WO2022049219A1

WO2022049219A1 - Methods for treating viral infection

Info

Publication number: WO2022049219A1
Application number: PCT/EP2021/074313
Authority: WO
Inventors: Stefan MATILE; Naomi Sakai; Takehiro Kato; Yangyang CHENG; Anh-Tuan PHAM; Bumhee LIM; John Maynard
Original assignee: Université De Genève
Priority date: 2020-09-02
Filing date: 2021-09-02
Publication date: 2022-03-10

Abstract

The present invention is directed to pharmaceutical compounds of formula (I), formula (l-A) and formula (l-B) and compositions thereof that can prevent or treat viral infection.

Description

Methods for treating viral infection

BACKGROUND

1. Field of the Disclosure

The present disclosure relates generally to the fields of medicine, infectious disease, and virology. More particular, the disclosure relates to pharmaceutical compounds/compositions for the treatment of viral infection.

2. Background

An epidemic of a novel coronavirus (SARS-CoV-2) affected mainland China in late 2019, with cases worldwide developing in 2020. The virus was identified in Wuhan, the capital of China's

Hubei province, after 41 people developed pneumonia without a clear cause. The virus, which causes acute respiratory disease designated coronavirus disease 2019 (COVID-19), is capable of spreading from person to person. The incubation period (time from exposure to onset of symptoms) ranges from 0 to 24 days, with a mean of 3-5 days, but it may be contagious during this period and after recovery. Symptoms include fever, coughing and breathing difficulties. An estimate of the death rate in February 2020 was 2% of confirmed cases, higher among those who require admission to hospital.

As of 31 August 2020, over 25 million cases have been confirmed with deaths nearing 850,000. While treatment and vaccine research is ongoing, as of 31 August 2020, no licensed vaccine and or treatment is available. Even with the development of such therapies and preventative measures, new and more effective means of controlling SARS-CoV-2 and other viral infections will need to be developed as the pandemic evolves. SUMMARY

In some embodiments, the present disclosure provides methods of treating or preventing a viral infection comprising administering to a subject infected with the coronavirus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

X₁ is -S-, -S(O)-, or -S(O)₂-; and

R₁, R₁', R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤i₂), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂- and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R_3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R₄, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

-OC(O)X₄RX, wherein: X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤i₂), hydroxyalkyl(c≤12), alkenyl(c≤i₂), aminoalkenyl(c≤12), hydroxyalkenyl(c≤i₂), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(0)₂-; and

R₁, R₁', R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤i₂), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤i₂), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a compound of the formula:

wherein: m is 0-10; L1 is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-, -OC(O)-, -NHC(O)-; -HNC(0)0- or -OC(G)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl₍c≤i₂₎, or Yi is absent; (as understood within the scope of the present disclosure, if Yi is absent, X₂ and X₃ are connected by a single covalent bond)

X1 is, in each instance independently, -S— , -S(O)-, or -S( O ); and R1, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein: X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein m is 0-10;

Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and X₃ are each independently a covalent bond, -O- , -NH-, -OC(O)-, or -NHC(O)-;

Y1 is alkanediyl(c≤12), substituted alkanediyl<c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12);

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂-; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

wherein: n is O, 1, 2, or 3;

Ri, Ri', R2, R2', R3, R3', Rn, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl<c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;

R4 is alkyl(c≤12), aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and

R5 is -SH, -S(0)H, -S(0)₂H, -S(0)0H, -S(0)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof, wherein the virus is not HIV.

In some aspects, the viral infection is a non-HIV infection, such as a non-retroviral infection For example in some aspects the infection is a coronavirus Dengue virus Ebola virus West nile virus, Rabies virus, Influenza virus, Chikungunya virus or Zika virus infection. In certain aspects, the infection is a coronavirus infection, such as a beta coronavirus infection. In certain specific aspects the infection can be an infections with MERS-CoV, SARS-CoV-1, or SARS-CoV-2. In further aspects, the coronavirus is MERS-Cov. In still further aspects, the subject has Middle East respiratory syndrome (MERS). In some aspects, the coronavirus is SARS-CoV- 1. In further aspects, the subject has severe acute respiratory syndrome (SARS). In some aspects, the coronavirus is SARS-CoV-2. In further aspects, tire subject has coronavirus disease 2019 (COVID-19). In some aspects, said subject has a confirmed diagnosis of SARS-CoV-2. In some aspects, said subject is suspected of begin infected with SARS-CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2.

In some aspects, administering comprises intravenous, intra-arterial, oral, intranasal, lung instillation, bronchial inhalation, topical or infusion. In some aspects, administering comprises twice daily administration, once daily administration, every other day administration, every three- day administration or weekly administration. In some aspects, administering continues for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months. In some aspects, the methods further comprise treating said subject with at least one other anti-coronavirus therapy. In some aspects, the methods further comprise treating said subject with at least one other SARS-CoV-2 therapy. In some aspects, said subject is a high-risk SARS-CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, bronchopulmonary disease, cardiovascular disease, hypertension, diabetes or COPD. In some aspects, said subject exhibits abnormally reduced blood oxygenation, such as 90% or less. In some aspects, said subject is concurrently receiving ventilation therapy.

In other embodiments, the present disclosure provides methods of treating a virus infection comprising administering to a subject at risk of being infected a compound of the formula:

wherein: n is O, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(0)z-; and

Ri, Ri', R₂, Ra', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein Ra/Ra¹ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably oxo group); or -C(O)R4, wherein:

-0C(0)X₄Rx, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c«i2), aminoalkyl(c¾i2), hydroxyalkyl(c¾ 12), alkenyl<c¾i2), aminoalkenyl(c< 12), hydroxyalkenyl(c=$ 12), alkynyl(c¾i2), aminoalkynyl(c< 12), hydroxyalkynyl(c< 12), or a substituted or protected version of any of these groups; preferably wherein: n is O, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(0)z-; and

Ri, Ri', R₂, Rz', R₃, Rs', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c«i2), heterocycloalkyl(c¾i2), aryl(c¾i2), aralkyl(c¾i2), heteroaryl(c¾i2), heteroaralkyl(c«i2), alkoxy(c¾i2), aryloxy(csi2), aralkoxy(c≤12), heteroaryloxy(c¾i2), heteroaralkoxy(c=s 12), alkylamino(c¾i2), dialkylamino(c¾i2), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein: X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, -NHC(O)-; -HNC(0)0- or -OC(0)NH-;

Y 1 is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12), or Yi is absent;

Xi is, in each instance independently, -S-, -S(O)-, or -S(0)₂~; and

Ri, R2, Rs, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-0C(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤i₂), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-, -OC(O)-, or -NHC(0)-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12);

Xi is, in each instance independently, -S-, -S(O)-, or -S(0)2^~; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12>, alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;or a compound of the formula:

wherein: n is 0 1 2 or 3; Ri, Ri', R2, R2', R3, Rs', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;

Rs is -SH, -S(0)H, -S(0)₂H, -S(0)0H, -S(0)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof.

In some aspects, said subject has a confirmed diagnosis of SARS-CoV-2. In some aspects, said subject is suspected of begin infected with SARS-CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2. In some aspects, administering comprises intravenous, intra-arterial, oral, intranasal, or bronchial inhalation. In some aspects, administering comprises twice daily administration, once daily administration, every other day administration, every three-day administration or weekly administration. In some aspects, administering continues for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months. In some aspects, the methods further comprise treating said subject with at least one other SARS-CoV-2 therapy. In some aspects, said subject is a high-risk SARS-CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, broncho-pulmonaiy disease, cardiovascular disease, or hypertension, diabetes. In some aspects, said subject exhibits abnormally reduced blood oxygenation, such as 90% or less. In some aspects, said subject is concurrently receiving ventilation therapy. In still other embodiments, the present disclosure provides methods of reducing one or more symptoms of a virus infection comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, R₂', R₃, Rs', Ro, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy<c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12). alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(0)₂-; and

Ri, Ri', R2, R2', R3, Rs', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤i₂), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl<c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

wherein: m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-0C(0)-, -NHC(O)-, -HNC(0)0- or -0C(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12), or Yi is absent;

Xi is, in each instance independently, -S-, -S(O)-, or -S(0)z-; and

Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl<c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R3 may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R3, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

R4 is hydroxy or amino; or alkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

-OC(O)X₄R_X, wherein:

X41S -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c<i₂), or a substituted or protected version of any of these groups; preferably wherein mis 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, or -NHC(O)-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂-; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl<c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', R₂, R₂', RJ, Ra', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy<c≤12), amido(c≤12>, or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is alkyl₍c≤i₂₎, aryl₍c≤i₂₎, a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and

Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. In yet other embodiments, the present disclosure provides methods of decreasing mortality from a viral infection comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is — S-, -S(O)-, or -S(O)2~; and

Ri, Ri^f, Ra, Ra', Ra, Ra', Rn, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R₃/R_3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c<i₂), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂~; and

Ri, Ri', Rz, Ra', Rs, Rs', R_n, and Ra' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12>, cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylaminO(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

Rt is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, -NHC(O)-, -HNC(0)0- or -0C(0)NH-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and

Ri, Ra, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl_(C≤i2), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaraIkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy<c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

Rt is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤]2), dialkylamino(c≤12), or a substituted version of any of these groups; or

-OC(O)X₄R_X, wherein:

X4IS -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c<i 2), hydroxyalkynyl(c≤i₂), or a substituted or protected version of any of these groups; preferably wherein m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

Xiz and X₃ are each independently a covalent bond, -0-, — NH-,

-OC(O)-, or-NHC(O)-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂-; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

Rt is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', R₂, R2', R3, R3', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. In other embodiments, the present disclosure provides methods of reducing duration of hospitalization from a virus infection comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)2~; and

Ri, Ri', R₂, R₂', R₃, Rj', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalky l(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(0)X₄RX, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤i₂), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R2, R2', R3, R3', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤i₂), heteroaralkyl(c≤12), alkoxy(c≤i₂), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤i₂), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

wherein: m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, -NHC(O)-; -HNC(0)0- or -0C(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12) , or Yi is absent;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂-; and

Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2 and R3 may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-0C(0)X₄Rx, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl<c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl₍c<i₂₎, or a substituted or protected version of any of these groups; preferably wherein m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and X3 are each independently a covalent bond, -0-, -NH-,

-OC(O)-, or-NHC(O)-;

Y 1 is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12);

Xi is, in each instance independently, — S— , -S(O)-, or -S(O)₂ ^~; and Ri, R2, R3, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', Rz, R₂', RS, RS', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c<i₂), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤i₂), acyl(c≤12), acyloxy(c≤12), amido(c≤i₂), or a substituted version of any of these groups; or -C(O)R4, wherein:

Ri is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;

Ri is alkyl₍c<i₂₎, aryl₍c≤i₂), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and

Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -8(O)₂0Η, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. In still other embodiments, the present disclosure provides methods of reducing the duration of infection with a virus comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is S , -S(O)-, or -S(O)₂ ^~; and

Ri, RV, R2, R2', R3, R3', Ro, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl₍c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy<c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2’ and Rs/Rs· may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or

-C(O)R4, wherein:

-OC(0)X4RX, wherein: X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤i₂), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤i₂), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤i₂), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, R₂', RS, R₃', Rn, and R_a' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤i₂), alkenyl(c≤i₂), alkynyl(c≤i₂), cycloalkyl(c≤i₂), heterocycloalkyl(c≤12), aryl(c≤i₂), aralkyl(c≤i₂), heteroaryl(c≤i₂), heteroaralkyl(c≤i₂), alkoxy(c≤12), aryloxy(c<i₂), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c<i₂), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;or a compound of the formula:

20

wherein: m is 0-10;

wherein:

Xz and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, -NHC(O)-; -HNC(0)0- or -0C(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl₍c<i₂₎, or Yi is absent;;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)z-; and

Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2_’ and R3/R3’ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

Xz and X₃ are each independently a covalent bond, -0-, -NH-, -OC(O)-, or -NHC(O)-;

Xi is, in each instance independently, -S— , -S(O)-, or -S(O)₂ ^~; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R_t is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', Ra, Ra', R3, Rs', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤ia>, alkenyl(c≤ia), alkynyl(c≤ia), cycloalkyl(c≤ia), heterocycloalkyl(c≤ia), aiyl(c<ia), aralkyl(c<ia), heteroaryl(c≤ia), heteroaralkyl(c≤ia), alkoxy(c≤ia), aiyloxy(c≤ia), aralkoxy(c≤12), heteroaryloxy(c≤ia), heteroaralkoxy(c≤ia), alkylamino(c≤ia), dialkylamino(c<ia), acyl(c<ia), acyloxy(c≤ia), amido₍c≤ia₎, or a substituted version of any of these groups; or -C(O)R4, wherein:

R4 is hydroxy or amino; or alkoxy<c<ia), alkylamino(c≤ia), dialkylamino(c≤ia), or a substituted version of any of these groups;

R* is alkyl(c≤ia>, aiyl(c≤ia), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and

Rs is -SH, -S(O)H, -S(O)aH, -S(O)0H, -S(O)aOH, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. In yet other embodiments, the present disclosure provides methods of reducing transmission of a virus comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, R₂', R3, R3', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12>, aryl(c≤i₂), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy<c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R3 may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12),hydroxyalkenyl(c≤12), alkynyl(c<i₂), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; preferably wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, R₂', RS, RS', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤i₂), alkynyl(c≤12), cycloalkyl(c<i₂), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤i₂), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤i₂), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

R* is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-,

-OC(O)-, -NHC(O)-; -HNC(0)0- or -OC(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12), or Yi is absent;;

Xi is, in each instance independently, -S— , -S(O)-, or -S(O)2^~; and

Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and Rj, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(0)Rt, wherein:

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl<c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤i₂), or a substituted or protected version of any of these groups; preferably wherein m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and Xs are each independently a covalent bond, -0-, -NH-, -OC(O)-, or -NHC(O)-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and Ri, R2, R3, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaiyloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl₍c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤ 12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12>, or a substituted version of any of these groups;

R₄ is alkyl(c≤i₂), aryl(c≤i₂), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and

Rs is -SH, -S(O)H, -S(O)₂H, -S(O)0H, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. With respect to any of the embodiments above, in some aspects, the compound is further defined as:

wherein: n is O, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂ ^~; and

Ri, Ri', R₂, Ra', R₃, Rj', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R3ZR3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤i₂₎, aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤i_2),hydroxyalkynyl₍c≤i_2),or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In some aspects, the compounds is further defined as

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, RZ', Ra, Ra', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤i₂), alkynyl(c≤12), cycloalkyl(c≤i₂), heterocycloalkyl(c≤i₂), aryl(c≤i₂), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤i₂), heteroaryloxy(c≤12), heteroaralkoxy(c≤i₂), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; ; or -C(O)R4, wherein:

R* is hydroxy or amino; or alkoxy(c≤i₂), alkylamino(c≤i₂), dialkylaminO(c≤12), or a substituted version of any of these groups;

In further aspects, the compound is further defined as:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂ ^~; and

Ri, RV, R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂- and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R₃/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group);or -C(O)R4, wherein:

-0C(0)X₄Rx, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12),hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof. In further aspects, the compound is further defined as:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', Ra, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤i₂), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R* is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

In further aspects, the compound is further defined as:

wherein: Xi is — S— , -S(O)-, or -S(O)2^_; and

R₂, Rz', R₃, and R3', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany R₂/R_2’ and R3/R3_’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(0)Rt, wherein:

-OC(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤i₂), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In further aspects, the compound is further defined as:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂-; and

R₂, R₂', R₃, and R₃', are each independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤i₂), alkenyl(c≤i₂), alkynyl(c≤i₂), cycloalkyl(c≤i₂), heterocycloalkyl(c≤i₂), aryl(c≤i₂), aralkyl(c≤i₂), heteroaryl(c≤i₂), heteroaralkyl(c≤i₂), alkoxy(c≤i₂), aiyloxy(c≤i₂), aralkoxy(c≤i₂), heteroaryloxy(c≤i₂), heteroaralkoxy(c≤i₂), alkylamino(c<i₂), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

In still further aspects, the compound is further defined as:

wherein:

R₂, R₂', R₃, and R₃', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c<i₂), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤i₂), aralkyl(c≤i₂), heteroaryl(c≤i₂), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤i₂), heteroaryloxy(c≤i₂), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤i₂), amido(c<i₂), or a substituted version of any of these groups; wherein R₂/Rr and R3/R_3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-0C(0)X₄RX, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤i₂), aminoalkyl(c≤12), hydroxyalkyl₍c≤12), alkenyl₍c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof. In still further aspects, the compound is further defined as:

wherein:

R2, R2', RS, and Rs', are each independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl₍c≤12), aryl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein: R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

In yet further aspects, the compound is further defined as:

wherein:

R2, R2', R3, and R3', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaiyloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylaminO(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxy alkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12),hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In yet further aspects, the compound is further defined as:

wherein:

R₂, R₂', R3, and R3', are each independently hydrogen, hydroxy, or amino; or alkoxy<c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

In further aspects, the compound is further defined as:

wherein:

R2, Ra', Rs, and R3', are each independently hydrogen or hydroxy; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c<i 2), heteroaralkoxy(c≤12), acyloxy(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or a pharmaceutically acceptable salt thereof.

