Application of (substituted 1H-imidazole-4-yl) (3, 4, 5-trimethoxyphenyl) ketone in preparation of medicine for treating coronavirus

Abstract

The present application relates to the use of (substituted 1H-imidazol-4-yl) (3, 4, 5-trimethoxyphenyl) methanones for the preparation of a medicament for the treatment of coronavirus, in particular the use of a compound of formula VII, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of coronavirus infection in an individual in need thereof. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese patent application No. 202180012981.X, filed on April 5, 2021, with the invention name “Method for Treating Coronavirus”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 004,781, filed on April 3, 2020, and No. 63 / 145,886, filed on February 4, 2021, which are incorporated herein by reference. Technical Field

[0004] The present invention relates to methods for treating coronaviruses using compounds having cytoskeleton disruptor activity, and preparations comprising the compounds with pharmaceutically acceptable excipients and / or additional cytoskeleton disruptor compounds. Background Art

[0005] Over the past two decades, several viral epidemics have posed serious global public health risks, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and Ebola in 2014-2016. In 2019, a new viral acute severe respiratory disease emerged. In February 2020, the World Health Organization (WHO) announced the name of the disease as COVID-19, for the coronavirus disease first identified in 2019. Due to its similarity to SARS-CoV, the coronavirus causing the disease was eventually named SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV). As of March 31, 2020, COVID-19 (SARS-CoV-2) has been declared a pandemic with more than 804,061 cases and 39,074 deaths worldwide. As of March 2021, the number of cases worldwide has increased to 128,109,427, with 2,800,279 deaths (3%) and 103,307,591 confirmed cures (97%). SARS-CoV-2 vaccines began to be approved in the United States in December 2020, and three emergency use authorizations (EUAs) were provided in March 2021; however, herd immunity has not yet been achieved. Despite ongoing social isolation and immunization efforts around the world, there are still 518,201 active cases, including approximately 100,000 critically ill patients worldwide.

[0006] Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. They infect birds and mammals, especially their respiratory and gastrointestinal systems. Due to the high mutation and recombination rates of coronaviruses, animal-to-animal and animal-to-human host-shift events occur frequently. During the outbreak of Severe Acute Respiratory Syndrome (SARS), bats were identified as the natural host.

[0007] SARS-CoV-2 is an enveloped, non-segmented, positive-sense, single-stranded RNA virus with an unusually large RNA genome, a nucleocapsid, and a club-shaped spike protruding from its surface, called the spike (S) protein. It belongs to the genus betacoronavirus, which includes SARS-CoV and MERS-CoV. These viruses have caused epidemics of varying severity with respiratory and extra-respiratory clinical manifestations, high infectiousness, and mortality rates ranging from 10-35%. The coronavirus superfamily (Coronaviridae) includes several human pathogens with large RNA genomes, such as influenza and viral encephalitis, which are divided into the alpha, beta, delta, and gamma coronavirus families, which are further divided into lineages A, B, C, and D. SARS-CoV-2 is a lineage B betacoronavirus.

[0008] The clinical manifestations of SARS-CoV-2 vary from asymptomatic to clinical illness characterized by pneumonia with respiratory failure, requiring mechanical ventilation and support in the intensive care unit (ICU), to sepsis, septic shock, and multi-organ failure. The China CDC reported the following disease classifications and rates of mild, severe, and critical illness in a Chinese population infected with SARS-CoV-2 in 2019-2020, which appear to be similar in other infected populations: (1) Mild illness (81%): symptoms of upper respiratory tract viral infection, including mild fever, cough (dry cough), sore throat, nasal congestion, headache, muscle pain, or malaise. No symptoms of more severe illness, such as dyspnea, were present; (2) severe illness (14%): dyspnea, respiratory rate ≥ 30 times / min, blood oxygen saturation (SpO2) ≤ 93%, PaO2 / FiO2 ratio or P / F [the ratio between blood pressure (oxygen partial pressure, PaO2) and oxygen delivery percentage (oxygen fraction, FiO2)] < 300, and / or lung infiltration > 50% on imaging within 24-48 hours; and (3) critical illness (5%): respiratory failure, septic shock and / or multiple organ dysfunction. In some cases, an abnormal overreaction of the immune system occurs, which is labeled a "cytokine storm." The cytokine storm clinically manifests as an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction. Cytokines and chemokines are induced by viral infections that overactivate inflammatory responses (such as NLRP3 inflammasome activation), which can lead to septic shock and extensive tissue damage.

[0009] The spectrum of disease and drug treatments for COVID-19 as of March 2021 (unless otherwise noted) is summarized in the following paragraphs: Potential therapeutic drug classes for COVID-19 include antibodies, antiviral, and anti-inflammatory therapies. Early in the infection, disease severity is relatively mild, and treatment can focus on preventing viral entry into cells (antibody therapy) or inhibiting viral replication (antiviral therapy). In more severe cases, patients progress to include lung infection, in which case the addition of anti-inflammatory therapy is recommended. For example, at the time of writing, hospitalized patients typically receive remdesivir (antiviral) and dexamethasone (anti-inflammatory) as standard of care, while non-hospitalized patients with mild to moderate disease who are at high risk for progression to critical illness may receive antiviral therapy alone. When lung infection develops, it can progress to severe acute respiratory syndrome (SARS), in which case supplemental oxygen is required, including through mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the late SARS phase of COVID-19 infection, an overwhelming inflammatory response is the primary cause of respiratory damage leading to acute respiratory distress syndrome (ARDS), necessitating the use of anti-inflammatory therapies for which there are limited efficacy data, less evidence for the efficacy of antiviral drugs, and no promising efficacy data for antibodies in SARS.

[0010] Despite multiple EUAs and approvals, drug treatments for early COVID-19 infection and SARS are poorly effective, and there remains an unmet clinical need for drug treatments at all stages of the disease process. Unfortunately, the mainstay of treatment for SARS remains supportive 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, while hemodynamic support is essential for the management of septic shock. The overall mortality rate for individuals infected with SARS-CoV-2 appears to be 3%-4%, and as high as 40% for patients with a World Health Organization severity score >4. Therefore, drug treatments currently available as of March 2021 are discussed as potential therapeutic classes. For example, only remdesivir is approved as an antiviral drug and its efficacy is very limited, while dexamethasone is recommended as an EUA anti-inflammatory therapy. In addition, a range of other novel and repurposed treatments for use under emergency use authorization (EUA) are rapidly evolving, which are briefly summarized below. In addition, many drugs such as hydroxychloroquine are widely used based on indirect evidence or case studies that were later refuted by randomized clinical trials. Other drugs in this category include vitamins C and D, zinc, famotidine, ivermectin, ACE inhibitors / ARBs, and antibacterial drugs such as azithromycin.

[0011] Antibody therapies such as convalescent plasma, IVIG (intravenous IgG) (not discussed below; see PMID: 33087047 for more information), and neutralizing antibodies (casirivimab plus imdevimab; and bamlanivimab plus etesevimab) are thought to be most likely to be effective early in infection because these antibodies are designed to prevent cell entry by binding to and neutralizing the viral spike (S) protein, thereby blocking binding to cellular receptors and co-receptors and preventing viral entry into cells. However, none of the antibody therapies are FDA-approved, and several have received EUAs, including convalescent plasma in August 2020, casirivimab plus imdevimab in November 2020 (EUA if given together), and bamlanivimab monotherapy, while bamlanivimab plus etesevimab received EUA in February 2021. Administered early in the course of the disease, the FDA indicates that infusions of high-titer COVID-19 convalescent plasma have the potential for clinical benefit. Alternatively, casirevir plus imipenem (REGEN-COVTM; two recombinant human monoclonal antibodies that bind to non-overlapping epitopes of the receptor binding domain (RBD) of the SARS-CoV-2 viral spike (S) protein) received EUA for the treatment of mild to moderate COVID-19 in adults, as well as pediatric patients at least 12 years of age and weighing at least 40 kg who have received a positive result on a direct SARS-CoV-2 viral test and are at high risk of developing severe COVID-19 and / or hospitalization. On March 23, 2021, Regeneron released Phase 3 data from a treatment population of infected non-hospitalized patients (n=4,567), demonstrating that this combination reduced hospitalization or death in non-hospitalized COVID-19 patients by 70%, further supporting its use in outpatient settings ( https: / / investor.regeneron.com / news- releases / news-release-details / phase-3-trial-shows-regen-covtm-casirivimab-imdevimab-antibody). Banivimab monotherapy (a recombinant neutralizing human IgG1κ monoclonal antibody that also binds to the RBD of the S protein of SARS-CoV-2 and prevents the S protein from attaching to the human ACE2 (cell surface protein) receptor) received an EUA for the same indication as REGEN-COV. EUA was also granted for the combination of banivimab plus etasimab (these bind to different but overlapping epitopes in the S protein RBD; use of both antibodies together is expected to reduce the risk of viral resistance) for the same indications as the other synthetic neutralizing antibodies. No benefit of monoclonal neutralizing antibody treatment was observed in patients hospitalized due to COVID-19 and may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 who require high-flow oxygen or mechanical ventilation. In summary, none of the antibody therapies are FDA-approved, but some of them have EUA for use in early infection in patients at high risk of progression.

