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WO2025057164A1 - Inhibiteurs d'entrée de coronavirus à large spectre - Google Patents

Inhibiteurs d'entrée de coronavirus à large spectre Download PDF

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Publication number
WO2025057164A1
WO2025057164A1 PCT/IL2024/050919 IL2024050919W WO2025057164A1 WO 2025057164 A1 WO2025057164 A1 WO 2025057164A1 IL 2024050919 W IL2024050919 W IL 2024050919W WO 2025057164 A1 WO2025057164 A1 WO 2025057164A1
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compound
coronavirus
derivative
isomer
pharmaceutically acceptable
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WO2025057164A9 (fr
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Ori Porat AVINOAM
Efrat Ozer PARTUK
Suman Khan
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Yeda Research and Development Co Ltd
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Yeda Research and Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Disclosed here are therapeutic compounds that inhibit Coronavirus infection mediated by the S glycoprotein of SARS-CoV-2 and MERS-CoV viruses. Methods of use inhibiting broadspectrum Coronavirus infection are described as are methods of treating a subject infected with a Coronavirus.
  • Coronaviruses have garnered global attention due to their potential for causing severe diseases in humans. The most notable among these are SARS-CoV, MERS-CoV, and SARS-CoV-2, each responsible for significant disease outbreaks. As zoonotic pathogens, CoVs continue to pose a constant threat to global health due to the potential for cross-species transmission, underscoring the need for broad-spectrum antiviral inhibitors.
  • the viral Spike (S) glycoprotein of CoVs mediates fusion of the viral envelope with the host cell membrane, which is essential for infection and delivery of the viral genetic material into host cells. This process is conserved across all coronaviruses, positioning the S glycoprotein as a promising target for broad-spectrum antiviral strategies.
  • the S glycoprotein is a class I viral fusogens, comprised of two subunits: SI, involved in host cell recognition and binding, and S2, which mediates membrane fusion.
  • CoV coronaviruses, including current and emerging variants.
  • the S2 domain presents as a promising target for managing CoV infection.
  • Cross-reactive neutralizing antibodies (nAbs) against the S2 domain have been identified in individuals who have not contracted SARS-CoV-2, as well as patients infected with various CoVs. This compelling evidence is reinforced by the essential role of the S2 domain in the universally conserved biophysical process of membrane fusion.
  • the S2 domain has exhibited lower mutation rates in emerging SARS-CoV-2 variants, which is further supported by phylogenetic analyses showing a higher degree of sequence conservation in the S2 domains of diverse CoV clades.
  • HTS High throughput screening
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CH2)n-cycloalkyl, -(CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n and m are each independently an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein said * indicates a chiral center.
  • a compound represented by the structure of Formula XII is represented by the structure of Formula XII-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein * indicates a chiral center.
  • a compound represented by the structure of Formula XII is represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein * indicates a chiral center.
  • a compound represented by the structure of Formula XII is represented by the structure of Compound 12a or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof,
  • a compound represented by the structure of Formula XII is represented by the structure of Compound 12b or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, [00015]
  • a derivative of Compound 12 is represented by the structure of
  • the isomer of Compound 12-X is represented by the structure of Compound 12-Xa, or a pharmaceutical acceptable salt thereof, or any combination thereof.
  • the isomer of Compound 12-X is represented by the structure of Compound 12-Xb, or a pharmaceutical acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising a compound represented by the structures of any one of Formulae XII, XII-A, 12a, 12b, 12-X, 12- Xa, or 12-Xb or an isomer thereof, a derivative thereof, or a pharmaceutical salt thereof.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula XII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n and m are each independently an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein said * indicates a chiral center;
  • the compound is represented by the structure of Formula XII- A, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; wherein * indicates a chiral center; and wherein said inhibiting is
  • the compound is represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein * indicates a chiral center.
  • the isomer is represented by the structure of Compound 12a or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof,
  • the isomer is represented by the structure of
  • a method of inhibiting or reducing a Coronavirus infection a derivative of Compound 12 is represented by the structure of Compound 12-X or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein * indicates a chiral center.
  • a method of inhibiting or reducing a Coronavirus infection the isomer of Compound 12-X is represented by the structure of Compound 12-Xa, or a pharmaceutical acceptable salt thereof, or any combination thereof.
  • a method of inhibiting or reducing a Coronavirus infection the isomer of Compound 12-X is represented by the structure of Compound 12-Xb, or a pharmaceutical acceptable salt thereof, or any combination thereof.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by any one of the structures of Compounds 1-11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a Coronavirus comprises SARS-CoV, SARS-CoV-2, or MERS-CoV.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula XII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • Ls and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CLEjn-cycloalkyl, - (CLEjn-heterocyclic ring, -(CEbjn-aryl, and -(CLLjn-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n and m are each independently an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein said * indicates a chiral
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • Ls and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CILjn-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein * indicates a chiral center.
  • the compound is represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein * indicates a chiral center.
  • a derivative of Compound 12 is represented by the structure of Compound 12-X or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein * indicates a chiral center.
  • X is represented by the structure of Compound 12-Xb, or a pharmaceutical acceptable salt thereof, or any combination thereof.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering to a subject in need, a compound represented by any one of the structures of Compounds 1-11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • the Coronavirus comprises SARS- CoV, SARS-CoV-2, or MERS-CoV.
  • FIGURES 1A-1G Production of high titer VSVAG pseudoviruses and quantification of single infection events.
  • FIG. 1A A schematic representation of the VSVAG pseudoviruses production process. Viral glycoproteins (yellow) are expressed by plasmid transfection on cell surface. Transfected cells were subsequently infected with recombinant VSV in which the endogenous G glycoprotein (VSV-G; purple) gene was replaced with a fluorescent reporter (VSVAG) and complemented with VSV-G (VSVAG-G). 1 hour postinfection, the residual VSVAG-G is thoroughly washed, and the culture is replenished with medium.
  • VSV-G endogenous G glycoprotein
  • VSVAG fluorescent reporter
  • FIGURE IB A widefield image of cells infected with VSVAG pseudoviruses expressing a fluorescent reporter (GFP; green). Infected cells become round after infection due to the virus-induced Cytopathic Effect (CPE).
  • FIGGURE 1C A high magnification overlay image showing the infected GFP -positive cells (green) and total nuclei (blue).
  • CPE virus-induced Cytopathic Effect
  • FIGURES 1D-1F Pseudoviral titers in infectious units/ml.
  • the neutralizing a-G antibody was added to all pseudoviruses, ensuring accurate titer calculation.
  • the activity of a-G was tested using VSVAG-G in the presence and absence of a-G. Two-tailed unpaired t-tests were used to evaluate the statistical significance of a-G activity (p. ** ⁇ o.oi, **** ⁇ 0.0001.
  • VSVAG-Sw complemented with the Wuhan variant of the SARS-CoV-2 Spike (VSVAG-Sw; SEQ ID NO: 1) in different cell types showing infection improves upon over-expression of the innate receptor, ACE2 and host protease, TMPRSS2.
  • FIGURE IE Titer of VSVAG-Sw in HEK-293T-ACE2- TMPRSS2 cells showing the effect of modifications to the cytosolic tail of Sw.
  • FIGURE IF Titer of VSVAG-G, VSVAG-Sw, VSVAG-Sa (Alpha - SEQ ID NO: 2), VSVAG-S s (Delta-SEQ ID NO: 3), VSVAG-So (Omicron-SEQ ID NO: 4), and VSVAG- SM (MERS-COV Spike-SEQ ID NO: 5) showing similar infection levels with and without DPP4.
  • VSVAG-G Pseudoviruses infected all cell lines at similar levels (FIGURES ID and IF).
  • FIGGURE 1G Pseudoviral infectious units/ml of VSVAGRFP-G and VSVAGGFP-SW separately or simultaneously result in equivalent infection titer measurements.
  • VSVAG-Sw and VSVAG-SW, VSVAG-S a and VSVAG-Sa, VSVAG-Ss and VSVAG-S6, VSVAG-S 0 and VSVAG-So, and VSVAG-SM and VSVAG-SM are interchangeable pairs, with each pair having identical meanings and qualities.
  • FIGURE 2 A Infectious units/ml of VSVAG-Sw pseudoviruses present in the harvested supernatant at different times, indicating optimal titers at 30 hours post-infection with the helper virus.
  • FIGGURE 2B Infectious units/ml of samples subjected to centrifugation, indicating a two-fold increase in viral titer with centrifugation. Experiments were performed in the presence of an a-G neutralizing antibody to exclude any residual infection from VSVAG-G that was left over from the production. The statistical significance of conditions was also determined. P: **** ⁇ 0.0001 (two-tailed unpaired t-tests).
  • FIGURES 3A-3C The pseudovirus-based High Throughput Screen (HTS) platform demonstrates high reproducibility.
  • FIGGURE 3A Schematic of the high content screening pipeline: plating, imaging, and analysis. Compounds were pre-plated. Then, pseudoviruses, pre-incubated with a-G to neutralize any residual VSVAG-G infection, were added in individual wells. This was followed by introducing HEK-293T cells stably overexpressing SARS-CoV-2 receptor ACE2 and protease TMPRSS2. After 24 hours, the nuclei were stained, and the plates were imaged. Images were subsequently segmented and quantified.
  • FIGURE 3B Overview image of a portion of a 384-well screening plate (orange box in FIGURE 3A)
  • the neutral control indicates 100% infection
  • the positive control magenta wells
  • the green well depicts an example of a compound with -90% inhibition.
  • FIGURE 3C Lower portion Examples of two inhibitors showing similar inhibition values after normalization and despite having different total cell and infection counts.
  • FIGURE 4 Overview of a 384-well plate from the screen.
  • Column 1 plated with pseudovirus and cells, serves as the neutral control and indicates 100% infection.
  • Columns 3-22 are spotted with compounds. All wells containing pseudovirus in Columns 1 and 3-22 are pre-incubated with the a-G neutralizing antibody to remove any residual VSVAG-G infection. To ascertain that the a-G antibody was active, VSVAG-G pseudovirus were plated in the presence and absence of a-G in Column 23 and 24 respectively. All columns contain 0.01% DMSO.
  • FIGURES 5A-5C The test sample was plated in the presence and absence of a-G in Column 23 and 24 respectively. All columns contain 0.01% DMSO.
  • FIG. 1A Schematic showing primary screening of -200,000 compounds against Wuhan SARS-CoV-2 Spike (VSVAG-Sw) yielded 733 putative Spike-specific and non-specific inhibitors. Sw specific inhibitors were identified by a secondary screen against VSV-G (VSVAG- G), yielding 65 putative inhibitors.
  • VSVAG-SM The tertiary screen with MERS-CoV Spike (VSVAG-SM) and initial validation resulted in 5 compounds that were putatively broad-spectrum inhibitors.
  • FIG. 5B Plots showing HTS parameters to determine the robustness of the screen: Z prime (Z 1 ) factor, signal-to-background, percentage of coefficient of variance for positive and negative for the primary screen. Red line denotes the cut off for a robust plate. Five plates that failed to meet the cut-off for Z prime were manually checked for data quality.
