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

A compound having a structure:

• 283
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2—;
• m is 0, 1, or 2;
• n is 1;
• R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3.

A compound having a structure:

• 286
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is —NO2;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the proviso that R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2.

A compound having a structure:

• 289
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is —C(═O)OCH2CH3;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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 R5;
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, and X is oxygen;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, and X is oxygen;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, and X is oxygen.

A compound having a structure:

• 292
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, and dialkyl;
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is
• 293
• and
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle.

A compound having a structure:

• 294
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, and dialkyl;
• R2 and R3 are independently selected from the group consisting of halogen, —R5, —OR5, —SR5, and —NR5R6;
• R4 is
• 295
• and
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• or R5 and R6 taken together with a nitrogen atom to which they are attached form a heterocycle or substituted heterocycle.

A compound having a structure:

• 296
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, and Y is —C(═O)OCH2CH3.

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:

• 323
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3.

A compound having a structure:

• 324
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3.

A compound having a structure:

• 325
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2—;
• m is 0, 1, or 2;
• n is 1;
• R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3.

A compound having a structure:

• 328
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is —C(═O)OCH2CH3;
• Z is —CH2— or —C(═O)—;
• m is O, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, and X is oxygen;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, and X is oxygen;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, and X is oxygen.

A compound having a structure:

• 331
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)RS, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• n is 0, 1, or 2, with the proviso that when n is 0, Z is —C(═O)—;
• R1 is —NCH2CH2CH2N(CH3)2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl.

A compound having a structure:

• 334
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is —NO2;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, dialkyl, and R′R″N(CH2)—, wherein x is 2 to 4, and wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the proviso that R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, and X is oxygen.

A compound having a structure:

• 337
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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
• 338
• R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl.

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:

• 357
• or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
• X is oxygen or sulfur;
• Y is selected from the group consisting of —NO, —NO2, —C(═O)R5, —C(═O)OR5, —C(═O)NR5R6, —NR5C(═O)R5, —NR5SO2R5, and —S(O)mR5;
• Z is —CH2— or —C(═O)—;
• m is 0, 1, or 2;
• 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, 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, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, 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, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• 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, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• with the provisos that:
• R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3;
• R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen, and Y is —NO2;
• R4 is not —CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is —C(═O)OCH2CH3;
• and
• R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen, and Y is —C(═O)OCH2CH3.

A process for preparing a compound comprising the steps of:

• reacting a compound of Formula I:
• 358
• with a compound of Formula II:
• 359
• thereby obtaining a compound of Formula III:
• 360
• wherein R3 is selected from the group consisting of R4 is amino, substituted amino hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• reacting the compound of Formula III with a compound comprising X—R4, wherein X is selected from the group consisting of Cl, Br, and I, and wherein R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, dialkyl, and aminoalkyl R′R″N(CH2)x—, wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, and dialkyl, wherein x is 2 to 4, thereby obtaining a compound of Formula IV:
• 361
• wherein the compound of Formula IV is suitable for use as a MIF inhibitor.

A process for preparing a compound comprising the steps of:

• reacting a compound of Formula AI:
• 364
• with a compound of Formula II:
• 365
• thereby obtaining a compound of Formula AIII:
• 366
• wherein R3 is selected from the group consisting of R4 is amino, substituted amino hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, and substituted heterocyclealkyl;
• and
• reacting the compound of Formula AIII with a compound comprising X—R4, wherein X is selected from the group consisting of Cl, Br, and I, and wherein R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl, dialkyl, and aminoalkyl R′R″ N(CH2)x—, wherein R′ and R″ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, and dialkyl, wherein x is 2 to 4, thereby obtaining a compound of Formula AIV:
• 367
• wherein the compound of Formula IV is suitable for use as a MIF inhibitor.