OA20816A

OA20816A - Methods of treating coronavirus.

Info

Publication number: OA20816A
Application number: OA1202200224
Authority: OA
Inventors: Kester Gary Barnette; Mitchell S Steiner
Original assignee: Veru Inc
Priority date: 2020-04-03
Filing date: 2021-04-05
Publication date: 2023-05-05

Abstract

The present invention relates to methods of treating Coronavirus infections using compounds having anti-tubulin or tubulin disruption activity.

Description

METHODS OF TREATING CORONAVIRUS

CROSS REFERENCE TO RELATED APPLICATIONS

This application daims the benefit of U.S. Provisîonal Application Nos. 63/004,781, filed April 3, 2020; and 63/145,886, filed February 4, 2021, hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention is directed to methods of treating a coronavîrus, using compounds having cytoskeleton disruptor activity, and formulations including the compounds with pharmaceutical acceptable excipients and/or addîtional cytoskeleton disruptor compounds.

BACKGROUND OF THE INVENTION

Over the last 20 years, a number of viral épidémies hâve posed a serions global public health risk including Severe Acute Respiratory Syndrome coronavîrus (SARS-CoV) in 2002-2003, the Middle East Respiratory Syndrome coronavîrus (MERS-CoV) in 2012, and Ebola in 2014-2016. On November 17, 2019, a new viral acute severe respiratory disease emerged in Wuhan, China. In February 2020, World Health Organization (WHO) announced the disease’s name as COVID19 for COronaVirus Disease first dîscovered in the year 2019. The coronavîrus causing the disease, as it was simîlar to SARS-CoV, was eventually named by the International Committee on Taxonomy of Viruses (ICTV) as SARS-CoV-2, COVID-19 (SARS-CoV-2) has been declared a pandémie with over 804,061 cases and 39,074 deaths worldwide and countîng as of March 31, 2020. By March 2021, these numbers increased to 128,109,427 cases and 2,800,279 deaths (3%) worldwide with 103,307,591 confirmed recoveries (97%). Vaccines for SARS-CoV-2 began to be approved in the United States in December 2020 with three emergency use authorizations (EUAs) provided by March 2021; however, herd immunity has not yet reached. Despite ongoing worldwide social distancing and immunization efforts, 518,201 active cases remain including about 100,000 critically ill patients currently worldwide.

Coronaviruses are enveloped positive-sense single-stranded RNA viruses. They infect birds and mammals, especially their respiratory and gastrointestinal Systems. Due to high mutation and recombination rates in coronaviruses, frequent host-shifting events from animal-to-animal and animal-to-human hâve occurred. Bats were identified as a naturel réservoir during the severe acute respiratory syndrome (SARS) outbreak.

SARS-CoV-2, îs an enveloped, nonsegmented, positive-sense, single stranded RNA virus with an unusually large RNA genome, a nucleocapsid, and club-like spikes that project from their surface called spîke (S) protein. It belongs to the betacoronavirus category which includes SARS-CoV and MERS-CoV. These viruses hâve been responsible for épidémies with variable severity with both respiratory and extra-respiratory clinical manifestations, hîghly contagious, and mortality rates between 10-35%. The Coronavîrus superfamily (Coronaviridaé) includes several human pathogens with large RNA genomes, e.g., influenza and viral encephalitis and they are classifîed into alpha, beta, delta, and gamma coronavîrus families and then further dîvided into Lineages A, B, C, and D. SARS-CoV-2 is a Lineage B betacoronavirus.

The clinical spectrum of SARS-CoV-2 varies from asymptomatic to clinical conditions characterized by pneumonia with respiratory failure necessitatîng mechanical ventilation and support în an intensive care unit (ICU) to sepsis, septic shock, and multiple organ failure. Chinese CDC clinical présentation reported the followîng disease classifications and rates of mild, severe, and critical disease in the Chinese population infected with SARS-CoV-2 in 20192020 which appear to be similar in other infected populations: (1) Mild disease (81%): symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, headache, muscle pain, or malaise. Signs of a more serions disease, such as dyspnea, are not present; (2) Severe disease (14%); dyspnea, respiratory frequency > 30 breaths/min, blood oxygen saturation (SpO2) < 93%, PaO2/FiO2 ratio or P/F [the ratio between the blood pressure of the oxygen (partial pressure of oxygen, PaO2) and the percentage of oxygen supplied (fraction of inspired oxygen, FiO2)] < 300, and/or lung infiltrâtes > 50% on imagîng study within 24 to 48 hours; and (3) Critical disease (5%): respiratory failure, septic shock, and/or multiple organ dysfunction. In some cases, an abnormal immune system over reaction takes place which has been labeled a 'cytokine storm. The cytokine storm is clînically manifested as an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction. Cytokines and chemokines are induced by the viral infection which over-actîvates an inflammatory response (e.g., NLRP3 inflammasomes activation) which can lead to septic shock and extensive tissue damage.

The spectrum of disease and pharmacotherapy of COVID-19 as of March 2021 (unless otherwise specified) is summarized in the following paragraphs: Potential therapeutic drug classes for COVID-19 include antibody, antiviral, and anti-inflammatory thérapies. Early in the time course of infection, the severity of disease îs relatively minor and treatment can be focused on prévention of virus entering cells (antibody thérapies) or inhibition of virus réplication (antiviral thérapies). In more severe cases, the patient progresses to include pulmonary infection, in which case, the addition of anti-inflammatory therapy is recommended. For example, at the time of wrîtîng, hospitalized patients typically get remdesivir (antïviral) and dexamethasone (antiinflammatory) as standard of care, whereas mild to moderate non-hospitalized with hîgh risk for progression to crîtical disease may receive an antiviral therapy alone. When pulmonary infection îs présent, it can progress to severe acute respiratory syndrome (SARS) in which case it îs necessary to supplément oxygen including by mechanical ventilation or extracorporeal membrane oxygénation (ECMO). In this later SARS phase of COVID-19 infection, an overwhelming inflammatory response is the primary cause of damage to the respiratory System leading to acute respiratory dîstress syndrome (ARDS), necessitating the use of anti-inflammatory thérapies which hâve limited efficacy data, less evidence for the efficacy of antivirals, and no promising efficacy data for antibodies in SARS.

Despîte multiple EUA’s and an approval, pharmacotherapeutic treatment efficacies of COVID-19 early infection and SARS are modest and drug treatment at ail points in the course of disease remains an unmet clinical need. Unfortunately, the principal treatment for SARS remains supportîve care and oxygen therapy for patients with severe infection. Mechanical ventilation or ECMO may be necessary in cases of respiratory failure refractory to oxygen therapy, whereas hémodynamie support is essential for managing septic shock. The overall mortality rate for individuals with a SARS-CoV-2 infection appears to be 3% to 4% and as high as 40% for patients with WHO severity scores of > 4. Accordingly, current pharmacotherapeutic treatments avaîlable as of March 2021 are discussed as potential therapeutic classes. For example, only remdesivir is approved as an antiviral and has very limited efficacy, whereas dexamethasone is recommended as an EUA anti-inflammatory treatment. Further, there is a rapidly evolving sériés of other novel and repurposed thérapies used under emergency use authorization (EUA) which îs briefly summarized below. Moreover, many drugs such as hydroxy chloroquine gained widespread use based on indirect evidence or case studies that were later refuted by randomized clinical trials.

Others in this category include vitamins C and D, zinc, famotidine, ivermectîn, ACEI/ARBs, and antibacterials such as azithromycin.

Antibody thérapies such as convalescent plasma, IVIG (Intravenous IgG) (not discussed below; see PMID: 33087047 for more information), and neutralizîng antibodies (casirivimab plus imdevimab; bamlanivimab; and bamlanivîmab plus etesevimab) are consîdered most likely to be effective early in the tîme course of infection as these are intended to prevent cell entry by binding to and neutralizîng viral spike (S) proteins, thereby blocking the binding to cell receptors and co-receptors and preventing viral entry into cells. None of the antibody thérapies are FDA approved, however, several were gîven EUA including convalescent plasma in August 2020, both casirivimab plus imdevimab (received EUA if administered together) and bamlanivimab monotherapy in November 2020, whereas bamlanivimab plus etesevimab received EUA in February 2021. Administered early in the course of disease, FDA indicated that transfusion of high titer COVID-19 convalescent plasma had the potential for clinical benefit. Altematîvely, casirivimab plus imdevimab (REGEN-COVTM; two recombinant human monoclonal antibodies that bind to nonoverlapping epîtopes of the spike (S) protein receptor-binding domain (RBD) of the SARS-CoV-2 virus) received EUA for the treatment of mild to moderate COVID-19 in adults, as weli as in pédiatrie patients at least 12 years of âge and weighing at least 40 kg, who hâve received positive results of direct SARS-CoV-2 viral testîng and are at high risk for progressîng to severe COVID-19 and/or hospitalizatîon. On March 23, 2021, Regeneron released Phase 3 data for a treated population of infected non-hospitalîzed patients (n=4,567) suggesting that this combination reduced hospitalizatîon or death by 70% in non-hospitalized COVID-19 patients; further supporting its use in an outpatîent setting (https://investor.regeneron.com/newsreleases/news-release-details/phase-3-trial-shows-regen-covtm-casirivimab-imdevimabantibody). Bamlanivimab monotherapy (a recombinant neutralîsing human IgGlK monoclonal antibody that also binds to the RBD of the S protein of SARS-CoV-2 and prevents the attachment of S protein with the human ACE2 (a cell surface protein) receptor) received EUA for the same indication as REGEN-COV. EUA was also granted for the combination of bamlanivimab plus etesevimab (these bind to different but overlapping epîtopes in the RBD of the S protein; using both antibodies together is expected to reduce the risk of viral résistance) for the same indication as the other synthetic neutralizîng antibodies. The benefit of treatment with monoclonal neutralizîng antibodies has not been observed in patients hospitalized due to COVID-19 and may be associated with worse clinical outcomes when administered to hospitalized patients requiring high flow oxygen or mechanical ventilation with COVID-19. In overview, none of the antibody thérapies are FDA approved but rather some of them hâve EUA for use in early infection in patients at high rîsk for progression.

Certain hospitalized adult and pédiatrie COVID-19 patient populations are candidates for the only FDA approved therapy, an antiviral remdesîvîr (approved as Veklury). Remdesivir is a nucléotide prodrug for intravenous use that inhibits RNA polymerase of SARS-CoV-2. On October 22. 2020, FDA approved Veklury (remdesivir) for use in adults and pédiatrie patients (12 years of âge and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization. Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care. This approval does not include the entire population that had been authorized to use Veklury under an EUA issued on May 1, 2020. Access for pédiatrie populations via the EUA continues for emergency use by licensed healthcare providers. The EUA allows treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pédiatrie patients weighing 3.5 kg to less than 40 kg or hospitalized pédiatrie patients less than 12 years of âge weighing at least 3.5 kg. Treatment algorithms are still uncertaîn for COVID-19 patients but some studies suggest modest mortality beneflt of remdesivir in hypoxia patients on supplémentai oxygen (ACTT-1 study) and severely îll patients not on mechanical ventilation (SIMPLE study), however, use of remdesivir in mechanically ventilated patients was not associated with a significant réduction of mortality (PMID: 33204761). Accordingly, as of January 2021, for hospitalized patients who require mechanical ventilation or ECMO, NIH recommends déxaméthasone monotherapy, not Veklury mono- or combination therapy.

Critically ill patients with COVID-19 may be best served via use of dexamethasone (équivalent alternatives to dexamethasone, Le,, corticosteroids, are acceptable) since most of the damage is from immune overreaction in the lung. Though dexamethasone use via EUA continues (March 2021), the RECOVERY randomized clinical trial only demonstrated modest improvements in 28day mortality with dexamethasone in ail hospitalized patents (22.9% for dexamethasone vs. 25.7% for usual care), but improved outcomes for higher oxygénation requirement subgroups (PMID: 32678530). Similarly, treatment recommendations are stratified by oxygénation requirement with dexamethasone monotherapy is strongly recommended by NIH for those hospitalized on invasive mechanical ventilation or ECMO. Recommendations change to dexamethasone monotherapy or the addition of remdesîvîr for those hospitalized on non-invasive ventilation, whereas those hospitalized on supplémentai oxygen can receive remdesîvîr or dexamethasone monotherapy, or their combination. However, dexamethasone îs not recommended for those patients that are not hospitalized or hospitalized without supplémentai oxygen requirement. Thus far, ail recommendations are based on limited évidence and World Health Organization (WHO) recommendations differ significantly from NIH. For example, per WHO, remdesîvîr is not recommended regardless of severity of illness; however, WHO agréés with systemic corticosteroids for severe and critical COVID-19.

