Therapeutic molecules and methods-1

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

• wherein
• X is —N(R6)—;
• Y is —N(R7)—;
• Z is —C(O)—;
• R1 is selected from hydrogen, or (CR5R5′)nhalo;
• R2 is selected from the group consisting of 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′)phalo, and (CR16R16′)pNO2
• R4 is hydrogen, or halogen;
• Each R5 and R5 is independently hydrogen,
• R6 is hydrogen, or C1-C3alkyl;
• R7 is hydrogen or C1-C3alkyl;
• R8 is selected from the group consisting of hydrogen, C1-C20alkyl, C2-C20alkenyl, C2-C20alkynyl, OR19, SR19, N(R20)2, [NH—CH(R21)—C(O)]q—OR29, pyranosyl and (CR12R12′)tR13;
• R9 is hydrogen;
• R10 and R11 are independently selected from hydrogen, and C(O)R23;
• Each R12 and R12′ is independently hydrogen;
• R13 is selected from OR25, SR25, halo, N(R25)2, and C(O)R31;
• R14 and R15 are each hydrogen;
• Each R16 and R16′ is hydrogen;
• R17 is hydrogen;
• R19 and each R20 are independently selected from hydrogen, C1-C20alkyl, and, (CR26R26′)tR27;
• R21 is the characterising group of an amino acid wherein the amino acid is alanine, phenylalanine, serine, homoserine or norvaline;
• R22 is NH(C1-6alkyl);
• R23 is (CR26R26′)tR27;
• Each R24 is independently selected from hydrogen and C1-C6alkyl;
• Each R25 is independently selected from hydrogen, and C1-C6alkyl;
• Each R26 and R26′ is independently hydrogen;
• R27 selected from, OR30, SR30, and aryl;
• Each R29 is independently selected from hydrogen and C1-C3alkyl;
• Each R30 is independently selected from, C1-C3alkyl, and heterocyclyl;
• R31 is 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.