Enzyme inhibitors and viral infection therapy

Patent metadata

Field	Value
Publication number	US-2024109859-A1
Application number	US-202218263582-A
Country	US
Kind code	A1
Filing date	Feb 1, 2022
Priority date	Feb 1, 2021
Publication date	Apr 4, 2024
Grant date	—

Abstract

The invention relates to antiviral compounds, compositions comprising antiviral compounds, and methods of use. In particular, the antiviral compounds are cytidine triphosphate synthetase 1 (CTPS1) inhibitors that are effective in treating and/or preventing viral infection and in particular, SARS-CoV-2 infection and/or COVID-19 disease.

First claim

1 . A compound of Formula I:

wherein,
G is

or S;
R 1 is —NH(C═O)CH 2 X wherein X is a leaving group;
R 2 is —(C═O)NR a R 3 or —NR a (C═O)R 3 , wherein R a is H or —(C 1 -C 6 )alkyl;
R 3 is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, phenyl-R 4 , or 5- or 6-membered heteroaryl; and
R 4 is —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl, halo, or H;

wherein R 1 is in the beta-position relative to R 2 , and each (C 1 -C 6 )alkyl moiety is independently saturated or unsaturated and optionally interrupted by a heteroatom.

2 . The compound of claim 1 wherein the compound is represented by Formula II:

3 . The compound of claim 1 wherein the compound is represented by Formula III:

4 . The compound of claim 3 wherein le is at the 4-position.

5 . The compound of claim 3 wherein le is at the 5-position.

6 . The compound of claim 1 wherein X is halo, N 3 , methanesulfonate (OMs), or p-toluenesulfonate (OTs).

7 . The compound of claim 1 wherein X is chloro.

8 . The compound of claim 1 wherein R 3 is pentyl, phenyl-OCH 3 , phenyl-H, or imidazolyl.

9 . The compound of claim 1 wherein R 3 is phenyl-R 4 and R 4 is ortho-OCH 3 .

10 . The compound of claim 1 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 10 wherein the compound is:

12 . The compound of claim 1 wherein the compound is:

13 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14 . A method for antiviral treatment comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 , thereby inhibiting replication of a virus that has infected the subject.

15 . The method of claim 14 wherein the method comprises administering the composition in combination with one or more additional therapeutic agents; wherein the combination is administered simultaneously or sequentially.

16 . The method of claim 14 wherein the virus is a coronavirus.

17 . The method of claim 16 wherein the coronavirus is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), or Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).

18 . The method of claim 14 wherein the compound is an inhibitor of cytidine triphosphate synthetase 1 (CTPS1).

19 . A method of treating a human subject identified as having or suspected of having COVID-19, the method comprising administering to the subject an effective amount of a cytidine triphosphate synthetase 1 (CTPS1) inhibitor effective to reduce interferon regulatory factor 3 (IRF3) deamidation, thereby treating the subject.

20 . The method of claim 19 wherein the CTPS1 inhibitor is a compound of claim 1 .

Assignees

• Univ Southern California

Inventors

• Feng Pinghui
• Zhang Chao
• Zhao Jun
• Espinosa Biancha
• Qin Chao
• Savas Ali
• Rao Youliang
• Wang Ting-Yu

Classifications

• C07D333/38 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/06

  Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title