In further aspects, the compound is further defined as:

wherein:

Ra, Ra', R₃, and R₃', are each independently hydrogen or hydroxy; or alkoxy(c≤ia), aryloxy(c≤ia), aralkoxy(c≤ia), heteroaryloxy(c≤12), heteroaralkoxy(c≤ia), acyloxy(c<i₂₎, or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

In some aspects, R₂ is hydrogen or hydroxy. In some aspects, R₂ is hydrogen. In other aspects, R₂ is hydroxy. In some aspects, Ra' is hydrogen or hydroxy. In some aspects, Ra' is hydrogen. In other aspects, Ra' is hydroxy. In some aspects, R3 is hydrogen or hydroxy. In some aspects, R₃ is hydrogen. In other aspects, R₃ is hydroxy. In some aspects, R3' is hydrogen or hydroxy. In some aspects, R₃' is hydrogen. In other aspects, R₃' is hydroxy. In some aspects, the compound is further defined as:

or a pharmaceutically acceptable salt thereof. In some aspects, the hydroxyl groups are in a cis relationship to one another. In some aspects, the compound according to formula (IV) is characterized in that R₃ or Rs' are hydroxyl, and R2 or R2' is -OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably, X₄ is -NH-. Further preferably, Rx is aminoalkyl(c≤i₂), or a protected version thereof. More preferably, Rx is -CH₂CH₂NHB0C. Thus, in some aspects the compound according to formula (IV) is a compound according to formula:

In some aspects, in the compound of formula (I) to (IV), R₂/R_2’ and R₃/R_3’ may be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R₂’ and R3/R3’. Preferably, the five-membered heterocyclic ring as defined herein is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane. More preferably, the five- membered heterocyclic ring as defined herein is 1,3-dioxolane. The five-membered heterocyclic ring may be optionally substituted, preferably with oxo or geminal methyl groups, more preferably with an oxo group. In certain aspects, the five-membered heterocyclic ring substituted with an oxo group is selected from: . As understood herein, the ring

atoms marked by * are preferably fused with ring atoms that otherwise carry R₂/R₂’ and R₃/R₃’. Preferably, the five-membered heterocyclic ring substituted with an oxo group is

In certain aspects, the compound of formula (I) to (IV) is a compound according to formula:

In certain aspects, the compound is further defined as a compound according to the formula:

wherein Li is a linker of the formula:

as defined herein.

Preferably, Li is a linker of the formula -NHC(0)NH-.

In a further preferred embodiment wherein m = 0, the compound of the present invention is a compound according to formula:

In certain embodiments, Li is a linker of the formula -HNC(0)0-(alkanediyl)₍c≤12₎-0C(0)NH-, preferably of the formula -0C(0)NH-(alkanediyl)₍c≤12₎-HNC(0)0-. In a further preferred embodiment wherein m = 0, the compound of the present invention is a compound according to formula:

preferably a compound according to formula:

preferably a compound according to formula:

The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The word “about” means plus or minus 5% of the stated number.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is ascribed to one particular generic formula doesn’t mean that it cannot also belong to another generic formula.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1. In thiol-mediated uptake, dynamic covalent exchange with exofacial thiols covalently attaches substrates to the cell surface for entry through different mechanisms. Inhibition of thiol-mediated uptake by removal of exofacial thiols could thus afford new antivirals.

FIG. 2. Structures of reporters 1 and 2 and inhibitor candidates 3-30 with their concentrations needed to inhibit the uptake of 1 (1 h pre-incubation, filled symbols) and 2 (1 h coincubation, empty symbols) by ~15% (MIC). Red squares: ETPs; orange circles: BPSs; blue upward triangles: Heteroaromatic sulfones; purple diamonds: Thiosulfonates; magenta downward triangles: Di- and polysulfides; brown hexagons: Thiosulfinates. Symbols with upward arrows indicate that the MIC was not reached at the highest concentration tested. Symbols with downward arrows indicate the lowest concentration tested already exceeds the MIC. a) Similarly active upon co-incubation of reporters and inhibitor; b) less active (~10x) with co-incubation in the presence of serum (6 h); c) pre-incubation for 15 min; d) similarly active upon co-incubation in the presence of serum (6 h); e) isomerizes into cis 21; f) V-shaped DRC (see FIG. 3E); g) pre-incubation for 4 h; h) mixture of regioisomers.

FIGS. 3A-F. (FIG. 3A) Fluorescence image of HCHT plates with HeLa cells preincubated with 6 (1 h) followed by co-incubation with 1 (left) and 2 (right, 10 μΜ each) for 30 min. (FIGS. 3B-F) HCHT data showing relative fluorescence intensity (filled symbols) and viability (empty symbols) of HeLa cells after (FIG. 3B) pre-incubation with 4 for 1 h, followed by washing and incubation with 1 for 30 min (top), or co-incubation with 4 and 2 (bottom, 10 μΜ) for 1 h. (FIG. 3C) As in FIG. 3B with 17. (FIG. 3D) As in FIG. 3B, with 15 (circles), after incubation with 15 for 5.5 h in the presence of FBS followed by incubation with 1 for 30 min (diamonds), or with 15 for 4 h followed by incubation with 2 for 30 min (triangles). (FIG. 3E) As in FIG. 3B after preincubation with 11 (circles), 14 (crosses), or 20 (diamonds) for 15 min, followed by washing and incubation with 1 for 30 min. (FIG. 3F) As in FIG. 3B after preincubation with 19 (30 min), followed by washing and incubation with 1 (30 min). FIGS. 4A-D. Viral entry inhibition test. Cells were treated either for 24h or lh with the compound non-diluted (lx) or ten times diluted (lOx), then lentivirus coding for the luciferase reporter was added for 6 hr. Finally, the culture media was changed, and cells were incubated for 3 additional days prior to Luciferase and cell viability measurement. A549 human lung alveolar basal epithelium cells overexpressing ACE2 and TMPRSS2 were transduced with lentivirus expressing the SARS-CoV-2 spike surface protein harboring the D614G mutation (FIGS. 4A-B). Alteratively, wild-type (WT) A549 cells were transduced with a standard lentivirus expressing the VSV-G surface protein (FIGS. 4C-D). Viral entry was measured by the lenti virus-mediated luciferase signal (FIGS. 4A and 4C) and normalized with WST8-cell viability displayed in (FIGS. 4B and 4D). For all conditions the concentrations of DMSO is equal to 0.1 %. All conditions were performed in triplicate, error bars represent standard deviation.

FIGS. 5A-B. Viral entry inhibition test Cells were treated for lh with the compounds at the concentration of 50 μΜ, then lentivirus coding for the luciferase reporter was added for 6 hr. Finally, the culture media was changed, and cells were incubated for 3 additional days prior to Luciferase and cell viability measurement. A549 human lung alveolar basal epithelium cells overexpressing ACE2 and TMPRSS2 were transduced with lentivirus expressing the SARS-CoV- 2 spike surface protein harboring the D614G mutation. Viral entry was measured by the lentivirus- mediated luciferase signal (FIGS. 5A) and normalized with WST8-cell viability displayed in (FIGS. 5B). For all conditions the concentrations of DMSO and distilled water is equal to 0.25% and 0.1%, respectively. All conditions were performed in triplicate, error bars represent standard deviation.

FIG. 6. Automatically analyzed HCHT data showing fluorescence intensity (filled symbols) and relative viability (empty symbols) of HeLa cells after A) pre-incubation with 16 for 1 h (dark grey circles), 2 h (grey circles) and 4 h (light grey circles) followed by incubation with 1 (10 μΜ) for 30 min; B) incubation with 16 for 5.5 h with FBS (dark grey squares) and 23.5 h with FBS (grey squares) followed by co-incubation with 1 (10 μΜ) for 30 min.

FIG. 7. Automatically analyzed HCHT data showing fluorescence intensity (filled symbols) and relative viability (empty symbols) of HeLa cells after pre-incubation with 16 for 4 h (blue circles) followed by incubation with 2 (10 μΜ) for 30 min. FIG. 8. Assessment of compound C, X2, X8 and X22 in the protease inhibition assay against A) Cathepsin L; B) Cathepsin B and C) Trypsin.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

As discussed above, SARS-CoV-2 is the single largest health concern for nearly every country in the world with active cases continuing to increase daily. Therefore, developing treatments that could reduce mortality, decrease hospitalizations, and possibly control the spread of SARS-CoV-2 and other viral infections is of paramount importance. Here, the inventors report a known chemical entity that shows promise for the treatment of viral infection, including SARS- CoV-2.

Thiol-mediated uptake^1"9 has been developed to explain surprisingly efficient cellular uptake of substrates attached to thiol-reactive groups, most notably disulfides. The key step of this mechanism is the dynamic covalent thiol-disulfide exchange between disulfides of the substrates and exofacial thiols on cell surfaces (FIG. 1). Then, the covalently surface bound substrate enters the cell either by fusion, endocytosis, or direct translocation across the plasma membrane into the cytosol. Similarly, thiol-disulfide exchange plays an essential role in the cellular entry of some viruses^1,10'13 and toxins.² Indeed, diphtheria toxin and HIV were among the first to be recognized to enter cells via thiol-mediated uptake.^1,2 The involvement of cell-surface thiols in cellular uptake is most often probed by inhibition with Ellman’s reagent (DTNB). However, this test is not always reliable, in part due to the poor reactivity of DTNB, and the high reactivity of disulfide obtained as a product. Thus, the importance of thiol-mediated uptake for viral entry and beyond remains, at least in part, unclear.

The inventors became interested in thiol-mediated uptake^3,4 while studying the cytosolic delivery of substrates such as drugs, probes and also larger objects like proteins or quantum dots with cell-penetrating poly(disulfide)s.⁵ Their recent focus shifted to cyclic oligochalcogenides (COCs) to increase speed and selectivity of dynamic covalent thiol-oligochalcogenide exchange, and, most importantly, to assure reversibility, i.e., mobility during uptake, with a covalently tethered, intramolecular leaving group.⁶ With increasingly unorthodox COC chemistry, from strained disulfides^6,7 and diselenides⁸ to adaptive dynamic covalent networks produced by polysulfanes,⁹ uptake activities steadily increased. Their high activities suggested that the same, or complementary, COCs could also function as powerful inhibitors of thiol-mediated uptake that may perhaps lead to antivirals.

Viral entry into cells can involve thiol-disulfide exchange with exofacial thiols on cell surfaces. The importance of thiol-mediated uptake for viral entry and beyond is poorly understood because efficient inhibitors do not exist. Here, the inventors used fluorescent cyclic oligochalcogenides that enter cells by thiol-mediated uptake to systematically screen for inhibitors, including epidithiodiketopiperazines, benzopolysulfanes, disulfide-bridged γ-tumed peptides, benzoxazolesulfates and cyclic thiosulfonates, thiosulfinates and disulfides. Different activities found with different reporters reveal thiol-mediated uptake as a complex multitarget process. Initial tests with pseudo-lentivectors expressing SARS-CoV-2 spike protein show potential for the development of new antivirals.

These and other aspects of the disclosure are described in detail below. I. Coronavirus 2019 (SARS-CoV-2)

SARS-CoV-2 is a contagious viras that causes the acute respiratory disease designated coronavirus disease 2019 (COVID- 19), a respiratory infection. It is the cause of the ongoing 2019- 20 coronavirus outbreak, a global health emergency. Genomic sequencing has shown that it is a positive-sense, single-stranded RNA coronavirus.

During the ongoing outbreak, the virus has often been referred to in common parlance as "the coronavirus", "the new coronavirus" and "the Wuhan coronavirus", while the WHO recommends the designation "SARS-CoV-2". The International Committee on Taxonomy of Viruses (ICTV) announced that the official name for the virus is SARS-CoV-2.

Many early cases were linked to a large seafood and animal market in the Chinese city of Wuhan, and the virus is thought to have a zoonotic origin. Comparisons of the genetic sequences of this virus and other virus samples have shown similarities to SARS-CoV (79.5%) and bat coronaviruses (96%). This finding makes an ultimate origin in bats likely, although an intermediate host, such as a pangolin, cannot be ruled out. The virus could be a recombinant virus formed from two or more coronaviruses.

Human-to-human transmission of the virus has been confirmed. Coronaviruses are primarily spread through close contact, in particular through respiratory droplets from coughs and sneezes within a range of about 6 feet (1.8 m). Viral RNA has also been found in stool samples from infected patients. It is possible that the virus can be infectious even during the incubation period.

Animals sold for food were originally suspected to be the reservoir or intermediary hosts of SARS-CoV-2 because many of the first individuals found to be infected by the virus were workers at the Huanan Seafood Market. A market selling live animals for food was also blamed in the SARS outbreak in 2003; such markets are considered to be incubators for novel pathogens. The outbreak has prompted a temporary ban on the trade and consumption of wild animals in China. However, some researchers have suggested that the Huanan Seafood Market may not be the original source of viral transmission to humans.

With a sufficient number of sequenced genomes, it is possible to reconstruct a phylogenetic tree of the mutation history of a family of viruses. Research into the origin of the 2003 SARS outbreak has resulted in the discovery of many SARS-like bat coronaviruses, most originating in the Rhinolophus genus of horseshoe bats. SARS-CoV-2 falls into this category of SARS -related coronaviruses. Two genome sequences from Rhinolophus sinicus published in 2015 and 2017 show a resemblance of 80% to SARS-CoV-2. A third virus genome from Rhinolophus affinis, "RaTG13” collected in Yunnan province, has a 96% resemblance to SARS-CoV-2.^28,29 For comparison, this amount of variation among viruses is similar to the amount of mutation observed over ten years in the H3N2 human influenza virus strain.

SARS-CoV-2 belongs to the broad family of viruses known as coronaviruses; "nCoV" is the standard term used to refer to novel coronaviruses until the choice of a more specific designation. It is a positive-sense single-stranded RNA (+ssRNA) virus. Other coronaviruses are capable of causing illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS) and Severe acute respiratory syndrome (SARS). It is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and SARS-CoV.

Like SARS-CoV, SARS-CoV-2 is a member of the subgenus Sarbecovirus (Beta-CoV lineage B). Its RNA sequence is approximately 30,000 bases in length. By 12 January, five genomes of SARS-CoV-2 had been isolated from Wuhan and reported by the Chinese Center for Disease Control and Prevention (CCDC) and other institutions; the number of genomes increased to 28 by 26 January. Except for the earliest GenBank genome, the genomes are under an embargo at GISAID. A phylogenic analysis for the samples is available through Nextstrain.

Publication of the SARS-CoV-2 genome led to several protein modeling experiments on the receptor binding protein (RBD) of the spike (S) protein of the virus. Results suggest that the S protein retains sufficient affinity to the Angiotensin converting enzyme 2 (ACE2) receptor to use it as a mechanism of cell entry. On 22 January, a group in China working with the full virus and a group in the U.S. working with reverse genetics independently and experimentally demonstrated human ACE2 as the receptor for SARS-CoV-2.

To look for potential protease inhibitors, the viral 3C-like protease M(pro) from the ORFla polyprotein has also been modeled for drug docking experiments. Innophore has produced two computational models based on SARS protease, and the Chinese Academy of Sciences has produced an unpublished experimental structure of a recombinant SARS-CoV-2 protease. In addition, researchers at the University of Michigan have modeled the structures of all mature peptides in the SARS-CoV-2 genome using I-TASSER.