  • FIG. 5C The chemical structures of the four novel compounds and Nafamostat that were commercially resourced.
  • FIGURE 5D Plot of the inhibition of the resourced compounds against the three viruses. All the compounds selectively inhibit SARS-CoV-2 and MERS-CoV Spikes without inhibiting VSV-G. Error bars represent the range. Values represent mean inhibitions ⁇ standard deviations.
  • FIGURE 6 presents a listing of the 733 compounds identified that were capable of inhibiting VSVAG-Sw infection. Each compound is presented with its IUPAC name, the percent inhibition (VSVAG-Sw), and the % cell viability. Note that molecule names were generated for this study and do not relate to specific compounds outside of this study.
  • FIGURE 7 presents a listing of the 65 Spike-specific inhibitors identified that inhibited VSVAG-Sw infection. Each compound is presented with its IUPAC name, % Inhibition (VSVAG-Sw), SD (% Inhibition of VSVAG-Sw), % Inhibition (VSVAG-G), SD (% Inhibition of VSVAG-G), % Cell viability, and SD (% Cell counts). Note that molecule names were generated for this study and do not relate to specific libraries or compounds outside of this study.
  • FIGURE 8 presents a listing of 22 putative S2-domain specific inhibitors that reduced VSV G-SM infection. Each compound is presented based on Structure and SMILE information. As well, the results showing % Inhibition (VSVAG-SM), SD (% Inhibition of VSVAG-SM), % Inhibition (VSVAG-G), SD (% Inhibition of VSVAG-G), % Inhibition (VSVAG-Sw), SD (% Inhibition of VSVAG-Sw), % Cell viability, and SD (% Cell counts) is included. Molecular Names were generated for this work and do not relate to specific compounds outside of this study. Compounds 1-11 are novel putative inhibitors for which no previous function had been defined. Compounds 13-23 present compounds previously reported in the literature for various functions.
  • FIGURE 9 Dose-response activity and cytotoxicity of compounds before HPLC.
  • Left Dose-response plot of the hits against VSVAG-Sw, VSVAG-SM, or VSVAG-G and their cytotoxicity profile.
  • Light Dose-response plots of hits against pseudoviruses with glycoproteins of SARS-CoV-2 variants (VSVAG-S a , VSVAG-Sa, VSVAG-S 0 ). Dose-response curves were fitted with a variable slope (four-parameter logistic model). Error bars represent the SEM.
  • PCM-0068389 represents Compound 1; PCM-0179622 represents Compound 5; PCM-0166392 represents Compound 6; PCM-0163855 represents Compound 11.
  • FIGURE 10 Dose-response activity and cytotoxicity of HPLC-purified compounds.
  • Left Dose-response plot of the purified candidates against VSVAG-Sw, VSVAG- SM or VSVAG-G and their cytotoxicity profile.
  • Light Dose-response plots of hits against pseudoviruses with glycoproteins of SARS-CoV-2 variants (VSVAG-S a , VSVAG-Sa, VSVAG- So). Dose-response curves were fitted with a variable slope (four-parameter logistic model). Error bars represent the SEM.
  • PCM-0068389 represents Compound 1; PCM-0179622 represents Compound 5; PCM- 0166392 represents Compound 6; PCM-0163855 represents Compound 11.
  • FIGURES 11A and 11B Validation ofPCM-0163855 against bona fide SARS-CoV- 2. Cytotoxicity profile of PCM-0163855 and dose-response plots comparing the inhibitory activity of PCM-0163855, and known inhibitors Nafamostat and Remdesivir on SARS-CoV-2 delta variant on viral replication in Vero E6 cells with (FIGURE 11A) and without (FIGURE 11B) TMPRSS2 over-expression. PCM-0163855 represents Compound 11.
  • FIGURE 12 General reaction scheme for synthesis of PCM-0163855 (Compound 11) and PCM-0282478 (Compound 12).
  • FIGURES 13A and 13B Validation of PCM-0163855 (Compound 11; resynthesized) and its sulfoxide derivative PCM-0282478 (Compound 12; Racemic mixture).
  • FIGURE 13A (from left to right) Structures of PCM-0163855 and its sulfoxide derivative PCM-0282478, the corresponding dose-response plots comparing the inhibitory activity against VSVAG-Sa, VSVAG-S 0 , VSVAG-SM or VSVAG-G, showing that PCM- 0282478 exhibits a broader selectivity for inhibition compared to PCM-0163855, and the corresponding cytotoxicity profiles and dose-response plots comparing the inhibitory activity against bona fide SARS-CoV-2 variants, Delta.Bl.617.2, XBB.1.5, or CH.1.1, viral replication in Vero E6 cells.
  • FIG. 13B (Left) Dose-response plots of the two enantiomers of PCM- 0282478 (Enantiomer 1 - Compound 12a; Enantiomer 2 - Compound 12b) comparing the inhibitory activity against VSVAG-Sa, VSVAG-S 0 , VSVAG-SM, or VSVAG-G, showing that only one enantiomer exhibits a broader selectivity for inhibition in pseudovirus based assay. (Right) The corresponding cytotoxicity profiles and dose-response plots comparing the inhibitory activity against bona fide SARS-CoV-2 variants.
  • PCM-0296174 The active enantiomer, PCM-0296174 was also tested against Delta.Bl.617.2 in presence of the multi drug resistance protein 1 (MDR1) inhibitor, CP 100356.
  • MDR1 multi drug resistance protein 1
  • CP 100356 The active enantiomer, PCM-0296174 was also tested against Delta.Bl.617.2 in presence of the multi drug resistance protein 1 (MDR1) inhibitor, CP 100356.
  • MDR1 multi drug resistance protein 1
  • FIGURES 14A and 14B Activity of controls against bona fide SARS-CoV-2 variants. Cytotoxicity profile and dose-response plots comparing the inhibitory activity of Nafamostat (FIGURE 14A) and Remdesivir (FIGURE 14B) against bona fide SARS-CoV-2 variants, Delta.Bl.617.2, XBB.1.5 and CH.1.1, on viral replication in Vero E6 cells.
  • FIGURES 15A-15C Plaque assay showing PCM-0296174 reduces infection of SARS-CoV-2 virus.
  • FIGURE 15A Plaque assay performed in Vero E6 cells in presence of PCM-0296174 (active enantiomer; Compound 12a) or PCM-0296173 (Compound 12b).
  • FIGURE 15B The active enantiomer results in 100 fold reduction in viral load.
  • FIGURE 15C RTqPCR done in parallel on the same samples reproduce the results shown in FIGURE 13B
  • FIGURE 16 PCM-0296174 does not inhibit SARS-CoV-2 Spike binding to ACE2.
  • FIGURES 17A and 17B Structure-activity relationship (SAR) of PCM-0282478 derivatives.
  • FIGURE 17A Structure of PCM-0282478 and dose-response plots comparing the inhibitory activity against VSVAG-Ss, VSVAG-S 0 , VSVAG-SM, or VSVAG-G.
  • FIGURE 17B Structure of PCM-0297098 (Compound 12-X) and dose-response plots.
  • the IC50 values presented in FIGURE 18 show that PCM-0297098, shows higher inhibitory activity against VSVAG-Sa, VSVAG-So, VSVAG-SM, and selectivity as compared to PCM-0282478.
  • FIG. 1 Racemic PCM-0297098 is more potent than the enantiomerically pure compound PCM-0296174 (Compound 12a).
  • Table summarizing the IUPAC names and IC50 values of racemic derivatives of PCM-0282478 that were synthesized and tested against VS VAG- S 5 , VSVAG-So, VSVAG-SM, or VSVAG-G. The IC50 values indicate that PCM-0297098 is the most potent derivative, and is more selective against CoVs than PCM-0282478.
  • Disclosed herein are screening methods used to identify broad-spectrum Coronavirus entry inhibitors. As well, disclosed herein are the compounds identified, derivatives and isomers thereof, methods of using these compounds to inhibit Coronavirus infection, and methods of using these compounds to treat a Coronavirus infection or to treat a subject at risk of contracting a Coronavirus infection.
  • the compounds described herein target entry of these Coronavirus downstream of receptor binding.
  • the compounds described herein may target entry of Coronaviruses at the level of the S2 domain of the spike protein, which plays a role in the cell membrane fusion process and entry of the virus into a cell, but the findings described herein are not bound to these compounds targeting the S2 domain.
  • Targeting S2 may be advantageous because it is independent of any specific receptor recognized by individual Coronaviruses.
  • a compound disclosed herein as a broad-spectrum inhibitor of Coronaviruses, inhibiting entry of the virus into the host cell.
  • a compound disclosed herein is a broad-spectrum inhibitor of Coronaviruses, inhibiting entry into a target cell of Coronaviruses including SARS-CoV, SARS-CoV-2, and MERS-CoV.
  • a compound disclosed herein is a broad-spectrum inhibitor of Coronaviruses, inhibiting entry of variants of SARS-CoV, SARS-CoV-2, and MERS-CoV Coronaviruses into a target cell.
  • a compound disclosed herein is a broad-spectrum inhibitor of Coronaviruses, inhibiting entry of SARS-CoV-2 variants.
  • a broad-spectrum inhibitor of Coronaviruses is an isomer or a derivative, or a pharmaceutically acceptable salt, or any combination thereof of a compound disclosed herein.
  • methods of inhibiting or reducing a Coronavirus infection described herein reduces a SARS-CoV, SARS-CoV-2, or MERS-CoV infection. In some embodiments, methods of inhibiting or reducing a Coronavirus infection described herein reduces the infection of a SARS-CoV-2 variant. In some embodiments, in the methods of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus described herein, the Coronavirus comprises a SARS-CoV, SARS-CoV-2, or MERS-CoV virus. In some embodiments, the subject has COVID-19 due to an infection by a SARS-CoV-2 variant or is at risk of developing CO VID-19. Subjects at risk of developing CO VID-19 include but are not limited to human adults over the age of 50 and or a subject suffering from a serious health problem.
  • the Coronavirus comprises a SARS-CoV-2 variant.
  • SARS-CoV-2 variants include variants of concern, variants of interest, and variants under monitoring.
  • SARS-CoV-2 variants comprise variants of concern, variants of interests, or variants under monitoring, or any combination thereof.
  • SARS-CoV-2 variants include but are not limited to the Wuhan variant, the alpha variant, the delta variant, and the omicron variant.
  • SARS-CoV-2 variants comprise emerging variants.
  • CoV coronaviruses, including current and emerging variants.
  • a compound described herein is a broad-spectrum Coronavirus entry inhibitor.
  • the terms “compound” and “broad-spectrum Coronavirus entry inhibitor compound” and the like may be used interchangeably having all the same qualities and meanings.
  • the compounds disclosed herein encompass inhibitors of Coronavirus entry into a cell. In certain embodiments, the compounds disclosed herein encompass inhibitors of Coronavirus infection. In certain embodiments, the compounds disclosed herein encompass inhibitors of Coronavirus entry into a cell and Coronavirus infection. In some embodiments, use of the compounds disclosed herein, inhibits viral replication. In some embodiments, the Coronavirus infection comprises a primary infection or a secondary infection. [00063] A skilled artisan would appreciate that the term “broad-spectrum Coronavirus entry inhibitor” encompasses a “broad-spectrum’ antiviral agent” that inhibits entry of a broad spectrum of Coronavirus into cells.