[0012] Certain populations of hospitalized adult and pediatric COVID-19 patients are candidates for treatment with the only FDA-approved antiviral drug, remdesivir (approved as Veklury). Remdesivir is a nucleotide prodrug for intravenous administration that inhibits the RNA polymerase of SARS-CoV-2. On October 22, 2020, the FDA approved Veklury (remdesivir) for use in adult and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization. Veklury may only be administered in a hospital or healthcare setting that can provide acute care equivalent to hospitalization care. This approval does not include the entire population authorized to use Veklury under the EUA issued on May 1, 2020. Pediatric populations continue to receive authorization for emergency use by healthcare providers through the EUA. The EUA allows for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients under 12 years of age who weigh at least 3.5 kg. Treatment norms remain uncertain for patients with COVID-19, but some studies have shown that remdesivir shows a modest mortality benefit in hypoxic patients receiving supplemental oxygen (ACTT-1 study) and in critically ill patients not using mechanical ventilation (SIMPLE study), however, the use of remdesivir in mechanically ventilated patients was not associated with a significant reduction in mortality (PMID: 33204761). Therefore, as of January 2021, the NIH recommends dexamethasone monotherapy instead of Veklury monotherapy or combination therapy for hospitalized patients requiring mechanical ventilation or ECMO.

[0013] Critically ill patients with COVID-19 are best treated with dexamethasone (equivalent alternatives to dexamethasone, i.e., corticosteroids, are acceptable) as most damage is caused by an immune overreaction in the lungs. Despite continued use of dexamethasone via EUA (March 2021), the RECOVERY randomized clinical trial demonstrated only a modest improvement in 28-day mortality with dexamethasone among all hospitalized patients (22.9% with dexamethasone vs. 25.7% with usual care), but with improved outcomes in the subgroup with high oxygenation requirements (PMID: 32678530). Similarly, treatment recommendations are graded by oxygenation requirements, with the NIH strongly recommending dexamethasone monotherapy for those hospitalized for invasive mechanical ventilation or ECMO. Switching to dexamethasone monotherapy or adding remdesivir for hospitalized noninvasive ventilation is recommended, while those hospitalized for supplemental oxygen may receive remdesivir or dexamethasone monotherapy or a combination of both. However, dexamethasone is not recommended for patients who are not hospitalized or hospitalized without supplemental oxygen requirements. To date, all recommendations are based on limited evidence, and the World Health Organization (WHO) recommendations differ significantly from those of the NIH. For example, according to the WHO, remdesivir is not recommended regardless of the severity of illness; however, the WHO endorses the use of systemic corticosteroids for severe and critical COVID-19.

[0014] Other unapproved anti-inflammatory therapies include IL-6 inhibitors (tocilizumab), interferons, IL-1 inhibitors, and kinase inhibitors; however, as of February 2021, the NIH ( www.covid19treatmentguidelines .nih.gov) either stated that there was insufficient data or recommended against routine use of these drugs. One exception is baricitinib, a JAK inhibitor approved for rheumatoid arthritis, which received an EUA in November 2020 for use in combination with remdesivir in hospitalized patients with mild, moderate, and severe COVID-19. The EUA states that this combination is for emergency use by healthcare providers to treat hospitalized adults and pediatric patients 2 years or older with suspected or laboratory-confirmed COVID-19 who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

[0015] It can be seen that SARS-CoV-2 drug treatment is based on limited data, and current drugs have limited efficacy in preventing the progression of SARS early infection and reducing mortality. Accordingly, not only for the current global epidemic, but also for future viral epidemics and pandemics, or in the case where SARS-CoV infection becomes endemic, better SARS-CoV-2 drug treatment is urgently needed. The present invention is intended to treat SARS-CoV-2 and future epidemics and pandemics derived from the Coronavirus family, which usually produce highly inflammatory lung infections and, despite emerging and existing therapies, still bring a high burden of morbidity and mortality. The virus has a mechanism of action that controls its host cell machinery to replicate, assemble, and flow out of the cell (excretion) to spread infectious viruses. Considering the spatial distance between the entry point of the virus particle at the plasma membrane and the position where the intracellular RNA replication (nucleus) and virus assembly occur in the endoplasmic reticulum and Golgi, and then the newly generated virus particles must travel back to the plasma membrane to leave the cell, it is not surprising that the most critical initial task of the virus is to hijack the host's internal transport system cytoskeleton. The cytoskeleton is composed of three major protein fibers: microfilaments (actin), microtubules (tubulin), and intermediate filaments. The major components involved in viral replication and trafficking (translocation) are microtubules and microfilaments, as these are the two major fiber systems involved in intracellular transport.

[0016] Microtubules are important for cell shape, transport, motility and cell division. Microtubules are dynamic long polar fibers / filaments polymerized from α and β tubulin heterodimer subunits with the plus end located at the plasma membrane and the minus end facing the microtubule organizing center (MTOC). From the MTOC, microtubule fibers radiate from the nuclear region to the cell periphery. Microtubules are a dynamic network system, which means that they undergo rapid polymerization, joining α and β tubulin subunit heterodimers together to produce a growing polymer chain, and then rapidly depolymerize (removing α and β tubulin subunit heterodimers) to disassemble and contract the polymer chain. This "dynamic" growth and contraction ability of microtubules meets the ever-changing transport requirements of the cell. Large macromolecules, such as viruses, are bound to specific motor proteins (kinesins and dyneins). Kinesins and dyneins connect, carry and move viral cargo on and off these microtubule tracks, like train cars, traveling long distances to different compartments within the cell.

[0017] Since many human and animal coronaviruses originated from bats and most eukaryotic cells contain microtubules, there seems to be a conserved microtubule-dependent coronavirus replication across species. In addition, viruses may have evolved microtubule-binding motifs or similar amino acid sequences that are complementary to motifs in kinesins and dyneins for successful transport interactions. Coronaviruses such as mouse hepatitis virus CoV utilize microtubules for neuronal dissemination, and feline infectious peritonitis virus (FIPV) transports to the MTOC via microtubules. For porcine transmissible gastroenteritis virus (TGEV), both α and β tubulin subunits are upregulated after infection. Therefore, targeting the cytoskeletal network as a drug with the goal of impairing intracellular transport and disrupting virus-host interactions may be an effective approach to treat coronavirus infections.

[0018] Viruses are obligate intracellular parasites, and therefore only rely on cellular mechanisms to carry out membrane transport, nuclear import and export, and gene expression. The viral particles entering move from the cell surface to the intracellular site of viral transcription and replication. In the assembly and discharge process, subviral nucleoprotein complexes and virions return to discharge plasma membrane. Due to the diffusion of macromolecules in the cytoplasm is severely restricted, the virus utilizes the host's ATP-hydrolysis molecular motor to advance along microtubules (which are the highways in the cell).

[0019] Microtubules are cytoskeletal filaments composed of α- and β-tubulin heterodimers and are involved in a wide range of cellular functions, including shape maintenance, vesicle transport, cell motility and division. Tubulin is the main structural component of microtubules and is a validated target for a variety of antiviral drugs. Compounds that can interfere with the balance of microtubules-tubulin in cells are effective in treating viruses because viruses often use microtubules as a source of intracellular transport. Other compounds that interfere with the balance of microtubules-tubulin in cells (such as paclitaxel and vinblastine) are limited by their toxicity.

[0020] Drugs that target the cytoskeleton, especially microtubule components, are important therapeutic agents for cancer and inflammation. The clinical activity of these compounds depends on the location at which they bind to the α and β-tubulin heterodimers that make up the microtubule filaments. Three major binding sites on the α and β-tubulin subunits have been identified as the taxane binding site, the vinca alkaloid binding site, and the colchicine binding site. Such drugs are generally divided into two major categories: microtubule stabilizers (such as taxanes) and microtubule destabilizers, or depolymerizing agents (such as vinca alkaloids and colchicine).