Other unapproved anti-inflammatory thérapies include IL-6 inhibitors (tocîlizumab), interferons, IL-l inhibitors, and kinase inhibitors, however, as of February 2021, NIH (www.covidl9treatmentguidelines.nih.gov) either indicates insuffîcient data or recommends agaînst the routine use of these agents. One exception is baricitinib, a JAK inhibitor approved for rheumatoid arthrîtîs, which as of November 2020 has EUA in combination with remdesivir for hospitalized patients with mild, moderate and severe COVID-19. EUA States for the combination is for emergency use by healthcare providers for the treatment of suspected or laboratoryconfirmed COVID-19 in hospitalized adults and pédiatrie patients 2 years of âge or older requiring supplémentai oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygénation (ECMO).

As can be seen, SARS-CoV-2 pharmacotherapy îs based on limited data and current agents hâve limited effîcacy at preventing early infection from progressing and decreasîng mortality in SARS. Correspondingly, better SARS-CoV-2 pharmacotherapy is urgently need not just for the current global pandémie but also for future viral épidémies and pandémies, or in the case the SARS-CoV infections become endemic. The instant invention is intended to treat SARS-CoV-2 as well as future épidémies and pandémies derived from the Coronaviridae which typically produce hyperinflammatory lung infections, and despite emerging and existing thérapies carry a high morbidîty and mortality burden. Viruses hâve efficient mechanisms that take control of their host’s cellular machinery to carry out viral réplication, assembly, and to exit (egress) from the cell to spread infections virions. Given the spatial distances between the point of virion entry at the plasma membrane to the location in the cell where RNA réplication (nucléus) and viral assembly occur in the endoplasmic réticulum and Golgi, and then the newly generated virions hâve to travel back out to the plasma membrane to egress out of the cell, it is no surprise that the vîrus’s most critical initial task is to hîjack the host’s internai transportation System, the cytoskeleton. The cytoskeleton is composed of three major types of protein filaments: microfilaments (actin), microtubules (tubulin), and intermediate filaments. The principal ones involved in viral réplication and trafficking (transport) are microtubules and microfilaments since these are two main filament Systems involved in intracellular transport.

Microtubules are important for cell shape, transport, motilîty, and cell division. Microtubules are dynamic long polar fibers/filaments that resuit from the polymerization of a and β tubulin heterodimer subunits with a positive end located at the plasma membrane and a minus end facing the nucléus at the microtubule organîzing center (MTOC). From the MTOC, microtubule fibers radiate out from the nuclear area towards the perîphery of the cell. Microtubules are dynamic network Systems, meaning that, they undergo rapîd polymerization adding a and β tubulin subunits heterodimers together to create a growing polymer chain, and subséquent rapîd depolymerizatîon (remove a and β tubulin subunits heterodimers) to deconstruct and shrink the polymer chain. This “dynamic” growing and shrînking ability of microtubules serves the constantly changing transportation requirements of the cell. Large macromolecules, lîke vîruses, engage with specialized motor proteins (kinesins and dyneins). KÎnesins and dyneins attach, carry, and move the virus cargo up and down these microtubule tracks, like train cars, to travel long distance to reach the different compartments within the cell.

As many human and animal coronaviruses originated from bats and most eukaryotic cells contain microtubules, there appears to be a conserved microtubule dépendent coronavirus réplication across species. Furthermore, vîruses may hâve evolved microtubule-binding motifs or similar amino acid sequences complementary to motifs in kinesins and dyneins for successful trafficking interactions. Coronaviruses like Mouse Hepatitis Virus CoV use microtubules for neuronal spread and the Feîine Infectious Peritonîtis Virus (FIPV) is transported by microtubules toward the MTOC. For the porcine transmissible gastroenteritis virus (TGEV), upregulation of both a and β tubulin subunits occurs after infection. Thus, focusing on the cytoskeleton network as a drug target with the goal of impairing intracellular trafficking and disrupting virus and host interactions may be an effective way to treat coronavirus infections.

Viruses are obligate intracellular parasites, and therefore, dépend solely on the cellular machinery for membrane trafficking, nuclear import and export, and gene expression. Incoming viral particles move from the cell surface to intracellular sites of viral transcription and réplication. During assembly and egress, subviral nucleoprotein complexes and virions travel back to egress the plasma membrane. Because diffusion of large molécules is severely restricted in the cytoplasm, viruses use ATP-hydrolyzing molecular motors of the host for propelling along the microtubules, which are the intracelluiar highways.

Microtubules are cytoskeletal filaments consisting of a- and β-tubulin heterodimers and are involved in a wîde range of cellular functions, including shape maintenance, vesicle transport, cell motility, and division. Tubulin is the major structural component of the microtubules and a verifîed target for a variety of antiviral drugs. Compounds that are able to interfère with mîcrotubule-tubulin equilibrium in cells are effective in the treatment of viruses as a virus generally uses microtubules as a source of transportation within the cell. Other compounds that interféré with microtubule-tubulîn equilibrium in cells, such as paclitaxel and vinblastîne, are limited by their toxicity.

Drugs that target the cytoskeleton, especially the mîcrotubule components, are important therapeutic agents for cancer and inflammation. The clinical activity of these compounds is dîctated by the location that these compounds bind on the a and β-tubulîn heterodimers that compose the mîcrotubule filament. Three major binding sites on a and β-tubulin subunits hâve been identified as taxanes-, vtnea alkaloid-, and colchicine-binding sites. Such drugs are commonly classified into two major categories: microtubule-stabilizing (e.g., taxanes) and microtubule-destabilîzing, or depolymerizing agents (e.g., vînea alkaloids and colchicine).

Colchîcine has a narrow therapeutic index with no clear distinction between nontoxic, toxic, and léthal doses. Metabolically, colchicine is eliminated via P-glycoproteîn (P-gp; also known as Multi-Drug Résistance l (MDRI) protein). Drug-drug interactions are common with CYP3A4 and P-glycoproteîn inhibîtors which can increase colchicine blood concentrations to toxic levels leading to colchicine poisoning and death. Lîfe-threatening and fatal toxicities hâve been observed when colchicine is administered with P-gp or strong CYP3A4 inhibîtors even at approved therapeutic doses. Additional serions toxicities including myelosuppression, disseminated întravascular coagulation, and cell damage in rénal, hepatic, circulatory, and central nervous Systems hâve been observed with approved therapeutic doses of colchicine. These observed serious adverse events limit the clinical use of colchicine.

The antiviral activity of combretastatin, colchicine, and colchicine dérivatives and their seiected prodrugs against DENV and Z1KV in cell culture was observed at low micromolar and submicromolar concentrations. A major problem with taxanes, as with many biologically active natural products, is its lipophilicîty and lack of solubîlîty in aqueous Systems. This leads to the use of emulsifiers like Cremophor EL and Tween 80 in clinical préparations, which leads to serious hypersensitîvity reactions.

Nocodazole is a synthetic compound identified in a screen for anthelminthic agents. Nocodazoîe is a mîcrotubule depolymerization agent as it bînds to free tubulin heterodimers and prevents them from incorporating into microtubules. It has not been used clinically because of poor bioavailability and high toxicity.

The cellular and viral solution to master intracellular trafficking is an organized network or filaments including microtubules. Cells require microtubules for long-terrn normal physiology, and viruses are obligate intracellular parasites that completely dépend on the physiology of the host cell. Thus, it is no surprise that most, if not ail, viral life cycles require microtubules for efficient réplication. The viral bînding sites on microtubules might provide new targets for antiviral therapy. The inventions of this application address a novel method of interfering with microtubules of the cytoskeleton to prevent virus intracellular transportation, réplication, and egress.

SUMMARY OF THE INVENTION

The invention encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of Formula (I)

(Rl)tn (I) wherein

A is phenyl, îndolyl, or indazolyl, optionally substituted wïth at least one of (Ci-CQalkyl, halo(Ci-C₄)alkyï, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, C(O)Ph, C(O)O-(Ci-C₄)alky1, C(O)H, -C(0)NH₃ orNO₂;

B is an imîdazole or benzimidazole, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-halo(Ci-C₄)alkyl, F, Cl, Br, l, CN, -CH₂CN, hydroxyl, or NO₂;

Ri, Rz and Ra are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(CiC₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, 1, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond or NH;

Y îs -C=O; and m is 1-3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

In an embodiment of the invention, the method encompasses compounds of Formula I wherein A is phenyl or îndolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O(Ci-C₄)alkyi, C(O)H, -C(O)NH₂ orNO₂;

B is an imîdazole, optionally substituted with at least one of (Ci-C₄)alkyl;

R_h R₂ and Ra are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(CiC₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamîno, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond or NH;

Y is -C=O; and m îs 1-3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof

In another embodiment of the invention, the method encompasses compounds of Formula I wherein A îs phenyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C4)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C4)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B is an imidazole, optionally substituted with at least one of (Ci-C₄)alkyl;

Ri, R₂ and R₃ are independently at least one of hydrogen, (Cj-C4)alkyl, halo(Ci-C4)alkyl, O-(CiC₄)alkyl, O-(Ci-C4)haloalkyI, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X îs a bond or NH;

Y is -C=O; and m is 1 -3, or a pharmaceutically acceptable sali, hydrate, polymorph, or isomer thereof

In yet another embodiment of the invention, the method encompasses compounds of Formula I wherein A is indolyl, optionally substituted with at least one of (Ci-C4)alkyl, halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-tCÆlalkyl, COOH, -C(O)Ph, C(O)O(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B îs an imidazole, optionally substituted with at least one of (Ci-C₄)alkyl;

Ri, R₂ and Rj are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(C)-C₄)alkyl, O-(CtC₄)alkyl, O-(Ci-C₄)haloaIkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)aIkyl, COOH, -C(O)Ph, C(O)O-(C_rC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond or NH;

Y is -C=O; and m is 1-3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

An embodiment of the invention, the method encompasses compounds of Formula l wherein A îs îndolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C4)alkyl, O-(CrC₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B îs an imidazole, optionally substituted with at least one of (Ci-C₄)alkyl;

Ri, Ri and R3 are independently at least one of hydrogen, (CrC₄)alkyl, halo(Ci-C₄)alkyl, O-(CiC4)alkyl, O-(Ci-C4)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(C!C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X îs a bond;

Y is -C=O; and m is 1 -3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Another embodiment of the invention encompasses methods of treating a coronavirus infection in a subject in need thereof by adminîstering to the subject a formulation having a therapeutically effective amount of a compound ofthe Formula Vil:

wherein

X is a bond or NFI ;

Q is NH; and

A is a phenyl, indolyl, or îndazolyl ring optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH3CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof. In another embodiment of the invention, the method encompasses compounds of Formula VII wherein X is NH. In y et another embodiment of the invention, the method encompasses compounds of Formula VII, wherien X is a bond; Q is NH;

and A is an indolyl ring optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C4)haloalkyl, (Ci-C4)alkylamino, amîno(Ci-C4)alkyl, F, Cl, Br, 1, CN, CH₂CN, NH_2î hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or N O₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

An embodiment of the invention encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VH(c):

wherein

R4 and Rs îndependently hydrogen, (Ci-C₄)alkyl, halo(C;-C4)alkyl, O-(Ci-C4)alkyl, O-(C|C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C4)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, C(O)NH₂ orNO₂; and n is 1 -4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Another embodiment of the invention, encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound 17ya represented:

Yet another embodiment of the invention encompasses methods of treating viral infections wherein the viral infection is caused by a Coronaviridae virus. An embodiment of the invention encompasses methods of treating coronavirus infections wherein the infection is caused by SARS-CoV, MERS-CoV, COV1D-19 or SARS-CoV-2. Another embodiment of the invention encompasses methods of treating coronavirus infections wherein the infection is caused by COVID-19.

An embodiment of the invention encompasses methods of treating virai infections in which the infection is caused by a coronavirus. Another embodiment of the invention encompasses, methods of treating a coronavirus infection caused by SARS-CoV, MERS-CoV, or SARS-CoV2. A preferred embodiment of the invention encompasses methods of treating a subject with SARS-CoV-2 infection. A further embodiment of the invention encompasses methods of treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS). Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces respiratory failure and/or mortality. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces morbidîty. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces morbidity. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection 14 reduces respiratory failure, days În ICU, days on mechanical ventilator, or improves WHO Ordinal Scale for Clinical Improvements. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces respiratory failure, days în ICU, days on mechanical ventilator, or improves WHO Ordinal Scale for Clinical Improvements. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces mortality or respiratory failure în subjects >60 years of âge. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality or respiratory failure in subjects >60 years of âge. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces mortality or respiratory failure when dosed in combination with remdesivîr and/or déxaméthasone. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality or respiratory failure when dosed in combination with remdesivîr and/or dexamethasone. As used herein, the réduction in mortality, morbîdity, or respiratory failure, days în ICU, days on mechanical ventilator, and the like means the réduction is in comparison to a subject (or subject population) treated with placebo. Lîkewise, any improvement, such as in WHO Ordinal Scale for Clinical Improvements, means an improvement in comparison to a subject (or subject population) treated with placebo.