The first known human infection occurred in early December 2019. An outbreak of SARS- Co V -2 was first detected in Wuhan, China, in mid-December 2019, likely originating from a single infected animal. The virus subsequently spread to all provinces of China and to more than two dozen other countries in Asia, Europe, North America, and Oceania. Human-to-human spread of the virus has been confirmed in all of these regions. On 30 January 2020, SARS-CoV-2 was designated a global health emergency by the WHO.

The basic reproduction number (R-zero) of the virus has been estimated to be between 1.4 and 3.9. This means that, when unchecked, the virus typically results in 1.4 to 3.9 new cases per established infection. It has been established that the virus is able to transmit along a chain of at least four people.

COVID-19 acute respiratory disease is a viral respiratory disease caused by SARS-CoV-2. It was first detected during the 2019-20 Wuhan coronavirus outbreak. Symptoms may include fever, dry cough, and shortness of breath. There is no specific licensed treatment available as of March 2020, with efforts focused on lessening symptoms and supporting functioning.

Those infected may either be asymptomatic or have mild to severe symptoms, like fever, cough, shortness of breath. Diarrhea or upper respiratory symptoms (e.g., sneezing, runny nose, sore throat) are less frequent. Cases of severe infection can progress to severe pneumonia, multiorgan failure, and death. The time from exposure to onset of symptoms is estimated at 2 to 10 days by the World Health Organization, and 2 to 14 days by the US Centers for Disease Control and Prevention (CDC).

Global health organizations have published preventive measures individuals can take to reduce the chances of SARS-CoV-2 infection. Recommendations are similar to those previously published for other coronaviruses and include: frequent washing of hands with soap and water; not touching the eyes, nose, or mouth with unwashed hands; and practicing good respiratory hygiene.

The WHO has published several testing protocols for SARS-CoV-2. Testing uses real time reverse transcription-polymerase chain reaction (rRT-PCR). The test can be done on respiratory or blood samples. Results are generally available within a few hours to days.

Research into potential treatments for the disease were initiated in January 2020. The Chinese Center for Disease Control and Prevention started testing existing pneumonia treatments in coronavirus-related pneumonia in late January. There has also been examination of the RNA polymerase inhibitor remdesivir, and interferon beta. In late January 2020, Chinese medical researchers expressed an intent to start clinical testing on remdesivir, (hydroxychloroquine, and lopinavir/ritonavir, all of which seemed to have "fairly good inhibitory effects" on SARS-CoV-2 at the cellular level in exploratory research. On 5 February 2020, China started patenting use of remdesivir for the disease.

Overall mortality and morbidity rates due to infection with SARS-CoV-2 are unknown, both because the case fatality rate may be changing over time in the current outbreak, and because the proportion of infections that progress to diagnosable disease remains unclear. However, preliminary research into SARS-CoV-2 acute respiratory disease has yielded case fatality rate numbers between 2% and 3%, and in January 2020 the WHO suggested that the case fatality rate was approximately 3%. An unreviewed Imperial College preprint study among 55 fatal cases noted that early estimates of mortality may be too high as asymptomatic infections are missed. They estimated a mean infection fatality ratio (the mortality among infected) ranging from 0.8% when including asymptomatic carriers to 18% when including only symptomatic cases from Hubei province.

Early data indicates that among the first 41 confirmed cases admitted to hospitals in Wuhan, 13 (32%) individuals required intensive care, and 6 (15%) individuals died. Of those who died, many were in unsound health to begin with, exhibiting conditions like hypertension, diabetes, or cardiovascular disease that impaired their immune systems. In early cases of SARS-CoV-2 acute respiratory disease that resulted in death, the median time of disease was found to be 14 days, with a total range from six to 41 days. π. Compound of the Present Disclosure

In some embodiments, the present disclosure provides compounds of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-;

Ri, Ri', R2, R2', RB, RB', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤i₂), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ZR_2’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or

-C(O)R4, wherein:

R₄ is hydroxy or amino; or alkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; ; or

-OC(0)X4RX, wherein: X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c_<i₂₎,hydroxyalkynyl₍c≤i₂₎,or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, R₂/R₂’ and Rs/Rs’are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group), preferably wherein the five-membered heterocyclic ring is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane, more preferably wherein the five- membered heterocyclic ring is 1,3-dioxolane; or at least one of R3, R3’, R2, R2’ is - 0C(0)X₄R_X, wherein: X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12). hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤i₂), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably Rx is aminoalkyl(c≤i₂), or a substituted or protected version of this group.

As understood herein when referring to a protected version of an aminoalkyl group, a modified aminoalkyl group is meant wherein amino group has been transformed to a protected amino group.

In some embodiments, the present disclosure provides a compound of the formula:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂~; and Ri, Ri', R₂, R₂', R3, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaiyl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R3 may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany R₂/R_2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or

-C(O)R4, wherein:

-OC(0)X₄RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, R2/R2’ and Ra/Rs’are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry Rz/Rr and R₃/R₃·, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group), preferably wherein the five-membered heterocyclic ring is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane, more preferably wherein the five- membered heterocyclic ring is 1,3-dioxolane; or at least one of R₃, Rv, R₂, R₂’ is - OC(O)X₄R_X, wherein: X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c<i₂), aminoalkyl(c<i₂₎, hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably Rx is aminoalkyl(c≤i₂₎, or a substituted or protected version of this group..

In some embodiments, the present disclosure provides a compound of the formula:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂-; and

R₂, R₂', R₃, and R3', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤i₂), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy«;<i2), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-0C(0)X₄RX, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl₍c≤i₂), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c<i₂₎,hydroxyalkynyl₍c<i₂₎,or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, R₂/R₂’ and Rg/Rs-are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R₃’, wherein the five- membered heterocyclic ring is optionally substituted (preferably with oxo group), preferably wherein the five-membered heterocyclic ring is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane, more preferably wherein the five-membered heterocyclic ring is 1,3-dioxolane; or at least one of R3, R3’, R2, R2’ is -0C(0)X₄Rx, wherein: Xds -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably Rx is aminoalkyl(c≤i₂₎, or a substituted or protected version of this group.

In some embodiments, the present disclosure provides a compound of the formula:

wherein:

R?, R₂ ^r, Rs, and R3', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaiyloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R2’ and R3/R3_’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -C(O)R4, wherein:

-0C(0)X₄RX, wherein:

Xt is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoaIkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, R₂/R₂’ and Rs/Rs-are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five- membered heterocyclic ring is optionally substituted (preferably with oxo group), preferably wherein the five-membered heterocyclic ring is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1 ,3-dioxolane, more preferably wherein the five-membered heterocyclic ring is 1 ,3-dioxolane; or at least one of R3, Rr, R₂, R2’ is -OC(O)X₄R_X, wherein: X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably Rx is aminoalkyl(c≤12), or a substituted or protected version of this group. In some embodiments, the present disclosure provides a compound of the formula:

wherein:

R₂, R₂', R3, and R3', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤i₂), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein Ra and R₃ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or -OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12),hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

R₂/R₂’ and Rs/Rs’are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R_2’ and R3/R3*, wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group), preferably wherein the five-membered heterocyclic ring is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane, more preferably wherein the five-membered heterocyclic ring is 1,3-dioxolane; or at least one of R3, R3’, R₂, R₂’ is -0C(0)X₄Rx, wherein: X₄ is -O- or -NH and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12). hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤12₎, hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups. Preferably Rx is aminoalkyl₍c≤ia₎, or a substituted or protected version of this group.

In some embodiments, the present disclosure provides a compound of the formula:

5

wherein:

Ra, Ra', Rs, and R₃', are each independently hydrogen or hydroxy; or alkoxy(c≤12), aryloxy(c≤ia), aralkoxy(c≤ia), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), acyloxy(c≤12), or a substituted version of any of these groups; wherein Ra and R3 are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany Ra/Ra· and R3/R3', wherein the five-membered heterocyclic ring is optionally substituted (preferably with oxo group); or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound of the formula:

WO2019/241644 and W098/01440 describe similar compounds to those described here. Both of these patent applications are hereby incorporated by reference in their entirety. In some embodiments the present disclosure provides a compound according to formula:

In some embodiments, the present disclosure provides a compound according to formula:

The compounds of the present invention (also referred to as “compounds of the present disclosure”) are shown, for example, above, in the summary of the invention section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section and Appendix A. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development - A Guide for Organic Chemists (2012), which is incorporated by reference herein.The compounds described herein may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or the R configuration.

All the compounds of the present invention may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and/or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all the compounds of the present invention are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices.

In some embodiments, the compounds of the present invention have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.

Compounds of the present invention may contain one or more asymmetrically-substituted carbon, sulfur, or phosphorus or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.

Chemical formulas used to represent compounds of the present invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.

In some embodiments, compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

In some embodiments, compounds of the present invention exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference. It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present invention.

The present inventors have surprisingly found, that the compounds as disclosed herein are useful as human protease inhibitors. Examples 5 presents inhibition data for the compound C, X2, X8 and X22 against Cathepsin B, Cathepsin L, and trypsin. However, proteases that may be inhibited by the compounds of the present invention are not limited to these three examples, and accordingly compounds of the present invention may inhibit PCI, Matriptase, Furin, Cathepsin L, Cathepsin B, Trypsin, and/or TMPRSS2.

ΠΙ. Treatment/Prevention of Viral infection, such as SARS-CoV-2 Infection A. Formulation and Administration

The present disclosure provides pharmaceutical compositions comprising anti-viral compounds and compositions. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.

Such compounds/compositions comprise a prophylactically or therapeutically effective amount, optionally disposed in a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a particular carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical agents are described in “Remington's Pharmaceutical Sciences.” Such compositions will contain a prophylactically or therapeutically effective amount of the compound/composition, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration, which can be oral, intravenous, intraarterial, intrabuccal, intranasal, nebulized, bronchial inhalation, intra-rectal, vaginal, topical or delivered by mechanical ventilation.

The compound/compositions could alteratively be administered by a topical route directly to the mucosa, for example, by nasal drops, inhalation, by nebulizer, or via intrarectal or vaginal delivery. Pharmaceutically acceptable salts include the acid salts and those which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the flee carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

Generally, the ingredients of compositions of the disclosure are supplied either separately or mixed together in unit dosage form, for example, as a diy lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The compositions of the disclosure can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

In some embodiments of the present disclosure, the compounds are included a pharmaceutical formulation. Materials for use in the preparation of microspheres and/or microcapsules are, e.g., biodegradable/bioerodible polymers such as polygalactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and, poly(lactic acid). Biocompatible carriers that may be used when formulating a controlled release parenteral formulation are carbohydrates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g. , polydimethyl siloxane) or biodegradable (e.g, poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters) or combinations thereof).

Formulations for oral use include tablets containing the active ingredient(s) (e.g, the compounds described herein) in a mixture with non-toxic pharmaceutically acceptable excipients. Such formulations are known to the skilled artisan. Excipients may be, for example, inert diluents or fillers (e.g, sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g, cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g, magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

Tablets may be uncoated or they may be coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby providing a sustained action over a longer period. The coating may be adapted to release the active drug in a predetermined pattern (e.g, in order to achieve a controlled release formulation) or it may be adapted not to release the active drug until after passage of the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g, based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose). Furthermore, a time delay material, such as, e.g., glyceryl monostearate or glyceryl distearate may be employed.

The present embodiments further encompass a method of treating blood supplies, body fluid samples or other material which can potentially be contaminated with a virus. For example, a composition of the present embodiments can be included in a tube or other sample device used for obtaining a fluid sample from a patient, human or other animal, which is potentially infected with a retrovirus. The presence of the composition in the sample device will inactivate the virus when the sample is obtained, thus reducing the risk to the sample handler. The composition of the present invention can be supplied from a manufacturer in pre-packaged sample devices or, alternatively, the compositions can be added to the sample devices by the end user in an appropriate amount to inactivate the virus.

B. Combination Therapies It is envisioned that the compounds/compositions described herein may be used in combination therapies with one or more anti-viral therapies or compounds which mitigate one or more of the symptoms experienced by the patient. It is common in the field of medicine to combine therapeutic modalities. The following is a general discussion of therapies that may be used in conjunction with the therapies of the present disclosure.

To treat SARS-CoV-2 using the methods and compositions of the present disclosure, one may generally treat the subject with the compound and at least one other therapy. These therapies would be provided in a combined amount effective to achieve a reduction in one or more disease parameters. This process may involve subjecting the patient to both agents/therapies at the same time, e.g., using a single composition or pharmacological formulation that includes both agents, or by providing to the patient two distinct compositions or formulations, at the same time, wherein one composition includes the compound and the other includes the other agent.

Alternatively, the compounds described herein may precede or follow the other treatment by intervals ranging from minutes to weeks. One would generally ensure that a significant period of time did not expire between the times of each delivery, such that the therapies would still be able to exert an advantageously combined effect on the cell/subject. In such instances, it is contemplated that one would contact the cell with both modalities within about 12-24 hours of each other, within about 6-12 hours of each other, or with a delay time of only about 1-2 hours. In some situations, it may be desirable to extend the time period for treatment significantly; however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

It also is conceivable that more than one administration of either the compound or the other therapy will be desired. Various combinations may be employed, where the compounds of the present disclosure is “A,” and the other therapy is “B,” as exemplified below:

A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B Other combinations are also contemplated.

Currently, no therapy has been approved as effective for the prevention of SARS-CoV-2. Despite this, around the world there are many drugs currently under investigation. Remdesivir, an antiviral drug, is a strong candidate. Sofosbuvir taken in combination with ribavirin is another promising candidate. Lopinavir, ritonavir taken alongside ribavirin and corticosteroids has also shown promise as a treatment option. Interferon alfacon-1 taken together with corticosteroids is another treatment with potential.

Supportive therapy including fluids, anti-inflammatories and ventilation are also employed in managing SARS-CoV-2.

IV. Definitions

When used in the context of a chemical group: “hydrogen” means -H; “hydroxy” means -OH; “oxo” means =0; “carbonyl” means -C(=0) ; “carboxy” means -C(=0)0H (also written as -COOH or -CO2H); “halo” means independently -F, -Cl, -Br or -I; “amino” means -NH2; “hydroxyamino” means -NHOH; “nitro” means -NO2; imino means =NH; “cyano” means -CN; “isocyanyl” means -N=C=0; “azido” means -N3; in a monovalent context “phosphate” means -OP(0)(OH)₂ or a deprotonated form thereof; in a divalent context “phosphate” means -0P(0)(0H)0- or a deprotonated form thereof; “mercapto” means -SH; and “thio” means =S; “thiocarbonyl” means -C(=S)-; “sulfonyl” means -S(O)₂ ^~; and “sulfinyl” means -S(O)-. In the context of chemical formulas, the symbol means a single bond, “=” means a double bond, and “≡” means triple bond. The symbol “- — ” represents an optional bond, which if present is either single or double. The symbol “==” represents a single bond or a double bond.

Thus, the formula covers, for example,

And it is

understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol “ '^ΛΛΛ ”, when drawn perpendicularly across a bond (e.g. , j— CH₃ for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol

means a single bond where the group attached to the thick end of the wedge is “out of the page.” The symbol means a single

bond where the group attached to the thick end of the wedge is “into the page”. The symbol

means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

When a variable is depicted as a “floating group” on a ring system, for example, the group “R” in the formula:

then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula:

then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter “y” immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group/class. “C<n” defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl(c≤8)’\ “alkanediyl(c<8)’\ “heteroaryl(c<8)’\ and “acyl(c<8>” is one, the minimum number of carbon atoms in the groups “alkenyl(c≤8)”, “alkynyl(c<8)’\ and “heterocycloalkyl(c<8)” is two, the minimum number of carbon atoms in the group “cycloalkyl(c<8)” is three, and the minimum number of carbon atoms in the groups “aryl(c≤₈)” and “arenediyl(c≤8)” is six. “Cn-n'” defines both the minimum (n) and maximum number (η') of carbon atoms in the group. Thus, “alkyl(C2-io)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “Ci-4-alkyl”, “Cl -4-alkyl”, “alkyl(ci-4)”, and “alkyl₍c≤4₎” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(ci2) group; however, it is not an example of a dialkylamino_(C6) group. Likewise, phenylethyl is an example of an aralkyl(c=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl which has a total of seven carbon atoms, is an example of a substituted alkyl(ci-6) Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.

