Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy

摘要

The present invention relates to aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives of the formula (I);;or a physiologically tolerated salt thereof;The invention relates to pharmaceutical compositions comprising such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, and the use of such aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquin oline derivatives for therapeutic purposes. The aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives are GlyT1 inhibitors.

主权项

1. Compounds of the formula (I) wherein A is a 5- or 6-membered ring; 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 M3-M12-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, M3-M12-heterocyclylsulfonylamino-C1-C4-alkoxy, M3-M12-heterocyclyl-C1-C4-alkoxy, C6-C12-aryloxy, M3-M12-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 M3-M12-heterocyclyl; W is —NR7− or a bond; A1 is optionally substituted C1-C4-alkylene or a bond; Q is —S(O)2— or —C(O)—; Y is —NR8— or a bond; n1 is 0, 1, 2, or 3; n2 is 0, 1, 2, or 3; X1 is >N— or >CH—; R6 is hydrogen, halogen, C1-C4-alkyl, halogenated C1-C4-alkyl, —CN, OH C1-C6-alkoxy or halogenated C1-C6-alkoxy, or two radicals R6 together with the carbon atom to which they are attached form a carbonyl group; R2 is hydrogen, halogen, C1-C6-alkyl, halogenated 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 M3-M12-heterocyclyl, or two radicals R2 together with the ring atoms of A to which they are bound form a 5- or 6 membered ring; A2 is —O—, —S— or —NR9—; 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; Y1 is a bond or optionally substituted C1-C4-alkylene; R4a 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, optionally substituted 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 optionally substituted M3-M12-heterocyclyl; or R4a is optionally substituted C1-C4-alkylene that is bound to a carbon atom in Y1; R4b is hydrogen, C1-C6-alkyl, halogenated C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, —CH2CN, —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 M3-M12-heterocyclyl; or R4a, R4b together are optionally substituted C2-C6-alkylene, wherein one —CH2— of C2-C6-alkylene may be replaced by an oxygen atom or —NR19; X2 is —O—, —NR11a—, —S—, >CR12aR12b or a bond; X3 is —O—, —NR11b—, —S—, >CR13aR13b or a bond; R5 is optionally substituted C6-C12-aryl, optionally substituted C3-C12-cycloalkyl or substituted M3-M12-heterocyclyl; R7 is hydrogen or C1-C6-alkyl; R8 is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl, amino-C1-C6-alkyl, optionally substituted C6-C12-aryl-C1-C4-alkyl or M3-M12-heterocyclyl; or R8, R1 together are C1-C4-alkylene; R9 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 M3-M12-heterocyclyl; R10 is hydrogen or C1-C6-alkyl; R11a is hydrogen or C1-C6-alkyl; R11b is hydrogen or C1-C6-alkyl; R12a is hydrogen, optionally substituted C1-C6-alkyl, C1-C6-alkylamino-C1-C4-alkyl, C6 alkylamino C1-C4 alkyl, M3-M12-heterocyclyl-C1-C6-alkyl, optionally substituted C6-C12-aryl or hydroxy; R12b is hydrogen or C1-C6-alkyl, or R12a, R12b together with the carbon atom to which they are attached form a carbonyl or are optionally substituted C2-C4-alkylene, wherein one —CH2— of C2-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, C6 alkylamino C1-C4 alkyl, M3-M12-heterocyclyl-C1-C6-alkyl, optionally substituted C6-C12-aryl or hydroxy; R13b is hydrogen or C1-C6-alkyl, or R13a, R13b together with the carbon atom to which they are attached form a carbonyl or are optionally substituted C2-C4-alkylene, wherein one —CH2— of C2-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.