Yet another embodiment of the invention, the methods further comprise at least one additional therapy. An embodiment of the method further comprises a second antiviral therapy such as a neuraminidase inhibitor, remdesivîr, hydro xy chloroquine, azithromycin, or hemagg lutin in inhibitor. An embodiment of the method further comprises médications that modulate the immune System or host cell factors such as dexamethasone or another corticosteroid, an lL-6 inhibitor such as tocilizumab, interferons, an IL-l inhibitor, or a kinase inhibitor such as baricitinib. Yet another embodiment of the invention, the methods further comprise an antibody therapy such as high titer COVID-19 convalescent plasma, intravenous immunoglobulin therapy (IVIG), a monoclonal antibody therapy such as casirivimab plus îmdevimab, bamlanivimab, or bamlanîvimab plus etesevimab. An embodiment of the method further comprises an additional therapy such as a remdesivîr and/or dexamethasone or other corticosteroids. An embodiment of the method further comprises an additional therapy such as tocilizumab. An embodiment of the method further comprises an additional therapy such as baricitinib. An embodiment of the method further comprises an additional therapy such as high title COVID-19 convalescent plasma. An embodiment of the method further comprises an additional therapy such as IVIG. An embodiment of the method further comprises an additional therapy such as casirivimab plus imdevimab. An embodiment of the method further comprises an additional therapy such as bamlanivimab. An embodiment of the method further comprises an additional therapy such as bamlanivimab plus etesevimab. Yet another embodiment of the methods includes a second antiviral therapy that is at least one of favîpîravir, lopinavir, ritonavir, remdesîvir, janus kinase inhibitors, hydroxychloroquine, azithromycin, amantadîne, rîmantadine, ribavirin, idoxuridine, trifluridîne, vîdarabîne, acyclovir, ganciclovir, foscarnet, zidovudine, didanosine, peramivîr, zalcitabine, stavudine, famciclovir, oseltamivir, zanamivir, or valaciclovir. Yet another embodiment of the methods includes a second therapy that is at least one of vitamins C or D, zinc, famotidine, ivermectin, or angiotensîn converting enzyme inhibitor (ACE1) or angiotensin receptor binding (ARB) agent.

An embodiment of the invention encompasses methods wherein the compound of the invention is administered in an amount of about l mg to about 100 mg. Another embodiment of the invention encompasses methods wherein the compound of the invention is administered in an amount of about 4 to about 90 mg. Another embodiment of the invention encompasses methods wherein the compound of the invention is administered in an amount of about 9 mg to about 18 mg. Another embodiment of the invention encompasses methods wherein the compound of the invention is administered in an amount of about 4 mg to about 45 mg. In yet another embodiment of the method encompasses at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the spécification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which: Figure 1 illustrâtes the mean WHO Ordinal Scale for Clinical Improvement by Day (0=baseline). The area underthe mean curve is 153 for the patient group treated with Compound I7ya and 182 for the group treated with placebo.

DETAILED DESCRIPTION OF THE INVENTION

Microtubule based macromolecule întracellular transport is a crîtical aspect of viral réplication. For viral infection, expression of viral proteins alters the organ ization of these microtubular networks to serve their need to replicate and spread infections virion.

Microtubules not only facilitate infection, but microtubules are actively manipulated by viruses. Furthermore, cytoskeleton disruptor agents suppress viral infection.

Not to be limited by theory, the invention is based, in part, on the fact that tubulin interacts with the cytoplasmic domain of alphacoronavirus and betacoronavirus SARS-CoV spike S proteins. The réduction in înfectious virus titer may follow by treatment with a drug that causes microtubule depolymerization, maînly because there is less S protein présent at the assembly site due to impaîred S protein-microtubule transport and that the incorporation process of S protein îtself into virions is tubulin-dependent. Furthermore, disruption of microtubule trafficking impaîred the egress out of the cell of these poorly assembled virions with less surface spike S proteins, making them less înfectious. A microtubule depûlymerîzing agent may be effective in treating coronavirus infection by disrupting microtubule trafficking which is crîtical for the virus réplication cycle.

The présent invention is dîrected to antiviral therapy based upon the cytoskeleton disruptor activity of the claimed compounds that interrupts the întracellular microtubules trafficking network. Intended to overcome the disadvantages of the prior art, including but not limited to toxicity, the methods are dîrected to compounds specifically activated within virus-infected cell or within those cells that are preferably targeted by the virus. Not to be limited by theory, the invention is based upon virus reliance on the host cell machineiy for successful réplication. For instance, coronavîruses use the host secretory pathway during their réplication cycle. The vesicular transport on secretory pathways is mostly mediated by microtubules and the corresponding motor proteins. The disruption of microtubules leads to decreased réplication, reduced amount of released înfectious particles, and decreased virus yîeld. Consequently, the virus load is reduced, thereby establishing an antiviral therapy. To address the need for novel, rapidly acting antiviral compounds, the inventors proposed a method of treating virus infections by the administration of the compounds described below.

In a particular embodiment, the compounds of the invention are orally bioavailable noncolchicine molécules that bind the “colchicine binding site” of a and β tubulin and inhibits tubuiin polymerîzatîon at low nanomolar concentrations. These colchicine binding site inhibitors (CB Sis) hâve a broad scope of structures but generally possess predominantly indolyl, phenyl, or indazolyl A-rings (leftmost ring in Formula I), direct bond or amino linkers (X) between A- and B-rings, imîdazole, or benzimidazole B-rings, methanone linkers (Y) between the B-ring and C-ring (rightmost ring in Formula I), and substîtuted phenyl Crings. The compounds used in the methods are neîther a substrate for MDRs including P-gp, MRPs, and BCRP, nor CYP3A4. The compounds used in the methods also decrease the transcription of βΐ, βΠΙ, and βΐν-tubulin isoforms (Li 2012). Further, the compounds used in the methods of the invention hâve good safety as they do not cause significant neurotoxicity, neutropenia, or myelosuppression and are well tolerated.

Further, the methods encompassed by the invention include compounds capable of influencing mîcrotubule dynamics such that the compounds could be administered in subcytotoxic concentrations as systemic antiviral agents. This is in strong contrast to colchicine and other tubulin polymerîzatîon destabilizers used as antiviral drugs which possess high systemic toxicity.

(Rl)m (I) wherein

A îs phenyl, indolyl, or indazolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(Cj-C₄)haloalkyl, (Ci-C₄)alkylamino_î amino(CiC₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(CiC₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

B is an imidazole, thiazole, or benzimidazole, optionally substituted with at least one of (CiC₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-halo(Cj-C₄)alkyl, F, Cl, Br, l, CN, -CH₂CN, hydroxyl, or NO₂;

Ri, R2 and R3 are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Cj-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHC0-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond, NH, (Ci-C₄)alkyl, O, or S;

Y is a bond, -C=O, -C=S, SO₂, SO or S; and m is 1-3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeuticaily effective amount of a compound of Formula (Π):

wherein

B is an imidazole, thiazole, or benzimidazole, optionally independently substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)aikyl, O-halo(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, hydroxyl, orNO₂;

Ri, Ri, Rj, R₄, Rs and Rc are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(CiC₄)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, ammo(Ci-C₄)alkyl, F, Cl, Br, L CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHC0-(O-C₄)alkyl, COOFI, C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

X is a bond or NH;

Y is -C=O; n is 1-3; and m is 1-3; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of Fonnula (III)

(III) wherein

B is an imidazole, thiazole or benzimidazole, optionally independently substîtuted with at least one of (Ci-C4)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-halo(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, hydroxyl, orNO₂;

R₄, Rs and Rô are independently at least one of hydrogen, (Cj-C₄)alkyl, halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl. Br, 1, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)aIkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

X is a bond or NH;

Y is -C=O; and n is l-3; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutîcally effective amount of a compound of Formula (IV)

(Rl)m (IV) wherein ring A is an indolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(CiC₄)alkyl, O-(Ci-C4)alkyl, O-(Cj-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)aIkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B is an imidazole or benzimidazole, optionally independently substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyI, O-halo(Ci-C₄)alkyl, F, Cl, Br, I, CN, CFhCN, hydroxyl, orNO₂;

Ri and R2 are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Cr C₄)alkyl, O-(Ci-C₄)haIoalkyl, (Ci-C4)alkylamino, amino(C]-C₄)alkyI, F, Cl, Br, I, CN, CH₂CN, NH_2î hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Cj-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond or NH;

Y îs -C=O; and m is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutîcally effective amount of a compound of Formula IV(a)

IV(a)

B is an imidazole or benzimidazole, optionally independently substîtuted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-halo(Cj-C₄)alkyl, F, Cl, Br, I, CN, 5 CH2CN, hydroxyl, or NO₂;

Ri, R₂, R₄ and Rs are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(CiC₄)alkyl, O-(Cj-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C4)alkyl_? F, Cl, Br, I, CN, CH2CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)aIkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(0)H, -C(O)NH₂ or NO₂; and

X is a bond or NH;

Y is -C=0;n is 1-2; and m îs 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in 15 need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of Formula (V)

(V)

B is an imidazole or benzimidazole, optionally independently substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C₄)alkyi, O-(Ci-C₄)alkyl, O-halo(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, hydroxyl, or NO₂;

R₄, Rs and Rô are independently hydrogen, (Ci-C₄)alkyl. halo(Ci-C₄)alkyl, O-(C]-C4)alkyl, 5 O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CjC₄)alkyl, C(0)H, -C(O)NH₂ orNO₂;

n is 1-3; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula (VI) (VI) wherein

R₄, Rs and Re are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyI, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Cj-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C4)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

Q is NH; and n is 1-3; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Preferably, the variables for the compounds of Formula (VIII) are R4, R5 and R& are independently hydrogen, (Ci-Cijalkyl, halo(Ci-C4)alkyl, O-((Ci-C4)alkyl, O(Ci-C4)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxyl,

OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(0)0-(Ci-C4)alkyl, C(O)H, 5 -C(O)NH₂ or NO2; Q is S or NH; and n is 1 -3; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VI in the followîng Table 1 A:

Table IA:

Formula VI	Compound	R4	r₅	Rô	Q
OMe ⁰ --Ç y—OMe Q _χ N OMe (R4L—¢- r₅	5e	H n=l	H	H	N

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VII:

OMe (VII) wherein

X is a bond, NH or S;

Q is NH; and

A is a phenyl, indoiyl, or indazolyl ring optionally substituted with at least one of (CiC₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, 5 amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyi, OC(O)CF₃, -OCH₂Ph, NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Cj-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Examples of compounds of Formula VII include, but are not limited to, (2-(phenylamino)10 lH-imidazol-4-y 1)(3,4,5-trimethoxyphenyl)methanone (5e), (2-(phenylamino)-lZ/-imidazol4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride sait (5He), and 2-(lH-indol-3 -y 1)l/f-imidazoI-4-y 1)(3,4,5-trimethoxyphenyl)methanone (17ya).

Preferably, the variables in the compounds of Formula VII are X is a bond; Q is NH; and A is 15 an indoiyl ring optionally substituted with at least one of (Ci-C₄)alkyl, halo(Cj-C₄)alkyl, O(Ci-C₄)alkyl, O-(Cj-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyi, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VII(a):

wherein R4 and Rs are independently hydrogen, (Ci-C4)alkyl, haio(Ci-C4)alkyl, O-(CiC₄)alkyl, O-(Cj-C4)haloaIkyl, (Ci-C₄)alkylamino, ammo(Cj-C₄)alkyl, F, Cl, Br, I, CN, CH2CN, NH₂, hydroxyl, 0C(0)CF_3s -OCH₂Ph_; -NHC0-(Ci-C4)alkyl, COOH, -C(O)Ph,

C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH? or NO₂; and n is 1-4; or a pharmaceutîcally acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VII(b):

wherein Ri and Rs are independently hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, O-(CiC4)a]kyl, O-(Ci-C₄)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C4)alkyl, F, CL Br, I, CN, CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; and n is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula VH(c):

wherein Ri and Rs independently hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, 0-(Ci-C4)alkyl, O-(Ci-C4)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C4)alkyI, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; and n is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof. Examples of compounds of Formula XI(e) include, but are not limited to, 2-(l//-indol-3-yl)l/7-imidazol-4-y 1)(3,4,5-trimethoxyphenyljmethanone (17ya).