[0021] Colchicine has a narrow therapeutic index, with no clear distinction between nontoxic, toxic, and lethal doses. During metabolism, colchicine is eliminated by P-glycoprotein (P-gp; also known as Multi-Drug Resistance 1 (MDR1) protein). Drug-drug interactions are common for CYP3A4 and P-glycoprotein inhibitors, which can increase colchicine plasma concentrations to toxic levels, leading to colchicine poisoning and death. Life-threatening and fatal toxicities have been observed when colchicine is administered with P-gp or strong CYP3A4 inhibitors, even at approved therapeutic doses. Additional serious toxicities have been observed with approved therapeutic doses of colchicine, including bone marrow suppression, disseminated intravascular coagulation, and cellular damage to the kidneys, liver, circulatory, and central nervous systems. These observed serious adverse events limit the clinical use of colchicine.

[0022] Antiviral activity of combretastatin, colchicine, and colchicine derivatives and selected prodrugs thereof against DENV and ZIKV in cell culture was observed at low micromolar and submicromolar concentrations. As with many biologically active natural products, the main problem with taxanes is their lipophilicity and lack of solubility in aqueous systems. This has led to the use of emulsifiers such as Cremophor EL and Tween 80 in clinical formulations, which have led to severe allergic reactions.

[0023] Nocodazole is a synthetic compound identified in a screen for anthelmintics. Nocodazole is a microtubule depolymerizing agent because it binds to free tubulin heterodimers and prevents them from entering microtubules. It has not been used clinically due to poor bioavailability and high toxicity.

[0024] The cell and virus solution that controls intracellular transport is a tissue network or filament that includes microtubules. Cells require microtubules for long-term normal physiology, and viruses are obligate intracellular parasites that are completely dependent on host cell physiology. Therefore, it is not surprising that most (if not all) viral life cycles require microtubules for effective replication. Viral binding sites on microtubules may provide new targets for antiviral therapy. The invention of the present application relates to new methods for interfering with cytoskeletal microtubules to prevent viral intracellular transport, replication and excretion. Summary of the invention

[0025] The present invention includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0026]

[0027] in

[0028] A is phenyl, indolyl or indazolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0029] B is imidazole or benzimidazole, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0030] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0031] X is a bond or NH;

[0032] Y is -C=O; and

[0033] m is 1-3.

[0034] In one embodiment of the invention, the method comprises a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein A is phenyl or indolyl, optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0035] B is imidazole, which is optionally substituted with at least one of (C1-C4)alkyl;

[0036] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0037] X is a bond or NH;

[0038] Y is -C=O; and

[0039] m is 1-3.

[0040] In another embodiment of the present invention, the method comprises a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein A is phenyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0041] B is imidazole, which is optionally substituted with at least one of (C1-C4)alkyl;

[0042] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0043] X is a bond or NH;

[0044] Y is -C=O; and

[0045] m is 1-3.

[0046] In yet another embodiment of the present invention, the method comprises a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein A is indolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0047] B is imidazole, which is optionally substituted with at least one of (C1-C4)alkyl;

[0048] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0049] X is a bond or NH;

[0050] Y is -C=O; and

[0051] m is 1-3.

[0052] In one embodiment of the present invention, the method comprises a compound of formula I, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein A is indolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0053] B is imidazole, which is optionally substituted with at least one of (C1-C4)alkyl;

[0054] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0055] X is a key;

[0056] Y is -C=O; and

[0057] m is 1-3.

[0058] Another embodiment of the present invention includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0059]

[0060] in

[0061] X is a bond or NH;

[0062] Q is NH; and

[0063] A is a phenyl, indolyl or indazolyl ring, which is optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2.

[0064] In another embodiment of the present invention, the method comprises a compound of formula VII, wherein X is NH. In yet another embodiment of the present invention, the method comprises a compound of formula VII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein X is a bond; Q is NH; and A is an indolyl ring, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2.

[0065] One embodiment of the present invention includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII(c), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0066]

[0067] in

[0068] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0069] n is 1-4.

[0070] Another embodiment of the present invention includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of compound 17ya represented by:

[0071]

[0072] Yet another embodiment of the present invention includes a method of treating a viral infection, wherein the viral infection is caused by a Coronaviridae virus. One embodiment of the present invention includes a method of treating a coronavirus infection, wherein the infection is caused by SARS-CoV, MERS-CoV, COVID-19, or SARS-CoV-2. Another embodiment of the present invention includes a method of treating a coronavirus infection, wherein the infection is caused by COVID-19.

[0073] One embodiment of the invention includes a method for treating a viral infection, wherein the infection is caused by a coronavirus. Another embodiment of the invention includes a method for treating a coronavirus infection caused by SARS-CoV, MERS-CoV, or SARS-CoV-2. A preferred embodiment of the invention includes a method for treating an individual infected with SARS-CoV-2. Another embodiment of the invention includes a method for treating an individual infected with SARS-CoV-2 who is at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS). Another embodiment of the invention includes a method in which treatment of an individual infected with SARS-CoV-2 reduces respiratory failure and / or mortality. Another embodiment of the invention includes a method in which treatment of an individual infected with SARS-CoV-2 who is at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality. Another embodiment of the invention includes a method in which treatment of an individual infected with SARS-CoV-2 reduces morbidity. Another embodiment of the invention includes a method in which treatment of an individual infected with SARS-CoV-2 who is at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces morbidity. Another embodiment of the invention includes a method in which a SARS-CoV-2 infected individual is treated to reduce respiratory failure, days in the ICU, days on a mechanical ventilator, or improve the World Health Organization Ordinal Scale for Clinical Improvements. Another embodiment of the invention includes a method in which a SARS-CoV-2 infected individual at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) is treated to reduce respiratory failure, days in the ICU, days on a mechanical ventilator, or improve the World Health Organization Ordinal Scale for Clinical Improvements. Another embodiment of the invention includes a method in which a SARS-CoV-2 infected individual is treated to reduce the mortality rate or respiratory failure of individuals aged >60 years. Another embodiment of the invention includes a method in which a SARS-CoV-2 infected individual at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) is treated to reduce the mortality rate or respiratory failure of individuals aged >60 years. Another embodiment of the invention includes a method in which when administered in combination with remdesivir and / or dexamethasone, a method in which a SARS-CoV-2 infected individual is treated to reduce the mortality rate or respiratory failure of individuals aged >60 years.Another embodiment of the present invention includes wherein when co-administered with redecivir and / or dexamethasone, treatment of individuals with SARS-CoV-2 infection at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) reduces mortality or respiratory failure. As used herein, mortality, morbidity or respiratory failure, days in the ICU, days on a mechanical ventilator, etc., are reduced compared to placebo-treated individuals (or individual groups). Similarly, any improvement, such as the World Health Organization Clinical Improvement Ordinal Scale, means an improvement compared to placebo-treated individuals (or individual groups).

[0074] Another embodiment of the present invention, the method further includes at least one other therapy. One embodiment of the method further includes a second antiviral therapy, such as a neuraminidase inhibitor, remdesivir, hydroxychloroquine, azithromycin or a hemagglutinin inhibitor. One embodiment of the method further includes drugs (such as dexamethasone or another corticosteroid) that regulate the immune system or host cytokines, IL-6 inhibitors (such as tocilizumab), interferons, IL-1 inhibitors or kinase inhibitors (such as baricitinib). Another embodiment of the present invention, the method further includes antibody therapy, such as high-titer COVID-19 convalescent plasma, intravenous immunoglobulin therapy (IVIG), monoclonal antibody therapy (such as casrevir monoclonal antibody plus imidvir monoclonal antibody, barnivir monoclonal antibody or barnivir monoclonal antibody plus ertesvir monoclonal antibody). One embodiment of the method further includes other therapies, such as remdesivir and / or dexamethasone or other corticosteroids. One embodiment of the method further includes other therapies, such as tocilizumab. One embodiment of the method further includes other therapies, such as baricitinib. One embodiment of the method further comprises additional therapies, such as high titer COVID-19 convalescent plasma. One embodiment of the method further comprises additional therapies, such as IVIG. One embodiment of the method further comprises additional therapies, such as casprevir monoclonal antibody plus imidavidin monoclonal antibody. One embodiment of the method further comprises additional therapies, such as banivamab. One embodiment of the method further comprises additional therapies, such as banivamab plus etasivir monoclonal antibody. Yet another embodiment of the method comprises a second antiviral therapy that is at least one of favipiravir, lopinavir, ritonavir, remdesivir, a janus kinase inhibitor, hydroxychloroquine, azithromycin, amantadine, rimantadine, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscarnet, zidovudine, didanosine, peramivir, zalcitabine, stavudine, famciclovir, oseltamivir, zanamivir, or valaciclovir. Yet another embodiment of the method comprises a second therapy which is at least one of vitamin C or D, zinc, famotidine, ivermectin, or an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor binding (ARB) agent.