  • broad-spectrum Coronavirus entry inhibitors have efficacy against known highly pathogenic human coronaviruses SARS-CoV, SARS-CoV-2, and MERS-CoV.
  • the broad-spectrum Coronavirus entry inhibitors disclosed herein have efficacy against additional novel Coronaviruses that may emerge in the future.
  • the broad-spectrum Coronavirus entry inhibitors have efficacy against Coronavirus variants including SARS-CoV-2 variants.
  • the SARS- CoV-2 variant is a variant of concern.
  • the variant is a variant of interest.
  • the variant is a variant under investigation.
  • SARS- CoV-2 variants comprise an alpha (a), beta (P), gamma (y), delta (6), or omicron (o) variant.
  • the broad-spectrum Coronavirus entry inhibitors disclosed herein have efficacy against additional novel SARS-CoV-2 variants that may emerge in the future.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula XII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CH2)n-cycloalkyl, -(CH2)n- heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le j oin together to form a 5 or 6 membered sub stituted or unsub stituted, aliphatic or aromatic, carbocycl
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Formula XII- A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl, single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CH2)n-cycloalkyl, -(CH2)n- heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le j oin together to form a 5 or 6 membered sub stituted or unsub stituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl are each independently substituted or unsubstituted; and wherein * indicates a chiral center
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl, single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or
  • L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring
  • p is an integer between 1-4
  • q is an integer between 1 -4
  • * indicates a chiral center.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein * indicates a chiral center.
  • a broad-spectrum Coronavirus entry inhibitor compound disclosed herein includes a stereogenic sulfur center, wherein the chiral sulfoxide is indicated by
  • a compound including a chiral sulfoxide may have an (S) or (R) configuration, wherein each enantiomer comprises exactly the same connectivity but opposite three-dimensional shapes.
  • Derivatives of a compound of Formula XII and/or XII-A, and/or XII-B, and of Compound 12 that maintain the chiral center similarly may have an (S) or (R) configuration, wherein each enantiomer comprises exactly the same connectivity but opposite three-dimensional shapes.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 12a, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • Compound 12a represents the (R) configuration enantiomer of Compound 12 (PCM- 0296174).
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 12b, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • Compound 12b represents the (S) configuration enantiomer of Compound 12 (PCM- 0296173).
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula I, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof wherein
  • Ri and R2 are each independently H, linear or branched alkyl, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; or Ri and R2 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • X is halo
  • R6-R9 are each independently H, linear or branched alkyl, alkoxy, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl, or Re and R7 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring, or Rs and R9 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • R and R' are each independently selected from H, linear or branched alkyl, C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula I- A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Ri and R2 are each independently H, linear or branched alkyl, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; or Ri and R2 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • X is halo
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula n, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Qi and Q2 are each independently CRR', O, NR, or S;
  • R6-R9 are each independently H, linear or branched alkyl, alkoxy, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; or Re and R7 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; or Rs and R9 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • W is a bond, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclic, aryl, heteroaryl, or an ether group;
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula II-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Qi and Q2 are each independently CRR', O, NR, or S;
  • R6-R9 are each independently H, linear or branched alkyl, alkoxy, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; or Re and R7 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring, or Rs and R9 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 2, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula HI, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Li, L2 and L3 are each independently H, linear or branched alkyl, alkoxy, C3 to C8 cycloalkyl, heterocyclic ring, aryl, heteroaryl, -(CH2)n-cycloalkyl, -(CtCjn-heterocyclic ring, - (CH2)n-aryl, or -(ClCjn-heteroaryl; or L2 and L3 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; Ai and A2 are each independently absent or O; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula III-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Ai and A2 are each independently absent or O;
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 3, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula IV, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • A is substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • Xu, X13, and X14 are each independently CR or N;
  • X is halo
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula IV-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Xn is CR orN
  • X12 is CRR, O, S, or NR
  • X is halo
  • R, R', and R" are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 4, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula V, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • R, R', and R" are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula V-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • R, R', and R" are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 5, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula VI, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Xu, X13, and X14 are each independently selected from CR and N;
  • X15 and Xi6 are each independently selected from CR, CRR, N, NR, O, and S;
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula VI-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Xn is CR orN
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 6, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula VII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Re and R7 are each independently H, substituted or unsubstituted, linear or branched alkyl, or substituted or unsubstituted alkoxy; or Re and R7 are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring;
  • R, R', R", Rie, and R17 are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • Ri6 and R17 are each independently selected from H and substituted or unsubstituted, linear or branched alkyl; k is an integer between 0-3;
  • R, R', and R" are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 7, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula VIII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a ring is a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, a substituted or unsubstituted single or fused C3-C10 cycloalkyl, or a substituted or unsubstituted single or fused heterocycloalkyl;
  • X12 is CR, O, S, or NR
  • R20 and R21 are each independently H, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted C3-C8 carbocyclic ring, -alkyl-C3-C8 carbocyclic ring, substituted or unsubstituted heterocyclic ring, or alkyl-substituted or unsubstituted heterocyclic ring; or R20 and R21 form together a substituted or unsubstituted 5-6 membered ring;
  • R is H, linear or branched alkyl, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula VIII-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Xu, X13, and X14 are each independently selected from CR and N;
  • R19, R20, and R21 are each independently H, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted C3-C8 carbocyclic ring, -alkyl-C3-C8 carbocyclic ring, substituted or unsubstituted heterocyclic ring, or alkyl-substituted or unsubstituted heterocyclic ring, or R20 and R21 form together a substituted or unsubstituted 5-6 membered ring;
  • R is H, linear or branched alkyl, C3 to C8 cycloalkyl, heterocyclic ring, aryl, or heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula IX, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a ring is a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, a substituted or unsubstituted single or fused C3-C10 cycloalkyl, or a substituted or unsubstituted single or fused heterocycloalkyl;
  • Xn is CR, O, S, or NR
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 9, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula X, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a ring is a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, a substituted or unsubstituted single or fused C3-C10 cycloalkyl, or a substituted or unsubstituted single or fused heterocycloalkyl;
  • R and R’ are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula X-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 10, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula XI, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Ai and Az are O;
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • R19, R20, and R21 are each independently H, linear or branched alkyl, C3-C8 carbocyclic ring, -alkyl ene-C3-C8 carbocyclic ring, heterocyclic ring, -alkylene-heterocyclic ring, aryl, - alkyl ene-aryl, heteroaryl, or alkylene-heteroaryl; or R20 and R21 form together a substituted or unsubstituted 5-6 membered ring; n is an integer of 0-10;
  • Ris selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a compound described herein as a broad-spectrum Coronavirus entry inhibitor is represented by the structure of Formula XI-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • Ai and A2 are O;
  • R19 is H, substituted or unsubstituted aromatic ring, or substituted or unsubstituted heteroaromatic ring;
  • R and R' are each independently selected from H, linear or branched alkyl C3 to C8 cycloalkyl, heterocyclic ring, aryl, and heteroaryl; and wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n- pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • cycloalkyl or “carbocyclic ring” refers to nonaromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups or carbocyclic rings can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups or carbocyclic rings can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups or carbocyclic rings can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds. Also included in the definition of cycloalkyl or carbocyclic rings are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • a cycloalkyl group or a carbocyclic ring having one or more fused aromatic rings can be attached through the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group or a carbocyclic ring can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups or carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like.
  • heterocycloalkyl or “heterocyclic ring” refers to a non-aromatic heterocycle where one or more of the ring-forming atoms are a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups or “heterocyclic rings” can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3 -dihydrobenzofuryl, 1,3 -benzodi oxole, benzo- 1,4-di oxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl and heterocyclic rings are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group or heterocyclic ring having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • moieties where one or more ring -forming atoms are substituted by 1 or 2 oxo or sulfido groups.
  • the heterocycloalkyl group or heterocyclic ring has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group or heterocyclic ring contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group or heterocyclic ring has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group or heterocyclic ring contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group or heterocyclic ring contains 0 to 2 triple bonds.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms. In some embodiments, “aryl” may be optionally substituted at any one or more positions. [000111] In some embodiments, the term “heteroaryl” refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, “heteroaryl” may be optionally substituted at any one or more positions capable of bearing a hydrogen atom.
  • alkylene refers to a straight or branched saturated divalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkylene, illustrative variations of those embodiments include, but are not limited to, C1-C12 alkylene, Ci-Cs alkylene, Ci-Ce alkylene, C1-C4 alkylene, C1-C3 alkylene, C1-C2 alkylene, Ci alkylene.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • alkenylene refers to a straight or branched divalent aliphatic hydrocarbon group, in certain embodiments having from 2 to about 20 carbon atoms and at least one double bond, e.g., having 2 to 6 carbons, 3 to 4 carbon atoms.
  • alkynylene refers to a straight or branched divalent aliphatic hydrocarbon group, in one embodiment having from 2 to about 20 carbon atoms and at least one triple bond, e.g., having 2 to 6 carbons, or 3 to 4 carbons, or 2 to 12 carbons.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • a “halogen-substitution” or “halo” substitution designates replacement of one or more hydrogen atoms with F, CI, Br, or I.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCh, C2CI5, and the like.
  • each of alkyl, alkylene, alkenylene, alkynylene, cycloalkyl, heterocycloalkyl or heterocyclic ring, aryl, heteroaryl, and alkoxy may be optionally substituted with independently selected groups such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acid and derivatives thereof, including esters, amides, and nitrites, hydroxy, alkoxy, acyloxy, amino, alky and dialkylamino, acylamino, thio, and the like, and combinations thereof.
  • the formulas also include any and all hydrates and/or solvates of the compound formulas. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulas are to be understood to include and represent those various hydrates and/or solvates.
  • a compound described herein include isomers, or derivatives, or pharmaceutically acceptable salts, or any combination thereof of the compounds described herein.
  • a compound may be a derivative and a pharmaceutically acceptable salt of a compound disclosed herein.
  • a compound may be a isomer and a pharmaceutically acceptable salt.
  • a compound may be an isomer and a derivative of a compound disclosed herein.
  • a compound disclosed herein comprises an isomer, a derivative, and a pharmaceutically acceptable salt of any of the formulae and compounds disclosed herein.
  • a compound may be a pharmaceutically acceptable salt of any of the compounds of Formulas I-XII. In some embodiments, a compound may be a pharmaceutically acceptable salt of any of the compounds of Formulas I-A through XII-A and XII-B. In some embodiments, a compound may be a pharmaceutically acceptable salt, of any of the Compounds 1-12. In some embodiments, a compound may be a pharmaceutically acceptable salt, of any of the Compounds 12-A-12-Y. In some embodiments, a compound may be a pharmaceutically acceptable salt of Compound 12a or Compound 12b. In some embodiments, a compound may be a pharmaceutically acceptable salt of Compound 12-Xa or Compound 12- Xb
  • a compound may be an isomer of any of the compounds of Formulas I-XII. In some embodiments, a compound may be an isomer of any of the compounds of Formulas I-A through XII-A and XII-B. In some embodiments, a compound may be an isomer of any of the Compounds 1-12. In some embodiments, a compound may concurrently be an isomer of any of the Compounds 12-A through 12- Y.
  • a compound may be a derivative of any of the compounds of Formulas I-XII. In some embodiments, a compound may be a derivative of any of the compounds of Formulas I-A through XII-A and XII-B. In some embodiments, a compound may be a derivative of any of the Compounds 1-12. In some embodiments, a compound may be a derivative of the Compounds 12-A through 12- Y. In some embodiments, a compound may be a derivative of Compound 12a or Compound 12b.
  • compounds described herein include isomers, derivatives, or pharmaceutically acceptable salts, or any combination thereof of the compounds of Formula I- XII and Formula 1-A through XII-A and XII-B, and Compounds 1-12 and Compounds 12A through 12Y.
  • a compound may be a derivative and a pharmaceutically acceptable salt of thereof of the compounds of Formula I-XII and Formula 1-A through XII-A and XH-B, and of Compounds 1-12 and Compounds 12A through 12Y.
  • a compound may be an isomer and a pharmaceutically acceptable salt of the compounds of Formula I-XII and Formula 1-A through XII-A and XH-B, and Compounds 1-12 and Compounds 12A-12Y.
  • a compound may concurrently be an isomer, a derivative, and a pharmaceutically acceptable salt of any of the compounds of Formulas I-XII. In some embodiments, a compound may concurrently be an isomer, a derivative, and a pharmaceutically acceptable salt of any of the compounds of Formulas I-A through XII-A and XII-B. In some embodiments, a compound may concurrently be an isomer, a derivative, and a pharmaceutically acceptable salt, of any of the Compounds 1-12. In some embodiments, a compound may concurrently be an isomer and a pharmaceutically acceptable salt, of any of the Compounds 12- A through 12- Y.
  • a compound may concurrently be a derivative or a pharmaceutically acceptable salt or a combination thereof, of Compound 12a or Compound 12b. In some embodiments, a compound may concurrently be an isomer or a pharmaceutically acceptable salt or a combination thereof, or Compound 12-Xa or Compound 12-Xb.
  • isomers of the broad-spectrum Coronavirus entry inhibitor compounds described herein are isomers of the broad-spectrum Coronavirus entry inhibitor compounds described herein.
  • the term “isomer” includes, but is not limited to, stereoisomers including optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.
  • the isomer is a stereoisomer.
  • the isomer is an optical isomer.
  • a compound disclosed herein may contain at least one chiral center.
  • a compound disclosed herein comprises cis- and trans-isomers, R- and S- enanti omers, diastereomers, the racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included herein.
  • a compound disclosed herein comprises a racemic mixture of enantiomers.
  • a compound disclosed herein comprises an A'-enantiomer.
  • a compound disclosed herein comprises an A’-enantiomer.
  • a compound disclosed herein comprises a substantially pure 5-enantiomer.
  • a compound disclosed herein comprises a substantially pure A’-enantiomer.
  • a compound disclosed herein for example but not limited to Compound 12 or any of Compounds 12A-12Y, comprises a racemic mixture of enantiomers.
  • a compound disclosed herein, for example but not limited to Compound 12 or any of Compounds 12A-12Y comprises an 5-enantiomer.
  • a compound disclosed herein for example but not limited to Compound 12 or any of Compounds 12A-12Y comprises an //-enantiomer.
  • a compound disclosed herein for example but not limited to Compound 12 or any of Compounds 12A-12Y comprises a substantially pure 5-enantiomer.
  • a compound disclosed herein for example but not limited to Compound 12 or any of Compounds 12A-12Y comprises a substantially pure //-enantiomer.
  • Compound 12a comprises a substantially pure //-enantiomer. In some embodiments, Compound 12b comprises a substantially pure 5-enantiomer.
  • a derivative of Compound 12 comprises an enantiomer. In some embodiments, a derivative of Compound 12 comprises an 5-enantiomer. In some embodiments, a derivative of Compound 12 comprises an //-enantiomer.
  • the compounds disclosed herein and used in the methods described below may exist in, and be isolated in, optically active or racemic forms.
  • the compounds may further exist as stereoisomers which may be also optically active isomers (e.g., enantiomers such as (R) or (S)), as enantiomerically enriched mixtures, racemic mixtures, or as single diastereomers, diastereomeric mixtures, or any other stereoisomers, including but not limited to:
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • the compounds disclosed herein can also be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers.
  • the compounds of can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure).
  • substantially pure it is intended that a stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure.
  • derivatives of refers to additional or removal of any functional group to or from the corresponding compound Formula.
  • Non-limiting examples are ketone, amine, amide, alcohol, ester, ather, alkane, alkene, alkyne, alkyl halide, thiol, aldehyde, or any combination thereof.
  • a compound including a chiral sulfoxide for example, but not limited to the derivatives of Compound 12, (Compounds 12-A-12-Y) may have an (S) or (R) configuration, wherein each enantiomer comprises exactly the same connectivity but opposite three-dimensional shapes.
  • a derivative of Compound 12 is represented by the structure of Compound 12-A, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-B, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-C, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-E, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-F, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-G, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: (12-G).
  • a derivative of Compound 12 is represented by the structure of Compound 12-H, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-1, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-J, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-K, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-L, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-M, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-N, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-0, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-P, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-Q, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-R, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-S, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12- T, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-U, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12- V, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-W, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a derivative of Compound 12 is represented by the structure of Compound 12-X, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • Compound 12-X may have an (S) or (R) configuration, wherein each enantiomer comprises exactly the same connectivity but opposite three-dimensional shapes.
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 12-Xa, or a pharmaceutically acceptable salt thereof, or any combination thereof c (12-Xa; (7?)-2-((l-(4-chlorophenyl)-4- phenyl-lH-imidazol-2-yl)sulfinyl)-N-(3-methoxy-2-methylphenyl)acetamide).
  • Compound 12-Xa represents the (R) configuration enantiomer of Compound 12-X (PCM-0297098).
  • a broad-spectrum Coronavirus entry inhibitor compound is represented by the structure of Compound 12-Xb, or a pharmaceutically acceptable salt thereof, or any combination thereof
  • Compound 12-Xb represents the (S) configuration enantiomer of Compound 12-X (PCM-0297098).
  • a derivative of Compound 12 is represented by the structure of Compound 12- Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof
  • a derivative of Compound 12 is represented by the structure of any of Compounds 12-A through 12-Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a derivative of Compound 12 is represented by an isomer of the structure of any of Compounds 12-A through 12-Y.
  • a derivative of Compound 12 is represented by a pharmaceutically acceptable salt of the structure of any of Compounds 12-A through 12-Y.
  • a derivative of Compound 12 is represented by an isomer and pharmaceutically acceptable salt of the structure of any of Compounds 12-A through 12- Y.
  • pharmaceutical salt refers to “pharmaceutically acceptable salts” of drug substances according to IUPAC conventions. Pharmaceutical salt is an inactive ingredient in a salt form combined with a drug.
  • pharmaceutically acceptable salt refers to salts of the compounds disclosed herein, for example but not limited to any of compounds of Formulas I-XII, of Formulas I-A through XII-A and XII-B, of Compounds 1-12, of Compounds 12a and 12b, of Compounds 12-A through 12- Y, and of Compounds 12- Xa and 12-Xb, or any other salt form encompassed by the isomers and or derivatives of these formulas, which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds disclosed herein with a pharmaceutically acceptable mineral, base, acid or salt as described herein. Acid salts are also known as acid addition salts. In some embodiments, the pharmaceutically acceptable salts include any pharmaceutically acceptable organic or inorganic acid or base.
  • the pharmaceutically acceptable organic or inorganic acid or residue of an acid In one embodiment, the pharmaceutically acceptable organic or inorganic acid or residue of an acid. In another embodiment, the pharmaceutically acceptable organic or inorganic acid or residue of an acid selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, citric acid, lactic acid, succinic acid, tartaric acid, boric acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic, toluenesulfonic acid, benzenesulfonic acid, ascorbic acid, sulfuric acid, maleic acid, formic acid, malonic acid, nicotinic acid, oxalic acid, camphorsulfonic acid, cyclamic acid, 2,2-dichloro-acetic acid, di(t-butyl)-naphthalenesulfonic acid, di(t-butyl)-naphthalenedisulfonic acid, dodecylsulfuric acid
  • compositions can be created from acids including aceturic, 4-acetamido-benzoic, adipic, aminohippuric, 4-amino-salicylic, alginic, aspartic, boric, butyric, capric (decanoic), caproic (hexanoic), carbonic, camphoric, camphorsulfonic, caprylic (octanoic), cyclamic, cinnamic, 2,2-dichloro-acetic, di(t-butyl)- naphthalenesulfonic, di(t-butyl)-naphthalenedisulfonic, dehydroacetic, diatrizoic, dodecyl sulfuric, ethane-l,2-disulfonic, edetic, ethanesulfonic, 2-ethyl-hexanoic, erythorbic, formic, fumaric, galactaric (mucic),
  • the pharmaceutically acceptable salt is inorganic cation selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, aluminum, zinc and ammonium.
  • the pharmaceutically acceptable organic amine salt selected from the group consisting of ammonium, a primary amine, a secondary amine, a tertiary amine, a quaternary ammonium compound, an amino alcohol and an amino sugar.
  • Non-limiting examples of organic amine base are benethamine, benzathine, betaine, t-butylamine (erbumine), deanol, dicyclohexylamine, diethylamine, 2-diethylamino-ethanol, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, morpholine, 4-(2 -hydroxy ethyl) morpholine, 1- (2-hydroxyethyl)-pyrrolidine (epolamine), imidazole, N-methylglucamine (meglumine), 4- phenylcyclohexylamine, piperazine, and tromethamine.
  • the compounds of any of Formulas I-XII, Formula I-A through Formula XII-A and XII-B, and compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12a, 12b, 12-A, 12-B, 12-C, 12-D, 12-E, 12-F, 12-G, 12-H, 12-1, 12-J, 12-K, 12-L, 12-M, 12-N, 12-0, 12-P, 12-Q, 12-R, 12-S, 12-T, 12-U, 12- V, 12-W, 12-X, 12-Xa, 12-Xb, and or 12- Y, for use in methods described herein below, may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salt forms of the compound disclosed herein.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the L-tartrate, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzene sulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthal ene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • Such salts may be formed by procedures well known and described in the art.
  • a pharmaceutical composition comprising any one of the broad-spectrum Coronavirus entry inhibitor compounds disclosed herein.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of any one of the broad-spectrum Coronavirus entry inhibitor compounds disclosed herein.
  • a pharmaceutical composition comprising any one of the broad-spectrum Coronavirus entry inhibitor compounds disclosed herein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a preparation of one or more of the broad-spectrum Coronavirus entry inhibitor compounds, described herein with other chemical components, such as physiologically (pharmaceutically) suitable carriers and excipients.
