Therapeutic molecules and methods-1

A method of inhibiting cytokine or biological activity of MIF comprising contacting MIF with a cytokine or biological activity inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof

• wherein
• X is selected from —O—, —S—, —C(R5)(R5′)— or —N(R6)—;
• Y is selected from —N(R7)—, —O—, —S— or —C(R7)2—;
• Z is selected from —C(O)—, —C(S)—, —C(═NR6)—, —S(O)— or —S(O)2—;
• R1 is selected from hydrogen, C1-3alkyl, (CR5R5′)nOR7, (CR5R5′)nSR7, (CR5R5′)nN(R6)2 and (CR5R5′)nhalo;
• R2 is selected from C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)mC(O)R8, (CR12R12′)mC(S)R8, (CR12R12′)mS(O)R8, (CR12R12′)mS(O)2R8, (CR12R12′)mOR9, (CR12R12′)mSR9, (CR12R12′)nNR10R11, (CR12R12′)mC(═NR24)R22 and (CR12R12′)mR13;
• R3 is selected from hydrogen, C1-C6alkyl, (CR16R16′)pNR14R15, (CR16R16′)pOR17, (CR16R16′)pSR17, (CR16R16′)phalo, (CR16R16′)pNO2, (CR16R16′)nC(O)R28, (CR16R16′)nC(═NR24)R22, (CR16R16′)nS(O)R17, (CR16R16′)nS(O)2R17, (CR16R16′)nS(O)3R17 and (CR16R16′)pC(R18)3;
• R4 is selected from hydrogen, halogen C1-C3alkyl, C2-3alkenyl, C2-3alkynyl and (CR12R2′)nC(R18)3;
• Each R5 and R5 is independently selected from hydrogen, C1-C3alkyl, halo, OR7, SR7 and N(R6)2;
• Each R6 is independently selected from hydrogen, C1-C3alkyl and OR7;
• Each R7 is independently selected from hydrogen and C1-C3alkyl;
• R8 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, OR19, SR19, N(R20)2, [NH—CH(R21)—C(O)]q—OR29, [sugar]q and (CR12R12′)tR13;
• R9 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)tR3, C(O)R23, CO2R23, C(S)R23, C(S)OR23, S(O)R23, S(O)2R23, [C(O)CH(R21)NH]q—R23 and [sugar]q;
• R10 and R11 are independently selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR12R12′)mR13, C(O)R23, C(S)R23, S(O)R23, S(O)2R23, [C(O)CH(R21)NH]q—R23, -[sugar]q and NHC(═NR25)—NH2;
• Each R12 and R12′ is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, OR24, SR24, halo, N(R24)2, CO2R24, CN, NO2, aryl or heterocyclyl;
• R13 is selected from OR25, SR25, halo, N(R25)2, C(O)R31, CN, C(R18)3, aryl or heterocyclyl;
• R14 and R15 are independently selected from hydrogen, C1-C3alkyl, OR17, (CR16R16′)pC(R18)3;
• Each R16 and R16 is independently selected from hydrogen, C1-C3alkyl, halo, OR17, SR17 and N(R17)2;
• Each R17 is independently selected from hydrogen and C1-C3alkyl;
• Each R18 is independently selected from hydrogen and halo;
• R19 and each R20 are independently selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, (CR26R26′)tR27;
• R21 is the characterising group of an amino acid;
• R22 is selected from C1-C6alkyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, OR29 or SR29;
• R23 is selected from hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, aryl (CR26R26′)tR27;
• Each R24 is independently selected from hydrogen and C1-C6alkyl;
• Each R25 is independently selected from hydrogen, C1-C6alkyl, C1-3alkoxyC1-3alkyl, aryl and heterocyclyl;
• Each R26 and R26′ is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, OR29, SR29, halo, N(R29)2, CO2R29, CN, NO2, aryl and heterocyclyl;
• R27 is selected from hydrogen, OR30, SR30, halo, N(R30)2, CO2R30, aryl and heterocyclyl;
• R28 is selected from hydrogen, C1-6alkyl, OR29, SR29 or N(R29)2;
• Each R29 is independently selected from hydrogen and C1-C3alkyl;
• Each R30 is independently selected from hydrogen, C1-C3alkyl, aryl and heterocyclyl;
• R31 is selected from C1-3alkyl, OH, C1-3alkoxy, aryl, aryloxy, heterocyclyl and heterocyclyloxy;
• n is 0 or an integer from 1 to 3;
• m is 0 or an integer from 1 to 20;
• p is 0 or an integer from 1 to 6;
• q is an integer from 1 to 5;
• t is an integer from 1 to 10;
• wherein alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted.