Kappa opioid receptor binding ligands

A kappa opioid receptor antagonist represented by the formula (I):

• wherein
• R is C1-8 alkyl, C1-8 haloalkyl, C3-8 alkenyl, C3-8 alkynyl, aryl substituted by one or more groups Y1 or CH2-aryl substituted by one or more groups Y1;
• R1 is one of the following structures:
• each Y1 is, independently, hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2;
• Y2 is hydrogen, CF3, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, or COCH2R9;
• Y3 is hydrogen, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, or CH2(CH2)nY2;
• R2 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl or CH2-aryl substituted by one or more groups Y1;
• R3 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl or CH2-aryl substituted by one or more groups Y1,
• wherein R2 and R3 may be bonded together to form a C2-8 alkyl group;
• R4 is hydrogen, C1-g alkyl, CO2C1-8 alkylaryl substituted by one or more groups Y1, CH2-aryl substituted by one or more groups Y1 or CO2C1-8 alkyl;
• Z is N, O or S, wherein when Z is O or S, there is no R5;
• R5 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, CH2CO2C1-8 alkyl, CO2C1-8 alkyl or CH2-aryl substituted by one or more groups Y1;
• n is 0, 1, 2 or 3;
• o is 0, 1, 2 or 3;
• R6 is a group selected from the group consisting of structures (a)-(p):
• Q is NR7, CH2, O, S, SO, or SO2;
• X1 is hydrogen, C1-8 alkyl, C3-8 alkenyl, or C3-8 alkynyl;
• X2 is hydrogen, C1-8alkyl, alkenyl, or C3-8 alkynyl;
• or X1 and X2 together form ═O, ═S, or ═NH;
• each R7 is, independently, H, C1-8 alkyl, CH2-aryl substituted by one or more substituents Y1, NR10R11, NHCOR12, NHCO2R13, CONR14R15, CH2(CH2)nY2, or C(═NH)NR16R17,
• each of R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 is, independently, hydrogen, C1-8 alkyl, CH2-aryl substituted by one or more substituents OH, Br, Cl, F, CN, CF3, NO2, N3, C1-6 alkyl, or CH2(CH2)Y2′;
• Y2′ is hydrogen, CF3, or C1-6 alkyl;
• R18 is hydrogen, C1-8 alkyl, C2-8 alkenyl, C3-8 alkynyl, or CH2-aryl substituted by one or more groups Y1;
• or a pharmaceutically acceptable salt thereof.