  • a pharmaceutical composition provides the pharmaceutical dosage form of a broad-spectrum Coronavirus entry inhibitor compound disclosed herein.
  • a pharmaceutical composition comprising a broad-spectrum Coronavirus entry inhibitor compound.
  • a pharmaceutical composition comprising a compound represented by the structure of any one of Formulas I-XII or Formulas I-A through XII-A and XII-B.
  • a pharmaceutical composition comprising a compound represented by the structure of any one of Formulas I-XII or Formulas I-A through XII-A and XII-B or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising a compound represented by the structure of any one of Formulas I, Formula I-A, Formulas II, Formula II- A, Formulas III, Formula HI- A, Formulas IV, Formula IV-A, Formulas V, Formula V-A, Formulas VI, Formula VI- A, Formulas VII, Formula VII- A, Formulas VIII, Formula VIII- A, Formulas IX, Formula IX- A, Formulas X, Formula X-A, Formulas XI, Formula XI- A, Formulas XII, Formula XII-A and Formula XII-B, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising any of Compounds 1-12, Compound 12a, Compound 12b, or Compounds 12-A through Compounds 12-Y.
  • a pharmaceutical composition comprising any of Compounds 1-12, or Compounds 12-A through Compounds 12-Y, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12a or Compound 12b, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-Xa or Compound 12-Xb, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 2, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 3, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 4, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 5, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 6, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 7, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 8, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 9, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 10, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12a, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12b, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12- A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-B, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-C, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-D, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-E, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-F, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-G, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-H, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-J, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-K, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-L, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-M, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-N, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-0, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-P, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-Q, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-R, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12-S, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12- T, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-U, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12- V, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12- W, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-X, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a pharmaceutical composition comprising Compound 12-Xa, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising Compound 12-Xb, or a pharmaceutically acceptable salt thereof.
  • provided herein is a pharmaceutical composition comprising Compound 12- Y, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof.
  • compositions comprising a broad-spectrum Coronavirus entry inhibitor compound can be provided to the subj ect with additional active agents to achieve an improved therapeutic effect as compared to treatment with each agent by itself.
  • a composition with an appropriate physiologically acceptable carrier may be formulated into preparations in solid, semi-solid, nanoparticle, or liquid forms, such as tablets, capsules, powders, granules, solutions, injections, ointments, inhalants, microspheres, and aerosols.
  • other pharmaceutically active ingredients and/or suitable excipients such as salts, buffers and stabilizers may, but need not, be present within the composition.
  • pharmaceutically acceptable carrier may in some embodiments be used interchangeably with the terms “physiological carrier,” “physiologically acceptable carrier”, “pharmaceutically acceptable diluent” or “pharmaceutically acceptable excipient” having all the same qualities and meanings.
  • a pharmaceutical composition may be in the form of a solid or liquid.
  • the pharmaceutically acceptable carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the pharmaceutically acceptable carrier(s) may be liquid, with the compositions being, for example, an oral oil, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
  • the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semiliquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like.
  • a solid composition will typically contain one or more inert diluents or edible pharmaceutically acceptable carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • a liquid pharmaceutically acceptable carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions may include one or more of the following adjuvants: steril ’ diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred
  • a liquid pharmaceutical composition intended for either parenteral or oral administration should contain an amount of a broad-spectrum Coronavirus entry inhibitor compound as herein disclosed, such that a suitable dosage will be obtained.
  • the pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredient a broad-spectrum Coronavirus entry inhibitor compound disclosed herein
  • the pharmaceutical composition in solid or liquid form may include an agent that binds to the broad-spectrum Coronavirus entry inhibitor compound as disclosed herein, and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include monoclonal or polyclonal antibodies, one or more proteins or a liposome.
  • the pharmaceutical composition may consist essentially of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One of ordinary skill in the art, without undue experimentation may determine preferred aerosols.
  • compositions may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a composition that comprises a broad-spectrum Coronavirus entry inhibitor compound as described herein, and optionally, one or more of salts, buffers and/or stabilizers, with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the broad-spectrum Coronavirus entry inhibitor compound composition so as to facilitate dissolution or homogeneous suspension of a broadspectrum Coronavirus entry inhibitor compound in the aqueous delivery system.
  • compositions may be administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the broad-spectrum Coronavirus entry inhibitor compound employed; the metabolic stability and length of action of the broad-spectrum Coronavirus entry inhibitor compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular allergic or respiratory disorder or condition; and the subject undergoing therapy.
  • a pharmaceutically acceptable carrier may be liquid, semi -liquid or solid.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application may include, for example, a sterile diluent (such as water), saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent; antimicrobial agents (such as benzyl alcohol and methyl parabens, phenols or cresols, mercurials, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride); antioxidants (such as ascorbic acid and sodium bisulfite; methionine, sodium thiosulfate, platinum, catalase, citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisol,
  • suitable pharmaceutically acceptable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • thickening and solubilizing agents such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.
  • compositions comprising a broad- spectrum Coronavirus entry inhibitor compound may be prepared with pharmaceutically acceptable carriers that protect the broad-spectrum Coronavirus entry inhibitor compound thereof against rapid elimination from the body, such as time release formulations or coatings.
  • pharmaceutically acceptable carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others known to those of ordinary skill in the art.
  • composition and “composition” may be used interchangeably herein, having all the same meanings and qualities.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula XII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CILjn-cycloalkyl, -(CILjn- heterocyclic ring, -(CFhjn-aryl, and -(CILjn-heteroaryl; or L5 and Le j oin together to form a 5 or 6 membered sub stituted or unsub stituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; and n and m are each independently an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted;
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula XII-A, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl, single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CICjn-cycloalkyl, -(CILjn- heterocyclic ring, -(CFhjn-aryl, and -(CILjn-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein * indicates a chiral center, wherein said inhibit
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula XII-B, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl, single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring p is an integer between 1-4; q is an integer between 1-4; and wherein * indicates a chiral center. [000202] In some embodiments, disclosed herein is a method of inhibiting or reducing a
  • Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein * indicates a chiral center, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, an isomer of Compound
  • said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection
  • said isomer is represented by the structure of Compound 12a or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, an isomer of Compound 12, wherein said isomer is represented by the structure of Compound 12b, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof,
  • inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, to a subject in need, a derivative of Compound 12, wherein said derivative is represented by any one of the structures of Compounds 12-A through 12- Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-A, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-B, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-C, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-D, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-E, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-F, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-G, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-H, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-1, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-J, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-K, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-L, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-M, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-N, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-0, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-P, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-Q, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-R, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-S, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12- T, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-U, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12- V, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-W, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12-X, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • disclosed herein is a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, an isomer of Compound 12-X, wherein said isomer is Compound 12-Xa, or a pharmaceutically acceptable salt thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, an isomer of Compound 12-X, wherein said isomer is Compound 12-Xb, or a pharmaceutically acceptable salt thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a derivative of Compound 12, wherein said derivative is Compound 12- Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula I-XI, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by the structure of Formula I-A through XI-A, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by any one of Compounds 1-11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 2, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 3, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 4, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 5, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 6, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 7, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 8, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 9, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 10, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering to a subject in need, a compound represented by Compound 11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said inhibiting is downstream of receptor binding and said administration inhibits or reduces the Coronavirus infection.
  • “inhibiting” or “reducing” a Coronavirus infection may encompass inhibiting or reducing a primary infection or a secondary infections, in both cases improving patient survival.
  • “inhibiting” or “reducing” a Coronavirus infection may encompass inhibiting or reducing entry of a Coronavirus into a cell.
  • a compound disclosed herein comprises a broad-spectrum Coronavirus entry inhibitor.
  • inhibiting or reducing a Coronavirus infection comprises use of any of the broad-spectrum Coronavirus compounds disclosed herein, wherein said compounds target viral entry at a point downstream of receptor binding, thereby inhibiting or reducing Coronavirus infection.
  • inhibiting or reducing a Coronavirus infection comprises inhibiting viral entry mediated by the Spike (S) glycoprotein. In some embodiments, inhibiting or reducing a Coronavirus infection comprises inhibiting viral entry mediated by the S2 component of the Spike (S) glycoprotein. In some embodiments, inhibiting or reducing a Coronavirus infection comprising use of a compound disclosed herein for inhibiting or reducing entry of the Coronavirus downstream of receptor binding. In some embodiments, inhibiting or reducing a Coronavirus infection comprises use of a compound disclosed herein for inhibiting or reducing infection mediated by the S glycoprotein of a Coronavirus.
  • inhibiting or reducing a Coronavirus infection comprising use of a compound disclosed, comprises inhibiting entry by interfering with S2 functionality. In some embodiments, inhibiting or reducing a Coronavirus infection comprises use of a compound disclosed herein for inhibiting or reducing Coronavirus entry into a host cell downstream of receptor binding. In some embodiments, inhibiting or reducing a Coronavirus infection occurs downstream of receptor binding to the SI component of the Spike (S) glycoprotein.
  • S Spike
  • a method of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in between about 35% - 100% inhibition of Coronavirus infection. In some embodiments, a method of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in between about 40% - 100% inhibition of Coronavirus infection. In some embodiments, inhibiting or reducing a Coronavirus infection, results in between about 50% - 100% inhibition of Coronavirus infection. In some embodiments, inhibiting or reducing a Coronavirus infection, results in between about 60% - 100% inhibition of Coronavirus infection. In some embodiments, inhibiting or reducing a Coronavirus infection, results in between about 70% - 100% inhibition of Coronavirus infection. In some embodiments, inhibiting or reducing a Coronavirus infection, results in between about 80% - 100% inhibition of Coronavirus infection.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% inhibition of Coronavirus infection.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in between about 35% - 100% inhibition of Coronavirus entry into a host cells.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in between about 40% - 100% inhibition of Coronavirus entry into a host cells.
  • inhibiting or reducing a Coronavirus entry into a host cells comprises between about 50% - 100% inhibition of Coronavirus entry into a host cells.
  • inhibiting or reducing a Coronavirus entry into a host cells comprises between about 60% - 100% inhibition of Coronavirus entry into a host cells. In some embodiments, inhibiting or reducing a Coronavirus entry into a host cells, comprises between about 70% - 100% inhibition of Coronavirus entry into a host cells. In some embodiments, inhibiting or reducing a Coronavirus entry into a host cells, comprises between about 80% - 100% inhibition of Coronavirus entry into a host cells.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% inhibition of Coronavirus entry into a host cells.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in at least 35% - 100% inhibition of Coronavirus infection.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering a broadspectrum Coronavirus entry inhibitor compound disclosed herein, results in at least 40% - 100% inhibition of Coronavirus infection.
  • inhibiting or reducing a Coronavirus infection results in at least 50% - 100% inhibition of Coronavirus infection.
  • inhibiting or reducing a Coronavirus infection results in at least 60% - 100% inhibition of Coronavirus infection.
  • inhibiting or reducing a Coronavirus infection results in at least 70% - 100% inhibition of Coronavirus infection.
  • inhibiting or reducing a Coronavirus infection results in at least 80% - 100% inhibition of Coronavirus infection.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% inhibition of Coronavirus infection.