[0075] One embodiment of the invention includes a method wherein the compound of the invention is administered in an amount of about 1 mg to about 100 mg. Another embodiment of the invention includes a method wherein the compound of the invention is administered in an amount of about 4 to about 90 mg. Another embodiment of the invention includes a method wherein the compound of the invention is administered in an amount of about 9 mg to about 18 mg. Another embodiment of the invention includes a method 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, at least one pharmaceutically acceptable excipient is included. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] The subject matter of the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the organization and method of operation of the invention, together with objects, features, and advantages thereof, may be best understood by reference to the following detailed description when read in connection with the accompanying drawings, in which:

[0077] Figure 1 The mean World Health Organization Ordinal Scale for clinical improvement (0 = baseline) is shown. The mean area under the curve was 153 for the group of patients treated with compound 17ya and 182 for the group treated with placebo. DETAILED DESCRIPTION

[0078] Microtubule-based macromolecular intracellular transport is an important aspect of viral replication. For viral infection, the expression of viral proteins changes the organization of these microtubule networks to meet their needs for replication and propagation of infectious virus particles. Microtubules not only promote infection, but also are actively manipulated by viruses. In addition, cytoskeleton disruptors inhibit viral infection.

[0079] Without being limited by theory, the present invention is based in part on the fact that tubulin interacts with the cytoplasmic domain of the SARS-CoV spike S protein of alphacoronavirus and betacoronavirus. A reduction in the titer of infectious virus may be accompanied by drug treatment that causes microtubule depolymerization, mainly due to the presence of less S protein at the assembly site due to impaired S protein-microtubule transport, and the process of S protein itself incorporating into virions depends on tubulin. In addition, the blockage of microtubule transport impairs the poor assembly of these less surface spike S protein virions to leave the cell, making them less infective. Microtubule depolymerizing agents may be effective in treating coronavirus infections by blocking microtubule transport, which is essential for the viral replication cycle.

[0080] The present invention relates to an antiviral therapy based on the activity of a cytoskeleton disruptor of a claimed compound, wherein the activity of the cytoskeleton disruptor blocks the intracellular microtubule transport network. In order to overcome the shortcomings of the prior art, including but not limited to toxicity, the method relates to a compound specifically activated in a virus-infected cell or in those cells preferably targeted by the virus. Without being limited by theory, the present invention is based on the virus's reliance on the host cell mechanism to successfully replicate. For example, coronavirus uses the host secretory pathway in its replication cycle. Vesicle transport on the secretory pathway is mainly mediated by microtubules and corresponding motor proteins. The blocking of microtubules leads to reduced replication, reduced infectious particle release, and decreased viral yield. Therefore, the viral load is reduced, thereby establishing an antiviral therapy. In order to address the need for new, fast-acting antiviral compounds, the inventors propose a method for treating viral infections by administering the following compounds.

[0081] In a specific embodiment, the compounds of the present invention are orally bioavailable non-colchicine molecules that bind to the "colchicine binding site" of α and β tubulin and inhibit tubulin polymerization at low nanomolar concentrations. These colchicine binding site inhibitors (CBSIs) have a wide range of structures, but generally have mainly indolyl, phenyl or indolyl A rings (the leftmost ring in Formula I), direct bonds or amino linkers (X) between A rings and B rings, imidazole or benzimidazole B rings, ketone linkers (Y) between B rings and C rings (the rightmost ring in Formula I), and substituted phenyl C rings. The compounds used in the method are neither substrates for MDRs (including P-gp, MRPs and BCRP) nor substrates for CYP3A4. The compounds used in the method also reduce the transcription of βI, βIII and βIV-tubulin isomers (Li 2012). In addition, the compounds used in the method of the present invention have good safety because they do not cause significant neurotoxicity, neutropenia or bone marrow suppression, and are well tolerated.

[0082] Furthermore, the methods encompassed by the present invention include compounds that are capable of affecting microtubule dynamics, allowing the compounds to be administered at subcytotoxic concentrations as systemic antiviral agents. This is in stark contrast to colchicine and other tubulin polymerization destabilizers as antiviral drugs, which have high systemic toxicity.

[0083] The present invention includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0084]

[0085] in

[0086] A is phenyl, indolyl or indazolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0087] B is imidazole, thiazole or benzimidazole, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0088] R1, R2 and R3 are independently at least one of hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo alkyl, (C1-C4) alkylamino, amino (C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0089] X is a bond, NH, (C1-C4)alkyl, O or S;

[0090] Y is a bond, -C=O, -C=S, SO2, SO or S; and

[0091] m is 1-3.

[0092] The present invention also includes a method of treating coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0093]

[0094] in

[0095] B is imidazole, thiazole or benzimidazole, which is independently optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0096] R1, R2, R3, R4, R5 and R6 are independently at least one of hydrogen, (C1-C4) alkyl, halo-(C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) halo-alkyl, (C1-C4) alkylamino, amino-(C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0097] X is a bond or NH;

[0098] Y is -C=O;

[0099] n is 1-3; and

[0100] m is 1-3.

[0101] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0102]

[0103] in

[0104] B is imidazole, thiazole or benzimidazole, which is independently optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0105] R4, R5 and R6 are independently at least one of hydrogen, (C1-C4) alkyl, halo(C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) haloalkyl, (C1-C4) alkylamino, amino(C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0106] X is a bond or NH;

[0107] Y is -C=O; and

[0108] n is 1-3.

[0109] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0110]

[0111] in

[0112] Ring A is indolyl, which is optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0113] B is imidazole or benzimidazole, which is independently optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0114] R1 and R2 are independently at least one of hydrogen, (C1-C4) alkyl, halo(C1-C4) alkyl, O-(C1-C4) alkyl, O-(C1-C4) haloalkyl, (C1-C4) alkylamino, amino(C1-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-(C1-C4) alkyl, C(O)H, -C(O)NH2 or NO2;

[0115] X is a bond or NH;

[0116] Y is -C=O; and

[0117] m is 1-4.

[0118] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula IV(a), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0119]

[0120] in

[0121] B is imidazole or benzimidazole, which is independently optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0122] R1, R2, R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2; and

[0123] X is a bond or NH;

[0124] Y is -C=O;

[0125] n is 1-2; and

[0126] m is 1-4.

[0127] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0128]

[0129] in

[0130] B is imidazole or benzimidazole, which is independently optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-halo(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, hydroxyl or NO2;

[0131] R4, R5 and R6 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2; and

[0132] n is 1-3.

[0133] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula (VI), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0134]

[0135] in

[0136] R4, R5 and R6 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0137] Q is NH; and

[0138] n is 1-3.

[0139] Preferably, for the variables of the compound of formula (VIII), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, R4, R5 and R6 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-((C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2; Q is S or NH; and n is 1-3.

[0140] The present invention also includes 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 VI in Table 1A below:

[0141] Table 1A:

[0142]

[0143] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0144]

[0145] in

[0146] X is a bond, NH or S;

[0147] Q is NH; and

[0148] A is a phenyl, indolyl or indazolyl ring, which is optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2.

[0149] Examples of compounds of formula VII include, but are not limited to, (2-(phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5e), ​​(2-(phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone hydrochloride (5He), and 2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0150] Preferably, for the variables in the compound of Formula VII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof: X is a bond; Q is NH; and A is an indole ring, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2.

[0151] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII(a), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0152]

[0153] in

[0154] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0155] n is 1-4.

[0156] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII(b), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0157]

[0158] in

[0159] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0160] n is 1-4.

[0161] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula VII(c), or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0162]

[0163] in

[0164] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0165] n is 1-4.

[0166] Examples of compounds of formula XI(e) include, but are not limited to, 2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0167] The present invention also includes a method 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 17ya:

[0168]

[0169] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of the formula in Table 1B below:

[0170] Table 1B:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] The present invention also includes a method 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 XIII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer:

[0182]

[0183] in

[0184] Z is O;

[0185] R1 and R4 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0186] R2 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0187] m is an integer between 1 and 4; and

[0188] n is an integer between 1 and 4.

[0189] The present invention also includes a method 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 XIV, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer:

[0190]

[0191] in

[0192] R1 and R4 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0193] R2 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0194] m is an integer between 1 and 4; and

[0195] n is an integer between 1 and 4.