The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.

The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).

The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4 n +2 electrons in a fully conjugated cyclic π system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:

is also taken to refer to

Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic π system, two non-limiting examples of which are shown below:

The term “alkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -CH₃ (Me), -CH₂CH₃ (Et), -CH2CH₂CH3 (n-Pr or propyl), -CH(CH3)2 (z-Pr, 'Pr or isopropyl), -CH₂CH₂CH2CH₃ (n-Bu), -CH(CH₃)CH₂CH₃ (sec-butyl), -CH₂CH(CH₃)₂ (isobutyl), -C(CH₃)₃ (tert- butyl, /-butyl, Z-Bu or ¾u), and -CH2C(CH3)3 (neo-pentyl) are nonlimiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH₂— (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group

=CRR' in which R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH₂, =CH(CH₂CH3), and =0(Ο¼)2. An “alkane” refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above.

The tom “cycloalkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH₂)₂ (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term “cycloalkanediyl” refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The group is a non-limiting example of cycloalkanediyl group. A

“cycloalkane” refers to the class of compounds having the formula H-R, wherein R is cycloalkyl as this term is defined above.

The term “alkenyl" refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon- carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH₂ (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH₂CH=CH₂ (allyl), -CH₂CH=CHCH3, and -CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon- carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH- -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH₂CH=CHCH₂ ^_ are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H-R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “a- olefin” are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.

The term “alkynyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH₂OCCH₃ are non-limiting examples of alkynyl groups. An “alkyne” refers to the class of compounds having the formula H-R, wherein R is alkynyl.

The term “aryl” refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C₆H₄CH₂CH₃ (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl {e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:

An “arene” refers to the class of compounds having the formula H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.

The term “aralkyl” refers to the monovalent group -alkanediyl-aiyl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Nonlimiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

The term “heteroaryl” refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (fin), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term ‘W-heteroaiyl” refers to a heteroaryl group with a nitrogen atom as the point of attachment. A “heteroarene” refers to the class of compounds having the formula H-R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes.

The term “heteroaralkyl” refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.

The term “heterocycloalkyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings are fused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term ‘W-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. /V-pyrrolidinyl is an example of such a group.

The term “heterocyclic ring” refers to a ring of preferably 3 to 8 ring atoms comprising no other atoms than carbon, hydrogen, oxygen, nitrogen, and sulfur, wherein at least one of the ring atoms is nitrogen, oxygen or sulfur. Heterocyclic ring as defined herein can be aromatic or nonaromatic. Heterocyclic ring that is not aromatic may also contain double bonds. As used herein, a five-member heterocyclic ring is a heterocyclic ring as defined herein of five ring atoms. Non limiting examples of five-member heterocyclic ring include pyrrolidine, 3-pyrroline, 2-pyrroline, 2H-pyrrole, lH-pyrrole, pyrazolidine, imidazolidine, 2-pyrazolidine, 2-imidazoline, pyrazole, imidazole, tetrahydrofuran, furan, 1,3-dioxolane, tetrahydrotiophene, tiophene, oxazole, isoxazole, isothiazole, thiazole, 1,2-oxathiolane, 1,3-oxathiolane, and oxazolidine. Preferably, a five member heterocyclic ring as defined herein is selected from pyrrolidine, imidazolidine, tetrahydrofuran, and 1,3-dioxolane. More preferably, a five member heterocyclic ring as defined herein is 1,3- dioxolane.

The term “acyl” refers to the group -C(0)R, in which R is a hydrogen, alkyl, cycloalkyl, or aiyl as those terms are defined above. The groups, -CHO, -C(0)CH₃ (acetyl, Ac), -C(0)CH₂CH₃, -C(0)CH(CH₃)2, -C(0)CH(CH₂)₂, -C(0)C₆H₅, and -C(0)C₆H₄CH₃ are nonlimiting examples of acyl groups. A “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, ~C(S)R. The term “aldehyde” corresponds to an alkyl group, as defined above, attached to a -CHO group.

The term “alkoxy” refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH₃ (methoxy), -OCH₂CH₃ (ethoxy), -OCH₂CH₂CH₃, -OCH(CH₃)₂ (isopropoxy), or -OC(CH₃)₃ (teri-butoxy). Preferably, the term alkoxy may also refer to a group -ORsi, wherein Rsi is an alkyl as defined herein wherein one carbon atom has been replaced with Si. An example ofa -ORsi group is -0-Si(CH3)2C(CH3)3, which may also be referred to as OTBS or OTBDMS. The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aiyloxy”, “aralkoxy”, “heteroaryloxy”, “heteroaralkoxy”, “heterocycloalkoxy”, and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and acyl, respectively. The term “alkylthio” and “acylthio” refers to the group -SR, in which R is an alkyl and acyl, respectively. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.

The term “alkylamino” refers to the group -NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -NHCH3 and -NHCH2CH3. The term “dialkylamino” refers to the group -NRR', in which R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N(CH3)2 and -NCCHsXCthCHs). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(0)CH3.

When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by a substituent group which is preferably selected from -OH, -F, -Cl, -Br, -I, -NH₂, -NO2, -CO2H, -CO2CH3, -CO2CH2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH₃, — NHCH3, -NHCH2CH3, -N(CH₃)2, -C(0)NH₂, -C(0)NHCH₃, -C(0)N(CH₃)₂, -0C(0)CH₃, -NHC(0)CH₃, -S(O)₂0H, or -S(O)₂NH₂. For example, the following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2CI, -CF3, -CH2CN, -CH₂C(0)0H, -CH₂C(0)OCH₃, -CH₂C(0)NH₂, -CH₂C(0)CH₃, -CH2OCH3, -CH₂0C(0)CH₃, -CH2NH2, -CH₂N(CH₃)2, and -CH2CH2CI. Moreover, when a chemical group carrying two (or more) hydrogen atoms is used with the “substituted” modifier, it may also refer to a corresponding chemical group wherein two hydrogen atoms (particularly two geminal hydrogen atoms) are replaced with a single oxo- group (i.e., =0), a single thio- group (i.e., =S) or with two geminal methyl groups, more preferably with an oxo-group or with geminal methyl groups, even more preferably with an oxo- group. Thus, for example, a “substituted” methyl group may also refer to -CHO, -CHS, or -CH(CH₃)CH₃. Alternatively, a substituent group may also preferably be selected from C₁-C₁2 alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ cycloalkyl, C₁-C₁₂ heterocycloalkyl, C5-C₁₂ aryl, C₅-C₁₂ arylalkyl, and C₁-C₁₂ acyl.

The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (/. e. -F, -Cl, -Br, or -I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, -CH2CI is a non-limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups. Non- limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl- eth-l-yl. The groups, -C(0)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcafboxyl), -CO2CH2CH3, -C(0)NH2 (carbamoyl), and -CON(CH3)2, are non-limiting examples of substituted acyl groups. The groups -NHC(0)0CH₃ and -NHC(0)NHCH₃ are non-limiting examples of substituted amido groups.

As understood herein, when referring to a substituted amino group, preferably at least one hydrogen atom where replaced by a group selected from C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ cycloalkyl, C1-C₁2 heterocycloalkyl, C5-C₁₂ aryl, C₅-C₁₂ arylalkyl, and C₁-C₁₂ acyl, any of which may further be optionally substituted as defined above.

When a chemical group is used with the “protected” modifier, preferably it has been reversibly modified (i.e. in a way that can be reversed) in a way that prevents certain chemical reactions of the group that are known to the skilled person. For example, a reactive group containing hydrogen atoms can be protected by replacement of one of hydrogen atoms by another moiety referred to as protecting group, provided that such replacement prevents certain reactivity of the reactive group. It is known to the skilled person that selection of the protecting group depends on the reactive group. For example, an amino group can be protected by replacement of one of its hydrogen atoms by another moiety referred to as a protecting group, such as a 9- fluorenylmethoxycarbonyl moiety (also referred to as Fmoc), a tert-butyloxycarbonyl moiety (also referred to as Boc), a benzyloxycarbonyl moiety (also referred to as Cbz or Z), or an allyloxycarbonyl moiety (also referred to as Alloc). However, this list is not limiting and any protecting group known to the skilled person may be used within the scope of the present invention.

Further exemplary protecting groups that can be used in accordance with the present invention include any of those referred to in: Wuts PGM, “Greene’s protective groups in organic synthesis”, John Wiley & Sons, 5^th edition, 2014, which is incorporated herein by reference; and any of those referred to in: Kocienski PJ, “Protecting Groups”, Thieme, 3^rd edition, 2003, which is incorporated herein by reference.

The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients. An “active ingredient” (AI) or active pharmaceutical ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug that is biologically active.

The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

The term “effective,” as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. “Effective amount,” “Therapeutically effective amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to the patient or subject, is sufficient to effect such treatment or prevention of the disease as those terms are defined below.

An “excipient” is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as “bulking agents,” “fillers,” or “diluents” when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.

The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.

As used herein, the term “IC50” refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.

An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.

As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1 -carboxylic acid),

4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauiylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, /7-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

A “pharmaceutically acceptable carrier,” “drug carrier,” or simply “carrier” is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled- release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

A “pharmaceutical drug” (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug, agent, or preparation) is a composition used to diagnose, cure, treat, or prevent disease, which comprises an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (defined above).

“Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

“Prodrug” means a compound that is convertible in vivo metabolically into an active pharmaceutical ingredient of the present invention. The prodrug itself may or may not have activity with in its prodrug form. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Non- limiting examples of suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl-sulfamates, quinates, and esters of amino acids. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains < 15%, more preferably < 10%, even more preferably < 5%, or most preferably < 1% of another stereoisomer(s).

A “repeat unit” is the simplest structural entity of certain materials, for example, frameworks and/or polymers, whether organic, inorganic or metal-organic. In the case of a polymer chain, repeat units are linked together successively along the chain, like the beads of a necklace. For example, in polyethylene, -[-CH2CH2-]_n-, the repeat unit is -CH2CH2-. The subscript “n” denotes the degree of polymerization, that is, the number of repeat units linked together. When the value for “n” is left undefined or where “n” is absent, it simply designates repetition of the formula within the brackets as well as the polymeric nature of the material. The concept of a repeat unit applies equally to where the connectivity between the repeat units extends three dimensionally, such as in metal organic frameworks, modified polymers, thermosetting polymers, etc.

“Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease or symptom thereof in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

The term “unit dose” refers to a formulation of the compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations.

The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.

V. Examples

The following examples are included to demonstrate preferred embodiments. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to fimction well in the practice of embodiments, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Preparative examples

Compounds C (also referred to as compound 16) and XI were synthesized as racemic mixtures with their corresponding enantiomers and purified according to procedures described in ref. 27.

Synthesis of Compound X2

To a solution of C (38 mg, 0.20 mmol, racemic mixture) and pyridine (97 pL, 1.2 mmol) in C¾CN (3.0 mL), a solution of triphosgene (31 mg, 0.11 mmol) in CH3CN (1.0 mL) was added at -45 °C. Then, the mixture was allowed to warm to room temperature and stirred for 3 h. Silica gel

(0.5 g) was added to the mixture, and the volatiles were evaporated under vacuum. The crude mixture absorbed on the silica was purified by flash column chromatography (SiCh, 1.5 g, CH2CI2 to CtfcCb/MeOH 10:1; R_f (CHzCh/MeOH 10:1): 0.50). The fractions containing X2 were concentrated, and the residue was triturated in QkCh/MeOH 10:1 (x3) and pentane to give a racemic mixture of compound X2 and its enantiomer (33 mg, 76%) as a colourless solid. ^!H NMR (400 MHz, DMSO-i/e): 5.42 (ddd, VH-H = 7.6, 5.7, 4.2 Hz, 1H), 5.25 (ddd, VH-H = 7.6, 4.8, 3.2 Hz, 1H), 4.35 (dd, VH-H = 14.8, VH-H = 5.7 Hz, 1H), 4.26 (dd, VH-H = 14.8, VH-H = 4.2 Hz, 1H), 3.90 (dd, VH-H = 15.7, VH-H = 4.8 Hz, 1H), 3.84 (dd, V_H-H = 15.7, V_H-H = 3.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-de): 153.0 (C), 74.8 (CH), 70.0 (CH), 56.0 (CH₂), 34.2 (CH₂).

Synthesis of Compound X8

Compound 31. To a solution of C (549 mg, 2.98 mmol, racemic mixture) and 2.6-lutidine (0.76 mL, 6.6 mmol) in tetrahydrofuran (THF) (30 mL), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.77 mL, 3.3 mmol) was added dropwise at -78 °C under N2 atmosphere. The dry ice was removed to gradually warm the reaction mixture to room temperature. After 5.5 h, MeOH was added and the resulting mixture was concentrated. The residue was purified by flash column chromatography (S1O2 10 g, pentane/ethyl acetate 7:1 -2:1; Rt (pentane/ethyl acetate 3:1): 0.29) to give a racemic mixture of compound 31 and its enantiomer (658 mg, 74%) as a colorless solid. Ή NMR (400 MHz, CDCb): 4.28 (ddd, VH-H = 10.8, 4.1, 2.7 Hz, 1H), 4.11 (ddd, VH-H = 4.5, 2.7, 1.6 Hz, 1H), 3.65 (dd, VH-H = 13.0, VH-H =10.8 Hz, 1H), 3.52 (dd, VH-H = 14.9, VH-H = 1.6 Hz, 1H), 3.39 (dd, VH-H = 14.9, VH-H = 4.5 Hz, 1H), 3.25 (dd, VH-H = 13.0, VH-H = 4.1 Hz, 1H), 0.91 (s, 9H), 0.15 (s, 6H); ¹³C NMR (100 MHz, CDCb): 71.5 (CH), 65.2 (CH), 60.5 (CH₂), 36.2 (CH₂), 25.7 (CH₃), 18.1 (C), -4.5 (CH₃), -4.7 (CH₃).

Compound 32. To a solution of 31 (50 mg, 0.17 mmol, racemic mixture) and pyridine (81 pL, 1.0 mmol) in CH2CI2 (1.7 mL), triphosgene (46 mg, 0.16 mmol) was added at 0 °C. The cooling bath was removed, and the reaction mixture was stirred for 2.5 h. The mixture was concentrated, and the residue was dissolved in CH3CN (1.7 mL). /V-Boc-ethylenediamine (53 pL, 0.34 mmol) was added to the mixture. The mixture was stirred for 1 h, and concentrated. The residue was purified by flash column chromatography (S1O2, 0.5 g, pentane/ethyl acetate 10:1 to 1.5:1; R_f (pentane/ethyl acetate 3:1): 0.41) to afford a racemic mixture of 32 and its enantiomer (70 mg, 85%) as a colorless solid. *H NMR (400 MHz, CDCb): 5.38 (hr s, 1H), 5.24 (m, 1H), 4.78 (hr s, 1H), 4.33 (ddd, VH-H = 10.8, 3.4, 3.4 Hz, 1H), 3.64 (dd, VH-H = 12.7, VH-H = 10.8 Hz 1H), 3.54 - 3.43 (m, 2H), 3.40 - 3.18 (m, 5H), 1.44 (s, 9H), 0.87 (s, 9H), 0.12 (s, 6H); ¹³C NMR (101 MHz, CDCI3): 156.6 (C), 155.6 (C), 80.0 (C), 70.1 (CH), 67.2 (CH), 62.1 (CHz), 42.1 (CH₂), 40.4 (CH₂), 35.3 (CH₂), 28.5 (CH₃), 25.7 (CH₃), 18.0 (C), -4.76 (CH₃), -4.79 (CH₃).