  • the term “about”, refers to a deviance of between 0.0001-5% from the indicated number or range of numbers. In one embodiment, the term “about”, refers to a deviance of between 1 -10% from the indicated number or range of numbers. In one embodiment, the term “about”, refers to a deviance of up to 25% from the indicated number or range of numbers.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by the structure of Formula XII, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • a and B rings are each independently a substituted or unsubstituted single or fused aromatic or heteroaromatic ring system, substituted or unsubstituted single or fused C3-C10 cycloalkyl, or substituted or unsubstituted single or fused heterocycloalkyl;
  • Ls and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CFFjn-cycloalkyl, -(CFhjn- heterocyclic ring, -(CFhjn-aryl, and -(CFFjn-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n and m are each independently an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein said * indicates a chiral
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by the structure of Formula XII-A, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • C and D rings are each independently a single or fused aryl or heteroaryl
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl; single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl -(CICjn-cycloalkyl, -(CILjn- heterocyclic ring, -(CFhjn-aryl, and -(CILjn-heteroaryl; or L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring; n is an integer between 0-10; wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic ring, aryl, and heteroaryl are each independently substituted or unsubstituted; and wherein * indicates a chiral center, and wherein said
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by the structure of Formula XII-B, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof: wherein
  • L5 and Le are each independently selected from H, linear or branched alkyl, linear or branched alkoxy, linear or branched haloalkyl, single or fused cycloalkyl, single or fused heterocyclic ring, single or fused aryl, single or fused heteroaryl, -(CH2)n-cycloalkyl, - (CH2)n-heterocyclic ring, -(CH2)n-aryl, and -(CH2)n-heteroaryl; or
  • L5 and Le join together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring
  • p is an integer between 1-4
  • q is an integer between 1-4
  • * indicates a chiral center.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by the structure of Compound 12, or an isomer thereof, or a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering an isomer of Compound 12, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells, wherein said isomer is represented by the structure of Compound 12a or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering an isomer of Compound 12, wherein said isomer is represented by the structure of Compound 12b, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof,
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is represented by any one of the structures of Compounds 12-A through 12- Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof:
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12- A, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-B, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-C, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-D, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-E, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-F, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-G, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-H, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-1, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-J, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-K, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-L, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-M, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-N, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-0, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-P, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-Q, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-R, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-S, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-T, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-U, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-V, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-W, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12-X, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering an isomer of Compound 12-X, wherein said isomer is Compound 12-Xa, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering an isomer of Compound 12-X, wherein said isomer is Compound 12-Xb, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a derivative of Compound 12, wherein said derivative is Compound 12- Y, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering a compound represented by the structure of any of Formula I-XI, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of inhibiting or reducing a Coronavirus infection comprising administering a compound represented by the structure of any of Formula I- A through XII-A and XII-B, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by any one of Compounds 1-11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof: wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 1, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 2, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 3, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 4, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 5, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 6, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 7, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 8, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 9, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 10, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • a method of treating a Coronavirus infection in a subject or treating a subject at risk of contracting a Coronavirus infection comprising administering a compound represented by Compound 11, or an isomer thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or any combination thereof, wherein said administration treats said Coronavirus infection or reduces said risk of Coronavirus infection by reducing viral entry into cells.
  • the terms “treating” or “treatment” and the like refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove.
  • the object is to prevent or lessen a Coronavirus infection.
  • the object is to prevent or lessen entry of a Coronavirus into a cell.
  • the targeted pathological condition or disorder is COVID-19.
  • the object is to prevent or lessen a SARS-CoV, SARS-CoV-2, or MERS-CoV infection.
  • the object is to prevent or lessen entry of SARS-CoV, SARS-CoV-2, or MERS-CoV into a cell.
  • treating may include directly affecting or curing, suppressing, inhibiting, preventing, reducing the severity of, delaying the onset of, reducing symptoms associated with the disease, disorder or condition, or a combination thereof.
  • “treating” refers inter alia to delaying progression, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
  • “preventing” refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof.
  • “suppressing” or “inhibiting”, refers inter alia to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease- related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in at least 35% - 100% inhibition of Coronavirus entry into a host cells.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in at least 40% - 100% inhibition of Coronavirus entry into a host cells.
  • inhibiting or reducing a Coronavirus entry into a host cells comprises at least 50% - 100% inhibition of Coronavirus entry into a host cells.
  • inhibiting or reducing a Coronavirus entry into a host cells comprises at least 60% - 100% inhibition of Coronavirus entry into a host cells. In some embodiments, inhibiting or reducing a Coronavirus entry into a host cells, comprises at least 70% - 100% inhibition of Coronavirus entry into a host cells. In some embodiments, inhibiting or reducing a Coronavirus entry into a host cells, comprises at least 80% - 100% inhibition of Coronavirus entry into a host cells.
  • methods of inhibiting or reducing a Coronavirus infection comprising administering a broad-spectrum Coronavirus entry inhibitor compound disclosed herein, results in about 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% inhibition of Coronavirus entry into a host cells.
  • a subject may encompass a vertebrate, in some embodiments, to a mammal, and in some embodiments, to a human.
  • a subject is a human child between the ages of newborn and 21.
  • a subject is a human adult.
  • subjects at risk of contracting a Coronavirus infection comprise human adults over the age of 50 and or a subject suffering from a serious health problem.
  • a serious health problem comprises a heart disease or condition, a lung disease or condition, a weakened immune system, obesity, diabetes, or any combination thereof.
  • a heart disease or condition comprises a cardiomyopathy, a congenital heart disease or condition, heart failure, or a coronary heart/artery disease, or any combination thereof.
  • a lung disease or condition comprises chronic obstructive pulmonary disease (COPD), lung cancer, cystic fibrosis, pulmonary hypertension, pulmonary embolism, pulmonary fibrosis, or moderate to severe asthma, or any combination thereof.
  • COPD chronic obstructive pulmonary disease
  • a subject comprising a weakened immune system has undergone an organ transplant, cancer treatment, a bone marrow transplant, or suffers from HIV/AIDS, or has long term use of prednisone or a similar drug that weakens the immune system.
  • diabetes comprises type 1 or type 2 diabetes.
  • serious health problems comprise a brain or nervous system condition including stroke and dementia, a cancer, sickle cell anemia, thalassemia, chronic liver disease, chronic kidney disease, or Downs syndrome, or any combination thereof.
  • a Coronavirus comprises SARS-CoV, SARS-CoV-2, or MERS-CoV.
  • a Coronavirus comprises SARS-CoV, SARS-CoV-2, or MERS-CoV, or any combination thereof.
  • a Coronavirus comprises SARS-CoV.
  • a Coronavirus comprises SARS-CoV-2.
  • a Coronavirus comprises MERS-CoV.
  • a Coronavirus comprises a novel Coronaviruses that may emerge in the future.
  • a Coronavirus comprises a variant of SARS-CoV, SARS-CoV-2, or MERS-CoV. In some embodiments of methods of use described herein, a Coronavirus comprises a variant of SARS-CoV, SARS-CoV-2, or MERS- CoV, or any combination thereof. In some embodiments of methods of use described herein, a Coronavirus comprises a variant of SARS-CoV. In some embodiments of methods of use described herein, a Coronavirus comprises a variant of SARS-CoV-2. In some embodiments of methods of use described herein, a Coronavirus comprises a variant of MERS-CoV.
  • SARS-CoV-2 is the virus that causes COVID- 19 in a subject.
  • a SARS-CoV-2 variant comprises a variant of concern, a variant of interest, or a variant under monitoring, or any combination thereof. In some embodiments of methods disclosed herein, a SARS-CoV-2 variant comprises a variant of concern. In some embodiments of methods disclosed herein, a SARS-CoV-2 variant comprises a variant of interest. In some embodiments of methods disclosed herein, a SARS-CoV- 2 variant comprises a variant under monitoring.
  • a SARS-CoV-2 variant comprises a variant listed by the World Health Organization (WHO) at https://www.who.int/publications/m/item/updated-working-definitions-and-primary-actions-for- -sars-cov-2 -variants.
  • WHO World Health Organization
  • a variant of SARS-CoV-2 comprises an alpha, beta, gamma, delta, epsilon, eta, iota, kappa, lambda, omicron, zeta, mu, or Wuhan variant.
  • a variant of SARS-CoV-2 comprises an alpha variant.
  • a variant of SARS-CoV-2 comprises a beta variant.
  • a variant of SARS-CoV- 2 comprises a gamma variant.
  • a variant of SARS-CoV-2 comprises a delta variant.
  • a variant of SARS-CoV-2 comprises an epsilon variant.
  • a variant of SARS-CoV-2 comprises an eta variant. In some embodiments, a variant of SARS-CoV-2 comprises an iota variant. In some embodiments, a variant of SARS- CoV-2 comprises a kappa variant. In some embodiments, a variant of SARS-CoV-2 comprises a lambda variant. In some embodiments, a variant of SARS-CoV-2 comprises an omicron variant. In some embodiments, a variant of SARS-CoV-2 comprises an omicron subvariant. In some embodiments, a variant of SARS-CoV-2 comprises a zeta variant. In some embodiments, a variant of SARS-CoV-2 comprises a mu variant.
  • a variant of SARS-CoV-2 comprises a Wuhan variant. In some embodiments, a variant of SARS-CoV-2 comprises a variant arising from an individual infected by two or more Coronaviruses. In some embodiments, what appears to be a variant of SARS-CoV-2 comprises a distinct Coronavirus.
  • VSV Vesicular Stomatitis Virus
  • Table 1 Amino Acid Sequences of Coronavirus Spike proteins.
  • pCAGGS-G encoding the Vesicular Stomatitis Virus G glycoprotein from the Indiana serotype (VSV-G), was a kind gift from Benjamin Podbilewicz (Technion - Israel Institute of Technology).
  • pcDNA3.1-SARS-CoV-2-Spike-C9 encoding the Spike glycoprotein of Wuhan SARS-CoV-2 fused to a C-terminal C9 tag (Sw) was a kind gift from Fang Li (Addgene plasmid # 145032;http://n2t.net/addgene: 145032; RRID:Addgene_145032) (Shang, J. et al.
  • pCGl-SARS2- Spike-HA encoding the Wuhan SARS-CoV-2 Spike protein fused to a C-terminal HA tag was a kind gift from Gideon Schreiber
  • pCMV3-SARS2-Spike-Flag encoding the Wuhan SARS-CoV- 2 Spike protein fused to a C-terminal FLAG tag
  • pCMV3-SARS2-SpikeA19 encoding the Wuhan SARS-CoV-2 Spike protein with 19 amino acids removed at the cytoplasmic tail
  • pCMV3-SARS2-SpikeA19-Flag were a kind gift from and Yosef Shaul (Weizmann Institute of Science) (Strobelt, R.
  • Imatinib inhibits SARS- CoV-2 infection by an off-target-mechanism. Sci. Reports 12, 5758).
  • pcDNA3.1 -SARS-CoV-2 - S a -C9, pcDNA3.1-SARS-CoV-2-S s -C9, and pcDNA3.1-SARS-CoV-2-S 0 -C9, encoding the Spike glycoprotein of Wuhan SARS-CoV-2 variants fused to a C-terminal C9 tag were generated by DNA synthesis (GeneScript, USA).