The invention also encompasses methods of treating a coronavirus infection in a subject in 20 need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula 17ya:

(17ya).

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective 5 amount of a compound of the Formula in the following Table IB:

Formula ΧΠΙ:

wherein

Zis O;

Ri and R4 are independently hydrogen, (Ci-C₄)alkyL halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiCQhaloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH₂, hydroxyl, 25 OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, C(O)NH₂ or NO₂;

R> and Rs are independently hydrogen, (Ci-C4)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CHiCN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, C(O)NH₂ or NO₂;

m is an integer between 1-4; and n is an integer between 1-4;

or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer.

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutîcally effective amount of a compound of the Formula XIV:

(XIV) wherein Ri and R₄ are independently hydrogen, (Cj-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ct-C₄)aIkyI, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, CI, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH2 orNO₂;

R₂ and Rs are independently hydrogen, (CrC₄)alkyl, haio(Ci-C4)alkyl, O-(Ci-C4)alkyl, O-(CiC₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyI, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂or NO₂;

m îs an integer between 1-4; and n is an integer between 1 -4;

or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Non limîting examples of compounds of formula XIV are selected from: (2-phenyl-lHimidazol-4-yl)(3,4,5-trimethoxyphenyI)methanone (12aa), (4-fluorophenyl)(2-phenyl-l//42 imidazoM-ylJmethanone (12af), (2-(4-fluorophenyl)-l/Mmidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)- \H- imidazol-4-y 1)(3,4,5trimethoxyphenyl)methanone (12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-l H-imidazol-4yl)methanone (12cb), (2-(p-tolyl)-1 H-imîdazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da), (4-fluorophenyl)(2-(p-tolyl)-l/7-imidazol-4-yl)methanone (12db), (4-hydroxy-3,5dimeÎhoxyphenyl)(2-(p-tolyl)-lH-imidazol-4-yl)methanone (12dc), (2-(4-chlorophenyl)-lÆimidazol-4-y 1)(3,4,5-trimethoxyphenyl)methanone (12fa), (2-(4-chiorophenyl)-17f-imidazol-4yl)(4-fluorophenyl)methanone (12fb), (2-(4-ch]oiOphenyl)-177-imidazol-4-yl)(4-hydroxy-3,5dimethoxyphenyl)methanone (12fc), (2-(4-(dimethylamino)phenyl)-l/7-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (12ga); (2-(4-(dimethylamino)phenyl)-l/7-imidazol-4-yI)(4fluorophenyl)methanone (12gb), (2-(3,4-dimethoxyphenyI)-l/7-nnidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (12ba), (2-(4-(benzyloxy)phenyl)-l/7-imidazol-4-yl)(4fluorophenyl)methanone (12jb), (2-(4-bromophenyl)-lH-imidazol-4-yi)(3,4.5trîmethoxyphenyl)methanone (121a), (2-(4-(trifluoromethyl)phenyl)-l/f-imidazol-4-yl)(3,4,5trimethoxyphenyl)meihanone (12pa).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Fonnula XTVa:

(XlVa) wherein Ri and R4 are independently hydrogen. (Ci-Qjalkyl, halo(Ci-C4)alkyl, O-(Ci-C4)alkyl, O-(Ci-C4)haloalkyl, (Ci-C4)alkylamîno, amino(Ci-C4)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

R₂ and Rs are independently hydrogen. (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Cj-C₄)alkyl, O-(CjC₄)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCFbPh, -NHCO-(C1-C₄)alkyl, COOH. -C(O)Ph, C(O)O-(Ci-C₄)aIkyl, C(O)H, C(O)NH₂ orNO₂;

R? is H, linear or branched, alkyl, aryl, CH₂Ph, benzyl, haloalkyl, aminoalkyl, OCHiPh, SO₂Aryl, -(C=O)-Aryl or OH, optionally substituted with at least one of hydrogen, hydroxyl, an alîphatic straight- or branched-chain Ci to Cio hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (e.g., F, Cl, Br, I), haloalkyl, dihaioalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂, -OC(O)CF₃, OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and Cs to C? cycloalkyl, arylalkyl, and combinations thereof;

m is an integer between 1-4; and n îs an integer between 1-4;

or a pharmaceutîcally acceptable sait, hydrate, polymorph, or isomer thereof.

Non limiting examples of compounds of formula XlVa are selected from: (4-iluorophenyl)(2phenyl-1 -(phenyisulfonyl)-l/f-imidazol-4-yl)methanone (liai), (4-fluorophenyl)(2-(4methoxypheny 1)-1 -(pheny Isulfonyl)-1 //-imidazol-4-yl)methanone (11 cb), (4-fluorophenyl)( 1 (phenylsulfonyl)-2-(p-tolyl)-l//-imidazol-4-yl)methanone (lldb), (2-(4-chlorophenyl)-l (pheny Isulfonyl)-! Æ-imidazol-4-yl)(4-fluorophenyl)methanone (11 fb), (2-(4(dimethylamino)phenyl)-l -(pheny Isulfonyl)-! H-imi dazol-4-yl )(3,4,5trîmethoxyphenyl)methanone (1 Iga), (2-(4-(dimethylamino)phenyl)-1 -(pheny Isulfony !)-1Himidazol-4-y! )(4-fluorophenyl)methanone (11 gb), (2-(3,4-dimethoxyphenyl)-1 (pheny Isulfonyl)-177-imidazol-4-y 1)(3,4,5-!rimethoxyphenyl)methanone (11 ha), (2-(4(benzyloxy)phenyl)-l-(phenylsulfonyl)-l/7-imidazol-4-yl)(4-fluorophenyl)methanone (Ujb), (2-(4-(dimethylamino)phenyl)-l-((4-methoxyphenyl)suIfonyl)-lH-iinidazol-4-yl)(4fluorophenyl)methanone (12gba), (1 -benzyl-2-(p-tolyl)- l//-îmidazol-4-yl)(3,4,5~ trimethoxyphenyl)methanone (12daa), ( 1 -methyl-2-(/?-tolyl)- lH-imidazol-4-yi)(3,4,5trimethoxyphenyl)methanone (12dab), (4-fluorophenyl)(2-(4-methoxyphenyl)-l-methyl- 1Himidazol-4-yl)methanone (12cba).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XV:

(XV) wherein Ri and Rs are independently hydrogen, (Ci-C₄)alkyl. halo(Ci-C4)alkyl, O-(Ci-C4)alkyl, O-(Ci-Q)haloalkyl, (Ci-C4)alkylamino_} ammo(Ci-C4jalkyl, F, Cl, Br, I, CN, -CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Cj-C4)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; and n is 1 -4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Non limiting examples of compounds of formula XV are seiected from: (2-phenyl-lffimidazol-4-yl)(3,4,5-trimethoxyphenyljmethanone (12aaj, (2-(4-fluorophenylj-1 //-imidazol-4ylj(3,4,5-trimethoxyphenyljmethanone (12ba), (2-(4-methoxyphenylj- 177-imîdazol-4-ylj(3,4,5trimethoxyphenyljmethanone trimethoxyphenyl)methanone 1 2/-imidazol-4-yl jniethanone trimethoxyphenyl)methanone trimethoxyphenyl)methanone trimethoxyphenyljmethanone trimethoxyphenyl)methanone trimethoxyphenyljmethanone trimethoxyphenyljmethanone trimethoxyphenyljmethanone (12ca), (2-(p-tolylj-1 H- imidazol-4-y 1)(3,4,5(12da), (3,4₎5-trimethoxyphenylj(2-(3,4,5-trimethoxyphenylj(12ea), (2-(4-chlorophenyl)-l //-imidazoI-4-y 1)(3,4,5(12fa), (2-(4-(dimethylaminojphenylj-l//-imidazol-4-ylj(3,4,5(12gaj, (2-(3,4-dimetlioxyphenylj-1//-imidazol-4-y 1)(3,4,5(12ha), (2-(2-(trifluoromethyljphenylj-l//-imidazol-4-yl)(3,4,5(12iaj, (12ja), (12kaj, (121a), (2-(4-(benzyloxyjphenylj-l//-imidazol-4-yl)(3,4,5(2-(4-hydroxyphenylj-1//-imidazol-4-ylj(3,4,5(2-(4-bromophenyl )-1/7-imidazol-4-y 1)(3,4,5and(2-(4-(trifluoromethyl)phenyl)-I/7-imidazol-4ylj(3,4,5-trimethoxyphenyljmethanone (12paj.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by adminîstering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XVI:

wherein Ri and Rs are independently hydrogen, (Ci-Qjalkyl, halo(Ci-C4)alkyl, O-(Ci-C4)alkyl, O-(Ci-C4)haloalkyI, (Ci-C4)alkylamino, amino(Ci-C4)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

Rj îs I, Br, Cl, or F; and n is 1 -4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer.

Non limiting examples of compounds of formula XVI are selected from: (4-fluorophenyl)(2phenyl- 17/-imidazol-4-yl)methanone (12af), (4-fluorophenyl)(2-(4-methoxyphenyl)-\Himidazol-4-yl)methanone (12cb), (4-fluorophenyl)(2-(p-tolyl)- lH-imidazol-4-yl)meÎhanone (12db), 4-fluorophenyl)(2-(3,4,5-trimethoxyphenyI)477-imidazol4-yl)methanone (12eb), (2(4-chlorophenyl)-1 H-imidazol-4-y l)(4-fluorophenyl)methanone ( 12 fb), (2-(4(dimethylamino)phenyl)-l/7-imidazol-4-yl)(4-tluorophenyl)methanone (12gb), ¢2-(4(benzyloxy)phenyl)-lff-imidazol-4-yl)(4-fluorophenyl)methanone (12jb).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by adminîstering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XVII:

(XVII) wherein R₄ is H_; O-(C]-C₄)alkyl, I, Br, Cl, F, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, amino(C_tC₄)alkyl, OCH₂Ph, OH, CN, NO₂, -NHCO-(C_I-C₄)alkyl, COOH, C(O)O-(Ci-C₄)alkyl or C(O)H;

wherein Ri and R2 are independently H, O-alkyl, I, Br, Cl, F, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, amîno(Ci-C₄)alkyl, OCH₂Ph, OH, CN, NO2, -NHCO-(Ci-C₄)alkyl, COOH, C(O)O-(CiC₄)alkyl or C(O)H; and m is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

Non limiting examples of compounds of formula XVII are selected from: (2-(4-fluorophenyl)1 H-imi dazol-4-y 1)(3,4,5-trimethoxyphenyl)methanone ( 12ba), (2-(4-methoxyphenyl)-1Himidazol-4-yl)(3,4,5-trimethoxyphenyI)methanone (12ca), (4-fluorophenyl)(2-(4methoxyphenyl)-1 H-imi dazol-4-yl)methanone ( 12cb), (2-(p-tolyl)- lH-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (12da), (4-fluorophenyl)(2-(p-tolyl)-1 H-imidazol-4-yI)methanone (12db), (4-Hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-lH-imidazol-4-yl)methanone (12dc), (2(4-chlorophenyl)-l H-imidazol-4-y 1)(3,4,5-trimethoxyphenyI)methanone (12fa), (2-(4chlorophenyl)-lH-imidazol-4-yI)(4-fluorophenyI)methanone (12fb), (2-(4-chlorophenyl)-lHimidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone (13ta), (2-(4-(dimethylamîno)phenyl)-lHimidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ga), (2-(4-(dimethylamino)phenyl)-1Himidazol-4-yl)(4-fluorophenyl)methanone ( 12gb), (2-(4-(benzyloxy)phenyl)-1 H-imidazol-4yl)(4-fluorophenyl)methanone (12jb), (2-(4-hydroxyphenyl)-1 H-imîdazol-4-y 1)(3,4,5trimethoxyphenyl)methanone ( 12ka), (2-(4-bromophenyl)-1 H-imîdazol-4-yl)(3,4,5trimethoxyphenyl)methanone ( 121a), (2-(4-(trifluoromethyl)phenyl)-l H-imidazol-4-y 1)(3,4,5trimethoxyphenyl)methanone (12pa).

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XVII represented by the structure of formula 12fb:

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XVII represented by the structure of formula 12cb:

(12cb).

Non limiting examples of compounds are selected from: (4-methoxyphenyi)(2-pheny 1-1/7imidazol-l-yl)methanone (12aba). (2-phenyl-l//-imidazol-l-yl)(3,4,5trimethoxyphenyljmethanone (12aaa), 2-phenyl-l-(phenylsulfonyl)-lif-imidazole (10a), 2-(4nitrophenyl)-1 -(phenylsulfonyl)-1 H-imidazole (lOx), 2-(4-(benzyloxy)phenyl)-1 15 (phenylsulfonyl)-lH-imidazole (lOj).

