US 2016/0096846 A1 · FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS

Abstract

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: wherein Z1, Z2, Z3, Z4, X, Y, R2, R3 and R4 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

A compound of Formula IA:

wherein:
Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;
Q is a covalent bond, —O—C0-2 alkylene, —NR11—C0-22 alkylene, C2 alkylene, C2 alkenylene or C2 alkynylene;
m is 0, 1, 2 or 3;
n is 0, 1, 2, 3, 4 or 5;
each R10 is independently selected from the group consisting of halo, —NO2, —CN, —SF5, —Si(CH3)3, —O—R20, —S—R20, —C(O)—R20, —C(O)—OR20, —N(R20)(R22), —C(O)—N(R20)(R22), —N(R20)—C(O)—R22, —N(R20)—C(O)—OR22, —N(R20)—S(O)2—R26, —S(O)2—R20, —O—S(O)2—R20, —S(O)2—N(R20)(R22), C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
wherein said C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, aryl, heterocyclyl, heteroaryl, C1-6 alkyl, C1-3 haloalkyl, cycloalkyl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
R2 is —C1-6 alkylene-R5, -L-R5, alkylene-R5, —C1-6 alkylene-L-R5 or —C1-6 alkylene-L-C1-6 alkylene-R5;
L is —O—, —S—, —C(O)—, —NHS(O)2—, —S(O)2NH—, —C(O)NH— or —NHC(O)—;
provided that when R2 is -L-R5 or -L-C1-6 alkylene-R5, then L is not —O—, —S—, —NHS(O)2— or —NHC(O)—;
and
each R3 is independently hydrogen, deuterium, C1-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
and
wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, —N(R20)(R22), —C(O)—R20, C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
or R2 and one of R3 can join together with the atom to which they are attached to form a heterocyclyl;
wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, —O—R20, —N(R20)(R22), —N(R20)—C(O)—OR20 and —C(O)—OR20;
and
wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;
each R4 is independently hydrogen, deuterium, C1-6 alkyl, —C(O)—OR26, —C(O)—N(R26)(R26), cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said C1-6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
and
wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, —NO2, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
R5 is cycloalkyl, aryl, heteroaryl or heterocyclyl;
wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C1-6 alkyl, C2-4 alkynyl, halo, —NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —N(R20)—S(O)2—R20, —N(R20)—C(O)—R22, —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN, oxo and —O—R20;
wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, —NO2, C1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN and —O—R20;
and
wherein said C1-6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, —NO2, —CF3, —N(R20)(R22), —C(O)—R20, —C(O)—OR20, —C(O)—N(R20)(R22), —CN, —S(O)2—R20 and —O—R20;
R17 is halo, —O—R20 or C1-6 alkyl;
R20 and R22 are in each instance independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, acylamino, oxo, —NO2, —S(O)2R26, —CN, C1-3 alkoxy, —CF3, —OCF3, —OCH2CF3, —C(O)—NH2, aryl, cycloalkyl and heteroaryl;
and
wherein said heteroaryl is optionally further substituted with C1-4 alkyl or cycloalkyl;
or
when R20 and R22 are attached to a common nitrogen atom R20 and R22 may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO2, —S(O)2R26, —CN, C1-3 alkoxy, —CF3, —OCF3, aryl, heteroaryl and cycloalkyl;
and
each R26 is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;
wherein the C1-4 alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, C1-4 alkoxy, —CF3 and —OCF3;
or a pharmaceutically acceptable salt, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;
provided that when each R4 is hydrogen, R2 and R3 together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl, Q is a bond and Cy is phenyl or morpholinyl, then n is 1, 2, 3, 4 or 5.

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Fused heterocyclic compounds as ion channel modulators

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Fused heterocyclic compounds as ion channel modulators

Life of this patent

Abstract

Claims67