  • pcDNA3.1-MERS-Spike-C9 encoding the Spike glycoprotein of the MERS-CoV (SM) fused to a C-terminal C9 tag was generated by sub-cloning the MERS Spike protein from a pLVX-EFlalpha-MERS-Spike plasmid (Weizmann Plasmid Bank) into a pcDNA3.1 expression plasmid using the GeneArt Gibson Assembly HiFi master mix (Thermo Fisher Scientific).
  • Primers VI CGCACAAGGTCCACGTCCACGGCTCCACCGAGACATCCC (SEQ ID NO: 6) and V2: AGAAAAACTGAATGAATCATGCTAGCCAGCTTGGGTC (SEQ ID NO: 7); template DNA: pcDNA3.1-SARS-Spike alpha) and the insert fragment (Primers II : GGAGACCCAAGCTGGCTAGCATGATTCATTCAGTTTTTCTGCTCATGTTTC (SEQ ID NO: 8) and 12: TGGGATGTCTCGGTGGAGCCGTGGACGTGGACCTTGTGC (SEQ ID NO: 9); template DNA: pLVX-EFlalpha-MERS-Spike).
  • Baby Hamster Kidney cells (BHK-21; ATCC) were maintained in Dulbecco's modified Eagle medium (DMEM, Gibco, USA) supplemented with 10% fetal bovine serum (FBS, Biological Industries, Israel), 1% penicillin-streptomycin (PS, Biological Industries) and 25mM HEPES (Biological Industries).
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • PS penicillin-streptomycin
  • 25mM HEPES Biological Industries
  • HEK-293T Human Embryonic Kidney-293T cells
  • HEK-293T-ACE2 HEK-293T-ACE2
  • TMPRSS2 HEK-293T-ACE2-TMPRSS2
  • ACE2 DPP4 and TMPRSS2 HEK-293T-ACE2-TMPRSS2-DPP4 were cultured in DMEM supplemented with 8.1% FBS, 1% PS, 25mM HEPES (Biological Industries).
  • HEK-293T-ACE2, HEK-293T-ACE2-TMPRSS2, HEK-293T-ACE2-DPP4-TMPRSS2 were maintained by supplementing the culture medium with 1 pg/ml Puromycin (Sigma-Aldrich, USA), and 1.5 ng/ml Blasticidin (InvivoGen, USA) respectively. All cell lines were cultured in a 5% CO 2 incubator at 37°C.
  • HEK-293T-ACE2 and HEK-293T-ACE2-TMPRSS2 were a kind gifts from Yosef Shaul (Weizmann Institute of Science).
  • HEK-293T-ACE2-TMPRSS2-DPP4 cells were established by lentiviral transduction.
  • HEK-293T-ACE2-TMPRSS2 cells were seeded in each well of a 6 well plate and cultured to 70-80% confluency.
  • the growth medium was replaced with 1 ml of medium containing human CD26/DPP4 pre-packaged lentiviral particles (LTV-CD26, G&P Biosciences) at a multiplicity of infection (MOI) of 5.
  • MOI multiplicity of infection
  • 1: 1000 of polybrene Infection Reagent (Sigma-Aldrich) was added to the medium.
  • the cells were incubated with the lentivirus for 24h at 37 °C with 5% CO2. After the transduction period, the viral supernatant was removed, and a fresh growth medium containing 1 pg/ml Puromycin was added to the cells to initiate the selection process.
  • Vero E6 ATCC
  • Vero E6-TMPRSS2 NIBSC, UK
  • Vero E6-TMPRSS2 were maintained by supplementing the culture medium with 1 mg/ml Geneticin (Thermo Fisher Scientific).
  • Delta B.1.617.2 The variant was supplied by Virus and Immunity Unit in Institut Pasteur headed by Olivier Schwartz. It was isolated from a nasopharyngeal swab of a hospitalized patient who had returned from India. The swab was provided and sequenced by the Laboratoire de Virologie of the Hopital Europeen Georges Pompidou (Assistance Clarque des Hopitaux de Paris).
  • XBB.1.5 The strain hCoV-19/France/PDL-IPP58867/2022 was supplied by the National Reference Centre for Respiratory Viruses hosted by Institut Pasteur (Paris, France) and headed by Dr. Etienne Simon -Lori ere. The human sample from which strain hCoV- 19/France/PDL-IPP58867/2022 was isolated has been provided from the Centre Hospitalier de Laval.
  • CELLI The strain hCoV-19/France/NAQ-IPP58166/2022 was also supplied by the National Reference Centre for Respiratory Viruses hosted by Institut Pasteur (Paris, France). The human sample from which strain hCoV-19/France/NAQ-IPP58166/2022 was isolated has been provided from the Selas Cerballiance Charentes.
  • VSVAG-X “glycoprotein X” complemented pseudoviruses
  • 1.2* 10 6 BHK-21 cells were plated in a 100 mm dish (Greiner, Austria) one day prior to transfection.
  • the cells were transfected using JetPrime transfection reagent (Polyplus, France) at 75-80% confluence with 15pg/ml of a plasmid expressing the viral glycoprotein.
  • 24 h after transfection cells were infected with VSVAG-G pseudovirus at a multiplicity of infection (MOI) of 5, with 1 : 1,000 polybrene infection reagent .
  • MOI multiplicity of infection
  • Cells were incubated for 1 h at 37°C in a 5% CO2 incubator shaking every 15 min.
  • Infectious units/ml were extrapolated by calculating the geometric mean of the number of infected cells multiplied by 100 to convert the units from pl to ml.
  • the pseudovirus containing supernatant was first incubated with anti-G neutralizing antibody (1 : 1000 dilution, clone 1E9F9 (a-G; Absolute Antibody, UK) at a 1 : 1000 dilution for 1 h at room temperature (RT) to remove residual VS VAG-G background infections before titering.
  • Phenotypic assay pseudotype-based HTS imaging inhibition assay
  • Icompound Number of infected cells in presence of compounds.
  • I max Number of infected cells in absence of compounds.
  • Imin Number of infected cells in absence of viruses.
  • the compounds were serially diluted to cover a range of 40- 0.31 pM.
  • the assay is identical to the phenotypic assay as described above.
  • Six different VSVAG viruses representing G, WT, Alpha, Delta, Omicron, and MERS were tested. Data were deposited in Collaborative Drug Discovery platform (CDD vault; Collaborative Drug discovery, USA) and dose response curves were analyzed from image analysis. Dose response curves were generated and fitted to the Levenberg-Marquardt algorithm that is used to fit a Hill equation to doseresponse data.
  • a 96-well nickel-coated plate was coated with ACE2-His and incubated for 60 min before washing. The plate was then incubated with a blocking buffer for 10 mins and removed. Next, the compounds or soluble Spike were added and incubated for 60 min at room temperature with slow shaking. Following incubation, SARS-CoV-2 spike (RBD)-Fc was added into all wells except for the blank, and the plate was left to sit with slow shaking. After 60 min, an anti -mouse Fc-HRP antibody was added, followed by the addition of an Enhanced chemiluminescence (ECL) solution to produce chemiluminescence. Finally, a Cytation 5 plate reader (BioTek, USA) was used to read and quantify the luminescence. The final concentration of DMSO was 5% in each wells.
  • Flash chromatography was first performed by automated CombiFlash Systems (Teledyne ISCO, USA) with RediSep Rf Normal -phase silica gel columns (Teledyne ISCO) or Silica gel Kieselgel 60 (0.04-0.06 mm) columns (Merck, USA). Purification of the compounds was then performed using preparative HPLC; Waters Prep 2545 Preparative Chromatography System (Waters, USA), with 2489 UV/Vis detector (Waters), using XBridge HPLC Column (Waters). Compounds purity was monitored by UPLC-MS system: Acquity UPLC H class with PDA detector and ELSD detector (Waters), and using Acquity UPLC BEH C18 Column (Waters).
  • MS-system SQ detector 2 (Waters). UPLC Method using HPLC grade solvents: 5 min gradient 95:5 Water (Merck): Acetonitrile (Merck) 0.05% formic acid (Bio-lab, Israel) to Acetonitrile 0.05% formic acid, flowrate 0.5 mL/min, column temp 40°C.
  • cytotoxicity was assessed using the CellTiter-Glo luminescent cell viability kit (Promega, USA). 3,000 cells/well of Vero E6 were seeded in white with clear bottom 384- well plates. The following day, compounds were added at concentrations indicated. 0.5% DMSO and 10 pM Camptothecin (Sigma Aldrich) controls were added in each plate. After 48 h incubation, 10 pl of CellTiter Gio reagent was added in each well and the luminescence was recorded using a luminometer (Berthold Technologies, Germany) with 0.5 sec integration time.
  • Plaque assay was performed to determine the viral load of bona fide SARS-COV-2 Delta variant with a dose-response of two enantiomers of PCM0282478 (in duplicates).
  • Vero E6 cells were seeded in 24-well plates at a concentration of 7.5 x 10 4 cells per well. The following day, serial dilutions of each supernatant were performed in serum-free DMEM medium. After I h absorption at 37 °C, 2/ overlay medium was added to the inoculum to give a final concentration of 2% (v/v) FBS in DMEM and 0.4% (w/v) agarose (Sigma Aldrich) to achieve a semi-solid overlay.
  • threshold for statistical significance was considered for p-values ⁇ 0.05, denoted by one asterisk (*), two (**) if P ⁇ 0.01, three (***) if P ⁇ 0.001 and four ( ****) if P ⁇ 0.001.
  • Example 2 Pseudoviruses expressing fluorescent reporters enable robust quantification of infection
  • HTS high-throughput screening
  • VSVAG-Sw S glycoprotein of the SARS-CoV-2 Wuhan variant
  • VSVAG VSV backbone lacking VSV-G
  • FIGURES 1A-1B VSVAG, which expresses a fluorescent reporter from the viral genome after infection was chosen for use throughout these studies.
  • a fluorescent reporter was employed, instead of the more commonly used luciferase, because it allows direct visualization and robust quantification of single infection events, overcoming the need for averaging and the additional processing steps for the Luciferase enzymatic reaction.
  • VSV-GAG which express a fluorescent reporter from the viral genome after infection were used.
  • VSVAG-Sw pseudoviruses The specific tropism of the VSVAG-Sw pseudoviruses was confirmed by comparing infected ACE2-overexpressing Human Embryonic Kidney (HEK-293T-ACE2) cells and ACE- 2-defici ent Baby Hamster Kidney (BHK-21) cells (FIGURE ID). To eliminate potential residual infections from VSVAG-G that might have been left over during production, all experiments were performed in the presence of a neutralizing antibody against VSV-G.
  • HEK-293T-ACE2 Human Embryonic Kidney
  • BHK-21 Baby Hamster Kidney
  • FIGURE IE modifications to the cytosolic tail of the S glycoprotein and optimizing the production and infection procedures
  • Modifications included truncating the 19-amino acid ER retention sequence and adding an HA, flag or C9 tag to the C-terminus of the S glycoprotein.