The invention also encompasses methods of treating a coronavîrus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XIX:

(XIX) wherein

W is 0=0, C=S, S0₂, S=0;

Ri, R* and R7 are independently hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, 0(Ci-C4)haloalkyl, (C]-C4)alkylammo, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(C_rC₄)alkyl, COOH, -C(O)Ph, C(O)O-(C_l-C₄)alkyl, C(O)H, -C(0)NH₂ or NOy

R2, Rs and Rs are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl. O(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Cj-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)aIkyl, C(O)H, -C(O)NH₂ or NO₂;

m is 1-4;

n is 1-4; and q is 1-4;

or its pharmaceutically acceptable sait, hydrate, polymorph, or isomer.

Non limitîng examples of compounds of formula XIX are selected from: (2-(4(dimethylamino)phenyl)-l-((4-methoxyphenyl)sulfonyl)-IH-imidazol-4-ylX3,4,5trimethoxyphenyl)methanone (1 Igaa); (2-(4-bromophenyl)-1 -(phenylsulfonyI)-lÆ-imidazol-4yl)(3,4,5-trimethoxyphenyl)methanone (11 la), (4-fluorophenyl)(2-(4-methoxyphenyl)-1 (pheny Isul fony 1)-1 H-imidazol-4-yl)methanone (11 cb), (2-(4-chlorophenyI)-1 -(pheny Isulfonyl) l//-imidazol-4-yl)(4-fluorophenyl)methanone (llfb), (4-fluorophenyl)(2-phenyl-l(phenylsulfonyl)- l//-imidazol-4-yl)methanone (11 af), (4-fluorophenyl)( 1 -(phenylsulfonyl)-2(p-tolyl)-l H-imidazol-4-yl)methanone (11 db), (2-(4-(dimethyiamino)phenyl)-1 (ph enylsulfonyl)-l //-imidazol-4-y 1)(3,4,5-trimethoxyphenyl)methanone (1 Iga), (2-(45 (dimethylammo)phenyl)-l-(pheny]sulfonyl)-lÆ-imidazoI-4-yl)(4-fiuorophenyl)methanone (llgb), (2-(3,4-dimethoxyphenyl)-l-(phenylsulfonyl)-l//-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (llha), (2-(4-(benzyloxy)phenyl)-l-(phenylsulfony 1)-1//imidazol-4-yl)(4-fluorophenyl)methanone (Hjb), (2-(4-(dimethylamino)phenyl)-l-((4methoxyphenyl)sulfonyl)-1 //-imidazol-4-yl)(4-fluorophenyl)methanone (12gba).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XIX represented by the structure of formula llcb:

(llcb).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XIX represented by the structure of formula llfb:

(llfb).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutîcally effective amount of a compound of the Formula XX:

OMe

OMe wherein

R4 is independently hydrogen, (Ci-C₄)alkyl, halo(Cj-C4)alkyl, O-(Ci-C₄)alkyl, O-(CiC4)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH₂, hydroxyl,

OC(O)CF₃, -OCHiPh, -NHCO-(Ci-C4)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C4)alkyl, C(O)I-I, C(O)NH₂ or NO₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer.

Non limiting examples of compounds of formula XX are selected from: (2-phenyl-lHimidazol-4-yl)(3,4,5-trimethoxyphenyI)methanone (12aa), (2-(4-fluorophenyl)-l/f-imidazol-4yl)(3,4,5-trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)-lff-imidazol-4-y 1)(3,4,5trimethoxyphenyljmethanone (12ca), (2-(p-toiyl)-lf/-imidazol-4-yl)(3,4,5trimethoxyphenyljmethanone (12da), (2-(4-chlorophenyI)-1 A-imidazol-4-yl)(3,4.5trimethoxyphenyljmethanone (12fa), (2-(4-(dimethylamino)phenyI)-l/i-imidazol-4-y 1)(3,4,5 trimethoxyphenyl)methanone (12ga), (2-(2-(trifluoromethyl)phenyl)-l/7-imidazol-4-yl)(3,4,5trimethoxyphenyljmethanone trimethoxyphenyl)methanone trimethoxyphenyl jmethanone (12ia), (2-(4-(benzyloxy)phenyl)-lA-imidazol-4-yl)(3,4,5(12ja), (2-(4-hydroxyphenyl)-1/7-imidazol-4-yl )(3,4,5(12ka), (2-(4-bromophenyl)-l/f-imidazol-4-y 1)(3,4,5 trimethoxyphenyl)methanone (121a), (2-(4-(trifluoromethy l)pheny 1)-1 A-imidazoi -4-yI)(3,4,5 trimethoxyphenyljmethanone (12pa).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutîcally effective amount of a compound of the Formula XX represented by the structure of formula 12da:

(12da).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XX represented by the structure of formula 12fa:

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount 10 of a compound of the Formula XXI:

wherein

A is indolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halojCrCjjalkyl, O-(Ci15 C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN,NH₂₎ hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph,

C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

Q is NH;

Ri and R₂ are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Cj-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, 1, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCFbPh, -NHCO-(Cj-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, C(O)NH₂ or NO₂; and m is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

In one embodiment of the method, A ring of compound of formula XXI is substituted 5-indolyh

In another embodiment the substitution is -(C=O)-Aryl. In another embodiment, the aryl is

3,4,5-(OCH₃)₃-Ph. In another embodiment, A ring of compound of formula XXI is 3-indolyl. In another embodiment, A ring of compound of formula XXI is 5-indolyl. In another embodiment, A ring of compound of formula XXI is 2-indolyl. Non limiting examples of compounds of formula XXI are selected from: (5-(4-(3,4,5-trimethoxybenzoyl)-l//-imidazol-2-yl)-l//-indol2-y I)(3,4,5-trimethoxyphenyl)methanone ( 15xaa); ( 1 -(phenyIsulfony 1)-2-( 1 -(phenyIsulfony 1)-2(3,4,5-trimethoxybenzoy 1)-1//- indol-5-yl)-I //-imidazol-4-y 1)(3,4,5trimethoxyphenyl)methanone trimethoxyphenyl)methanone trimethoxyphenyl)methanone (16xaa); 2-(l//-indol-3-yl)-l//-imidazol-4-y 1)(3,4,5(17ya); (2-(l//-indol-2-yl)thiazol-4-y 1)(3,4,5 (62a); and (2-( l//-indol-5-yl )thiazoI-4-y 1)(3,4,5trimethoxyphenyl)methanone (66a).

A particularly preferred method of treating a coronavirus infection of the invention uses at least one compound of formula XXI including 2-(l//-indol-l-yI)-l//-imidazol-4-yI)(3,4,5trimethoxyphenyl)methanone; 2-( l//-indoI-2-yl)-1 //-imidazol-4-yl)(3,4,5trîmethoxyphenyl)methanone; 2-(l/7-indol-3-yl)-l//-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (17ya); 2-(l //-indol-4-yl)-1//-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone; 2-(l//-indol-5-yl)- l//-imidazol-4-yl)(3,4,5trîmethoxyphenyl)methanone; 2-(l//-indoi-6-yl)-l//-imidazol-4-yi)(3,4,5trimethoxyphenyl)methanone; or 2-( l//-indol-7-yl)-1 //-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone.

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XXIa:

(R₇)q (XXIa) wherein

W is C=O, C=S, SO₂, or S=O;

A is îndolyl optionally substituted with at least one of (Ci-C₄)alkyl, haIo(C]-C4)alkyI, O-(Cr C₄)alkyl, O-(Ci~C₄)haloalkyl, (Ci-C₄)alkylamino, amîno(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₃ or NO₂;

Ri and R2 are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (CrC₄)alkyIamino, amino(Ci-C₄)alkyI, F, Cl, Br, I, CN, -CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Cj-C₄)aikyl, C(O)H, C(O)NH₂ or NO₂;

R? and Rs are independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH2CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, C(O)NH₂ or NO2;

m îs 1-4; and q îs 1 -4; or a pharmaceutically acceptable sait, hydrate, polymorph, or îsomer thereof.

Non limiting examples of compounds of formula XXIa are selected from: (l-(phenylsulfonyl)2-( 1 -(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-l/f-indol-5-yl)- l/f-imidazol-4-yi)(3,4,554 trimethoxyphenyl)methanone (16xaa); ( 1 -(phenylsulfony 1)-2-(1 -(phenylsulfonyl)-1 Tf-indol-3yl)-l/7-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XXII:

wherein

A is indolyl optionally substîtuted with at least one of (Ci-C₄)alkyl, halo(Cj-C₄)aIkyI, O-(CiC₄)alkyl, O-(Cj-C₄)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, CH₂CN,NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

In one embodiment of the method, A ring of compound of formula XXII is substîtuted 5indolyl. In another embodiment the substitution is -(C=O)-Aryl. In another embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph. In another embodiment, A ring of compound of formula XXII is 3îndolyl. Non limiting examples of compounds of formula XXII are selected from: (5-(4-(3,4,5trimethoxybenzoyl)-lÆ-imidazol-2-yl)-lH-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone (15xaa); and (2-(l//-indol-3-yl)-lff-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

The invention also encompasses methods of treating a coronavirus infection in a subject in need thereof by administering to the subject a formulation having a therapeutically effective amount of a compound of the Formula XXI or XXII represented by the structure of formula 17ya:

(17ya).

In one embodiment of the method, R4 and R5 of compounds of formula XIII-XVI are hydrogens. Non-limiting examples of compounds of formula ΧΙΠ-XVI wherein R4 and R5 are hydrogens are selected from (2-phenyl-l//-imidazol-4-yl)(3,4_f5-trimethoxyphenyl)methanone (12aa); (4-methoxyphenyl)(2-phenyl-lff-imidazol-4-yl)methanone (12ab); (3methoxyphenyl)(2-phenyl- l//-imidazol-4-yl)methanone (12ac); (3,5-dimethoxyphenyl)(2phenyl-1 H-imidazol-4-yIjmethanone (12ad); (3,4-dimethoxyphenyl)(2-pheny 1-1 Æ-imidazol-4yl)methanone (12ae); (4-fluorophenyl)(2-phenyl-l/7-imidazol-4-yl)methanone (12af); (3fluorophenyl)(2-phenyl-lH-imidazol-4-yl)methanone (12ag); (2-phenyl-lff-imidazol-4-yI)(ptolyl)methanone(12ah); and (2-phenyl-lH-imidazol-4-yl)(m-tolyl)methanone (I2ai).

In one embodiment of the method, P of compound of formula XII is H and Q f/ W—C y is . In another embodiment W is C=O. In another embodiment, W of compound of formula XVIII is C=O. Non-limiting examples of compound of formula XVIIl wherein W is C=O are selected from (4-methoxyphenyl)(2-phenyl-177-imidazol-lyl)methanone (12aba) and (2-phenyl-lH“imidazoM-yl)(3,4,5-trimethoxyphenyl)methanone (12aaa).

In one embodiment of the method, the compounds of this invention are the pure (TsHsomers. In another embodiment, the compounds of this invention are the pure (Z)-isomers. In another embodiment, the compounds of this invention are a mixture of the (E) and the (Z) isomers. In one embodiment, the compounds of this invention are the pure (À)-isomers. In another embodiment, the compounds of this invention are the pure (Sj-isomers. In another embodiment, the compounds of this invention are a mixture of the (R) and the (S) isomers.

The compounds of the present invention can also be present in the form of a racemic mixture, containing substantially équivalent amounts of stereoisomers. In another embodiment, the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure). As used herein, the term “substantially pure” refers to stereoisomer is at least about 95% pure in one isomer. Altematively, the stereoisomer purity may be at least about 98% pure, and more preferably at least about 99% pure.

Compounds can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The invention includes “pharmaceutically acceptable salts” of the compounds used in the method of the invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a sait, preferably a pharmaceutically acceptable sait. As used herein, the term pharmaceutically acceptable sait refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganîc acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propîonic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonîc acid, salicylic acid, A-acetylcysteine and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.

Suitable pharmaceutically-acceptable salts of amines of compounds used in the method of the invention may be prepared from an inorganîc acid or from an organic acid. In one 57 embodiment, examples of inorganîc salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.

Examples of organic salts of amines include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acétates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edîsylates, estolates, esyiates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycérophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobîonates, laurates, malates, maleates, methylenebîs(beta-oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, jV-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmîtates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stéarates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trîhaloacetates, triethîodide, tricarboxylates, undecanoates and valerates. Examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, césium; alkaline earth metals to include calcium, magnésium, aluminium; zinc, barium, cholines, quatemary ammoniums.

Examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, r-butylamines, benethamînes (A-benzylphenethylamine), dîcyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, À^r-methyl-Û-glucamines, 7V,jV-dibenzylethylenediammes, nicotînamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamïnes and ureas.

Typical salts include, but are not limited to, hydrofluoric, hydrochloric, hydrobromic, hydroîodic, boric, nitric, perchloric, phosphoric, sulfuric, acetate, citrate, maleate, malate, or mesylate. Preferred salts include hydrofluoric, hydrochloric, hydrobromic, hydroiodic, acetate, citrate, maleate, or mesylate. More preferred salts include hydrochloric, acetate, or maleate.

The salis may be formed by conventionai means, such as by reacting the free base or free acid form of the product with one or more équivalents of the appropriate acid or base in a solvent or medium in which the sait is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing sait for another ion or suitable ion-exchange resin.

The compounds used in the methods of the invention were synthesized using the methodology described in US Patent Nos. 8,592,465; 8,822,513; 9,029,408; 9,334,242; 9,447,049; and 10,301,285 and US publication No. 2020/24270, hereby incorporated by reference.

Pharmaceutical composition

The methods of the invention include the administration of a pharmaceutical composition including a pharmaceutically acceptable carrier and at least one compound described herein. Typically, the pharmaceutical composition may include a compound or its pharmaceutically 59 acceptable sait, and at least one pharmaceutically acceptable excipient. The term pharmaceutically acceptable excipient refers to any suitable adjuvants, carriers, excipients, flavorant, or stabilizers, and can be used in pharmaceutical formulations either in solid or liquîd form. Such forms include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or émulsions.

The amount of compound used in the method and the dosage regimen for treating a disease condition dépends on a variety of factors, including the âge, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.

Typically, the formulations hâve from about 0.01 to about 99 percent by weight of at least one compound by weight, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients. Whîle indivîdual needs may vary, détermination of optimal ranges of effective amounts of each component is within the skill of the art. Typical daily dosages include about 2 mg to about 200 mg or about 1 mg to about 100 mg, preferred daily dosages include about 4 mg to about 90 mg, and the most preferred dosages include about 4 mg to about 80 mg of the compound. Other preferred dosages include the antiviral compound in an amount of about 4 mg to about 45 mg, or 9 mg to about 18 mg. Altematively, a dose is from about 0.01 to 150 mg/kg body weight, preferably from about 1 mg to about 100 mg/kg body weight, and more preferably from about 2 to 50 mg/kg body weight, may be appropriait. The daily dose can be administered in one to four doses per day. Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any sîde effects.

Lower or higher doses than those recited above may be required. Spécifie dosage and treatment regimens for any particular subject will dépend upon a variety of factors, including the activity of the spécifie compound employed, the âge, body weight, general health status, sex, diet, time of administration, rate of excrétion, drug combination, the severity and course of the disease, 60 condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon împrovement of a subject's condition, a maintenance dose of a compound, composition or formulation may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms hâve been alleviated to the desired level, Subjects may, however, require intermittent treatment on a long-tenn basis upon any récurrence of disease symptoms,

The methods may include additional therapeutic agents including, but are not limited to, immune thérapies (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthînes (e.g., theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g., ICAM antagonists), anti-oxidants (e.g., /V-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g., ribavirin and amantidine). The methods of the invention may also be used in combination with gene replacement therapy.

The methods of the invention may be administered in conjunction with other antiviral thérapies to treat the infection or disease associated with the coronavirus infection, e.g., combination therapy. Suitable antiviral agents contemplated for use in combination with the methods of the invention may include nucleoside and nucléotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs. Examples of suitable NRTIs include zidovudine (AZT); dîdanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-Z-2',3'-dicleoxy-5-fluorocytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721 ; AG-1549; MKC-442 ( 1 -(ethoxy-methyl)-5-( 1 61 methyleÎhyi)-6-(phenylmeÎhyl)-(2.4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.

Other antiviral agents include, but are not limited to, neuraminidase inhibitors, hemagglutinin inhibitor, hydroxychloroquine, azithromycin, or médications that modulate the immune System or host cell factors such dexamethasone. Examples include, but are not limited to, favipiravir, lopinavir, ritonavir, remdesîvir, janus kinase inhibitors, hydroxychloroquine, azithromycin, amantadine, rimantadine, ribavirin, idoxuridine, trifluridîne, vidarabine, acyclovir, ganciclovîr, foscamet, zidovudine, didanosine, peramivir, zalcîtabîne, stavudine, famciclovir, oseltamivir, zanamivir, and valaciclovir. An embodiment of the method further comprises an additional therapy such as a remdesîvir and/or dexamethasone. An embodiment of the method further comprises an additional therapy such as casirivimab plus imdevimab. An embodiment of the method further comprises an additional therapy such as bamlanivimab.

The methods of treating coronavîrus infections may further comprise other thérapies. For example, the methods may include a second antiviral therapy such as a neuraminidase inhibitor, remdesîvir, hydroxychloroquine, azithromycin, or hemagglutinin inhibitor. Other thérapies included in the methods are médications that modulate the immune System or host cell factors such as dexamethasone; cortîcosteroids; an IL-6 inhibitor such as tocilizumab; interferons; an IL-1 inhibitor; or a kinase inhibitor such as baricitinib. The methods may further comprise an antibody therapy such as high titer COVID-19 convalescent plasma, IVIG, a monoclonal antibody therapy such as casirivimab plus imdevimab, bamlanivimab, or bamlanivimab plus etesevimab. The methods may further comprise tocilizumab or baricitinib. The methods may further comprise an additional therapy such as high title COVID-19 convalescent plasma; IVIG; casirivimab plus imdevimab; bamlanivimab; or bamlanivimab plus etesevimab. The methods may include a second antiviral therapy that is at least one of favipiravir, lopinavir, ritonavir, remdesivir, janus kinase inhibitors, hydroxychloroquine, azithromycin, amantadine, 62 rimantadine, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscamet, zidovudine, didanosine, peramivir, zalcîtabine, stavudine, famciclovir, oseltainivir, zanamîvîr, or valaciclovir. The methods may include a second therapy that is at least one of vitamîns C or D, zinc, famotidine, ivermectin, or angîotensin converting enzyme inhibitor (ACEI) or angiotensin receptor binding (ARB) agent.

The solid unit dosage forms can be of the conventîonal type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds and a carrier. Carriers include, but are not limited to, lubricants and inert fillers such as, castor oil and similar materials, lactose, sucrose, or comstarch. The formulations may be tabulated with conventional tablet bases such as lactose, sucrose, or comstarch in combination with binders like acacia, comstarch, or gelatin, disîntegrating agents, such as comstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnésium stéarate.

The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, com starch, or gelatin; excipients such as dicalcium phosphate; a disîntegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnésium stéarate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form îs a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

The invention can be mixed at cold températures, room température, or eievated températures with a liquid carrier such as a fatty oil, castor oil, or other similar oil to manufacture tablets, capsules, and the like.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with shellac, sugar, or both. A syrup can contain. in addition to active ingrédient, sucrose as a sweetening agent, methyl and propylparabens as preservatîves, a dye, and flavoring such as cherry or orange flavor.

For oral therapeutic administration, the formulation may include excipients and used in the form of tablets, capsules, élixirs, suspensions, syrups, and the like. Such compositions and 63 préparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Typical compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 100 mg of active compound, and preferred oral compositions contain between 1 mg and 50 mg of active compound.

The formulations may be orally administered with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet. A preferred formulation is an oral formulation.

The pharmaceutical forms suitable for injectable use include stérile aqueous solutions or dispersions and stérile powders for the extemporaneous préparation of stérile injectable solutions or dispersions. In ail cases, the form should be stérile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, éthanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds or pharmaceutical compositions used in the method of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriers and/or excipients include, but are not limited to, stérile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleurn, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or minerai oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

The formulation may also be administered parenterally. Solutions or suspensions of these formulations can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycérol, lîquid polyethylene glycols, and mixtures thereof in oils. Illustrative oîls are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or minerai oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordînary conditions of storage and use, these préparations contain a preservative to prevent the growth of microorganisms.

For use as aérosols, the formulations may be in solution or suspension may be packaged in a pressurized aérosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The formulations also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

When administering the formulations in the methods of the invention, the formulations may be administered systemically or sequentially. Administration can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the site of viral infection. Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, întralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes,

Biological Activity

The invention is directed to methods of treating coronavîrus infections and anti-viral formulations with the compounds and formulations described above. The compounds and formulations thereof hâve utility in treating viral infections by disrupting microtubule polymerization. The formulations may optionally comprise additional active ingrédients, whose activity is usefui for treating coronavîrus viral infections, treat adverse effect 65 associated with the compounds or dosages of a particular formulation, and/or delay or extend the release of the ingrédients.

In particular, the methods of the invention may be used to treat infections caused by viruses including those of the superfamilies of Coronaviridae. Also, the methods of the invention may be used to treat infections caused by viruses including, but not limited to, SARS, MERSCoV, and COVID-19. Preferably, the methods of the invention treat viral infections caused by SARS-CoV, MERS-CoV, or COVID-19. More preferably, the methods of the invention treat viral infections caused by COVID-19 (SARS-CoV-2).

The methods of the invention may be used to treat infections caused by SARS-CoV, MERSCoV, or SARS-CoV-2, and in particular SARS-CoV-2 infection. The methods of the invention may be used to treat subjects with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS). The subject may hâve a SARS-CoV-2 infection that reduces mortality. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces morbidity. Another embodiment of the invention encompasses methods wherein treating a subject with SARSCoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces morbidity. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces respiratory failure, days in ICU, days on mechanical ventilator, or improves WHO Ordinal Scale for Clinical Improvements. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces respiratory failure, days in ICU, days on mechanical ventilator, or improves WHO Ordinal Scale for Clinical Improvements. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces mortality or respiratory failure in subjects >60 years of âge. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for 66 acute respiratory dîstress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortalîty or respiratory failure in subjects >60 years of âge. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection reduces mortalîty or respiratory failure when dosed in combination with remdesivir and/or dexamethasone. Another embodiment of the invention encompasses methods wherein treating a subject with SARS-CoV-2 infection at high risk for acute respiratory dîstress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortalîty or respiratory failure when dosed in combination with remdesivir and/or dexamethasone.

The invention encompasses methods for treating coronavirus infections in a subject in need thereof comprising administering to the subject a formulation having a compound described herein or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof in a therapeutically effective amount to treat the coronavirus infection. The methods include at least one of compound 12db, compound 1 leb, compound 1 Ifb, compound 12da, compound 12fa, compound 12fb, compound 12cb, compound 55, compound 66a, or compound 17ya. In a particular method, the method includes compound 17ya.

As used herein unless otherwise stated, the term “subject or patient” refers to any mammalian patient, including without limitation, humans, other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In particular, the subject is a human, and altematively may be only male or only female.

When administering the compounds and formulations described herein, the formulations can be administered systemically or directly to a spécifie site where the viral infection is présent. Administration may be accomplished in any manner effective for delîvering the compounds or the pharmaceuticai compositions to the viral infection site. Administration methods include, but are not limited to, oral, topical, transdermal, parentéral, subeutaneous, intravenous, intramuscular, intraperitoneal, intranasal, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional, or by application to the mucous membrane. Mucous membranes include those found in the nose, throat, and/or bronchial tubes, among others. Preferably, the formulation îs administered oraily. Administration may be simultaneous or sequential with additional antiviral compounds or formulations, or treatments used to address side effects associated with the compounds or dosages.

Treatment of COVID-19 with compound 17ya had significant biological advantages over treatment with placebo. For example, at least about 30% to about 100% of compound 17ya treated patients were kept alive without respiratory failure (prîmary endpoint) versus the patients treated with “placebo” (existing standard of care - remdesîvîr, dexamethasone. convalescent plasma, etc.). For example, compound 17ya reduced the proportion of patients who died up to 60 days after initiation of treatment from 30% (6/20) in the placebo group to 5% (1/19) after treatment with compound 17ya. The mortality réduction is about 82% réduction in the compound 17ya treated group. Therefore, treatment with compound 17ya is expected to reduce death by about 30% to about 100% of the treated group as compared to the group treated with placebo. During the study, treatment failures (defined as death or respiratory failure) were 35% in the placebo group while the treatment failures were reduced to 15.8% in group treated with compound 17ya after 15 days of treatment. The numbers réduction improved as treatment continued where treatment failures were about 30% in the placebo treated group to 10.5% in the compound 17ya treated group after 29 days on study. The results represent a 55% réduction in treatment failures after 15 days of treatment and a 65% réduction in treatment failures after 29 days on study with compound 17ya when compared to the placebo treated group. Thus, it is expected that compound 17ya will reduce treatment failures by about 30% to about 100% during treatment. Other measures of success were observed on Covid-19 treated patients.

