Pyrazole-containing macrophage migration inhibitory factor inhibitors

A method of treating or ameliorating an inflammatory disease, a neurological disorder, or cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a salt, solvate, stereoisomer, or tautomer thereof, or any mixtures thereof:

• wherein:
• (a) Y is selected from the group consisting of —S—, —S(═O)—, and —S(═O)2—, and
• R1 is selected from the group consisting of H, C1-C6 alkyl, phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, and biphenyl;
• or
• (b) Y is —CH2—, and
• R1 is selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, and biphenyl;
• Z is selected from the group consisting of —C(═O)OR, —S(═O)R, —S(═O)2R, and —S(═O)2NRR;
• X is selected from the group consisting of H, C1-C3 alkyl, and halogen;
• wherein the phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)—phenyl, or biphenyl is independently optionally substituted with at least one group independently selected from the group consisting of halogen, —OH, —C(═O)OR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, —(CH2)1-6NRR, —O(CH2)1-6NRR, —(CH2)1-6NR(C1-C6 acyl), —O(CH2)1-6NR(C1-C6 acyl), —(CH2)1-6OR, —O(CH2)1-6OR, —(CH2)1-6C(═O)OR, —O(CH2)1-6C(═O)OR, —(CH2)1-6OR, —O(CH2)1-6OR, —(OCH2CH2)1-6NRR, and —(OCH2CH2)1-6C(═O)OR;
• and
• wherein each occurrence of R is independently selected from the group consisting of H and C1-C6 alkyl, or two R groups combine with the N atom to which they are both bound to form a 3-8 membered heterocyclyl or heteroaryl group;
• wherein the inflammatory disease is rheumatoid arthritis, Crohn's disease, or inflammatory bowel syndrome,
• wherein the neurological disorder is schizophrenia, and
• wherein the cancer is colorectal cancer, lung cancer, breast cancer, or prostate cancer.

A method of inhibiting macrophage migration inhibitory factor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a salt, solvate, stereoisomer, or tautomer thereof, or any mixtures thereof:

• wherein:
• (a) Y is selected from the group consisting of —S—, —S(═O)—, and —S(═O)2—, and
• R1 is selected from the group consisting of H, C1-C6 alkyl, phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, and biphenyl;
• or
• (b) Y is —CH2—, and
• R1 is selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, and biphenyl;
• Z is selected from the group consisting of —C(═O)OR, —S(═O)R, —S(═O)2R, and —S(═O)2NRR;
• X is selected from the group consisting of H, C1-C3 alkyl, and halogen;
• wherein the phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, or biphenyl is independently optionally substituted with at least one group independently selected from the group consisting of halogen, —OH, —C(═O)OR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 halocycloalkyl, C3-C6 halocycloalkoxy, —(CH2)1-6NRR, —O(CH2)1-6NRR, —(CH2)1-6NR(C1-C6 acyl), —O(CH2)1-6NR(C1-C6 acyl), —(CH2)1-6OR, —O(CH2)1-6OR, —(CH2)1-6C(═O)OR, —O(CH2)1-6C(═O)OR, —(CH2)1-6OR, —O(CH2)1-6OR, —(OCH2CH2)1-6NRR, and —(OCH2CH2)1-6C(═O)OR;
• and
• wherein each occurrence of R is independently selected from the group consisting of H and C1-C6 alkyl, or two R groups combine with the N atom to which they are both bound to form a 3-8 membered heterocyclyl or heteroaryl group.