Compound X8. To a solution of 32 (20 mg, 41 jumol, racemic mixture) and AcOH (14 pL, 0.25 mmol) in THF (2.1 mL), tetra-N-butylammonium fluoride (TBAF) (1.0 M in THF, 0.12 mL, 0.12 mmol) was added at 0 °C. After the mixture was stirred for 25 min, sat. NH4CI aq. was added. The resultant mixture was extracted with ethyl acetate (x3), and the combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography twice (S1O2, 1 g, CH2CI2 to CH₂Cl2/MeOH 40:1; S1O2, 0.5 g, CH2CI2 to CHaCk/MeOH 40:1, Rt (CH2Cl2/MeOH 10:1): 0.35) to afford a racemic mixture of X8 and its enantiomer (12 mg, 80%) as a colorless solid. ^JH NMR (500 MHz, CDCI3, 50 °C): 5.50 (br s, 1H), 5.31 (br s, 1H), 4.82 (br s, 1H), 4.41 (ddd, V_H-H = 10.2, 4.4, 2.8 Hz, 1H), 3.82 - 3.04 (m, 8H), 1.45 (s, 9H); ¹³C NMR (126 MHz, CDCls, 50 °C): 157.0 (C), 156.0 (C), 80.4 (C), 69.7 (CH), 68.2 (CH), 62.0 (CH₂), 42.6 (CH2), 40.4 (CH₂), 35.0 (CH₂), 28.6 (CH₃).

Synthesis of Compound X22

Compound 34. To a solution of 33 (140 mg, 0.60 mmol) in CH2CI2 (6.0 mL), meta- chloroperoxybenzoic acid (mCPBA) (77% with H2O, 340 mg, 1.52 mmol) was added at room temperature. After 22 h, the mixture was diluted with CH2CI2, washed with sat. NaHCOs aq. (x3), dried over Na2SC>4, filtered and concentrated to afford 34 (105 mg, 66%; regioisomers 34a/34b 6:1) as a colorless solid. 34a (major): *H NMR (500 MHz, DMSO-Je): 7.28 (d, VH-H = 7.4 Hz,

1H), 3.94 - 3.84 (m, 1H), 3.77 - 3.64 (m, 2H), 3.36 (dd, VH-H = 13.8, VH-H = 3.1 Hz, 1H), 3.27 (dd, VH-H = 13.8, V_H-H = 8.8 Hz, 1H), 2.27 - 2.18 (m, 2H), 1.39 (s, 9H); ¹³C NMR (126 MHz, DMSO-i/e): 154.8 (C), 78.4 (C), 58.0 (CH₂), 45.2 (CH), 37.9 (CHz), 30.9 (CH2), 28.2 (CH3); 34b (minor): ¾ NMR (500 MHz, DMSO-t/e, some peaks were deduced from HSQC and HMBC): 7.25 (d, VH-H = 7.4 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.71 (1H), 3.45 (ddd, VH-H = 14.3, V_H-H = 4.6, 3.2

Hz, 1H), 3.25 - 3.15 (m, 2H), 2.24 (1H), 1.75 - 1.65 (m, 1H), 1.39 (s, 9H); ¹³C NMR (125 MHz, DMSO-tfc): 154.3 (C), 78.6 (C), 63.3 (CH₂), 48.4 (CH), 31.60 (CH₂), 31.57 (CH₂), 28.1 (CH₃). Compound X22. Compound 34 (49 mg, 0.19 mmol) was dissolved in a solution of HC1 in 1,4- dioxane (4.0 M, 6.2 mL) and the solution was stirred for 63 h at room temperature. The mixture was concentrated and azeotropically dried with MeOH (x3) to give a crude product 35 (a mixture of regioisomers 35a and 35b), which was used in the next reaction without further purification.

A stock solution of triphosgene (21 mg, 70 μπιοΐ) in CH3CN (1.3 mL) was prepared. To a solution of 35 and EtsN (0.10 mL, 0.74 mmol) in CH3CN (1.0 mL) at room temperature, the stock solution of triphosgene (0.14 mL, 7.5 pmol) was added. The same amount of the stock solution was added every 10 min for additional 5 times. After the mixture was stirred for additional 1 h, MeOH was added to the mixture, and the resultant solution was concentrated. The residue was purified by reverse phase flash column chromatography (H2O + 0.1% TFA/CH3CN + 0.1% TFA gradient from 100:0 to 60:40, TFA being trifluoroacetic acid). The solvent was removed by lyophilization to give X22 (X22a/X22b/X22c ~100:20:0.5, 18 mg, 54% over 2 steps) as a colorless solid. X22a: ^lE NMR (500 MHz, DMSO -d₆): 6.53 (d, VH-H = 8.0 Hz, 2H), 4.11 - 4.01 (m, 2H), 3.75 - 3.65 (m, 2H), 3.59 (ddd, V_H-H = 14.0, VH-H = 8.4, 3.7 Hz, 2H), 3.51 - 3.41 (m, 2H), 3.31 (dd, VH-H = 14.0, VH-H = 7.7 Hz, 2H), 2.33 - 2.16 (m, 4H) ;¹³C NMR (126 MHz, DMSCMs): 154.4 (C), 55.8 (br, C¾), 41.6 (br, CH), 37.2 (br, CH₂), 29.5 (CH₂).

Synthesis of Compound 4-8

Compound 4-8. To a solution of 31 (107 mg, 0.359 mmol, racemic mixture) and pyridine (0.17 mL, 2.2 mmol) in CH2CI2 (3.6 mL), triphosgene (107 mg, 0.359 mmol) was added at 0 °C (ice bath). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 5.5 h. The mixture was concentrated, and the crude chlorofonnate was dissolved in C¾CN (1.4 mL). A solution of hexamethylenediamine (17.0 mg, 0.146 mmol, azeotropically dried with toluene) and EtsN (41 pL, 0.293 mmol) in CH3CN (0.74 mL) was added portionwise (5 times over 1.5 h) to the solution of the crude chloroformate at room temperature, and the mixture was stirred for an additional 1 h. MeOH was added to the mixture to precipitate an isomeric mixture of 4-8 (10.8 mg, 9.2%), comprising 4-8a (racemic mixture of both enantiomers) as well as 4-8b. The supernatant was concentrated, and the residue was purified by flash column chromatography (S1O2, 10 g, CH₂Cl₂/MeOH 100:1 - 50:1, R_f (CH₂Cl₂/MeOH 20:1): 0.40). The purified product was triturated in a 1:1 mixture of Et₂Q and pentane (x2) and in Et₂0 (xl) to afford an isomeric mixture of 4-8 (27.5 mg, 23%) as a colorless solid. *H NMR (400 MHz, CDCI3): 5.27 - 5.19 (m, 2H), 4.97 - 4.84 (br m, 2H), 4.33 (ddd, VH-H = 10.8, 3.6, 3.4 Hz, 2H), 3.65 (dd, VH-H = 13.0, V_H- _H = 10.8 Hz, 2H), 3.54 - 3.45 (m, 4H), 3.33 (dd, VH-H = 13.0, VH-H = 3.6 Hz, 2H), 3.24 - 3.12 (m, 4H), 1.58 - 1.48 (m, 4H), 1.40 - 1.30 (m, 4H), 0.88 (s, 18H), 0.12 (s, 12H); ¹³C NMR (100 MHz, CDCh): 155.3 (C), 70.1 (CH), 67.0 (CH), 62.1 (CH₂), 41.1 (CH₂), 35.4 (CH₂), 29.9 (CH₂), 26.3 (CH₂), 25.7 (CH₃), 18.0 (C), -4.75 (CH₃), -4.78 (CH₃); HRMS (ESI, +ve) calcd for

C₂₈H₅₆N₂OioS₄Si₂ ([M+H]⁺): 765.2430, found: 765.2412.

Synthesis of Compound 5-8

Compound 36. To a solution of compound C (190 mg, 1.03 mmol, racemic mixture) and KI (0.242 mmol) in DMF (5.0 mL), benzyl bromide BnBr (0.59 mL, 5.0 mmol) and NaH (60% with mineral oil, 42.3 mg, 1.06 mmol) were successively added at -45 °C (CHgCN/diy ice bath). The cooling bath was removed and the mixture was stirred at room temperature for 25 h. Sat. NH4CI aq. was added, and the mixture was extracted with CH₂C1₂ (x3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The residue was purified by flash column chromatography (Si0₂, 5 g, CH₂C1₂ -CH₂C½/MeOH 10:1) and reverse phase flash column chromatography (SNAP Ultra C18 12 g, H₂0 + 0.1% TFA/CH₃CN + 0.1% TFA gradient from 9:1 to 4:6). The purified product was triturated in CHCb to afford a regioisomerically pure, racemic mixture of 36 and its enantiomer (42.9 mg, 16%) as a colorless solid. *H NMR (400 MHz, CDCb): 7.43 - 7.35 (m, 3H), 7.35 - 7.30 (m, 2H), 4.69 (d, VH-H = 1 1.6 HZ, 1 H), 4.62 (d, VH-H = 11.6 Hz,

1H), 4.39 - 4.26 (m, 1H), 4.07 (ddd, VH-H = 10.9, 3.9, 2.6 Hz, 1H), 3.71 (dd, VH-H = 13.0, VH-H = 10.9 Hz, 1H), 3.49 (dd, VH-H = 14.9, V_H-H = 1.7 Hz, 1H), 3.46 (dd, VH-H = 13.0, VH-H = 3.9 Hz, 1H), 3.38 (dd, VH-H = 14.9, VH-H = 4.8 Hz, 1H), 2.57 (br s, 1H); ^I3C NMR (101 MHz, CDCb): 136.6 (C), 129.0 (CH), 128.8 (CH), 128.1 (CH), 77.3 (CH), 72.0 (CH₂), 63.3 (CH), 58.2 (CH₂), 36.6 (CH₂); MS (ESI): 292 ([M+NH₄]⁺).

Compound 37. To a solution of compound 36 (45.2 mg, 0.165 mmol, racemic mixture) in CH2CI₂ (1.7 mL), /7-nitrophenyl chloroformate (33.4 mg, 0.166 mmol) and pyridine (27 pL, 0.33 mmol) were successively added at 0 °C (ice bath). The cooling bath was removed, and the mixture was stirred at room temperature for 3.5 h. Pyridine (0.11 mL, 1.32 mmol) and /7-nitrophenyl chloroformate (140 mg, 0.694 mmol) were added. The mixture was stirred at room temperature for further 2 h and passed through a pad of silica gel (5 g, CH₂CI₂), and the filtrate was concentrated. The residue was purified by PTLC (CH₂Cl₂/acetone 50: 1 , R_t (CH₂Cb/acetone 50: 1): 0.38) to afford a racemic mixture of 37 (72.2 mg, 100%) as a colorless foam. *H NMR (400 MHz, CDCb): 8.30 - 8.23 (m, 2H), 7.45 - 7.28 (m, 7H), 5.56 - 5.52 (m, 1H), 4.71 (d, VH-H = 11.4 Hz, 1H), 4.67 (d, VH-H = 11.4 Hz, 1H), 4.23 (ddd, VH-H = 11.2, 3.9, 2.6 Hz, 1H), 3.80 (dd, VH-H = 13.2, VH-H = 11.2 Hz, 1H), 3.67 - 3.54 (m, 3H); ¹³C NMR (101 MHz, CDCb): 155.3 (C), 152.0 (C), 145.8 (C), 136.4 (C), 129.0 (CH), 128.8 (CH), 128.2 (CH), 125.5 (CH), 121.9 (CH), 75.7 (CH), 72.4 (CH₂), 69.0 (CH), 59.6 (CH₂), 34.7 (CH₂).

Compound 5-8. Hexamethylenediamine (28.8 mg, 0.248 mmol, azeotropically dried with toluene) and EtsN (115 pL, 0.83 mmol) were dissolved in CH₃CN (13.5 mL). The stock solution was added portionwise (6x0.20 mL over 1.5 h) to the solution of 37 (16.1 mg, 36.6 pmol, racemic mixture) in CH3CN (0.63 mL) at room temperature, and the mixture was stirred for an additional h. The mixture was concentrated, and the residue was purified by flash column chromatography (S1O₂, 0.5 g, CH₂Cl₂/MeOH 100:1 - 20:1, R_f (CH₂Cl₂/MeOH 30:1): 0.33) and PTLC (CHzCla/MeOH 30:1; CH₂Cl₂/acetone 10:1) to afford an isomeric mixture of 5-8 (8.4 mg, 64%), comprising of 5-8a (racemic mixture of both enantiomers) and 5-8b, as a white solid. *H NMR (400 MHz, CDCI3): 7.51 - 7.29 (m, 10H), 5.56 - 5.44 (m, 2H), 4.94 (br t, VH-H = 5.6 Hz, 2H), 4.71 (d, VH-H = 11.5 Hz, 2H), 4.57 (d, VH-H = 11.5 Hz, 2H), 4.10 (ddd, VH-H = 11.2, 3.8, 2.6 Hz, 2H), 3.69 (dd, VH-H = 12.1, VH-H = 11.2 Hz, 2H), 3.60 - 3.34 (m, 6H), 3.19 (td, VH-H = 6.8, 5.6

Hz, 4H), 1.56- 1.43 (m, 4H), 1.39- 1.29 (m, 4H). ¹³CNMR (101 MHz, CDCI3): 155.2 (C), 136.7 (C), 128.9 (CH), 128.6 (CH), 128.1 (CH), 75.8 (CH), 72.0 (CH₂), 64.1 (CH), 59.8 (CH₂), 41.1 (CH₂), 35.7 (CH₂), 29.7 (CH₂), 26.3 (CH₂); MS (ESI): 739 ([M+Na]⁺). General Procedure of the High-Content High-Throughput (HCHT) Inhibitor Screening

Pre-Incubation of Inhibitors and Reporters

HeLa Kyoto cells were seeded at 8 x 10⁴ cells/mL in FluoroBrite DMEM + 10% FBS on μ-Plate 96-well Black ibiTreat sterile and kept at 37 °C with 5% C0₂ overnight. Next day, serial dilutions of die inhibitors in phosphate buffered saline (PBS) (1 Ox final concentration), reporter 1 or 2 (100 μΜ in PBS) and a solution of Hoechst 33342 (100 μg/mL) and propidium iodine (PI) (10 pg/mL) in PBS were prepared freshly in a 96-well V-bottom plate. Then, cells were washed with PBS (3 x 3 mL/well) and the media was exchanged to FluoroBrite DMEM (4 x 150 pL/well) using a plate washer (Biotek EL406®), keeping a final volume of 135 pL/well. The inhibitor solutions from the V-bottom plate were added to the cells (15 pL/well, lOx final concentration in PBS) to reach a final volume of 150 pL/well. Cells were incubated for the time of interest (for details of each inhibitors, see Section 4.3 and 4.4) at 37 °C with 5% CCh. After this, cells were washed again using the plate washer and reporter solution 1 or 2 from the V-bottom plate was added (15 pL/well) to reach a final volume of 150 pL/well and a final concentration of 10 μΜ, except for the control wells, where only PBS was added (15 pL/well). After 30 min of incubation at 37 °C with 5% C0₂, the plate was washed again using the plate washer. Then, the solution of Hoechst 33342 and PI from V-bottom plate was added (15 pL/well) using to reach a final volume of 150 pL/well. After 15 min of incubation at 37 °C with 5% C0₂, the plate was washed one last time and the cells were kept in clean FluoroBrite DMEM. During imaging, samples were kept at 37 °C with 5% C0₂.

Co-Incubation of Inhibitors and Reporters HeLa Kyoto cells were seeded at 8 x10⁴ cells/mL in FluoroBrite DMEM + 10% FBS on μ-Plate 96-well Black ibiTreat sterile and kept at 37 °C with 5% COz overnight. Next day, serial dilutions of the inhibitors in PBS (lOx final concentration), reporter 1 or 2 (110 μΜ in PBS) and a solution of Hoechst 33342 (100 μg/niL) and PI (10 μg/mL) in PBS were prepared freshly in a 96-well V- bottom plate. Then, cells were washed with PBS (3 x 3 mL/well) and the media was exchanged to FluoroBrite DMEM (4 x 150 pL/well) using a plate washer (Biotek EL406®), keeping a final volume of 135 pL/well. The inhibitor solutions from the V-bottom plate were added to the cells (15 pL/well, lOx final concentration in PBS) to reach a final volume of 150 pL/well. Cells were incubated for the time of interest (for details of each inhibitors, see Section 4.3 and 4.4) at 37 °C with 5% CO2. Reporter solution 1 or 2 from V-bottom plate was then added (15 pL/well) to reach a final volume of 165 pL/well and a final concentration of 10 μΜ 30 min before the next washing process, except for the control wells, where only PBS was added (15 pL/well). The plate was washed again using the plate washer. The solution of Hoechst 33342 and PI from V-bottom plate was added (15 pL/well) to reach a final volume of 150 pL/well. After 15 min of incubation at 37 °C with 5% CO2, the plate was washed one last time and the cells were kept in clean FluoroBrite DMEM.