[0196] Non-limiting examples of compounds of formula XIV are selected from: (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa), (4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af), (2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ca), (4-fluorophenyl) (2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db), (4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12dc), (2-(4-chlorophenyl ...dc), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dc), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dc), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dc), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12d methoxyphenyl) ketone (12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl) ketone (12fb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl) ketone (12fc), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) ketone (12ga); (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl) ketone (12fb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl) ketone (12fc), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) ketone (12ga); (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl) ketone (1 2gb), (2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12ha), (2-(4-benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)ketone (12jb), (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12la), (2-(4-trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12pa).

[0197] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XIVa, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0198]

[0199] in

[0200] R1 and R4 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0201] R2 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0202] R9 is H, linear or branched alkyl, aryl, CH2Ph, benzyl, haloalkyl, aminoalkyl, OCH2Ph, SO2-aryl, -(C=O)-aryl or OH, which is optionally replaced by hydrogen, hydroxyl, aliphatic linear or branched C1-C 10 substituted with at least one of hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halogen (e.g., F, Cl, Br, I), haloalkyl, dihaloalkyl, 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, methanesulfonylamino, dialkylamino, arylamino, amide, NHC(O)-alkyl, urea, alkyl-urea, alkylamide (e.g., acetamide), haloalkylamide, arylamide, aryl and C5-C7 cycloalkyl, arylalkyl and combinations thereof;

[0203] m is an integer between 1 and 4; and

[0204] n is an integer between 1 and 4.

[0205] Non-limiting examples of compounds of formula XIVa are selected from: (4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11af), (4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11cb), (4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone (11db), ( 2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11fb), (2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11ga), (2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11gb), (2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11ha), (2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11jb), (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4- 1-Methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12dab), (4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)ketone (12cba).

[0206] The present invention also includes a method 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 XV, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0207]

[0208] in

[0209] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0210] n is 1-4.

[0211] Non-limiting examples of compounds of formula XV are selected from: (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa), (2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ca), (2-(p-tolyl) -1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da), (3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone (12ea), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12fa), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl )(3,4,5-trimethoxyphenyl)methanone (12ga), (2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ha), (2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ia), (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5- (trimethoxyphenyl)methanone (12ja), (2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ka), (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12la), and (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).

[0212] The present invention also includes a method 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 XVI, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0213]

[0214] in

[0215] R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0216] R3 is I, Br, Cl or F; and

[0217] n is 1-4.

[0218] Non-limiting examples of compounds of formula XVI are selected from: (4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db), (4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone (12 1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb).

[0219] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XVII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0220]

[0221] in

[0222] R4 is H, O-(C1-C4)alkyl, I, Br, Cl, F, (C1-C4)alkyl, halo-(C1-C4)alkyl, amino-(C1-C4)alkyl, OCH2Ph, OH, CN, NO2, -NHCO-(C1-C4)alkyl, COOH, C(O)O-(C1-C4)alkyl, or C(O)H;

[0223] wherein R1 and R2 are independently H, O-alkyl, I, Br, Cl, F, (C1-C4)alkyl, halo(C1-C4)alkyl, amino(C1-C4)alkyl, OCH2Ph, OH, CN, NO2, -NHCO-(C1-C4)alkyl, COOH, C(O)O-(C1-C4)alkyl or C(O)H; and

[0224] m is 1-4.

[0225] Non-limiting examples of compounds of Formula XVII are selected from: (2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb), (2-(p-tolyl)-1H-imidazol-4-yl)methanone (12d), (2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12e), (2-(p-tolyl)-1H-imidazol-4-yl)methanone (12f), (2-(4-methoxyphenyl ...p-tolyl)-1H-imidazol-4-yl)methanone (12f 1H-imidazol-4-yl) ketone (12dc), (2-(4-chlorophenyl)-1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl) ketone (12fa), (2-(4-chlorophenyl)- ... oxazol-4-yl)(4-fluorophenyl)methanone (12fb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone (13fa), (2-(4-dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ga), (2-(4-dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gb), (2-(4-benzyloxy)phenyl )-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb), (2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ka), (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12la), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).

[0226] The present invention also includes methods of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XVII represented by the structure of Formula 12fb:

[0227]

[0228] The present invention also includes methods of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XVII represented by the structure of Formula 12cb:

[0229]

[0230] Non-limiting examples of compounds are selected from: (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone (12aba), (2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone (12aaa), 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a), 2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x), 2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

[0231] The present invention also includes a method 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 XIX, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0232]

[0233] in

[0234] W is C=O, C=S, SO2, S=O;

[0235] R1, R4 and R7 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0236] R2, R5 and R8 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2;

[0237] m is 1-4;

[0238] n is 1-4; and

[0239] q is 1-4.

[0240] Non-limiting examples of compounds of formula XIX are selected from: (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11gaa); (2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11la); (4-fluorophenyl)(2-(4- methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11cb), (2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone ((11fb), (4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11af), (4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl) )-1H-imidazol-4-yl)methanone (11db), (2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11ga), (2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11gb), (2-(3,4-dimethoxyphenyl)-1-( phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11ha), (2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (11jb), (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gba).

[0241] The present invention also includes methods of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XIX represented by the structure of Formula 11cb:

[0242]

[0243] The present invention also includes methods of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XIX represented by the structure of Formula 11fb:

[0244]

[0245] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula XX, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer:

[0246]

[0247] in

[0248] R4 is independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2.

[0249] Non-limiting examples of compounds of formula XX are selected from: (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa), (2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ba), (2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ca), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12fa), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl)ketone (12ga), (2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12ia), (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12ja), (2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12ka), (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12la), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)ketone (12pa).

[0250] The present invention also includes a method of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of Formula XX represented by the structure of Formula 12da:

[0251]

[0252] The present invention also includes methods of treating a coronavirus infection in an individual in need thereof by administering to the individual a formulation having a therapeutically effective amount of a compound of formula XX represented by the structure of formula 12fa:

[0253]

[0254] The present invention also includes a method 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 XXI, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0255]

[0256] in

[0257] A is indolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0258] Q is NH;

[0259] R1 and R2 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; and

[0260] m is 1-4.

[0261] In one embodiment of the method, the A ring of the compound of formula XXI is a substituted 5-indolyl. In another embodiment, the substitution is -(C=O)-aryl. In another embodiment, the aryl is 3,4,5-(OCH3)3-Ph. In another embodiment, the A ring of the compound of formula XXI is 3-indolyl. In another embodiment, the A ring of the compound of formula XXI is 5-indolyl. In another embodiment, the A ring of the compound of formula XXI is 2-indolyl. Non-limiting examples of compounds of formula XXI are selected from: (5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone (15xaa); (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4 ,5-trimethoxyphenyl)methanone (16xaa); 2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya); (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a); and (2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a).

[0262] Particularly preferred methods of treating coronavirus infections of the present invention use at least one compound of formula XXI, which includes 2-(1H-indol-1-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; 2-(1H-indol-2-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; 2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya); 2-(1H-indol-4-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; 2-(1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; 2-(1H-indol-6-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; or 2-(1H-indol-7-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone.

[0263] The present invention also includes a method 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 XXIa, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0264]

[0265] in

[0266] W is C=O, C=S, SO2, or S=O;

[0267] A is indolyl, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0268] R1 and R2 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0269] R7 and R8 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN, NH2, hydroxy, OC(O)CF3, -OCH2Ph, -NHCO-(C1-C4)alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2;

[0270] m is 1-4; and

[0271] q is 1-4.

[0272] Non-limiting examples of compounds of formula XXIa are selected from: (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (16xaa); (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa).

[0273] The present invention also includes a method 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 XXII, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof:

[0274]

[0275] in

[0276] A is indolyl, which is optionally substituted by at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-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-(C1-C4)alkyl, C(O)H, -C(O)NH2 or NO2.

[0277] In one embodiment of the method, the A ring of the compound of formula XXII is a substituted 5-indolyl. In another embodiment, the substitution is -(C=O)-aryl. In another embodiment, the aryl is 3,4,5-(OCH3)3-Ph. In another embodiment, the A ring of the compound of formula XXII is 3-indolyl. Non-limiting examples of compounds of formula XXII are selected from: (5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone (15xaa); and (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0278] The present invention also includes a method 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 XXI or XXII represented by the structure of Formula 17ya:

[0279]

[0280] In one embodiment of the method, R4 and R5 of the compound of formula XIII-XVI are hydrogen. Non-limiting examples of compounds of formula XIII-XVI wherein R4 and R5 are hydrogen are selected from: (2-phenyl-1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl) ketone (12aa); (4-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) ketone (12ab); (3-methoxyphenyl) (2-phenyl-1H-imidazol-4-yl) ketone (12ac); (3,5-dimethoxyphenyl) (2-phenyl-1H-imidazol-4-yl) ketone ( 12ad); (3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae); (4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af); (3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag); (2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah); ​​and (2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai).

