QUINOXALINE DERIVATIVES AS GPR6 MODULATORS

摘要

The present invention provides compounds of Formula (I):;;that are GPR6 modulators and are therefore useful for the treatment of diseases treatable by modulation of GPR6, in particular treating Parkinson disease, levodopa induced dyskinesias, Huntington's disease, other dyskinesias, akinesias, and motor disorders involving dysfunction of the striatum, schizophrenia and drug addiction. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

主权项

1. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:
R1 is a heterocycloamino ring substituted with Ra, Rb, and Rc wherein:
Ra is —Z—Ar where Z is C1-6 alkylene, C1-6 haloalkylene, —O—, —C(O)—, —NH—, or —S(O)n- wherein n is 0, 1, or 2; and Ar is C3-10 cycloalkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, C6-10 aryl, or C1-9 heteroaryl wherein C3-10 cycloalkyl, C3-7 heterocycloalkenyl, C3-7 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 thioalkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 haloalkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulphonyl, cyano, C2-12 alkoxyalkyloxy, C1-9 amide, or C1-6 hydroxyalkyloxy; andRb and Rc are independently hydrogen, C1-6 alkyl, hydroxy, or halo; R2 is —ORe or —NRdRe wherein Rd is hydrogen or C1-6 alkyl and Re is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-12 alkoxyalkyl, C1-12 aminoalkyl, C3-10 cycloalkyl, C4-16 cycloalkylalkyl, C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, or C3-7 heterocycloalkenyl wherein C6-10 aryl, C1-9 heteroaryl, C3-7 heterocyclyl, and C3-7 heterocycloalkenyl are optionally substituted with 1 to 3 substituents independently selected from C1-6 alkyl, halo, hydroxy, oxo, C1-6 alkoxy, C1-6 haloalkyl or C1-6 haloalkoxy, or cyano; all X1-X4 are carbon or one or two of X1-X4 are N and the rest of X1-X4 are carbon; R3, R4, R5, and R6 are independently absent, hydrogen, C1-6 alkyl, halo, hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-9 amide, C3-7 heterocyclyl, C1-8 alkylamino, or cyano; wherein the disease, disorder or condition is selected from Parkinson disease, levodopa induced dyskinesia, non-levodopa induced dyskinesias, akinesias, motor disorders involving dysfunction of the striatum, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorders, and depression.