Note: For each of both pre-incubation and co-incubation experiment, 4 images at lOx were recorded per well using three channels: blue for Hoechst 33342 (excitation filter: 377/50 nm; emission filter: 477/60 nm), green for FITC (fluorescein isothiocyanate) reporters (excitation filter: 475/34 nm; emission filter: 536/40 nm) and red for PI (excitation filter: 531/40 nm; emission filter: 593/40 nm). Duplicates were performed for each condition.

Data Analysis for HCHT Inhibitor Screening To first mask each cell, blue channel (Hoechst 33342) was used to detect the nucleus and the cell body (thanks to background signal in the cytoplasm).

To be able to extract the fluorescent integrated intensity information (sum of the intensities of all the pixels included in the mask) from the green channel for live cell only, the image analysis pipeline contains several steps of cell filtering and selection: 1) Firstly, PI is used to stain any remaining nuclei of dead cell. In the analysis pipeline, all the

“dead” nuclei are detected based on their fluorescent intensity in the PI channel. 2) Elimination of non-full cells from the border of the image is performed, to avoid inaccurate fluorescent integrated intensity quantification (fluorescent integrated intensity = sum of intensity of all the pixel of the object).

3) Finally, the analysis pipeline includes a detection of fluorophore aggregates which could highly affect the quantification. The very bright aggregates are detected based on their size and brightness. The resulting object is then slightly grown (5 pixels) and used to remove all cells in the vicinity. The aggregate object is even removed from the master image object which ensure that no fluorescent intensity data can be retrieved from those area. HCHT Inhibitors Screening Results using 1 as the Reporter

Integrated fluorescent intensity values (per cell) for each condition in the presence of inhibitors were normalized using the value of integrated fluorescent intensity (per cell) with addition of reporter 1, Hoechst 33342 and PI as maximum signal (7_rei = 1) and the value of integrated fluorescent intensity (per cell) with only addition of Hoechst 33342 and PI as minimum (/_rei = 0), for each set of experiments. Duplicates were performed for each condition. The resulting dependence of the relative fluorescent intensity values (/_rei) to the concentration of inhibitors (ex_hi_bi_tor) was plotted and fitted with Equation 1 to retrieve the half maximal inhibitory concentration (IC50) value and the Hill coefficient («).

Relative cell viability (R V) for each condition in the presence of inhibitors were calculated using the count value of living cells by dividing the count value of living cells with addition of reporter 1, Hoechst 33342 and PI, for each set of experiments. Duplicates were performed for each condition. The resulting dependence of the relative cell viability (/ZFrei) to the concentration of inhibitors (ex_hi_bi_tor) was plotted and fitted with Equation 2 to retrieve the concentration causing 50% cell growth inhibition (GI50) value and the Hill coefficient (»).

It is to be noted that reporter 1 was not toxic for 1 h at 10 μΜ. Also in this study, the count value of living cells with addition of reporter 1, Hoechst 33342 and PI is always similar to that of living cells with only addition of Hoechst 33342 and PI.

Example 1 Fluorescentiy labeled COCs l⁷ and 2⁹ were selected as reporters for the screening of thiol- mediated uptake inhibitors because of their high activity and their different characteristics (FIG. 2). The COC in 1 is an epidiketodithiopiperazine (ETP). With a CSSC dihedral angle ~0°, ETPs drive disulfide ring tension to the extreme.¹⁴ Ring-opening thiol-disulfide exchange is ultrafast, and the released thiols are acidic enough to continue exchange in neutral water, including ring closure.⁹ This unique exchange chemistry coincides with efficient cellular uptake and poor retention on thiol affinity columns ⁹

The COC in 2 is a benzopolysulfane (BPS). Like ETPs, BPSs occur in natural products and have inspired total synthesis.¹⁵ Unlike ETPs, BPSs are not strained but evolve into adaptive networks of extreme sulfur species for cells to select from. Uptake efficiencies and retention on thiol affinity columns exceed other COCs by far.^9,16

With COCs 1 and 2 as cell-penetrating reporters, a fully automated, fluorescent microscopy image-based high-content high-throughput (HCHT)¹⁷ inhibitor screening assay was developed. HeLa cells in multiwell plates are incubated with a reporter at constant and inhibitors at varying concentrations. Hindered reporter uptake causes decrease of fluorescence inside of cells (FIG. 3A). Automated data analysis¹⁷ was established to extract average fluorescence intensity per cell and the number of healthy, attached cells from the same experiment (FIGS. 3A-F; Appendix A). Standard assay conditions consist of pre-incubation of HeLa cells with inhibitors for different periods of time, followed by the removal of inhibitors and the addition of reporters, thus excluding possible interactions between the two. In alternative co-incubation conditions, inhibitors were not removed before the addition of reporters to allow for eventual interactions between the two.

Reporters 1 and 2 and candidates 3-29 were prepared by multistep synthesis by following or adapting related reported procedures (Appendix A; commercially available: 19, 24, 28, 29). Inhibitors are numbered in the order of efficiency against reporter 1, evaluated by their minimum inhibitory concentrations (MICs), i.e., concentrations that cause a ~15% reduction of reporter uptake in cells (FIG. 2; Appendix A). The inventors chose to use MICs here because the half- maximal inhibitions could not always be reached due to the onset of toxicity, anti-cooperative, or even V-shaped dose-response curves (DRCs, e.g., FIGS. 3B-F; Appendix A).

Among the most potent inhibitors of ETP reporter 1 were ETPs 4 and 5 (FIGS. 2 and 3B). This intriguing self-inhibition was even surpassed by the expanded cyclic tetrasulfide ETP43 (MIC < 0.1 μΜ), which was of interest because they are much poorer transporters.⁹ Further formal ring expansion leads to cyclic pentasulfides BPSs 6 as equally outstanding inhibitors (MIC ~ 0.3 μΜ). This trend toward the adaptive networks reminiscent of pure sulfur chemistry did not extend toward inorganic polysulfides 13 (MIC ~ 30 μΜ). ETPs 3 and 5 were sensitive to modification of the carboxylate, with the cationic 12 being the worst (MIC ~ 30 μΜ) and the neutral glucose hemiacetal 7 the most promising (MIC ~ 0.6 μΜ).

Nucleophilic aromatic substitution of heteroaromatic sulfones¹⁸ converts exofacial thiols into sulfides. Weaker than dynamic covalent COCs, this irreversible inhibition was best with benzoxazole 11 (MIC ~ 20 μΜ) and weakened in accordance with reactivity to oxadiazole 14 and benzothiazole 20 (MIC ~ 500 μΜ, FIG. 3E).

At constant pH, Ellman’s reagent 19 was confirmed to be erratic also in this assay. The DRC showed minor inhibition up to around 2 mM, which disappeared again at higher concentrations (FIG. 3F). Other cyclic disulfides were inactive as well (27-29). Also disappointing were oxidized disulfides, that is thiosulfinates, including allicin 24, the main odorant component of garlic,^19,20 oxidized cystine 25 or lipoic acid 26. Thiosulfinates were of interest because they should selectively target the vicinal thiols of reduced disulfides bridges, producing two disulfides.²¹ The most active trans DTT thiosulfinate 16 isomerized with time into the less active, hydrogen-bonded cis isomer 21 (Appendix A).

Reporter 2 was more difficult to inhibit than 1, as expected from high activity with extreme retention on thiol affinity columns.^9,16 For instance, BPS 6 was very efficient against ETP 1 but failed to “self-inhibit” BPS 2 (FIG. 3 A). The complementary ETP 4 “self-inhibited” ETP 1 but was also unable to inhibit BPS 2 (FIG. 3B). The best inhibitors of BPS 2 upon co-incubation were disulfide bridged γ-tum²² peptides 17 and 18 (MIC ~ 5 μΜ), both only weakly active against 1 (MIC ~ 300 μΜ, FIG. 3C). Disulfide-bridged γ-tum CXC peptides produce an 11 -member ring with significant Prelog strain. They have been introduced by Wu and coworkers as transporters for efficient cytosolic delivery.⁴ The cyclic thiosulfonate 15 showed promising activities against both 1 and 2 (FIGS. 2 and 3D).

The orthogonal inhibition profiles found for reporters 1 and 2 supported that thiol-mediated uptake proceeds through a series of at least partially uncoupled parallel multitarget systems instead of a specific single target. Proteomics analysis done for asparagusic acid derived transporters supports the involvement of many targets beyond the commonly considered protein disulfide isomerases and the confirmed transferrin receptor.^23,11"13 The unusual, formally anti-cooperative (Hill coefficient < 1) DRCs were further in support of thiol-mediated uptake as complex multitarget systems.

Despite the complexity of these systems, results did not much depend on assay conditions. Compared to the standard protocol of pre-incubation with inhibitors followed by inhibitor removal and incubation with reporters 1 or 2 for detection, the co-incubation protocol, in which preincubation with inhibitors is followed by co-incubation with reporters 1 or 2 without inhibitor removal, gave reasonably similar results (FIG. 2). Mostly increasing MICs suggested that direct reporter-inhibitor interactions are not involved. Inhibition characteristics naturally depended on pre-incubation time, with weaker activities at shorter and longer times, reflecting incomplete exchange and cellular response or other ways of inhibitor destruction, respectively. In the presence of serum, activities were unchanged (FIG. 2, group d), or decreased slightly (FIG. 2, group b).

Preliminary studies on antiviral activity were performed with pseudo-lentivectors that express the D614G mutant¹⁰ of the SARS-CoV-2 spike protein and code for a luciferase reporter gene, which is expressed by the infected cells.¹¹ A549 human lung alveolar basal epithelium cell line constitutively overexpress ACE2 and TMPRSS2 was selected to facilitate the entry of the SARS-CoV-2 spike pseudo-lentivirus. The onset of inhibition could be observed for tetrasulfide ETP 3 at 50 μΜ, but it coincided with the appearance of cytotoxicity, while another compound showed promising activity. Activity with wild-type A549 cells transduced with a standard lentivirus expressing vesicular-somatitis virus G surface protein VSVG disfavored protease inhibition as mode of action.¹² Incubation times of virus and inhibitor before addition to cells limited to 1 hour disfavored contributions from changes in gene expression. More detailed studies are ongoing.

The lessons learned from this study are as follows: Firstly, thiol-mediated uptake can be inhibited efficiently by thiol-reactive reagents, confirming that thiol-mediated uptake exists and transporters like ETP 1 and BPS 2 do not simply diffuse into cells; the best inhibitors are 5000 times better than Ellman’s reagent. Secondly, inhibitor efficiencies vary with the transporters, supporting that thiol-mediated uptake operates as a complex multitarget system. The best inhibitors are COCs that operate with fast dynamic covalent exchange, suggesting that the reversibility provided by COCs, and thus mobility, are important. The inhibition of thiol-mediated uptake might contribute to activities of thiol-reactive antivirals such as ETPs or ebselen, although they have been shown to bind to zinc fingers or inhibit proteases.^14d’^24,25 Finally, the inhibitors reported here and in future^24'26 of thiol-mediated uptake could also be of interest for delivery applications and might be worth investigating for antiviral activity.

Example 2

Aim. This study aims at testing organic compounds for the inhibition of SARS-CoV-2 entry. Infection of SARS-CoV-2 in human cells is essentially mediated by two host proteins: at first the angiotensin converting enzyme 2 (ACE2) serves as a receptor for the viral spike protein. Then the transmembrane protease serine 2 (TMPRSS2) cleaves the viral spike protein, allowing the virus-host cell membranes fusion and delivery of viral material inside the cell.¹¹

Since the beginning of the SARS-CoV-2 mutation, the mutation D614G mutation has appeared on the spike protein sequence and confers enhanced infectivity.¹⁰ Because this new mutation stands for >90% of current infections (nextstrain.org) the D614G mutant will be used in this experimental setup.

To avoid biosecurity constraints of P3 laboratory, pseudo-lentivectors expressing the SARS-CoV-2 spike protein were generated. These pseudolentivector code for a luciferase reporter gene which is expressed by the infected cells. Thus, upon inhibition of the viral entry, the reporter signal should decrease.

Results. The A549 human lung alveolar basal epithelium cell line constitutively overexpress ACE2 and TMPRSS2 to facilitate the entry of the SARS-CoV-2 spike pseudo- lentivirus. These cells were treated prior to viral addition for 24h to observe effect linked with changes in gene expression, or lh to observe impairment of cellular mechanisms and proteases.

Compound C appears to inhibit significantly the entry of the SARS-CoV-2 pseudo- lentivirus with an IC50 of about 50 JJM (lOx dilution, FIG. 4A). Only at highest 500 μΜ (lx dilution) cell viability appears to be affected and decreased down to 53% (FIG. 4B). All other compounds did not show any significant phenotype.

To test the specificity of the phenotype, similar experiment was performed with wild-type A549 cells transduced with a standard lentivirus (expressing vesicular-somatitis virus G surface protein VSVG). Analogous inhibition by compound C was observed with an IC₅0 between 50 and 500 μΜ.

Discussion. SARS-CoV-2 entry requires the enzymatic processing of its surface protein spike by proteases such as TMPRSS2. In sharp contrast, the VSV-G protein does not require any proteolytic cleavage for viral entry (Sun et al, 2010, Future Virol). Because compound C inhibits both SARS-CoV-2 spike and VSV-G lentivectors (FIGS. A and 4C), it is very likely that this drug inhibits a downstream viral mechanism such as proteases, reverse transcription or reporter expression ; due to the short lh treatment time one can exclude that this compound requires changes in gene expression to be active. Hence this compound inhibits HIV and SARS-CoV-2 entry and may be used to treat these viruses.

Interestingly, compound F shows a tendency of inhibiting standard VSV-G lentivector in a specific manner (FIG. 4C). One may hypothesize that at higher concentration it may specifically inhibit VSV-G entry, if its cytotoxicity remains low.

Example 3

The experiments to measure inhibition of viral entry and impact on cell viability as described in Example 2 were repeated for compounds C, XI, X2, X8, X22, 4-8 and 5-8 (Figure 5, panel on the right). Compounds XI, X2, X8, and X22 showed significant inhibition of viral entry (75%) (Figure 5A) at a concentration of 50 μΜ, without significant reduction of cell viability (Figure 5B). Compounds 4-8 and 5-8 showed good efficiency with IC50 ~10 μΜ (Figure 5C).

Example 4

Screening Results using 1 as a Reporter

HCHT screening as described above has been performed for compound 16 (also referred to as compound C), using compound 1 as reporter. Automatically analyzed HCHT data is shown in Figure 6. Fluorescence intensity (filled symbols), and relative viability (empty symbols) are shown for HeLa cells after A) pre-incubation with 16 for 1 h (dark grey circles), 2 h (grey circles) and 4 h (light grey circles) followed by incubation with 1 (10 μΜ) for 30 min; B) incubation with 16 for 5.5 h with FBS (dark grey squares) and 23.5 h with FBS (grey squares) followed by co-incubation with 1 (10 μΜ) for 30 min. Data is further summarized in Table 1.

Table 1. MICs, ICso and GIso values of 16 under each condition.

“^"^Pre-incubation with 16 for 1 h, 2 h and 4 h followed by incubation with 1 for 30 min, respectively. ^{d e}Incubation with 16 for 5.5 h with FBS and 23.5 h with FBS followed by coincubation with 1 for 30 min, respectively.

Screening Results using 2 as a Reporter

HCHT screening as described above has been performed for compound 16 (also referred to as compound C), using compound 2 as reporter. Automatically analyzed HCHT data showing fluorescence intensity (filled symbols) and relative viability (empty symbols) of HeLa cells after pre-incubation with 16 for 4 h (blue circles) followed by incubation with 2 (10 μΜ) for 30 min is presented in Figure 7. Data is further summarized in Table 1.

Table 2. MICs, ICso and GIso values of 16 under each condition.

“Pre-incubation with 16 for 4 h followed by incubation with 2 for 30 min.