[0281] In one embodiment of the method, P of the compound of formula XII is H and Q is In another embodiment, W is C=O. In another embodiment, W of the compound of formula XVIII is C=O. Non-limiting examples of compounds of formula XVIII wherein W is C=O are selected from (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone (12aba) and (2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone (12aaa).

[0282] In one embodiment of the method, the compound of the invention is a pure (E)-isomer. In another embodiment, the compound of the invention is a pure (Z)-isomer. In another embodiment, the compound of the invention is a mixture of the (E) and (Z) isomers. In one embodiment, the compound of the invention is a pure (R)-isomer. In another embodiment, the compound of the invention is a pure (S)-isomer. In another embodiment, the compound of the invention is a mixture of the (R) and (S) isomers.

[0283] The compounds of the present invention may also exist as racemic mixtures containing substantially equal amounts of stereoisomers. In another embodiment, the compounds of the present invention may be prepared or otherwise separated using known methods to obtain stereoisomers substantially free of their corresponding stereoisomers (i.e., substantially pure). As used herein, the term "substantially pure" refers to a stereoisomer that is at least about 95% pure in one isomer. Alternatively, the stereoisomer purity may be at least about 98% pure, and more preferably at least about 99% pure.

[0284] The compounds may 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.

[0285] The present invention includes "pharmaceutically acceptable salts" of the compounds used in the methods of the present invention, which can be prepared by reacting the compounds of the present invention with an acid or base. Certain compounds, particularly those having acidic or basic groups, can also be in the form of salts, preferably pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be easily adapted for use according to the present invention.

[0286] Suitable pharmaceutically acceptable salts of the amines of the compounds used in the methods of the invention can be prepared from inorganic or organic acids. In one embodiment, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromides, hydrochlorides, 2-hydroxyethanesulfonates (hydroxyethanesulfonates), iodates, iodides, isosulfates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen-substituted alkylsulfonates, halogen-substituted arylsulfonates), sulfonates, and thiocyanates.

[0287] Examples of organic salts of amines include, but are not limited to, aliphatic, alicyclic, aromatic, aromatic, heterocyclic, carboxylic and sulfonic organic acids, examples of which are acetates, arginine, aspartate, ascorbate, adipate, anthranilate, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, isocyanate ... Calcium diastatate, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, heptanoates, ethanesulfonates, edetates, edisylate, estolates, esylates, fumarates, formates, fluorides, galacturonates, gluconates, glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates, gluceptates, glycollyla rsanilates, glutarate, glutamate, heptanoate, caproate, hydroxydiacidate, hydroxymaleate, hydroxybenzoate, hexylisophthalate, paraben, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis(beta-oxynaphthoate), malonate, mandelate, methanesulfonate, methanesulfonate, methyl bromide, methylnitrate, methanesulfonate, potassium maleate, mucates, monocarboxylates, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, naphthalenesulfonate, N-methylglucosamine, oxalate, octanoate, oleic acid Salts, pamoates, phenylacetates, picrates, phenylbenzoate, pivalates, propionates, phthalates, phenylacetates, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilates, subacetates, tartrates, theophylline acetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethyl iodide, tricarboxylates, undecanoates, and valerates.

[0288] Examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium; alkali metals including lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium.

[0289] Examples of organic salts of carboxylic acids or hydroxy groups may be selected from arginine, organic amines including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, tert-butylamine, benethamines (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamines, imidazoles, lysine, methylamine, meglamines, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picolies, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine and urea.

[0290] Typical salts include, but are not limited to, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, borate, nitrate, perchlorate, phosphate, sulfate, acetate, citrate, maleate, malate, or methanesulfonate. Preferred salts include hydrofluoride, hydrochloride, hydrobromide, hydroiodide, acetate, citrate, maleate, or methanesulfonate. More preferred salts include hydrochloride, acetate, or maleate.

[0291] These salts can be formed by conventional methods, for example by reacting the free base or free acid form of the product with one or more equivalents of an appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, removed in vacuo or by freeze drying or by exchanging the ion of the existing salt for another ion or a suitable ion exchange resin.

[0292] The compounds used in the methods of the present invention are synthesized using the methods described in U.S. Pat. Nos. 8,592,465; 8,822,513; 9,029,408; 9,334,242; 9,447,049; and 10,301,285 and U.S. Publication No. 2020 / 24270, which are incorporated herein by reference.

[0293] Pharmaceutical composition

[0294] The methods of the present invention include administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound described herein. Typically, the pharmaceutical composition may include a compound, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any suitable adjuvant, carrier, excipient, flavoring agent or stabilizer, and may be used in a pharmaceutical formulation in solid or liquid form. Such forms include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0295] The amount of the compound used in the methods and dosing regimens for treating disease conditions depends on a variety of factors, including age, weight, sex, physical condition of the individual, type of disease, severity of disease, route and frequency of administration, and the specific compound used. Thus, dosing regimens may vary widely but can be routinely determined using standard methods.

[0296] Typically, the formulation has about 0.01% to about 99% by weight of at least one compound, preferably about 20% to 75% by weight of one or more active compounds, and adjuvants, carriers and / or excipients. Although individual needs may vary, it is within the technical scope of the art to determine the optimal range of the effective amount of each component. Typical daily doses include about 2mg to about 200mg or about 1mg to about 100mg, preferred daily doses include about 4mg to about 90mg, and the most preferred doses include about 4mg to about 80mg of the compound. Other preferred doses include about 4mg to about 45mg or 9mg to about 18mg of antiviral compounds. Alternatively, a dose of about 0.01 to 150mg / kg body weight, preferably about 1 to about 100mg / kg body weight, and more preferably about 2 to 50mg / kg body weight, may be appropriate. The daily dose can be administered one to four times a day. Those of ordinary skill in the art can also easily determine the therapeutic regimen for administration of the compounds of the present invention. That is, the frequency of administration and the size of the dose can be determined by conventional optimization, preferably while minimizing any side effects.

[0297] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular individual will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptoms, the patient's predisposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0298] When the individual's condition improves, if necessary, a maintenance dose of the compound, composition or formulation may be administered. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, may be reduced to a level that maintains the improved condition when the symptoms have been alleviated to the desired level. However, once disease symptoms recur, the individual may require long-term intermittent treatment.

[0299] The method may include "additional therapeutic agents", which include but are not limited to immunotherapy (e.g., interferon), therapeutic vaccines, anti-fibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytics, antimuscarinics, anti-leukotrienes, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants, and / or antimicrobial and antiviral agents (e.g., ribavirin and amantadine). The method described in the present invention may also be used in combination with gene replacement therapy.

[0300] The methods described herein can be administered in combination with other antiviral therapies to treat infections or diseases associated with coronavirus infection, such as combination therapy. Suitable antiviral agents contemplated for use in combination with the methods described herein may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs. Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated as β-L-2',3'-dioxy-5-fluoro-cytosine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calendulide A (NSC-675451) 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, pentafusi, and Yissum Project No. 11607.

[0301] Other antiviral agents include but are not limited to neuraminidase inhibitors, hemagglutinin inhibitors, hydroxychloroquine, azithromycin or drugs that regulate the immune system or host cell factors such as dexamethasone.Examples include but are not limited to favipiravir, lopinavir, ritonavir, remdesivir, janus kinase inhibitors, hydroxychloroquine, azithromycin, amantadine, rimantadine, ribavirin, iodine, trifluridine, vidarabine, acyclovir, ganciclovir, foscarnet, zidovudine, didanosine, peramivir, zalcitabine, stavudine, famciclovir, oseltamivir, zanamivir and valacyclovir.An embodiment of the method also includes other therapies, such as remdesivir and / or dexamethasone.An embodiment of the method also includes other therapies, such as casprevir monoclonal antibody plus imidavidin monoclonal antibody.An embodiment of the method also includes other therapies, such as banivamab.

