Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy

Isoindoline derivatives of the formula (I)

• wherein
• R is R1—W-A1-Q-Y-A2-X1— or —CN;
• R1 is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C1-C6-alkylamino-C1-C4-alkyl, di-C1-C6-alkylamino-C1-C4-alkyl, C1-C6-alkylcarbonylamino-C1-C4-alkyl, C1-C6-alkyloxycarbonylamino-C1-C4-alkyl, C1-C6-alkylaminocarbonylamino-C1-C4-alkyl, di-C1-C6-alkylaminocarbonylamino-C1-C4-alkyl, C1-C6-alkylsulfonylamino-C1-C4-alkyl, (optionally substituted C6-C12-aryl-C1-C6-alkyl)amino-C1-C4-alkyl, optionally substituted C6-C12-aryl-C1-C4-alkyl, optionally substituted C3-C12-heterocyclyl-C1-C4-alkyl, C3-C12-cycloalkyl, C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonyl, halogenated C1-C6-alkoxycarbonyl, C6-C12-aryloxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, (halogenated C1-C4-alkyl)aminocarbonyl, C6-C12-arylaminocarbonyl, C2-C6-alkenyl, C2-C6-alkynyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, halogenated C1-C6-alkoxy, C1-C6-hydroxyalkoxy, C1-C6-alkoxy-C1-C4-alkoxy, amino-C1-C4-alkoxy, C1-C6-alkylamino-C1-C4-alkoxy, di-C1-C6-alkylamino-C1-C4-alkoxy, C1-C6-alkylcarbonylamino-C1-C4-alkoxy, C6-C12-arylcarbonylamino-C1-C4-alkoxy, C1-C6-alkoxycarbonylamino-C1-C4-alkoxy, C6-C12-aryl-C1-C4-alkoxy, C1-C6-alkylsulfonylamino-C1-C4-alkoxy, (halogenated C1-C6-alkyl)sulfonylamino-C1-C4-alkoxy, C6-C12-arylsulfonylamino-C1-C4-alkoxy, (C6-C12-aryl-C1-C6-alkyl)sulfonylamino-C1-C4-alkoxy, C3-C12-heterocyclylsulfonylamino-C1-C4-alkoxy, C3-C12-heterocyclyl-C1-C4-alkoxy, C6-C12-aryloxy, C3-C12-heterocyclyloxy, C1-C6-alkylthio, halogenated C1-C6-alkylthio, C1-C6-alkylamino, (halogenated C1-C6-alkyl)amino, di-C1-C6-alkylamino, di-(halogenated C1-C6-alkyl)amino, C1-C6-alkylcarbonylamino, (halogenated C1-C6-alkyl)carbonylamino, C6-C12-arylcarbonylamino, C1-C6-alkylsulfonylamino, (halogenated C1-C6-alkyl)sulfonylamino, C6-C12-arylsulfonylamino or optionally substituted C3-C12-heterocyclyl;
• W is —NR8— or a bond;
• A1 is optionally substituted C1-C4-alkylene or a bond;
• Q is —S(O)2— or —C(O)—;
• Y is —NR9— or a bond;
• A2 is optionally substituted C1-C4-alkylene, C1-C4-alkylene-CO—, —CO—C1-C4-alkylene, C1-C4-alkylene-O—C1-C4-alkylene, C1-C4-alkylene-NR10-C1-C4-alkylene, optionally substituted C2-C4-alkenylen, optionally substituted C2-C4-alkynylene, optionally substituted C6-C12-arylene, optionally substituted C6-C12-heteroarylene or a bond;
• X1 is —O—, —NR11—, —S—, optionally substituted C1-C4-alkylene, optionally substituted C2-C4-alkenylen, optionally substituted C2-C4-alkynylene;
• R2 is hydrogen, halogen, C1-C6-alkyl, halogenated C1-C4-alkyl, hydroxy-C1-C4-alkyl, —CN, C2-C6-alkenyl, C2-C6-alkynyl, optionally substituted C6-C12-aryl, hydroxy, C1-C6-alkoxy, halogenated C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C2-C6-alkenyloxy, C6-C12-aryl-C1-C4-alkoxy, C1-C6-alkylcarbonyloxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, aminosulfonyl, amino, C1-C6-alkylamino, C2-C6-alkenylamino, nitro or optionally substituted C3-C12-heterocyclyl, or two radicals R2 together with the ring atoms of A to which they are bound form a 5- or 6 membered ring;
• R3 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, or two radicals R3 together with the carbon atom to which they are attached form a carbonyl group;
• R4 is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl-C1-C4-alkyl, halogenated C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, CH2CN, C6-C12-aryl-C1-C4-alkyl, C3-C12-cycloalkyl, —CHO, C1-C4-alkylcarbonyl, (halogenated C1-C4-alkyl)carbonyl, C6-C12-arylcarbonyl, C1-C4-alkoxycarbonyl, C6-C12-aryloxycarbonyl, C1-C6-alkylaminocarbonyl, C2-C6-alkenyl, —C(═NH)NH2, —C(═NH)NHCN, C1-C6-alkylsulfonyl, C6-C12-arylsulfonyl, amino, —NO or C3-C12-heterocyclyl;
• X2 is —O—, —NR6—, —S—, >CR12aR12b or a bond;
• X3 is —O—, —NR7—, —S—, >CR13aR13b or a bond;
• R5 is optionally substituted C6-C12-aryl, optionally substituted C3-C12-cycloalkyl or optionally substituted C3-C12-heterocyclyl;
• R6 is hydrogen or C1-C6-alkyl;
• R7 is hydrogen or C1-C6-alkyl;
• R8 is hydrogen or C1-C6-alkyl;
• R9 is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl, amino-C1-C6-alkyl, optionally substituted C6-C12-aryl-C1-C4-alkyl or C3-C12-heterocyclyl;
• or
• R9, R1
• together are C1-C4-alkylene;
• or
• R9 is C1-C4-alkylene that is bound to a carbon atom in A2 and A2 is C1-C4-alkylene or to a carbon atom in X1 and X1 is C1-C4-alkylene;
• R10 is hydrogen, C1-C6-alkyl or C1-C6-alkylsulfonyl;
• R11 is hydrogen or C1-C6-alkyl, or
• R9, R11
• together are C1-C4-alkylene,
• R12a is hydrogen, optionally substituted C1-C6-alkyl, C1-C6-alkylamino-C1-C4-alkyl, di-C1-C6-alkylamino-C1-C4-alkyl, C3-C12-heterocyclyl-C1-C6-alkyl, optionally substituted C6-C12-aryl or hydroxy;
• R12b is hydrogen or C1-C6-alkyl, or
• R12a, R12b
• together are carbonyl or optionally substituted C1-C4-alkylene, wherein one —CH2— of C1-C4-alkylene may be replaced by an oxygen atom or —NR14—;
• R13a is hydrogen, optionally substituted C1-C6-alkyl, C1-C6-alkylamino-C1-C4-alkyl, di-C1-C6-alkylamino-C1-C4-alkyl, C3-C12-heterocyclyl-C1-C6-alkyl, optionally substituted C6-C12-aryl or hydroxy;
• R13b is hydrogen or C1-C6-alkyl, or
• R13a, R13b
• together are carbonyl or optionally substituted C1-C4-alkylene, wherein one —CH2— of C1-C4-alkylene may be replaced by an oxygen atom or —NR15—;
• R14 is hydrogen or C1-C6-alkyl;
• and
• R15 is hydrogen or C1-C6-alkyl;
• or a physiologically tolerated salt thereof.