Example 5

Compounds C, X2, X8 and X22 were tested in an in vitro protease inhibition assay against cathepsin L, cathepsin B and trypsin using a peptide derived from SARS-CoV2 as a substrate at the concentration of 50 μΜ.

According to the experimental design, quenched fluorescent peptides with sequences mimicking that of the S1/S2 spike cleavage site (peptide 1 for SARS-CoV2, peptide 2 for SARS-CoV) that is recognized by the proteases of interest is used. The fiuorophore moiety used in these experiments is (7-methoxycoumarin-4-yl)acetyl (MCA), and the quencher used in these experiments is 2,4- dinitrophenyl (DNP). Upon cleavage, fiuorophore is no longer in spatial proximity to the quencher, which results in observed increase in fluorescence emission. Upon inhibition of the protease activity, and thus of the peptide cleavage by protease, the observed increase in fluorescence emission is decreased.

Table 3. Equipment, products and chemicals as used in Example 5.

Stock solutions and buffer solutions used in the experiments of Example 5.

Reaction buffers:

PCI buffer reaction solution pH=6 25 mM MES

5 mM CaCk i.e. 36.75 mg in 50 ml 0.1% Brij-35 i.e. 100 μΐ in 50 ml

Cathepsin B buffer pH=5 25 mM MES

Cathepsin L buffer pH=6 0.005% Brij-35 i.e. 8.3 pi from 30% stock in 50 ml H₂0 1 mM EDTA i.e. 100 pi from 0.5 M EDTA stock in 50 ml H₂0 5 mM DTT i.e. 38.55 mg in 50 ml ¾0 50 mM MES

Trypsin buffer pH=7.4 PBS pH=7.4, ready to use

Furin buffer pH=7.5 100 mM HEPES i.e. 1191.5 mg in 50 ml H₂0

1 mM CaCh i.e. 7.351 mg in 50 ml H₂0 0.5 % Triton X 100 i.e. 250 μΐ in 50 ml H₂0 1 mM 2-Mercaptoethanol Matriptase buffer pH=9

50 mM Tris i.e. 394 mg in 50 ml H₂0 50 mM NaCl i.e. 146.1 mg in 50 ml U2O 0.01 % Tween 20 i.e. 50 pi in 50 ml H₂0 Protease stock solutions:

Trypsin stock: 800 nM, final concentration needed 8 nM Cathepsin L stock: 10 pg in 30 μΐ i.e. 333 ng per ul. Final concentration: 2.2 ng/μΐ Cathepsin B stock: 10 pg in 30 μΐ i.e. 333 ng/μΐ. Final concentration: 2.2 ng/μΐ Matriptase stock: 10 pg in 25 μΐ i.e. 400 ng/pl. Final concentration: 2.2 ng/pl Furin stock: 2000 U/ml. Final concentration: 10 U/ml PCI stock: 10 pg in 30 pi i.e. 333 ng/pl. Final concentration 2.2 ng/pl

Peptide stock solutions

Peptides 1 and 2 were resuspended in PBS at a concentration of 500 μΜ. Sequence for peptide 1 (SARS-CoV2): TNSPRRARSVA with modification MCAZLys(DNP) fluorophore/quencher pair. Sequence for peptide 2 (SARS-CoV): HTVSLLRSTSQ with modification MCA/Lys(DNP) fluorophore/quencher pair.

Preparation of reaction mixtures The reactions were conducted in 96 well black plates Costar with black bottom. The reactions were made up so that the final concentration of each protease was as shown in the section Protease stock solutions, and the compound concentration was set at 50 μΜ. Compound was added as 500 μΜ DMSO stock. The reactions were initiated by addition of 500 μΜ peptide stock solution in PBS to a final concentration of 50 μΜ, shortly before measurements. Final reaction volume was 50 \\L (Cathepsin B, Cathepsin L, Matriptase, Furin, PCI) or 100 pL (trypsin). In addition, control samples were measured, including negative control of reaction buffer with protease without peptide, and positive control of reaction buffer with protease and peptide, but without inhibitor (compound). Blank sample for measurements included reaction buffer and peptide. Fluorescence measurements

Fluorescence measurements were performed using FLEXSTATION 3 plate reader (Molecular Devices). The measurements were performed over 45 minutes at the temperature of 30 °C with excitation wavelength of 330 nm and emission wavelength of 390 nm. First 10 minutes of measurements were subjected to linear regression to extract the maximum reaction rate value (Vmax) as expressed in RFU (relative fluorescence units) per minute (RFU/min). Statistical analysis of data was performed to average experimental duplicates and compute standard deviation. The results for compounds C, X2, X8 and X22 tested against cathepsin L, cathepsin B and trypsin using peptide 1 as a substrate as described herein at the concentration of 50 μΜ are summarized in Figure 8. * * * * * * * * * * * * * * * * *

All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

Further aspects and /or embodiments of the invention are disclosed in the following numbered items:

1. A method of treating or preventing a viral infection comprising administering to a subject infected with the virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂ ^~; and

Ri, Ri\ Ra, Ra', Rs, Rs', Rn, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups wherein R₂/R₂’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄1S -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12),hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

Xi and X₃ are each independently a covalent bond, -0-, -NH-, -OC(O)-, -NHC(O)-; -HNC(0)0- or -0C(0)NH-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and Ri, R₂, R3, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl₍c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12>, aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: nis 0, 1, 2, or 3;

Ri, Ri', R₂, R₂', R₃, R₃ ^r, R_n, and Ro' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤i2), alkenyl(c≤i2), alkynyl(c≤i2), cycloalkyl(c≤i2), heterocycloalkyl(c≤i2), aryl(c≤i2), aralkyl(c≤i2), heteroaiyl(c<i2), heteroaralkyl(c≤i2), alkoxy(c≤i2), aryloxy(c≤i2), aralkoxy(c≤i2), heteroaryloxy(c≤i2), heteroaralkoxy(c<i2), alkylamino(c<i2), dialkylaminO(c≤i2), acyl(c≤i2), acyloxy(c≤i2), amido(c≤i2), or a substituted version of any of these groups; or -C(0)R₄, wherein:

R4 is hydroxy or amino; or alkoxy(c≤i2), alkylamino(c<i2), dialkylamino(c<i2), or a substituted version of any of these groups;

R₄ is alkyl(c≤12), aryl(c<i2), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)0H, or -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof, wherein the vims is not HIV. 2. The method of item 1, wherein the viral infection is not retrovirus infection.

3. The method of item 1, wherein the viral infection is a coronavims, Dengue vims, Ebola vims, West nile vims, Rabies virus, Influenza vims, Chikungunya vims or Zika vims infection. 4. The method of item 3, wherein the viral infection is a coronavims infection.

5. The method of item 4, wherein the coronavims is a beta coronavims.

6. The method of item 4, wherein the coronavims is MERS-CoV, SARS-CoV-1, or SARS- CoV-2.

7. The method of item 6, wherein the coronavims is MERS-Cov. 8. The method of item 7, wherein the subject has Middle East respiratory syndrome (MERS).

9. The method of item 6, wherein the coronavims is SARS-CoV-1.

10. The method of item 9, wherein the subject has severe acute respiratory syndrome (SARS).

11. The method of item 6, wherein the coronavims is SARS-CoV-2.

12. The method of item 11, wherein the subject has coronavims disease 2019 (COVED- 19). 13. The method of item 11, wherein said subject has a confirmed diagnosis of SARS-CoV-2.

14. The method of item 11, wherein said subject is suspected of begin infected with SARS- CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2.

15. The method of items 1-14, wherein administering comprises intravenous, intra-arterial, oral, intranasal, bronchial inhalation, parenterally, orally; as a suppository or topically. 16. The method of items 1-15, wherein administering comprises twice daily administration, once daily administration, every other day administration, every three-day administration or weekly administration. 17. The method of items 1-16, wherein administering continues for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months.

18. The method of any one of items 1-17, further comprising treating said subject with at least one other anti-coronavirus therapy.

19. The method of item 18, further comprising treating said subject with at least one other antiviral therapy.

20. The method of items 1-18, wherein said subject is a high-risk SARS-CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, broncho-pulmonary disease, cardiovascular disease, hypertension, or diabetes.

21. The method of item 4, wherein said subject exhibits abnormally reduced blood oxygenation, such as 90% or less.

22. The method of item 4, wherein said subject is concurrently receiving ventilation therapy. 23. A method of preventing viral infection comprising administering to a subject at risk of being infected with a virus a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)2^~; and RI, Rr, R2, R2', R3, R3', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R3/R3_’ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and Rj, wherein the five-membered heterocyclic ring is optionally substituted; or -C(0)Rt, wherein:

-0C(0)X₄RX, wherein:

Xt is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12),hydroxyalkynyl(c≤12),or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

Χ₂ and X₃ are each independently a covalent bond, -0-, -NH-, -0C(0)-, -NHC(O)-, -HNC(0)0- or -OC(0)NH-;

Y1 is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl(c≤12), or Yi is absent;

Xi is, in each instance independently, -S— , -S(O)-, or -S(O)₂~; and Ri, R₂, R₃, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12>, heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy<c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amidO(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤12_),hydroxyalkynyl₍c≤12₎,or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', R₂, Ra', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaiyloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylaminO(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R₄ is alkyl(c≤12), aryl(c<i₂), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof 24. The method of item 23, wherein the viral infection is not retrovirus infection.

25. The method of item 23, wherein the viral infection is a coronavirus, Dengue virus, Ebola virus, West nile virus, Rabies virus, Influenza virus, Chikungunya virus or Zika virus infection.

26. The method of item 25, wherein the viral infection is a coronavirus infection.

27. The method of item 26, wherein said subject has a confirmed diagnosis of SARS-CoV-2.

28. The method of item 26, wherein said subject is suspected of begin infected with SARS- CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2.

29. The method of any one of items 23-28, wherein administering comprises intravenous, intraarterial, oral, intranasal, orbronchial inhalation.

30. The method of any one of items 20-23, wherein administering comprises twice daily administration, once daily administration, every other day administration, every three-day administration or weekly administration.

31. The method of any one of item 23-30, wherein administering continues for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months.

32. The method of any one of items 23-31, further comprising treating said subject with at least one other antiviral therapy.

33. The method of any one of items 23-32, wherein said subject is a high-risk SARS-CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, broncho-pulmonary disease, cardiovascular disease, hypertension, or diabetes. 34. The method any one of claims of items 23-33, wherein said subject exhibits abnormally reduced blood oxygenation, such as 90% or less. 35. The method of any one of items 20-28, wherein said subject is concurrently receiving ventilation therapy.

36. A method of reducing one or more symptoms of a viral infection comprising administering to a subject infected with the virus a compound of the formula:

5

wherein: nis 0, 1, 2, or 3;

Xi is — S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', Rz, Rz', R3, Rs', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤iz), alkynyl(c≤12), cycloalkyl(c≤iz), heterocycloalkyl<c≤12), aryl(c≤iz), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤iz), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤iz), dialky lamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R₃/R_3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry Ra/Ra· and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted; or

-C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

wherein: m is 0-10;

wherein:

X₂ and X₃ are each independently a covalent bond, -0-, -NH-, -OC(O)-, -NHC(O)- , -HNC(0)0- or -OC(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤12), arenediyl(c≤12), or substituted arenediyl₍c≤12) , or Yi is absent;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)2~; and Ri, R2, Rs, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl<c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12>, aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or

-C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12>, hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxy alkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxy alkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', R2, Ra', R3, R3', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

Rt is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups;

R4 is alkyl(c≤12₎, aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)0H, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. 37. A method of decreasing mortality from SARS-CoV-2 comprising administering to a subject infected with SARS-CoV-2 a compound of the formula:

wherein: n is 0, 1, 2, or 3; Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R2, R2', R3, Rs', Rn, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl<c≤12), alkynyl(c≤12), cycloalkyl(c≤12),

5 heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R₃/R₃’

10 may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany Rz/Rr and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

15 R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c<i₂₎,

20 hydroxyalkyl(c<]2), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c<i₂), alkynyl(c<i₂), aminoalkynyl(c<i₂), hydroxyalkynyl(c<i₂), or a substituted or protected version of any of these groups; or a compound of the formula:

25 wherein: m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

Xa and X3 are each independently a covalent bond, -0-, -NH-, -OC(O)-, -NHC(O)-, -HNC(0)0- or -OC(0)NH-;

Yi is alkanediyl(c≤12), substituted alkanediyl(c≤ia), arenediyl(c≤12), or substituted arenediyl(c≤12), or Yi is absent;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)a-; and

Ri, Ra, R3, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or ammo; or alkyl(c≤12), alkenyl(c≤ia), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤ia), aralkyl(c<ia), heteroaryl(c≤ia), heteroaralkyl(c<ia), alkoxy(c≤ia), aryloxy(c≤12), aralkoxy(c≤ia), heteroaryloxy(c≤12), heteroaralkoxy(c≤ia), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤ia), acyloxy(c≤ia), amido(c≤ia), or a substituted version of any of these groups; wherein Ra and Rs may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry Ra and R3, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤ia), aminoalkyl(c≤12), hydroxy alkyl(c≤12), alkenyl(c≤ia), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', Rz, Rz', R3, Rs', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

Rt is alkyl(c≤12), aiyl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof. 8. A method of reducing duration of hospitalization from SARS-CoV-2 comprising administering to a subject infected with SARS-CoV-2 a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R₂, Ra', Rs, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R3/R3' may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

wherein: m is 0-10;

wherein:

X2 and X3 are each independently a covalent bond, -0-, -NH-, -OC(O)-, -NHC(O)-, -HNC(0)0- or -OC(0)NH-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and Ri, Rz, Rs, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

wherein: n is 0, 1, 2, or 3;

Ri, Ri', Rz, R2', R3, R3', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤i 2), alkylamino(c≤12), dialkylamino(c≤12), acyl<c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R4 is alkyl(c≤12), aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and R5 is -SH, -S(O)H, -S(O)₂H, -S(O)0H, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof.

39. A method of reducing the duration of infection SARS-CoV-2 comprising administering to a subject infected with SARS-CoV-2 a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and Ri, Ri', R₂, R₂', Rs, Rs', Ro, and Re' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12>, cycloalkyl(c≤12), heterocycloalky l(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups wherein R2/R2’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(0)Rt, wherein:

-OC(0)X4RX, wherein:

wherein: m is 0-10; Li is, in each instance independently, an oligoethyleneglycol linker (PEG), wherein the PEG comprises 1-50 repeat units, a peptide linker, wherein the peptide linker comprises 1-50 amino acids, a carbohydrate linker, wherein the carbohydrate linker comprises 1-50 repeat units, or a linker of the formula:

wherein:

X₂ and X₃ are each independently a covalent bond, -O-, -NH-, -OC(O)-, -NHC(O)-, -HNC(0)0- or -OC(0)NH-;

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and Ri, R2, R3, and Rn are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X4IS -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c<i₂), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c<i 2), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: nis 0, 1, 2, or 3;

Ri, Ri', R₂, R₂', R3, R}', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R* is alkyl(c≤12₎, aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)OH, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof.

40. A method of reducing transmission of SARS-CoV-2 comprising administering to a subject infected with SARS-CoV-2 a compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂-; and

Ri, Ri', R2, R2', R3, Rs', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12>, aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R3/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or

-C(O)R4, wherein:

Rt is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or -OC(O)X₄R_X, wherein:

wherein: m is 0-10;

wherein:

X2 and X3 are each independently a covalent bond, -0-, -NH-, -0C(0)-, -NHC(O)-, -HNC(0)0- or -0C(0)NH-;

Xi is, in each instance independently, -S-, -S(O)— , or -S(O)2~; and Ri, R2, R3, and Rn are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted or

-C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

wherein: n is 0, 1, 2, or 3; Ri, Ri', R₂, R₂', R₃, Rs', R_n, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R* is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c<i 2), or a substituted version of any of these groups;

Ri is alkyl(c≤12), aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, — S(O)2H, -S(O)0H, -S(O)20H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof.