[0302] The method for treating coronavirus infection may further include other therapies. For example, the method may include a second antiviral therapy, such as a neuraminidase inhibitor, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. Other therapies included in the method are drugs that modulate the immune system or host cytokines, such as dexamethasone; corticosteroids; IL-6 inhibitors (such as tocilizumab); interferons; IL-1 inhibitors; or kinase inhibitors (such as baricitinib). The method may further include antibody therapy, such as high-titer COVID-19 convalescent plasma, IVIG, monoclonal antibody therapy (such as casrevir monoclonal antibody plus imidizumab), baricitinib, or baricitinib plus ertesvir monoclonal antibody. The method may further include tocilizumab or baricitinib. The method may further include another therapy, such as high-titer COVID-19 convalescent plasma; IVIG; casrevir monoclonal antibody plus imidizumab; baricitinib; or baricitinib plus ertesvir monoclonal antibody. The method may include a second antiviral therapy, which is at least one of favipiravir, lopinavir, ritonavir, remdesivir, janus kinase inhibitors, hydroxychloroquine, azithromycin, amantadine, rimantadine, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscarnet, zidovudine, didanosine, peramivir, zalcitabine, stavudine, famciclovir, oseltamivir, zanamivir or valacyclovir. The method may include a second therapy, which is at least one of vitamin C or D, zinc, famotidine, ivermectin or angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor binding (ARB) agents.

[0303] Solid unit dosage forms can be conventional types. Solid forms can be capsules, etc., such as ordinary gelatin types containing compounds and carriers. Carriers include, but are not limited to, lubricants and inert fillers such as castor oil and similar materials, lactose, sucrose or corn starch. Preparations can be made of conventional tablet bases such as lactose, sucrose or corn starch in combination with adhesives such as gum arabic, corn starch or gelatin, disintegrants such as corn starch, potato starch or alginic acid and lubricants such as stearic acid or magnesium stearate.

[0304] The tablets, capsules, etc. may also contain a binder such as tragacanth, gum arabic, corn starch or gelatin; an excipient such as calcium hydrogen phosphate; a disintegrant such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned types of materials.

[0305] The present invention can be mixed with a liquid carrier (such as fatty oil, castor oil or other similar oils) at low temperature, room temperature or high temperature to prepare tablets, capsules and the like.

[0306] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. Syrups may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings such as cherry or orange flavors.

[0307] For oral therapeutic administration, the formulation may include excipients and be used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the compound in these compositions can vary, and can be conveniently between about 2% to about 60% of the unit weight. The amount of active compound in such therapeutically useful compositions can obtain a suitable dosage. Typical compositions according to the present invention are prepared so that the oral dosage unit contains about 1 mg to 100 mg of active compound, and preferably the oral composition contains 1 mg to 50 mg of active compound.

[0308] The preparations can be administered orally with an inert diluent, or with an absorbable edible carrier, or they can be enclosed in a hard or soft shell capsule, or they can be compressed into tablets, or they can be combined directly with food in the diet. The preferred preparation is an oral preparation.

[0309] The pharmaceutical form suitable for injection includes sterile aqueous solution or dispersion and sterile powder for extemporaneous preparation of sterile injection solution or dispersion. In all cases, this form should be sterile and should be liquid, existing to the extent of convenient injection. It should be stable under preparation and storage conditions, and should prevent microorganisms, such as contamination by bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, containing water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol), its suitable mixture and vegetable oil.

[0310] The compound or pharmaceutical composition used in the method of the present invention can also be administered in an injectable dose by these materials in a physiologically acceptable diluent with a solution or suspension of a pharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriers and / or excipients include but are not limited to sterile liquids, such as water and oil, with or without surfactants and other pharmaceutically and physiologically acceptable components. Exemplary oils are those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil or mineral oil. Typically, water, saline, aqueous glucose and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) are preferred liquid carriers, particularly for injectable solutions.

[0311] The preparations can also be administered parenterally. Solutions or suspensions of these preparations can be prepared in water suitably mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Exemplary oils are those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil or mineral oil. Usually, water, saline, aqueous glucose and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) are preferred liquid carriers, particularly for injectable solutions. Under common storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0312] For use in aerosol form, the preparation can be a solution or suspension, which can be packaged in a pressurized aerosol container with a suitable propellant (e.g., a hydrocarbon propellant, such as propane, butane or isobutane and conventional adjuvants). The preparation can also be administered in a non-pressurized form, such as in a nebulizer or a sprayer.

[0313] When applying the preparation described in the inventive method, the preparation can be administered systemically or sequentially. Administration can be completed in any manner that effectively compounds or pharmaceutical compositions are delivered to viral infection sites. Exemplary modes of administration include but are not limited to oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, by intranasal instillation, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional, or by being applied to mucosal (e.g., mucosal of nose, throat and bronchus) administration compounds or compositions.

[0314] Biological Activity

[0315] The present invention relates to methods and antiviral preparations for treating coronavirus infection using the above compounds and preparations. The compounds and preparations thereof are used to treat viral infection by disrupting microtubule polymerization. The preparations may optionally include additional active ingredients whose activity can be used to treat coronavirus infection, treat adverse events associated with the compounds or doses of a particular preparation, and / or delay or prolong the release of the ingredients.

[0316] In particular, the methods described herein can be used to treat infections caused by viruses, including those of the Coronaviridae superfamily. In addition, the methods described herein can be used to treat infections caused by viruses, including but not limited to SARS, MERS-CoV, and COVID-19. Preferably, the methods described herein treat viral infections caused by SARS-CoV, MERS-CoV, or COVID-19. More preferably, the methods described herein treat viral infections caused by COVID-19 (SARS-CoV-2).

[0317] The methods of the present invention can be used to treat infections caused by SARS-CoV, MERS-CoV or SARS-CoV-2, particularly SARS-CoV-2 infections. The methods of the present invention can be used to treat individuals with SARS-CoV-2 infections at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS). The individual may have a SARS-CoV-2 infection that reduces mortality. Another embodiment of the present invention includes a method in which individuals with SARS-CoV-2 infections at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) are treated to reduce mortality. Another embodiment of the present invention includes a method in which individuals with SARS-CoV-2 infections are treated to reduce morbidity. Another embodiment of the present invention includes a method in which individuals with SARS-CoV-2 infections at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) are treated to reduce morbidity. Another embodiment of the present invention includes a method in which individuals with SARS-CoV-2 infections at high risk of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) are treated to reduce morbidity. Another embodiment of the present invention includes a method in which individuals with SARS-CoV-2 infections are treated to reduce respiratory failure, days in the ICU, days on a mechanical ventilator, or improve the World Health Organization Clinical Improvement Order Scale. Another embodiment of the invention includes a method in which treatment of individuals 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 the ICU, days on a mechanical ventilator, and improves the World Health Organization Clinical Improvement Order Scale. Another embodiment of the invention includes a method in which treatment of individuals with SARS-CoV-2 infection reduces mortality or respiratory failure in individuals aged >60 years. Another embodiment of the invention includes a method in which treatment of individuals 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 individuals aged >60 years. Another embodiment of the invention includes a method in which when administered in combination with remdesivir and / or dexamethasone, treatment of individuals with SARS-CoV-2 infection reduces mortality or respiratory failure. Another embodiment of the invention includes a method in which when administered in combination with remdesivir and / or dexamethasone, treatment of individuals 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.

[0318] The present invention includes a method for treating coronavirus infection in an individual in need thereof, comprising administering to the individual a preparation having a compound described herein, or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof, wherein the therapeutically effective amount is used to treat coronavirus infection. The method includes at least one of compound 12db, compound 11cb, compound 11fb, compound 12da, compound 12fa, compound 12fb, compound 12cb, compound 55, compound 66a or compound 17ya. In a specific method, the method includes compound 17ya.

[0319] Unless otherwise indicated, the term "subject or patient" as used herein refers to any mammalian patient, including but not limited to humans, other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice and other rodents. In particular, the subject is a human, or can be only male or only female.

[0320] When administering the compounds and preparations described herein, the preparations can be systemically administered or directly administered to a specific site where there is a viral infection. Administration can be completed in any manner that effectively delivers the compound or pharmaceutical composition to the site of viral infection. The method of administration includes, but is not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional, or by application to mucosa. Mucosa includes those found in the nose, throat, and / or bronchus, etc. Preferably, the preparation is administered orally. Administration can be performed simultaneously or continuously with another antiviral compound or preparation, or for the treatment of side effects associated with the compound or dosage.

[0321] Compared with placebo, the treatment of COVID-19 with compound 17ya has significant biological advantages. For example, compared with patients treated with "placebo" (existing standard of care - remdesivir, dexamethasone, convalescent plasma, etc.), at least about 30% to about 100% of patients treated with compound 17ya remained alive without respiratory failure (primary endpoint). For example, compound 17ya reduced the proportion of patients who died within 60 days after starting treatment from 30% (6 / 20) in the placebo group to 5% (1 / 19) after treatment with compound 17ya. The mortality rate in the compound 17ya treatment group was reduced by about 82%. Therefore, compared with the placebo treatment group, the mortality rate in the compound 17ya treatment group is expected to be reduced by about 30% to about 100%. During the study, treatment failure (defined as death or respiratory failure) was 35% in the placebo group, while treatment failure was reduced to 15.8% after 15 days of treatment in the group treated with compound 17ya. The number of reductions improved as treatment continued, with treatment failures of approximately 30% in the placebo-treated group and 10.5% in the 17ya-treated group after 29 days of the study. The results showed that compound 17ya reduced treatment failures by 55% after 15 days of treatment and 65% after 29 days of treatment when compared to the placebo-treated group. Therefore, it is expected that compound 17ya will reduce treatment failures from approximately 30% to approximately 100% over the course of treatment. Other indicators of success have been observed in patients treated for Covid-19.