Treatment with compound 17ya reduced the days on mechanical ventilation from an average of 5.4 days in the placebo group to 1.6 days in the group treated with compound 17ya. Those treated with placebo had about a 3.4-fold increase in days on mechanical ventilation compared to the compound 17ya treated group. Consequently, it is expected that treatment with compound 17ya will reduce the days on mechanical ventilation by about 30% to about 100% as compared to the patients treated with placebo. Another réduction was observed with patients treated with compound 17ya with regard to the days spent in ICU. The placebo treated group spent an average of 9.6 days in ICU, while those treated with compound 17ya 68 spent about 3 days in the 1CU. The placebo treated group spent an additional 3.2-fold more days în the ICU, in contrast to those patients treated with compound I7ya. Therefore, treatment with compound 17ya is expected to reduce the days spent in ICU by about 30% to about 100%.

The study sponsor (Veru) has conducted post-hoc, sub-group analyses of the data from the study. The following additional observations are made from this study: (1) In the compound 17ya treated group there was one patient who was noncompliant with oxygen supplémentation. This patient noncompliant wîth standard of care in this study. An analysis of the primary endpoint excluding this patient (MITT population) from the analysis shows a 30% failure rate in the Placebo group (same as Table 2) compared to a 5.6% failure rate in the compound 17ya treated group at Day 29 (lower than in Table 2). This represents an 81% réduction in treatment failures. (2) It is well recognized that older patients are at higher risk for death and respiratory failure in patients with COVID-19 compared to younger patients. In an analysis of treatment failures in patients >60 years of âge showed that a statistically significant (p-value of 0.0456 (chi-square)) and clinically meaningful réduction in treatment failures were observed in the compound 17ya treated (1/11 or 9%) group compared to placebo (4/8 or 50%) in this high-risk population. (3) A risk factor for an adverse clinical outcome în a patient with COVID-19 is the severity of disease at présentation. To assess this risk factor, an analysis of patients with a WHO Score of Disease Severity >5 at baseline was performed. The outcome of this analysis shows a clinically meaningful réduction (78%) in mortality were observed in the compound 17ya treated (1/10 or 10%) group compared to placebo (6/13 or 46%) in this high-risk population. (4) An analysis of the days in ICU în évaluable patients showed a statistically significant (p-value of 0.0469 (t-test)) and clinically meaningful réduction in days in ICU in the compound 17ya treated (3 days; N =18 subjects) group compared to placebo (9.55 days; N = 20 days). (5) Additionally, the proportion of patients that were in the ICU for >3 days on study is statistically significantly hîgher (p-value of 0.0390 (chi-square)) in the placebo group (11/20 or 55%) compared to the compound 17ya treated (4/18 or 22%) group. (6) In this study, patients were permîtted to receîve standard of care. At the time of the study, the standard of care included treatment with remdesivir and/or dexamethasone under an Emergency Use Authorization. There were 11 patients in the study 69 that did not receive either remdesivir or dexamethasone (6 in the compound 17ya treated group and 5 in the placebo group). An analysis of patients that received the recognized standard of care was conducted. Specifically, the days in ICU and the days on mechanical ventilation were compared between the treatment groups. In this population, in patients that received standard of care, no patient treated with compound 17ya required admission in the ICU or mechanical ventilation and there were no mortaiities in this patient group. In the placebo group, 53% (8/16) required ICU admission with an average of 9.5 days in the ICU, 20% (3/15) required mechanical ventilation with an average of 3.9 days of mechanical ventilation, and 27% (4/15) died on study.

Overall, the study sponsor proposes that compound 17ya shows strong clinically meaningful outcomes in this small, proof-of-concept, Phase 2 study with statistically signifîcant observations in réductions in death in the ITT population and in post-hoc, high-risk sub-group analyses, and days in ICU. It is important to note that ail the parameters measured in the study show clinically meaningful outcomes with compound 17ya compared to placebo and there are no parameters that do not indicate benefit with compound 17ya treatment compared to placebo although some parameters do not reach statistical significance in this small study.

Safety: The overall safety conclusions are: (1) There were no treatment related serions adverse events observed on the study; and (2) there were no treatment related adverse events observed on the study. The treatment emergent adverse events that were observed in at least 2 patients in either treatment group in the study are presented in Example 1. The treatment emergent serions adverse events observed in the study are also presented in Example 1. There is no imbalance against compound 17ya in serions adverse events observed in the study. Overall, compound 17ya was well tolerated in this patient population with no clinically relevant safety observations in the compound 17ya treated group.

The use of remdesivir and dexamethasone did not hâve a signifîcant effect on patient outcomes in the study. “Signifîcant outcome” for the purposes of the clinical trial above would be réduction in treatment faîlures (death or respiratory failure), increase in treatment success (alive without respiratory failure), decrease in death (all-cause mortality), decrease in 70 days in ICU, decrease in days on mechanical ventilation, or decrease în subjects requiring mechanical ventilation, or possîbly further improvements in subject outcome that may become apparent with further analysis.

Given these data, it is expected that compounds of the invention would also work to treat patients with other types of coronaviruses.

The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.

EXAMPLES

The Examples set forth below are for illustrative purposes only and are not intended to limit, in any way, the scope of the présent invention.

Materials andMethods·.

In Vitro Tubulin Polymerization Assay. Bovine brain tubulin (0.4 mg, >97% pure) (Cytoskeleton, Denver, CO) was mixed with 10 μΜ of the test compounds and incubated in 100 pL of general tubulin buffer (80 mM PIPES, 2.0 mM MgCh, 0.5 mM EGTA, and 1 mM GTP) at pH 6.9. The absorbance of wavelength at 340 nm was monitored every 1 min for 20 min by the SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, VT). The spectrophotometer was set at 37°C for tubulin polymerization.

EXAMPLE 1

Treatment of Subjects with COVID-19

Efficacy: Described in this example are the results of a clinical trial (COVID-19 study) that was a Phase 2, doubie-blind, placebo-controlled, proof-of-concept study of approximately 40 hospitalîzed patients with COVID-19 at high risk for acute respiratory dîstress syndrome (ARDS). The primary endpoint of this study was the proportion of patients alîve without respiratory failure at Day 29. Key secondary endpoînts include the following: proportion of 71 patients alive without respiratory failure at Day 15 and Day 22, all-cause mortality, days in intensive care unit (ICU), and days on mechanical ventilation. A summary of the efficacy observations in the intent to treat (ITT) population from this study are listed below. The pvalues presented are from a chi-square analysis for responder analysis and t-test for continuous variables. Please note that no a was set in the Phase 2 study, however for small studies such as this, the a is generally set at 0.1. Therefore, any p-value <0.1 is considered statistically significant.

This protocol employed a responder analysis. A group of 39 subjects hospitaiized for COVID-19 infection at high risk for acute respiratory distress syndrome (ARDS) were divîded into two groups, a placebo group of 20 subjects and a treated group (group treated with compound 17ya) of 19 patients. The treated group was given a powder filled capsule containing 18 mg of compound 17ya taken by mouth daily until hospital discharge, up to a maximum of 21 days of dosîng.

These hospitaiized subjects were qualified as responders if they were alive without respiratory failure on Day 15, Day 22, and Day 29. A non-responder is a subject that EITHER died before the analysis day OR had respiratory failure on the analysis day. After a subject was discharged/deceased, to establîsh responder/non-responder status, a phone call was made to see if the subject was alive and had no evidence of respiratory failure on Day 15, Day 22, and Day 29 and in the safety follow-up of the study. For example, if a patient died on Day 8, they were a non-responder at Day 15, Day 22, and Day 29. If a patient had respiratory failure on Day 15, but not on Day 22 or Day 29, they would be a non-responder on Day 15, but not on Day 22 or Day 29. For this analysis, “all-cause mortality” was evaluated and anyone who died was taken as a non-responder. Responders also included subjects who were discharged from the hospital or hâve Grade 0-4 on the WHO Ordinal Scale for Clinîcal improvement on Day 15, Day 22, or Day 29 (évaluation day), and nonresponders were subjects who died before the évaluation day or had Grade 5-8 on the WHO Ordinal Scale for Clinîcal Improvement on the évaluation day.

Primary endpoint: Compound 17ya reduced the proportion of patients that are nonresponders, i.e., death or respîratory failure from 35.0% in the piacebo group (7/20) to 15.8% (3/19) in the compound 17ya treated group at Day 15 (p=0.1697) and from 30.0% (6/20) in the placebo group to 10.5% (2/19) in the compound 17ya treated group at Day 29 (p=0.1322).

See Table 2. This represents an approximately 55% réduction in treatment failures at Day 15 and a 65% réduction in treatment failures at Day 29 in the compound 17ya treated group compared to placebo.

Table 2. Proportion of subjects alive and free of respîratory failure by visit (ITT population)

	Response	17ya (n=19)	Placebo (n=20)	Odds ratio/95% CI/pvalue
Day 15	Responder	16 (84.2%)	13 (65.0%)	2.56 / (0.38,17.23) / 0.3342
Nonresponder	3 (15.8%)	7 (35.0%)
Day 22	Responder	16(84.2%)	14(70.0%)	2.14 / (0.31,14.88) / 0.4433
Nonresponder	3 (15.8%)	6 (30.0%)
Day 29	Responder	17 (89.5%)	14(70.0%)	2.69 / (0.36,20.39) ! 0.3379
Non- responder	2 (10.5%)	6 (30.0%)

Compound 17ya reduced the proportion of patients who died up to 60 days after initiation of treatment from 30% (6/20) in the placebo group to 5% (1/19) in the compound 17ya treated group. This is an approximately 82% réduction in mortality in the compound 17ya treated group.

i5 Compound 17ya reduced the days on mechanical ventilation from an average of 5.4 days in the placebo group to 1.6 days in the compound 17ya treated group. This represents a 3.4-fold increase in the days on mechanical ventilation in the placebo group compared to the compound 17ya treated group. See Table 3.

Compound 17ya reduced the days in ICU from an average of 9.6 days in the placebo group to 3.0 days in the compound 17ya treated group. This represents a 3.2-fold increase in the days in the ICU in the placebo group compared to the compound 17ya treated group. See Table 3.

Table 3. Days on Mechanical Ventilation
Treatment	N	mean	SD	P-value
Compound 17ya	19	1.6	6.64	0.4836
Placebo	20	5.4	10.16

Days in ICU
Compound 17ya	19	3.0	7.16	0.0742
Placebo	20	9.6	11.54

Figure 1 illustrâtes the mean WHO Ordinal Scale for Clinical Improvement by Day (0=baseline). The area under the mean curve is 153 in the group treated with compound 17ya and 182 in the Placebo group, indicating greater morbidity in the placebo population and suggesting a clinical improvement associated with receiving compound 17ya.

As the study was limited in sample size based on FDA comments received during the IND review process, the study sponsor (Veru, Inc.) has conducted post-hoc, sub-group analyses of the data from the study. The following additional observations are made from this study:

In the compound 17ya treated group there was one patient who was noncompliant with oxygen supplémentation. This patient was noncompliant with standard of care in this study. An analysis of the primary endpoînt excluding this patient (MITT population) from the analysis shows a 30% failure rate in the Placebo group (same as Table 2) compared to a 5.6% failure rate in the compound 17ya treated group at Day 29 (lower than in Table 2). This represents an 81% réduction in treatment failures.

It is well recognized that older patients are at higher risk for death and respiratory failure in patients with COVID-19 compared to younger patients. In an analysis of treatment failures in patients >60 years of âge showed that a statistically sîgnificant and clinically meaningful réduction in treatment failures were observed in the compound 17ya treated group compared to placebo in this high-risk population.

	N	T reatment failures at Day 29	p-value
Compound 17ya	11	1 (9%)	0.0456 (chî-square)
Placebo	8	4 (50%)

A risk factor for an adverse clinical outcome in a patient with COVID-19 is the severity of disease at présentation. To assess this risk factor, an analysis of patients with a WHO Score of Disease Severity >5 at baseline was performed. The outcome of this analysis shows a statistically sîgnificant and clinically meaningful réduction in treatment failures were observed in the compound 17ya treated group compared to placebo in this high-risk population. Also, clinically meaningful réduction (78%; not shown) in mortality was observed in the compound 17ya treated (1/10 or 10%) group compared to placebo (6/13 or 46%) in this high risk population.

