Amine Derivatives as Potassium Channel Blockers

摘要

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

主权项

1. A compound of Formula (I): wherein X is selected from a single bond, an alkylene group having 1 to 6 carbon atoms optionally substituted with 1 or 2 substituents selected from fluoro or C1-C6-alkyl, Y is selected from an alkylene group having 1 to 6 carbon atoms optionally substituted one or two times with C3-C8-cycloalkyl or C1-C3-alkyl; or a 3-8-membered cycloalkylene group, Q is selected from O, NH or a single bond, W is selected from SO, SO2 or a single bond, U is cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl, each of the above groups being optionally substituted with 1 to 3 substituents selected from Hal, NO2, CN, —SO2—C1-C6-alkyl, —S—C1-C6-alkyl, NMe2, C1-C6-alkyl, —C(O)O—C1-C6-alkyl, O—C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, —C1-C6-halo-alkyl, or a 5-6-membered heteroaromatic group being optionally substituted by Hal, V is an aryl group optionally substituted with 1 to 3 substituents selected from Hal, NO2, CN, SO2—C1-C6 alkyl, NMe2, C1-C6-alkyl, O—C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, —C1-C6-halo-alkyl, O—C1-C6-halo-alkyl or a 5-6-membered heteroaromatic group, T denotes phenyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, or pyrazolyl, R1 is Hal, —C1-C6-alkyl, O—C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, O—C1-C6-halo-alkyl, —(CH2)m—O—C1-C6-halo-alkyl, —SO2—C1-C6-alkyl, —(CH2)m—SO2—C1-C6-alkyl, —SO2—C1-C6-halo-alkyl, —(CH2)m—SO2—C1-C6-halo-alkyl, —SO2-3-8-cycloalkyl, —(CH2)m—SO2-3-8-cycloalkyl, cyano or —C1-C6-halo-alkyl, R2 and R2′ are independently from one another H, Hal, —C1-C6-alkyl, —O—C1-C6-alkyl, —(CH2)m-O—C1-C6-alkyl, O—C1-C6-halo-alkyl, —(CH2)m-O—C1-C6-halo-alkyl, —SO2-C1-C6-alkyl, —(CH2)m-SO2-C1-C6-alkyl, —SO2-C1-C6-halo-alkyl, —(CH2)m-SO2-C1-C6-halo-alkyl, —SO2-3-8-cycloalkyl, —(CH2)m-SO2-3-8-cycloalkyl, —C1-C6-halo-alkyl, or R1 and R2 are linked to form with the ring T to which they are attached a 7-12-membered fused heterocyclyl or 7-12-membered fused cycloalkyl, each of which may be optionally substituted with 1 to 3 Hal, —C1-C6-halo-alkyl, NO2, CN, C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, or —O—C1-C6-alkyl, R3 is C1-C6-alkyl, C1-C6-haloalkyl, —(CH2)m—O—C1-C6-alkyl, or —(CH2)m—O—C1-C6-haloalkyl; a 3-8-membered cycloalkyl group, optionally substituted with 1 to 3 substituents independently selected from Hal, —C1-C6-halo-alkyl, or C1-C6-alkyl; or a 3-8-membered heterocyclic group, optionally substituted with 1 to 3 substituents independently selected from Hal, —C1-C6-halo-alkyl, NO2, CN, C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, —(CH2)m—SO2—C1-C6-alkyl, —SO2—C1-C6-alkyl, —O—C1-C6-alkyl, —(CH2)m—O—C1-C6-halo-alkyl, —(CH2)m—SO2—C1-C6-halo-alkyl, —SO2—C1-C6-halo-alkyl, —O—C1-C6-halo-alkyl, —C(O)—C1-C6-alkyl, or —C(O)O—C1-C6-alkyl, R4 denotes H, C1-C6-alkyl, or forms together with R3 a 3-8-membered cycloalkyl ring, optionally substituted with Hal, —C1-C6-halo-alkyl, NO2, CN, C1-C6-alkyl, —(CH2)m—O—C1-C6-alkyl, —O—C1-C6-alkyl, —C(O)—C1-C6-alkyl, or —C(O)O—C1-C6-alkyl, m is selected from 1, 2, 3 or 4, Hal is F, Cl, Br, or I, wherein C(O)—Y—W— together is at least 3 atoms in length, or a pharmaceutically acceptable salts thereof, or an enantiomeric mixture of 2 enantiomers in all ratios, and/or as a mixture of diastereoisomers in all ratios.