# US 11,999,723 B2 · Pyrazole-containing macrophage migration inhibitory factor inhibitors

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- Number: US 11,999,723 B2
- Document ID: US11999723B2
- Status: Granted
- Kind: B2
- Application number: 17/897,961
- Filed: 2022-08-29
- Published: 2023-02-23
- Granted: 2024-06-04
- Earliest claimed: 2018-03-15
- Assignees: Yale University
- Applicants: Yale University
- Inventors: William L. Jorgensen; Vinay Trivedi-Parmar
- Web page: https://patentgrep.com/patent/US11999723B2

## CPC

- A61K 31/415: 1,2-Diazoles
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 231/16: Halogen atoms or nitro radicals
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

In one aspect, the invention comprises compounds that bind and inhibit macrophage migration inhibitory factor. In another aspect, the invention provides methods of treating, ameliorating, and/or preventing inflammatory disease, neurological disorders and cancer using the compounds of the invention.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of phenyl and naphthyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of methylphenyl, methoxyphenyl, fluorophenyl, ethylnapthyl, cyclopropylnaphthyl, methylbiphenyl, ethoxybiphenyl, and N-morpholinopropoxybiphenyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X is fluorine.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.

### Claim 6

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.

### Claim 7

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.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Y is —CH2—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein Y is —S—.

### Claim 10 (depends on 1)

The compound of claim 1, wherein Y is —S(═O)—.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Y is —S(═O)2—.