  • Optimal titers were achieved with C9 and HA tagged S glycoproteins without further modifications (FIGURE IE).
  • peak titers were obtained when the cell supernatant containing VSVAG-Sw was harvested 30 hours after infection with the VSVAG-G helper virus.
  • infection rates doubled when cultures were centrifuged post-infection (FIGURES 2A- 2B)
  • VSVAG-SM SARS-CoV-2 variants Alpha
  • VSVAG-S a SARS-CoV-2 variants Alpha
  • VSVAG-Sa SARS-CoV-2 variants Alpha
  • VSVAG-Sa SARS-CoV-2 variants Alpha
  • VSVAG-Sa SARS-CoV-2 variants Alpha
  • VSVAG-Sa SARS-CoV-2 variants Alpha
  • VSVAG-Sa SARS-CoV-2 variants Alpha
  • VSVAG-Sa Delta
  • VSVAG-So Omicron
  • the second column of each plate contained only cells and served as the baseline for 0% infection as the geometric mean of counts in these wells, which also served as the positive controls (FIGURE 3B and FIGURE 4)
  • All wells without compounds were supplemented with DMSO to achieve a final concentration of 0.1%.
  • Example 4 A three-tiered screen identifies CoV entry inhibitors downstream of receptor binding
  • Results' The primary screen evaluated an extensive library of approximately 200,000 compounds against VSVAG-Sw at a single concentration of 10 pM. This process identified 733 compounds capable of inhibiting VSVAG-Sw infection by at least 35% while maintaining a cell viability of 65% (FIGURE 6 (Table 2)). For the secondary screen, the 733 compounds were tested against VSVAG-G to distinguish Sw-specific inhibitors from non-specific ones. Since VSVAG-Sw and VSVAG-G share the VSVAG backbone and only differ in the surface glycoproteins, compounds inhibiting VSVAG-Sw but not VSVAG-G were deemed Sw-specific. The screening identified 65 Spike-specific inhibitors that inhibited VSVAG-Sw infection by at least 35% without inhibiting VSVAG-G infection more than 35% (FIGURE 7 (Table 3)).
  • HTS parameters were calculated such as Z' factor, signal-to-background (S/B), and coefficient of variation (%CV) for 569 plates from all three screening levels (FIGURE 5B) (Zhang et al (1999).
  • S/B signal-to-background
  • %CV coefficient of variation
  • Example 5 Dose response and cytotoxicity of putative candidate compounds
  • Nafamostat showed similar IC50 values against VSVAG-Sw (0.90 pM vs 1.31 pM) and VSVAG-SM (0.13 pM vs 0.21 pM) before and after purification, with no significant activity against VSVAG-G, and was also active against VSVAG-S a (0.92 pM vs 0.93 pM), and VSVAG- Sa (0.31 pM vs 0.94 pM), and VSVAG-S 0 , but the latter only after purification (Not calculated vs 1.81 pM) (FIGURE 9 and FIGURE 10).
  • PCM-0068389 while showing extremely promising activity and selectivity before purification, completely lost all activity against VSVAG-Sw, its variants and VSVAG-SM after purification and showed some activity against VSVAG-G at concentrations higher than 10 pM (FIGURE 9 and FIGURE 10).
  • PCM-0166392 and PCM- 0179622 while retaining relatively high activity against VSVAG-Sw and its variants was not selective against VSVAG-SM yielding a dose-response curves that were not significantly different from VSVAG-G (FIGURE 9 and FIGURE 10)
  • PCM-0163855 retained high selectivity to VSVAG-Sw (0.60 pM vs 0.70 pM), VSVAG-S a (0.37 pM vs 0.40 pM), and VSVAG-Sa (0.45 pM vs 0.49 pM), with only moderate activity against VSVAG-S 0 (41.18 pM vs 30.77 pM) but was inactive against VSVAG-SM, showing no significant difference from VSVAG-G above 10 pM concentration (FIGURE 9 and FIGURE 10).
  • PCM-0163855 inhibited the replication of bona fide SARS-CoV-2 Delta (B.1.617.2) in VeroE6 cells with and without TMPRSS2 overexpression (6.71 pM and 6.43 pM respectively; FIGURE 11 A).
  • Example 6 A PCM-0163855 derivative (Compound 12), is a broad-spectrum candidate
  • PCM-0163855 may also be a broad-spectrum Coronavirus entry inhibitor candidate.
  • PCM-0282478 inhibited bona fide SARS-CoV-2 Delta (B.1.617.2) replication in VeroE6 cells (4.49 pM; FIGURE 13A), and neither inhibited XBB.1.5 and CH.1.1 at the concentration range tested.
  • PCM-0282478 was synthesized as a racemic mixture. To evaluate the contribution of each enantiomer, the enantiomers were separated and are identified herein as PCM-0296173 (5- enantiomer; Compound 12b) and PCM-0296174 ( ’-enantiomer; Compound 12a), and evaluated their IC50 value against VSVAG-Sa, VSVAG-S 0 , VSVAG-G, and VSVAG-SM (FIGURE 13B). Only PCM-0296174 potently inhibited VSVAG-Sa and was selective against VSVAG-So and VSVAG-SM (12.75 pM and 30.19 pM, respectively).
  • PCM- 0296174 against VSVAG-Sa The IC50 of value of PCM- 0296174 against VSVAG-Sa was approximately half compared to the racemic mixture PCM- 0282478 (0.56 pM vs 1.13 pM, respectively), showing potency increased two-fold. Both PCM- 0296173 and PCM-0296174 did not inhibit VSVAG-G up to 10 pM. Further, only PCM-0296174 inhibited SARS-CoV-2 Delta (B. l.617.2) replication, and its IC50 improved by 2-folds in presence of an inhibitor against the multi drug resistance protein 1 (MDR1) efflux transporter (1.88 pM vs 0.89 pM respectively; FIGURE 13B).
  • MDR1 multi drug resistance protein 1
  • PCM-0296174 reduced the infectivity by 100 folds in a plaque assay (FIGURES 15A-15C). Finally, PCM-0296174 did not inhibit Spike-mediated receptor interactions (FIGURE 16). Taken together, these experiments suggest that PCM-0296174 is abroad-spectrum selective S glycoprotein inhibitor downstream of receptor binding.
  • FIGURE 17A and FIGURE 17B As part of a structure-activity relationship (SAR) study, 24 racemic derivatives of PCM-0282478 were synthesized and evaluated for their inhibitory activity against VSVAG-S s , VSVAG-S 0 , VSVAG-SM, and VSVAG-G (FIGURE 18).
  • PCM-097098 emerged as the most potent compound, exhibiting lower IC50 values against VSVAG-Ss (1.12 pM), VSVAG-S 0 (6.97 pM), and VSVAG-SM (7.22 pM) compared to the parent compound PCM-0282478 (IC50 values: 5.43 pM, 23.72 pM, and 21.42 pM, respectively).
  • PCM-097098 showed no inhibitory activity against VSVAG-G at concentrations up to 10 pM, indicating a high degree of selectivity for CoVs.
  • racemic PCM-0282478 was more potent against VSVAG-Ss, VSVAG-S 0 , and VSVAG-SM than enantiomerically pure PCM-0296174 (5.21 pM, 18.64 pM, and 15.12 pM, respectively).
  • enantiomerically pure PCM-0296174 5.21 pM, 18.64 pM, and 15.12 pM, respectively.
  • its enantiomerically pure form may be even more potent and selective against VSVAG-Ss, VSVAG- S o , and VSVAG-SM.
  • the Covid-19 pandemic highlighted the pressing need for antiviral therapeutics capable of mitigating infection and spread of emerging coronaviruses (CoVs).
  • a promising therapeutic strategy lies in inhibiting viral entry mediated by the Spike (S) glycoprotein.
  • S Spike
  • HTS high- throughput screening
  • a three-step process was employed to screen nearly 200,000 small molecules. First, potential inhibitors were identified by assessing their ability to inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein.
  • VSV-G Vesicular Stomatitis Virus glycoprotein
  • MERS-CoV S glycoprotein MERS-CoV S glycoprotein
  • Nafamostat five compounds including the known broad-spectrum inhibitor Nafamostat, were subjected to further validation, testing them against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as against bona fide SARS-CoV- 2 in vitro.
  • This rigorous approach revealed a novel inhibitor and a derivative thereof (Compound 12 and Compound 12a, respectively, as potential broad-spectrum antivirals.
  • Fluorescent reporters were employed instead of the more commonly used luciferase, demonstrating their advantages which include direct measurement of single infection events, high signal -to-noise ratio, and reduced processing (FIGURES 1B-1C). Moreover, fluorescent reporters with different wavelengths enable the simultaneous examination of multiple viruses under the same experimental conditions (FIGURE 1G).
  • the HTS platform was leveraged to screen a comprehensive library of approximately 200,000 compounds, targeting potential CoV fusion inhibitors (FIGURE 5A).
  • the three-tiered assay incorporated two class I viral glycoproteins from phylogenetically distant CoVs (SARS- CoV-2 & MERS-CoV), and a class III glycoprotein from VSV (FIGURE 5A).
  • the primary screen against VSVAG-Sw yielded 733 compounds with inhibitory activity, including known inhibitors of proteases, ubiquitin-specific peptidases, and viral gene expression regulated by the HSP90 protein family.
  • the secondary screen showed that most of these compounds also inhibit VSVAG-G, yielding only 65 putative spike-specific inhibitors.
  • the tertiary screen against VSVAG-SM separated receptor binding and putative S2-specific inhibitors, highlighting four compounds, Compounds 1, 5, 6, and 11, and the known TMPRSS2 inhibitor Nafamostat (FIGURES 5C-5D)
  • PCM-0163855 was retained as a potential selective S glycoprotein inhibitor (FIGURE 10).
  • PCM-0282478 inhibited VSVAG-Sw, VSVAG-S 0 , VSVAG-SM and bona fide SARS-CoV-2 delta virus replication (FIGURES 13A and 13B).
  • This rigorous approach revealed a novel inhibitor, Compound 11, and its derivative, Compound 12, as potential broad-spectrum antiviral compounds.
  • PCM- 0296174 inhibits VSVAG-Sw, VSVAG-S 0 , VSVAG-SM and bona fide SARS-CoV-2 delta virus replication, highlighting its potential as a broad-spectrum inhibitor of CoVs (FIGURES 13A and 13B).
  • Nafamostat failed to inhibit bona fide SARS-CoV-2 delta virus replication, perhaps due to the capacity of CoVs to infect cells in a TMPRSS2-independent pathway (FIGURE 14)

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Abstract

L'invention concerne des composés inhibiteurs d'entrée de coronavirus à large spectre et leurs méthodes d'utilisation. Les méthodes de l'invention comprennent l'inhibition d'une infection à coronavirus, le traitement d'une infection à coronavirus, et le traitement d'un sujet présentant un risque de contracter une infection à coronavirus. Les composés décrits ici ciblent l'entrée de coronavirus en aval de la liaison du récepteur viral.
PCT/IL2024/050919 2023-09-13 2024-09-12 Inhibiteurs d'entrée de coronavirus à large spectre Pending WO2025057164A1 (fr)

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