41. The method according to any one of items 1-40, wherein the compound is further defined as:

wherein: n is 0, 1, 2, or 3;

Xi is — S-, -S(O)-, or -S(O)2^~; and

Ri, Ri', R₂, R₂', R₃, Rs', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy<c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂ZR_2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-0C(0)X₄RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl<c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof. 42. The method according to any one of claims 1-41, wherein the compound is further defined as:

wherein:

Xi is -S-, -S(O)-, or -S(O)₂-; Ri, Ri', R₂, R₂', R3, Rf, R_n, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2’ and R3/R3_’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany R2/R2_’ and R3/R3_’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl<c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤12), hydroxyalkynyl(c<i₂), or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof.

43. The method according to any one of items 1-42, wherein the compound is further defined as:

wherein: Xi is -S-, -S(O)-, or -S(O)₂-;

R₂, R₂', R3, and R3', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy<c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy<c≤12), amido(c≤12), or a substituted version of any of these groups wherein R₂/R₂’ and R₃/R_3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12>, or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof.

44. The method according to any one of items 1-43, wherein the compound is further defined as:

wherein:

R₂, R₂ ^f, R₃, and R₃', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12>, aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R3/R3_’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R3/R3_’, wherein the five-membered heterocyclic ring is optionally substituted or -C(0)Ri, wherein:

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤12₎,hydroxyalkynyl₍c≤12₎,or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

45. The method according to any one of items 1-44, wherein the compound is further defined as:

wherein:

R₂, Ra', Rs, and R3', are each independently hydrogen, hydroxy, amino, substituted amino or protected amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R2’ and R3/R3’ may also be replaced by a five- membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; preferably wherein:

R₂, Ra', Ra, and R3', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof. 46. The method according to any one of items 1-45, wherein the compound is further defined as:

wherein:

Ra, R2', Rs, and Rs', are each independently hydrogen or hydroxy; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), acyloxy(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof. 47. The method according to any one of items 1 -46, wherein R2 is hydrogen or hydroxy.

48. The method according to any one of items 1-47, wherein R2 is hydrogen.

49. The method according to any one of items 1-47, wherein R2 is hydroxy.

50. The method according to any one of items 1-49, wherein R2' is hydrogen or hydroxy.

51. The method according to any one of items 1 -50, wherein R2' is hydrogen. 52. The method according to any one of items 1 -50, wherein R2' is hydroxy.

53. The method according to any one of items 1 -52, wherein R3 is hydrogen or hydroxy.

54. The method according to any one of items 1 -53, wherein R3 is hydrogen.

55. The method according to any one of items 1-53, wherein R3 is hydroxy.

56. The method according to any one of items 1-55, wherein R3' is hydrogen or hydroxy. 57. The method according to any one of items 1 -56, wherein R3' is hydrogen.

58. The method according to any one of items 1 -56, wherein R3' is hydroxy. 59. The method according to any one of items 1-58, wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof. 60. The method of item 59, wherein the hydroxyl groups are in a cis relationship to one another; or a pharmaceutically acceptable salt thereof

61. A compound of the formula:

wherein:

R2, R2', R3, and R3', are each independently hydrogen or hydroxy; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), acyloxy(c≤12), or a substituted version of any of these groups; wherein R3/R3_’ and R2/R2’ are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2' and R₃/R3_’, wherein the five-membered heterocyclic ring is optionally substituted; or a pharmaceutically acceptable salt thereof 62. The compound of item 61 , selected from:

63. A compound of the formula:

wherein:

R₂, R₂', R₃, and R₃', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R3/R3’ and R₂/R_2’ may be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or

-0C(0)X4RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof, wherein at least one of R3, R3’, R2, R2’ is - 0C(0)X4RX, wherein preferably Rx is aminoalkyl(c≤12), or a substituted or protected version of this group.

64. The compound of item 63, according to formula:

V. REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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Claims

1. A compound for use in treating or preventing a viral infection in a subject infected with the virus, a compound of the formula:

wherein: n is 0, 1, 2, or 3;

X₁ is -S-, -S(O)-, or -S(O)₂-; and

R₁, R₁', R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups wherein R₂/R₂’ and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein: R₄ is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), or a substituted version of any of these groups; or

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12),hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12),hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

X2 and X3 are each independently a covalent bond, -0-, — NH-, -OC(O)-, -NHC(O)-; -HNC(0)0- or -OC(0)NH-;

Xi is, in each instance independently, — S— , -S(O)-, or -S(O)2^~ ; and Ri, Ra, R3, aind R_a are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy<c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂ and R₃ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry Rz and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-0C(0)X₄RX, wherein:

wherein: n is 0, 1, 2, or 3;

R₁, R₁', R₂, R₂', R₃, R₃', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylaminO(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

Rt is alkyl₍c≤12₎, aryl₍c≤12₎, a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)0H, or -S(O)₂0H, or a depratonated version of any of these groups; or or a pharmaceutically acceptable salt thereof, wherein the virus is not HIV.

2. The compound for use of claim 1, wherein the viral infection is not retrovirus infection.

3. The compound for use of claim 1, wherein the viral infection is a coronavirus, Dengue virus, Ebola virus, West nile virus, Rabies virus, Influenza virus, Chikungunya virus or Zika virus infection.

4. The compound for use of claim 3, wherein the viral infection is a coronavirus infection.

5. The compound for use of claim 4, wherein the coronavirus is a beta coronavirus.

6. The compound for use of claim 4, wherein the coronavirus is MERS-CoV, SARS-CoV-1, or SARS-CoV-2.

7. The compound for use of claim 6, wherein the coronavirus is MERS-Cov.

8. The compound for use of claim 7, wherein the subject has Middle East respiratory syndrome (MERS).

9. The compound for use of claim 6, wherein the coronavirus is SARS-CoV-1.

10. The compound for use of claim 9, wherein the subject has severe acute respiratory syndrome (SARS).

11. The compound for use of claim 6, wherein the coronavirus is SARS-CoV-2.

12. The compound for use of claim 11, wherein the subject has coronavirus disease 2019 (COVID-19).

13. The compound for use of claim 11, wherein said subject has a confirmed diagnosis of SARS-CoV-2.

14. The compound for use of claim 11 , wherein said subject is suspected of being infected with SARS-CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2.

15. The compound for use of claims 1-14, wherein the compound is to be administered intravenously, intra-arterially, orally, intranasally, by bronchial inhalation, parenterally, orally; as a suppository or topically.

16. The compound for use of claims 1-15, wherein the compound is to be administered twice daily, once daily, every other day, every three-days or weekly.

17. The compound for use of claims 1-16, wherein the compound is to be administered for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months.

18. The compound for use of any one of claims 1-17, wherein the compound is to be coadministered with at least one other anti-coronavirus therapy.

19. The compound for use of claim 18, wherein the compound is to be co-administered with at least one other antiviral therapy.

20. The compound for use of any one of claims 1-18, wherein said subject is a high-risk SARS- CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, broncho-pulmonary disease, cardiovascular disease, hypertension, or diabetes.

21. The compound for use of claim 4, wherein said subject exhibits abnormally reduced blood oxygenation, such as 90% or less.

22. The compound for use of claim 4, wherein said subject is concurrently receiving ventilation therapy.

23. A compound for use in preventing viral infection, the compound of the formula:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, -S(O)-, or -S(O)₂ ^~; and

Ri, Ri', R₂, R₂', R₃, R₃', R_n, and RV are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12>, heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2· and R₃/R₃’ may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry R₂ and R₃, wherein the five-membered heterocyclic ring is optionally substituted; or C(0)R h i R4 is hydroxy or amino; or alkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤i 2), or a substituted version of any of these groups; or

-OC(O)X₄R_X, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoaIkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

wherein: m is 0-10;

wherein:

Xi is, in each instance independently, -S-, -S(O)-, or -S(O)₂ ^~; and Ri, R2, R3, and R_n are, in each instance independently, hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aiyl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaiyloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2 and R3 may also be replaced by a five membered heterocyclic ring, which is fused to the ring carbon atoms that otherwise carry Ra and R3, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(0)X₄Rx, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a compound of the formula:

h i n is 0, 1, 2, or 3;

Ri, Ri', Rz, Rz', Rs, Rs', Rn, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, or amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or -C(O)R4, wherein:

R4 is alkyl(c≤12), aryl(c≤12), a peptide, wherein the peptide comprises 1-50 amino acids, a protein or a fragment thereof; and Rs is -SH, -S(O)H, -S(O)₂H, -S(O)0H, -S(O)₂0H, or a deprotonated version of any of these groups; or or a pharmaceutically acceptable salt thereof.

24. The compound for use of claim 23, wherein the viral infection is not retrovirus infection.

25. The compound for use of claim 23, wherein the viral infection is a coronavirus, Dengue virus, Ebola virus, West nile virus, Rabies virus, Influenza virus, Chikungunya virus or Zika virus infection.

26. The compound for use of claim 25, wherein the viral infection is a coronavirus infection.

27. The compound for use of claim 26, wherein said subject has a confirmed diagnosis of SARS-CoV-2.

28. The compound for use of claim 26, wherein said subj ect is suspected of begin infected with SARS-CoV-2 but does not have a confirmed diagnosis of SARS-CoV-2.

29. The compound for use of any one of claims 23-28, wherein the compound is to be administered intravenously, intra-arterially, orally, intranasally, or by bronchial inhalation.

30. The compound for use of any one of claims 20-23, wherein the compound is to be administered twice daily, once daily, eveiy other day, every three-days or weekly.

31. The compound for use of any one of claims 23-30, wherein the compound is to be administered for one week, for two weeks, for three weeks, for one month, for 6 weeks, for two months, for three months, for four months, for five months or for six months.

32. The compound for use of any one of claims 23-31, wherein the compound is to be coadministered with at least one other antiviral therapy.

33. The compound for use of any one of claims 23-32, wherein said subject is a high-risk SARS-CoV-2 subject, such as a subject 65 years or older, a subject who is immunocompromised, or a subject having one or more of cancer, broncho-pulmonary disease, cardiovascular disease, hypertension, or diabetes.

34. The compound for use of any one of claims of claims 23-33, wherein said subject exhibits abnormally reduced blood oxygenation, such as 90% or less.

35. The compound for use of any one of claims 20-28, wherein said subject is concurrently receiving ventilation therapy.

36. The compound for use of any one of claims 1 to 22, for use in reducing one or more symptoms of a viral infection, for use in decreasing mortality from SARS-CoV-2, for use in reducing duration of hospitalization from SARS-CoV-2 or for use in reducing transmission of SARS-CoV-2.

37. The compound for use of any one of claims 1-36, wherein the compound is further defined as:

wherein: n is 0, 1, 2, or 3;

Xi is -S-, — S(O)— , or -S(O)₂-; and

Ri, Ri', R2, R₂', RS, RS', R_n, and R_n' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(csi2), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(csi2), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(csi2), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(csi2), acyloxy(c≤12), amido(csi2), or a substituted version of any of these groups; wherein R₂/R₂· and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to tiie ring carbon atoms that otherwise cany R₂/R₂· and R3/R3·, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(0)X₄RX, wherein:

X4 is -O- or -NH-, and Rx is hydrogen, alkyl<c≤12), aminoalkyl<c≤12), hydroxyalkylicsiz). alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12). alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof.

38. The compound for use of any one of claims 1-37, wherein the compound is further defined as:

wherein:

Xi is -S-, -S(0h, or -S(O)₂-; Ri, Ri', R2, R2', R3, Rs', Rn, and Rn' are, in each instance, independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy<c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R_2' and R₃/R₃’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany R₂/R₂’ and R₃/R₃’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof.

39. The compound for use of any one of claims 1 -38, wherein the compound is further defined as:

wherein: Xi is -S-, -S(O)-, or -S(O)₂-;

R₂, R₂', Rs, and R3', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl(c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c≤12), alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups wherein R2/R2’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R₂’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or -C(O)R4, wherein:

-OC(O)X₄R_X, wherein:

X₄IS -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl₍c≤ ₁₂), hydroxyalkynyl(c≤ ₁₂), or a substituted or protected version of any of these groups;or a pharmaceutically acceptable salt thereof.

40. The compound for use of any one of claims 1-39, wherein the compound is further defined as:

wherein:

Ra, R₂', R₃, and R₃', are each independently hydrogen, hydroxy, halo, amino, substituted amino or protected amino; or alkyl(c≤12), alkenyl<c≤12), alkynyl(c≤12), cycloalkyl(c≤12), heterocycloalkyl(c≤12), aryl(c≤12), aralkyl(c≤12), heteroaryl(c≤12), heteroaralkyl(c<]2), alkoxy(c≤12), aryloxy(c≤12>, aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyl(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R2/R2’ and R3/R3’ may also be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted or -C(O)R4, wherein:

-OC(0)X₄RX, wherein:

¾ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12₎,hydroxyalkynyl₍c≤12_),or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof.

41. The compound for use of any one of claims 1-40, wherein the compound is further defined as:

wherein:

R2, R2', R3, and R3', are each independently hydrogen, hydroxy, amino, substituted amino or protected amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R₂/R₂’ and R₃/R₃’ may also be replaced by a five- membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R2ZR₂’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; preferably wherein:

R2, R2', R3, and R3', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

42. The compound for use of any one of claims 1-41, wherein the compound is further defined as:

wherein:

Ra, Ra', R₃, and R₃', are each independentiy hydrogen or hydroxy; or alkoxy(c≤ia), aiyloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), acyloxy(c≤12), or a substituted version of any of these groups; or a pharmaceutically acceptable salt thereof.

43. The compound for use of any one of claims 1-42, wherein Ra is hydrogen or hydroxy.

44. The compound for use of any one of claims 1-43, wherein Ra is hydrogen.

45. The compound for use of any one of claims 1-43, wherein Ra is hydroxy.

46. The compound for use of any one of claims 1-45, wherein Ra' is hydrogen or hydroxy.

47. The compound for use of any one of claims 1-46, wherein Ra' is hydrogen.

48. The compound for use of any one of claims 1-46, wherein Ra' is hydroxy.

49. The compound for use of any one of claims 1-48, wherein R3 is hydrogen or hydroxy.

50. The compound for use of any one of claims 1-49, wherein R3 is hydrogen.

51. The compound for use of any one of claims 1-49, wherein R3 is hydroxy.

52. The compound for use of any one of claims 1-51, wherein R3' is hydrogen or hydroxy.

53. The compound for use of any one of claims 1-52, wherein R3' is hydrogen.

54. The compound for use of any one of claims 1-52, wherein R3' is hydroxy.

55. The compound for use of any one of claims 1-54, wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof.

56. The compound for use of claim 55, wherein the hydroxyl groups are in a cis relationship to one another; or a pharmaceutically acceptable salt thereof.

57. A compound of the formula:

wherein:

R2, R2', R3, and R3', are each independently hydrogen or hydroxy; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), acyloxy<c≤12), or a substituted version of any of these groups; wherein R3/R3’ and R2/R2’ are replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise cany R2/R2’ and R3/R3’, wherein the five-membered heterocyclic ring is optionally substituted; or a pharmaceutically acceptable salt thereof.

58. The compound of claim 57, selected from:

59. A compound of the formula:

wherein:

R₂, R₂', R₃, and R₃', are each independently hydrogen, hydroxy, or amino; or alkoxy(c≤12), aryloxy(c≤12), aralkoxy(c≤12), heteroaryloxy(c≤12), heteroaralkoxy(c≤12), alkylamino(c≤12), dialkylamino(c≤12), acyloxy(c≤12), amido(c≤12), or a substituted version of any of these groups; wherein R3/R3’ and R₂/R₂’ may be replaced by a five-membered heterocyclic ring which is fused to the ring carbon atoms that otherwise carry R₂/R_2’ and R3/R3·, wherein the five-membered heterocyclic ring is optionally substituted; or

-OC(O)X₄R_X, wherein:

X₄ is -O- or -NH-, and Rx is hydrogen, alkyl(c≤12), aminoalkyl(c≤12), hydroxyalkyl(c≤12), alkenyl(c≤12), aminoalkenyl(c≤12), hydroxyalkenyl(c≤12), alkynyl(c≤12), aminoalkynyl(c≤12), hydroxyalkynyl(c≤12), or a substituted or protected version of any of these groups; or a pharmaceutically acceptable salt thereof, wherein at least one of R₃, R₃’, R₂, R₂’ is - OC(O)X₄R_X, wherein preferably Rx is aminoalkyl(c≤12), or a substituted or protected version of this group.

60. The compound of claim 59, according to formula: