US-12624066-B2 - Inhibitors of coronavirus protease

Abstract

The present document describes compounds that are inhibitors of coronavirus proteases, and more particularly to compounds that are inhibitors of SARS-CoV-2 viral proteases. Also, the present document describes methods and uses of the compounds for the treatment or prevention of viral infection, such as SARS-CoV-2 infections, in a subject in need of treatment.

Inventors

• Steve N. Slilaty

Assignees

• SUNSHINE BIOPHARMA INC.

Dates

Publication Date

20260512

Application Date

20210430

Claims (2)

1. 1 . A compound of formula II, or a pharmaceutically acceptable salts thereof, and stereoisomers thereof:
2. 2 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase application under 35 U.S.C. § 371 of PCT/IB2021/053645, filed Apr. 30, 2021, which claims priority from and the benefit of U.S. Provisional Patent Application No. 63/028,871 filed on May 22, 2020, the specifications of which are hereby incorporated by reference in their entireties. BACKGROUND (A) Field The subject matter disclosed generally relates to compounds that are inhibitors of coronavirus proteases, and more particularly to compounds that are inhibitors of SARS-CoV-2 viral proteases. (b) Related Prior Art Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, the pandemic that has claimed the lives of millions of people worldwide since it first appeared in the fall of 2019. SARS-CoV-2 is a Betacoronaviruses, one of four genera of Coronaviruses belonging to the family, Coronaviridae. The three genera are Alpha, Gamma and Delta Coronavirus. The Gamma and Delta Coronaviruses do not infect humans while the Alpha genus is responsible for about 30% of the common cold. The Betacoronavirus genus is comprised of: (i) SARS-CoV which appeared in 2002 and had an associated mortality rate of 10 to 15 percent, (ii) MERS-CoV which came on the scene in 2015 wielding a case-fatality rate of 34 to 37 percent, and (iii) SARS-CoV-2, the causative agent of the 2020 pandemic with a mortality rate of 3 to 5 percent. In addition to the main protease (Mpro), which is shared among coronaviruses, Betacoronaviruses have a second virus-encoded protease called papain-like protease (PLpro). These two proteases are responsible for cleaving the initial expression products of the viral genome (polyproteins 1a and 1ab) at 15 different sites to produce 16 different mature virus proteins essential for viral replication. While Mpro cleaves the viral polyproteins 1a and 1ab at 12 different locations, PLpro cleaves polyprotein 1a at only 3 sites. PLpro however is also involved in cleaving certain host proteins (various ubiquitinated proteins and ISG15) resulting in suppression of the host innate immune response thereby allowing virus replication to proceed unchecked. It is believed that enhanced pathogenicity is related to this additional protease activity that Betacoronaviruses possess. Consequently, in view of the global pandemic of SARS-CoV-2, the Mpro and PLpro of this novel coronavirus may be critical drug targets, suggesting that inhibitors of these enzymes may be beneficial in its inactivation for prevention or treatment of the COVID-19 disease. SUMMARY According to an embodiment, there is provided a compound of formula I, or a pharmaceutically acceptable salts thereof, and stereoisomers thereof: wherein R1 is NH2 or NHR1′ where R1′ is a suitable protecting group for an amine group;R2 is selected from the group consisting of R3 is ═O, —OH or absent;R4 is ═O, —OH, —SH, or absent;R5 is absent or is selected from the group consisting of —CH3, —CH2—OH, and andR6 is —C(O)OH or —C(O)OR6′, where R6′ is a or a suitable protecting group for a hydroxyl group, wherein is a point of attachment with the R1, R2, R3, R4, R5 or R6. The compound of formula I may be a compound of formula Ia The compound of formula I may be The R3 and R4 may be absent. The R3 may be absent and R4 may be —SH. The compound of formula I may be The suitable protecting group for an amine group may be selected from the group consisting of carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (MeOZ), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-Methoxyphenyl (PMP), tosyl (Ts), troc (trichloroethyl chloroformate), 4-nitrobenzene-1-sulfonyl chloride (Nosyl) and 2-Nitrophenylsulfenyl (Nps). The suitable protecting group for a hydroxyl group may be selected from the group consisting of alkyl, acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-Methoxyethoxymethyl ether (MEM), [bis-(4-methoxyphenyl)phenylmethyl] (DMT), methoxymethyl ether (MOM), methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT), p-Methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), tetrahydrofuran (THF), trityl (triphenylmethyl, Tr), trimethylsilyl (TMS), tertiobutyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), methyl ethers, and ethoxyethyl ethers (EE). According to another embodiment, there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. According to another embodiment, there is provided a use of a compound of any one of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment or prevention of a viral infection in a subject in need thereof. According to another embodiment, there is provided