# US 12,180,156 B2 · Deuterated protease inhibitors

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- Number: US 12,180,156 B2
- Document ID: US12180156B2
- Status: Granted
- Kind: B2
- Application number: 17/343,334
- Filed: 2021-06-09
- Published: 2021-12-09
- Granted: 2024-12-31
- Earliest claimed: 2020-06-09
- Assignees: Kansas State University Research Foundation; Wichita State University; University of Iowa Research Foundation
- Applicants: Kansas State University Research Foundation; Wichita State University; University of Iowa Research Foundation
- Inventors: Kyeong-Ok Chang; Yunjeong Kim; William C. Groutas; Stanley Perlman
- Web page: https://patentgrep.com/patent/US12180156B2

## CPC

- C07D 207/26: 2-Pyrrolidones
- A61P 31/14: for RNA viruses
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Compounds and treatment methods with compounds exhibiting antiviral activity and/or inhibition of viral replication against viruses, particularly those belonging to the picornavirus-like supercluster, including coronavirus having a formula: or a prodrug or pharmaceutically-acceptable salt thereof, where: each X comprises at least one cyclic moiety directly attached to the oxygen or connected via an alkyl linkage, where at least one of the linkage and/or the X moiety comprises a deuterium substitution; and Z is selected from the group consisting of aldehydes and bisulfite salts, or the ester or carbamate prodrugs thereof.

## Claims

### Claim 1

A deuterated compound having the structure of formula I, or a prodrug or pharmaceutically-acceptable salt thereof:
where:
each X is at least one cyclic moiety directly attached to the oxygen or connected via an alkyl linkage, where at least one of the linkage and/or the cyclic moiety comprises a deuterium substitution; and
Z is selected from the group consisting of aldehydes and bisulfite salts, or the ester or carbamate prodrugs thereof.

### Claim 2 (depends on 1)

The compound, salt, or prodrug of claim 1, wherein Z is —CHO, —SO3Na, —CH(OH)SO3−Na+, —(C═O)(C═O)NHbenzyl, or —CH [O(C═O)Rw]SO3−Na+, where Rw is an alkyl or arylalkyl.

### Claim 3 (depends on 1)

The compound, salt, or prodrug of claim 1, wherein said compound is a prodrug wherein Z comprises an ester or carbamate moiety.

### Claim 4 (depends on 1)

The compound, salt, or prodrug of claim 1, wherein X is a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted 3-7 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, or a substituted or unsubstituted C6-10 aryl group.

### Claim 5 (depends on 1)

The compound, salt, or prodrug of claim 1, wherein said alkyl linkage comprises a branched or unbranched and substituted or unsubstituted C1-C6 alkyl linkage.

### Claim 6 (depends on 1)

The compound, salt, or prodrug of claim 1, wherein X—O has a structure selected from the group consisting of:

### Claim 7 (depends on 1)

The compound, salt, or prodrug of claim 1, having the structure of formula:
or a prodrug or pharmaceutically-acceptable salt thereof, where each of Ra and Rb, independently, is hydrogen or deuterium, provided that at least one of Ra or Rb is a deuterium atom, optionally wherein at least one Ra is a halogen.

### Claim 8 (depends on 7)

The compound, salt, or prodrug of claim 7, wherein at least one Ra is a halogen.

### Claim 9 (depends on 7)

The compound, salt, or prodrug of claim 7, wherein each of said Ra and Rb groups are deuterium.

### Claim 10 (depends on 1)

The compound, salt, or prodrug of claim 1, said compound comprising a deuterated formula selected from the group consisting of:

### Claim 11 (depends on 1)

The compound, salt or prodrug of claim 1, wherein said compound is a deuterated formula from Table 2:
TABLE 2
Compound
Z
X
1 2 3 4 5
CHO CH(OH)SO3Na CH(O(C═O)CH3)SO3Na CH(O(C═O)n-pentyl)SO3Na (C═O)(C═O)NHbenzyl
6 7 8
CHO CH(OH)SO3Na CH(O(C═O)n-pentyl)SO3Na
9 10 11
CHO CH(OH)SO3Na CH(O(C═O)n-pentyl)SO3Na

### Claim 12 (depends on 1)

A kit comprising a compound, salt, or prodrug according to claim 1; and instructions for administering said compound to a subject in need thereof.

### Claim 13 (depends on 12)

The kit of claim 12, wherein the compound, salt, or prodrug is provided in unit dosage form.

### Claim 14 (depends on 12)

The kit of claim 12, wherein the compound, salt, or prodrug is provided in a first container, said kit further comprising a carrier in a second container; and instructions for preparing said compound, salt, or prodrug for administration to said subject.