Inhibitors of macrophage migration inhibitory factor and methods for identifying the same

A compound having a structure:

• 182
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of —CH2)nCOOR′″, —(CH2)nN(R′″)2, —(CH2)nC(O)N(R′″)2,
• 183
• wherein n is an integer of from 1 to 4;
• R12 is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl;
• R4 is selected from the group consisting of
• 184
• R′″ is independently selected from the group consisting of hydrogen, fluorine, chlorine, linear C1-C5 alkyl, and branched C1-C5 alkyl;
• and
• R′″ is selected from the group consisting of hydrogen, halogen, alkyl, cyano, nitro, —COOR′″, —N(R′″)2, —OR′″, —NHCOR′″, and OCF3.

A compound having a structure:

• 185
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of:
• 186
• R12 is selected from the group consisting of hydrogen, chlorine, fluorine, and methyl;
• and
• R4 is selected from the group consisting of
• 187

A method for reducing MIF activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound having the structure:

• 188
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Z is —CH2— or —C(═O)—;
• n is 0, 1, or 2, with the proviso that when n is 0, Z is —C(═O)—;
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7,
• 189
• and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, substituted alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A compound having a structure:

• 190
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Z is —CH2— or —C(═O)—;
• n is 0, 1, or 2, with the proviso that when n is 0, Z is —C(—O)—;
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7,
• 191
• and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A method for reducing MIF activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound having the structure:

• 192
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Z is —CH2— or —C(═O);
• —
• n is 0, 1, or 2, with the proviso that when n is 0, Z is C(═O);
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7, and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A process for preparing a compound of Formula IVa comprising the steps of:

• reacting a compound of Formula I:
• 193
• with a compound of Formula II:
• 194
• thereby obtaining a compound of Formula III:
• 195
• and reacting the compound of Formula III with a compound of formula X—R1, thereby obtaining a compound of Formula IVa:
• 196
• wherein the compound of Formula IVa is suitable for use as a MIF inhibitor, and wherein:
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7, and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R′″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x— wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• X is selected from the group consisting of Cl, Br, and I;
• and
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A process for preparing a compound of Formula IVb comprising the steps of:

• reacting a compound of Formula I:
• 197
• with a compound of Formula II:
• 198
• thereby obtaining a compound of Formula III:
• 199
• reacting the compound of Formula III with a compound comprising X—R1, wherein X is selected from the group consisting of Cl, Br, and I, and wherein R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted acylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl, wherein x is 2 to 4, thereby obtaining a compound of Formula IVb:
• 200
• wherein the compound of Formula IVb is suitable for use as a MIF inhibitor.

A process for preparing a compound of Formula IVa comprising the steps of:

• reacting a compound of Formula I:
• 201
• with piperazine, thereby obtaining a compound of Formula IIIa:
• 202
• and thereafter reacting the compound of Formula ma with a compound of the formula R4—C(O)—X, thereby obtaining a compound of Formula IVa:
• 203
• wherein the compound of Formula IVa is suitable for use as a MIF inhibitor, and wherein:
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7, and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• X is selected from the group consisting of Cl, Br, and I;
• and
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A process for preparing a compound of Formula IVb comprising the steps of:

• reacting a compound of Formula I:
• 204
• with piperazine, thereby obtaining a compound of Formula IIIa:
• 205
• and thereafter reacting the compound of Formula IIIa with a compound of the formula R4—C(O)—X, thereby obtaining a compound of Formula Ivb:
• 206
• wherein the compound of Formula IVb is suitable for use as a MIF inhibitor, and wherein:
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of CH2R7, —C(═O)NR5R6, —(═O)OR7, —(═O)R7, and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′″N(CH)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• X is selected from the group consisting of Cl, Br, and I;
• and
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.

A process for preparing an intermediate compound of Formula I comprising the steps of:

• reacting a compound of Formula Iaa:
• 207
• with cyclohexanamine, thereby obtaining a compound of Formula IIIaa:
• 208
• reacting the compound of Formula IIIaa with POCl3, thereby obtaining a compound of Formula Ia
• 209
• and thereafter reacting the compound of Formula I a with ammonium acetate in acetic acid, thereby obtaining an intermediate compound of Formula I:
• 210
• wherein the compound of Formula I is suitable for use in preparing a MIF inhibitor, and wherein:
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is selected from the group consisting of —CH2R7, —C(═O)NR5R6, —C(═O)OR7, —C(═O)R7, and R8;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;
• R7 is selected from the group consisting of alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′R″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclearyl, dialkyl, and R′″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl;
• X is selected from the group consisting of Cl, Br, and I;
• and
• R1 is selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, dialkyl, and R′″N(CH2)x—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, alkylaryl, substituted alkylaryl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, substituted acylalkyl, acylaryl, substituted acylaryl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, heterocyclearyl, substituted heterocyclearyl, and dialkyl.