Pyrimido 4,5-b quinoline-4,5 (3h, 10h) -diones as suppressors of nonsense mutations

摘要

A compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, which is ** Formula ** wherein R1 is a non-aromatic, monocyclic, saturated or unsaturated ring system, of five to seven members, wherein said ring system may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and wherein said ring system may be substituted once or more than once with R6; and R2 is C2-6 alkyl which may be substituted once or more than once with R7; or R2 is -X1-R8; -X1- is -O-, -S- or -N (R9) -; R9 is hydrogen or C1-4 alkyl; and R8 is C1-6 alkyl which may be substituted once or more than once with R10; or R2 is a non-aromatic, monocyclic, saturated or unsaturated aromatic ring system, with three to seven members, wherein said ring system may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and wherein said system of ring may be substituted once or more than once with R11; ** Formula ** wherein the phenyl ring is attached through the link marked with an asterisk; each of R12 independently is hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-4 alkyl, C1-4 halogenoalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy-C1-4 alkyl, amino-C1-4 alkyl, C 1-4 alkyl-C 1-4 alkyl, di (C 1-4 alkyl) -amino-C 1-4 alkyl, C 1-4 alkoxy, C 1-4 halogenoalkoxy, C 1-4 alkyl or di (C 1-4 alkyl) amino ; or C3-6 cycloalkyl, wherein a carbon atom can be replaced by an oxygen atom, where the C3-6 cycloalkyl can be attached directly or through a C1-2 alkylene, and where the C3-6 cycloalkyl can be substituted once or more than once with halogen; and R2 is C2-7 alkyl which may be substituted once or more than once with R13; or R2 is -X2-R14; -X2- is -O-, -S- or -N (R15) -; R15 is hydrogen or C1-4 alkyl; and R14 is C1-6 alkyl which may be substituted once or more than once with R16; or R2 is a non-aromatic, monocyclic, saturated or unsaturated ring system, with three to seven members, wherein said ring system may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and wherein said ring system it may be substituted once or more than once with R17; R3 is hydrogen or -CH2R18; R18 is hydrogen, C1-4 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C1-3 alkoxy-C1-3 alkyl, hydroxy C1-3 alkyl or C1-3 aminoalkyl; and R 4 is hydrogen, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 1-4 halogenoalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy-C 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkyl aminoC 1-4 alkyl, di (C 1-4 alkyl) -amino-C 1-4 alkyl, C 1-4 alkoxy, C 1-4 halogenoalkoxy, C 1-4 alkyl or di (C 1-4 alkyl) amino; or a monocyclic aromatic ring system, three to seven members, unsaturated saturated or unsaturated aromatic, wherein said ring system may contain 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein said ring system may be attached directly or through a C1-2 alkylene, and wherein said ring system may be substituted once or more than once with R19; R3 and R4, taken together, are -CH2-CH2-; R 5 is hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 halogenoalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy-C 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkyl-amino-alkyl C1-4, di (C1-4 alkyl) -amino-C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy or C1-4 halogenoalkoxy or C3-4 cycloalkyl, wherein a carbon atom it may be replaced by an oxygen atom, wherein the C3-4 cycloalkyl may be attached directly or through a C1-2 alkylene, and where the C3-4 cycloalkyl may be substituted once or more than once by halogen; R6, R11, R17 and R19, each independently, is halogen, hydroxyl, amino, cyano, nitro, C1-4 alkyl, halogen C1-4 alkyl, hydroxy C1-4, C1-4 alkoxy-C1-4 alkyl, amino- C 1-4 alkyl, C 1-4 alkyl-C 1-4 alkyl, di (C 1-4 alkyl) -amino-C 1-4 alkyl, C 1-4 alkoxy, C 1-4 halogenoalkoxy, C 1-4 alkyl or di (alkyl C1-4) amino; or C3-6 cycloalkyl, wherein a carbon atom can be replaced by an oxygen atom, where the C3-6 cycloalkyl can be attached directly or through a C1-2 alkylene, and where the C3-6 cycloalkyl can be substituted once or more than once with halogen; or two R6, R11, R17 or R19 in the same ring atom together are oxo; or two R6, R11, R17 or R19 in the same carbon atom of the ring, together with said carbon atom, form a C3-6 cycloalkyl; R7, R10, R13 and R16, each independently, is halogen, hydroxyl, amino, cyano, nitro, C1-4 alkoxy, C1-4 halogenoalkoxy, C1-4 alkyl or di (C1-4 alkyl) amino; or C3-6 cycloalkyl, wherein a carbon atom can be replaced by an oxygen atom, where the C3-6 cycloalkyl can be attached directly or through a C1-2 alkylene, and where the C3-6 cycloalkyl can be substituted once or more than once with halogen; or two R7, R10, R13 or R16 in the same carbon atom together are oxo; or two R7, R10, R13 or R16 in the same carbon atom, together with said carbon atom, form a C3-6 cycloalkyl; for use as a medicine for the treatment of a disease caused by a nonsense mutation.