	N	Treatment failures at Day 29	p-value
Compound 17ya	9*	1 (11%)	0.0827 (chi-square)
Placebo	13	6 (46%)

*one patient in the compound 17ya treated group was noncompliant with oxygen therapy and is excluded from this modified întent to treat (MITT) analysis.

An analysis of the days in ICU în évaluable patients showed a statistically significant and clinically meanîngful réduction in days in ICU in the compound 17ya treated group compared to placebo.

	N	Mean days in ICU (±st.dev)	p-value
Compound 17ya	18	3.00±7.37	0.0469 (t-test)
Placebo	20	9.55±12.56

Additionally, the proportion of patients that were in the ICU for >3 days on study is statistically significantly higher in the placebo group compared to the compound 17ya treated group.

	N	Treatment failures at Day 29	p-value
Compound 17ya	18	4 (22%)	0.0390 (chi-square)
Placebo	20	H (55%)

In this study, patients were permitted to reçoive standard of care. At the time of the study, the standard of care included treatment with remdesivir and/or dexamethasone under an Emergency Use Authorization. There were eleven patients in the study that did not receive either remdesivir or dexamethasone (6 in the compound 17ya treated group and 5 in the 15 placebo group). An analysis of patients that received the recognized standard of care was conducted. Specifically, the days in ICU and the days on mechanical ventilation were compared between the treatment groups. In this population, in patients that received standard of care, no patient treated with compound 17ya required admission in the ICU or mechanical ventilation and there were no mortalîties in this patient group. In the placebo group, 53% 20 (8/16) required ICU admission with an average of 9.5 days in the ICU, 20% (3/15) required mechanical ventilation with an average of 3.9 days of mechanical ventilation, and 27% (4/15) dîed on study.

Overall, the study sponsor proposes that compound 17ya shows strong clinically meaningful outcomes in this small, proof-of-concept, Phase 2 study with statistically significant observations in réductions in death in the ITT population and in post-hoc, high-risk sub-group analyses, and days in ICU. It is important to note that ail the parameters measured in the study show clinically meaningful outcomes with compound 17ya compared to placebo and there are no parameters that do not indicate benefit with compound 17ya treatment compared to placebo although some parameters do not reach statistical significance in this small study.

Safety: The overall safety conclusions are: (1) There were no treatment related serions adverse events observed on the study; (2) There were no treatment related adverse events observed on the study; and (3) The treatment emergent adverse events that were observed in at least 2 patients in either treatment group in the study are présented in Table 4. There is no imbalance against compound 17ya in adverse events observed in the study.

Table 4: COVID-19 Study: Treatment Emergent Adverse Events Observed in > 2 Patients in Either Treatment Group by Preferred Term

Preferred Term	Compound 17ya 18 mg (n=19) N (%)/ events	Placebo (n=20) N (%)/events
Any	10 (52.6)/27	11 (55.0)/41
Constipation	2 (10.5)/2	2 (10.0)/2
Septic shock	1 (5.3)/1	2 (10.0)/2
Alanine aminotransferase increased	1 (5.3)/1	2(10.0)/2
Aspartate aminotransferase increased	2(10.5)/2	1 (5.0)/1

Preferred Term	Compound 17ya 18 mg (n=19) N (%)/ events	Placebo (n=20) N (%)/events
Acute kidney injury	0	2 (10,0)/2
Pneumomediastînum	0	2 (10.0)/2
Pneumothorax	1 (5.3)/1	3 (15.0)/3
Respiratory failure	0	4 (20.0)/4

The treatment emergent serions adverse events observed in the study are presented in Table 5. There is no imbalance against compound 17ya in serions adverse events observed in the study.

Table 5: COVID-19 Study: Serions Adverse Events Observed by System Organ Class and Preferred Term

System Organ Class Preferred Term	Compound 17ya 18 mg (n=19) N (%)/ events	Placebo (n=20) N (%)/events
Any	3 (15.8)/3	4 (20.0)/4
Cardiac disorders	1 (5.3)/1	0
Cardîac arrest	1 (5.3)/1	0
Infections and infestations	1 (5.3)/1	2 (10.0)/2
COVID-19	0	1 (5.0)/1
Septic shock	1 (5.3)/1	1 (5.0)/1
Nervous System disorders	0	1 (5.0)/1
Encephalopathy	0	1 (5.0)/1
Rénal and urinary disorders	0	1 (5.0)/1
Acute kidney injury	0	1 (5.0)/1
Respiratory, thoracic and médiastinal disorders	1 (5.3)/1	2 (10.0)/2
Epistaxis	1 (5.3)/1	0
Respiratory failure	0	2 (10.0)/2

Overall, compound 17ya was well tolerated in this patient population with no clinically relevant safety observations in the compound 17ya treated group.

Ail of the features described herein (including any accompanying daims, abstract and drawings), and/or ail of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Although preferred embodiments hâve been depicted and described in detail herein, it will be apparent to those skilled in the relevant 10 art that varions modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the daims which follow.

Claims

1. A therapeutically effective amount of a compound of Formula (I) for use in treating a coronavîrus infection in a subject in need thereof:

(Rl)m (I) wherein

A is phenyl, indolyl, or indazolyl, optionally substituted with at least one of (Ci-C₄)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyL (Ci-C₄)alkylamino, amino(CiC₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(CiC₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

B is an imidazole or benzimidazole, optionally substituted with at least one of (Ci-C₄)alkyL halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-halo(Ci-C₄)alkyl, F, Cl, Br, 1, CN, -CH₂CN, hydroxyl, or NO₂;

Ri, R₂ and Ra are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamîno, amino(Ci-C₄)alkyl_; F, Cl, Br, I, CN, CH₂CN, NH_2s hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

X is a bond or NH;

Y is -C=O; and m îs 1-3, or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

2. The compound for use according to claim 1, wherein A is phenyl or indolyl, optionally substituted with at least one of (Ci-C₄)alkyl, haio(Ci-C₄)alkyl, O-(Ci-C4)alkyl, O(Ci-C₄)haloalkyl, (Cj-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CFbCN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(C₁-C4)alkyl, COOH, -C(O)Ph, C(O)O-(Cr C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B îs an imidazole, optionally substituted with at least one of (Ci-C₄)alkyl;

Ri, R₂ and Rs are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyi, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (CL-C₄)alkylamino, amino(Ci-C₄)aIkyl, F, Cl, Br, I, CN,

CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond orNH;

3. The compound for use according to claim 1, wherein A is phenyl, optionally substîtuted with at least one of (C]-C4)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, O-(CjC₄)haloalkyl, (Cj-C4)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(C]-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B is an imidazole, optionally substîtuted with at least one of (Ci-C₄)alkyl;

Ri, R₂ and R₃ are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(C!-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, 1, CN, CH₂CN, NH2, hydroxyl, OC(O)CF_3f -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

X is a bond or NH;

4. The compound for use according to claim 1, wherein A is indolyl, optionally substîtuted with at least one of (Ci-C₄)alkyl, halo(Cj-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

B is an imidazole, optionally substîtuted with at least one of (Cj-C₄)alkyl;

Ri, R: and R3 are independently at least one of hydrogen, (Ci-C₄)alky], halo(Ci-C₄)alkyl, O(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, 1, CN, CH₂CN, NH2, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond orNH;

5. The compound tbr use accordîng to claim 1, wherein A is indolyl, optionally substituted with at least one of (Ci-C4)alkyl, halo(Ci-C4)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Ci-C4)alkylamino, amino(Ci-C₄)alkyl. F, Cl, Br_} I, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(CiC₄)alkyl, C(O)H, -C(O)NH₂ orNO₂;

B is an imidazole, optionally substituted with at least one of (Ci-C₄)alkyl;

Ri, R₂ and R3 are independently at least one of hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyL O(Ci-C₄)alkyl_} O-(Ci-C₄)haloalkyl, (Ci-C₄)alkylamino, amîno(C]-C4)alkyl, F, Cl, Br, I, CN, CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, -NHCO-(C₁-C4)alkyl, COOH, -C(O)Ph, C(O)O-(Cj-C₄)aIkyl, C(O)H, -C(O)NH₂ or NO₂;

X is a bond;

Y is -C=O; and m is 1-3, or a phannaceutically acceptable sait, hydrate, polymorph, or isomer thereof,

6. The compound for use accordîng to claim 1, wherein the compound is a compound of the Formula VII:

wherein

X is abond or NH;

Q is NFI and

A is a phenyl, indolyl, or indazolyl ring optionally substituted with at least one of (CiC₄)alkyl, halo(C j -C₄)alkyl, O-(Ci -C₄)alkyl, O-(C i-C4)haloalkyl, (C 1 -C₄)alky lamino, amîno(Ci-C₄)alkyl, F, Cl, Br, T, CN, -CH₂CN, NH₂, hydroxyl, OC(O)CF₃, -OCH₂Ph, NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; or a phannaceutically acceptable sait, hydrate, polymorph, or isomer thereof

7. The compound for use accordîng to claim 6, wherein X is a bond; or wherein X is NH; or wherein X is a bond; Q is NH; and A is an indoiyl ring optionally substituted with at least one of (C_t-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(Ci-C₄)haloalkyl, (CiC₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, 1, CN, -CH₂CN, NH₂, hydroxyi, OC(O)CF₃, OCH₂Ph, -NHCO-(Ci-C₄)alkyl, COOH, -C(O)Ph, C(O)O-(Ci-C₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof.

8. The compound for use according to claim 1, wherein the compound is a compound of the Formula VII(c):

wherein

R₄ and Rs independently hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, O-(Ci-C₄)alkyl, O-(CiC₄)haloalkyl, (Ci-C₄)alkylamino, amino(Ci-C₄)alkyl, F, Cl, Br, I, CN, -CH₂CN, NH₂, hydroxyi, OC(O)CF₃, -OCH₂Ph, -NHCO-iC^alkyl, COOH, -C(O)Ph, C(O)O-(CjC₄)alkyl, C(O)H, -C(O)NH₂ or NO₂; and n is 1-4; or a pharmaceutically acceptable sait, hydrate, polymorph, or isomer thereof, preferably wherein the compound is compound 17ya:

9. The compound for use according to any one of daims 1-8, wherein the coronavîrus infection is caused by SARS-CoV-2, SARS-CoV, or MERS-CoV.

10. Compound 17ya for use in treating coronavîrus infection, particularly wherein the coronavîrus infection is caused by SARS-CoV-2.

11. The compound for use according to claîm 9 or 10, wherein the subject with SARS-CoV-2 infection is at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS).

12. The compound for use according to any of daims 9-11, wherein the coronavîrus infection is caused by SARS-CoV-2, and wherein the compound reduces mortality as compared to a patient population treated with placebo; or wherein the compound reduces morbidîty as compared to a patient population treated with placebo; or wherein the compound reduces respiratory failure, days in 1CU, days on mechanical ventilator, or improves WHO Ordinal Scale for Clinîcal Improvements as compared to a patient population treated with placebo; or wherein the compound reduces mortality or respiratory failure in subjects >60 years of âge as compared to a patient population treated with placebo; or wherein the compound reduces mortality or respiratory failure when dosed in combination with remdesîvir and/or dexamethasone as compared to a patient population treated with placebo.

13. The compound for use according to any of claim 9-11, wherein an additional therapeutic agent is administered to the subject, for example, wherein the additional therapeutic agent is remdesîvir, dexamethasone or another corticosteroid, or remdesîvir plus a corticosteroid; or wherein the additional therapeutic agent is a médication that modulâtes the immune System or host cell factors, such as dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, interferons, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib; or wherein the additional therapeutic agent is an antibody therapy such as high titer COVID-19 convalescent plasma, IVTG, a monoclonal antibody therapy such as casirivimab plus imdevimab, bamlanivimab, or bamlanivimab plus etesevîmab; or wherein the additional therapeutic agent is a second antiviral therapy that îs at least one of favîpiravir, lopinavir, ritonavir, remdesivir, janus kinase inhibitors, hydroxychloroquine, azithromycin, a neuraminidase inhibitor, amantadine, rimantadîne, a hemagglutinin inhibitor, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscamet, zidovudine, didanosine, peramivir, zalcîtabîne, stavudine, famciclovir, oseltamivir, zanamivir, or valaciclovir; or wherein the additional therapeutic agent is at least one of vîtamins C or D, zinc, famotidine, ivermectin, or angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor binding (ARB) agent.

14. The compound for use according to any of claims 9-11, wherein the compound is admînistered in an amount of about 1 to about 100 mg, or in an amount of about 4 mg to about 90 mg, or in an amount of about 4 mg to about 45 mg.

15. The compound for use according to any one of claims 1-14, wherein the compound is admînistered în a formulation further comprising a pharmaceutically acceptable excipient.