinyl or homopipearzinyl (each optionally substituted with 1 1-6C alkyl); R5 = H, Cl, F, Br, I, OH, NO2, CF3, CN; NR11R12, NHCOR13, (1-4C alkyl)-CONHR13, COR8, (0-4C alkyl)-OCOR13, phenyl-1-4C alkyl; phenyl, CO2-1-4C alkyl, or saturated or unsaturated 1-6C alkyl, 1-4C alkoxy or 1-4C alkylthio (each optionally substituted with 1 or 2 R6); R6 = H, Cl, F, Br, I, 1-6C alkyl, OH, NO2, CF3, CN, NR11R12, NHCOR13, or 1-4C alkoxy; R7 = H, 1-6C alkyl, phenyl optionally substituted with 1-3 Q, NR11R12, or a saturated 3-7 membered cyclic amino group or homopiperazinyl (each optionally substituted with 1 1-6C alkyl); Q = OH, 1-6C alkyl, 1-4C alkoxy, Cl, Br, I, F, CF3, NO2, or NH2; R8 = 1-6C alkyl, CF3, phenyl, or phenyl-1-4C alkyl optionally substituted with 1 or 2 Q; R9 = H, 1-6C alkyl, Ph-1-4C alkyl, CO2-(1-4C alkyl)-Ph, CO2-1-4C alkyl, SO2-Ph, COR8, or Ph; Ph = phenyl optionally substituted 1 or 2 Q; compounds are excluded when: (a) X2 = X3 = N; (b) G1 = G2 = G3 = H or a bond; and (c) two of G1-G3 = H or a bond when p = s = 0 and q or r = 1 or p. q and r = 0.