[0322] Treatment with compound 17ya reduced the number of days of mechanical ventilation from an average of 5.4 days in the placebo group to 1.6 days in the group treated with compound 17ya. The number of days of mechanical ventilation for placebo treatment increased 3.4 times compared to the group treated with compound 17ya. Therefore, treatment with compound 17ya will reduce the number of days of mechanical ventilation by about 30% to about 100% compared to patients treated with placebo. It was observed that the number of days spent in the ICU for patients treated with compound 17ya was also reduced. The placebo-treated group spent an average of 9.6 days in the ICU, while those treated with compound 17ya spent about 3 days in the ICU. The placebo-treated group spent an additional 3.2 times more days in the ICU compared to those patients treated with compound 17ya. Therefore, it is expected that treatment with compound 17ya will reduce the number of days spent in the ICU by about 30% to about 100%.

[0323] The study sponsor (Veru) conducted a post hoc subgroup analysis of the data from this study. The following additional observations were made in this study: (1) There was one patient in the compound 17ya treatment group who was not compliant with oxygen supplementation. This patient did not meet the standard of care for this study. Analysis of the primary endpoint showed that at day 29, the failure rate in the placebo group was 30% (same as Table 2), while the failure rate in the compound 17ya treatment group was 5.6% (lower than Table 2). This represents an 81% reduction in treatment failure. (2) It is well known that elderly patients are at higher risk of death and respiratory failure in COVID-19 patients compared with younger patients. In the analysis of treatment failure in patients >60 years of age, treatment failure was statistically significantly reduced (P value of 0.0456 (chi-square test)) and clinically meaningfully reduced in the compound 17ya treatment group (1 / 11 or 9%) compared with placebo (4 / 8 or 50%) in this high-risk population. (3) A risk factor for adverse clinical outcomes in patients with COVID-19 is the severity of disease manifestations. To assess this risk factor, an analysis of patients with a baseline World Health Organization Severity of Disease score ≥5 was performed. The results of this analysis showed that the mortality rate in this high-risk population was clinically significantly reduced (78%) in the compound 17ya treatment group (1 / 10 or 10%) compared with placebo (6 / 13 or 46%). (4) Analysis of the number of days in the ICU for evaluable patients showed a statistically significant (P value of 0.0469 (t test)) and clinically meaningful reduction in the number of days in the ICU in the compound 17ya treatment group (3 days; N = 18 individuals) compared with placebo (9.55 days; N = 20 days). (5) In addition, the proportion of patients in the ICU for ≥3 days at the time of study in the placebo group (11 / 20 or 55%) was statistically significantly higher (p value of 0.0390 (chi-square test)) compared with the compound 17ya treatment group (4 / 18 or 22%). (6) In this study, patients were allowed to receive standard of care. At the time of the study, the standard of care included treatment with remdesivir and / or dexamethasone under Emergency Use Authorization. Eleven patients in the study did not receive remdesivir or dexamethasone (6 in the compound 17ya treatment group and 5 in the placebo group). Patients who received the recognized standard of care were analyzed. Specifically, the number of days in the ICU and the number of days on mechanical ventilation in the two treatment groups were compared. In this group, among patients receiving the standard of care, no patient treated with compound 17ya required admission to the ICU or mechanical ventilation, and there were no deaths in this patient group. In the placebo group, 53% (8 / 16) required admission to the ICU, with an average ICU stay of 9.5 days, 20% (3 / 15) required mechanical ventilation, with an average mechanical ventilation of 3.9 days, and 27% (4 / 15) died during the study.

[0324] In summary, the study sponsors suggest that compound 17ya demonstrated strong clinically meaningful results in this small proof-of-concept Phase 2 study, with statistically significant reductions in mortality in the ITT population and in post hoc high-risk subgroup analyses, as well as in the number of days in the ICU. Notably, all parameters measured in the study showed clinically meaningful results for compound 17ya compared with placebo, and there were no parameters that did not suggest a benefit of compound 17ya treatment compared with placebo, although some parameters did not reach statistical significance in this small study.

[0325] Safety: The overall safety conclusion is: (1) No treatment-related serious adverse events were observed in this study; (2) No treatment-related adverse events were observed in this study. Example 1 shows the treatment-emergent adverse events observed in at least 2 patients in both treatment groups in this study. Example 1 also shows the treatment-emergent serious adverse events observed in this study. Among the serious adverse events observed in this study, there was no imbalance for compound 17ya. In summary, compound 17ya was well tolerated in this patient population, and there were no clinically relevant safety observations in the compound 17ya treatment group.

[0326] In this study, the use of remdesivir and dexamethasone had no significant effect on patient recovery outcomes. For the purposes of the above clinical trials, a "significant outcome" would be a reduction in treatment failure (death or respiratory failure), an increase in treatment success (survival without respiratory failure), a reduction in death (all-cause mortality), a reduction in the number of days in the ICU, a reduction in the number of days on mechanical ventilation, or a reduction in individuals requiring mechanical ventilation, or a possible further improvement in individual outcomes that becomes apparent through further analysis.

[0327] In view of these data, it is expected that the compounds of the invention will also be useful in treating patients suffering from other types of coronaviruses.

[0328] In order to more fully illustrate the preferred embodiments of the present invention, the following examples are provided. However, they should in no way be construed as limiting the broad scope of the present invention.

[0329] Example

[0330] The examples set forth below are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0331] Materials and methods:

[0332] In vitro tubulin polymerization assay: Bovine brain tubulin (0.4 mg, >97% pure) (Cytoskeleton, Denver, CO) was mixed with 10 μM test compound and then incubated in 100 μL of normal tubulin buffer (80 mM PIPES, 2.0 mM MgCl2, 0.5 mM EGTA and 1 mM GTP) at pH 6.9. The absorbance at a wavelength of 340 nm was monitored every 1 minute for 20 minutes using a SYNERGY 4 microplate reader (Bio-Tek Instruments, Winooski, VT). The spectrophotometer was set at 37°C for tubulin polymerization.

[0333] Example 1

[0334] Treatment of individuals with COVID-19

[0335] Efficacy: This example describes the results of a clinical trial (COVID-19 study), which was a Phase 2, double-blind, placebo-controlled, proof-of-concept study of approximately 40 hospitalized COVID-19 patients at high risk for acute respiratory distress syndrome (ARDS). The primary endpoint of this study was the proportion of patients alive without respiratory failure at day 29. Key secondary endpoints included the following: the proportion of patients alive without respiratory failure at days 15 and 22, all-cause mortality, number of days in the intensive care unit (ICU), and number of days on mechanical ventilation. The efficacy observations of this study's intended-to-treat (ITT) population are summarized below. The p-values ​​provided are from the chi-square test analysis for response analysis and the t-test for continuous variables. Note that alpha was not set in the Phase 2 study, but for small studies like this one, it is typically set to 0.1. Therefore, any p-value < 0.1 is considered statistically significant.

[0336] The protocol adopted a response analysis. A group of 39 high-risk acute respiratory distress syndrome (ARDS) individuals hospitalized due to COVID-19 infection were divided into two groups, a placebo group of 20 individuals and a treatment group of 19 patients (the group treated with compound 17ya). The treatment group took a powder-filled capsule containing 18 mg of compound 17ya orally daily until discharge, with a maximum of 21 days of medication.

[0337] These hospitalized individuals qualified as responders if they survived without respiratory failure on Day 15, Day 22, and Day 29. Non-responders were individuals who died before the analysis date or had respiratory failure on the analysis date. To determine responder / non-responder status after the individual was discharged / died, calls were made on Days 15, 22, and 29 and at the safety follow-up of the study to see if the individual was alive and had no evidence of respiratory failure. For example, if a patient died on Day 8, they were a non-responder on Days 15, 22, and 29. If a patient had respiratory failure on Day 15, but not on Days 22 or 29, they were a non-responder on Day 15, but not on Days 22 or 29. In this analysis, "all-cause mortality" was assessed and anyone who died was considered a non-responder. Responders also included individuals who were discharged on day 15, 22, or 29 (assessment date) or had a grade of 0-4 on the World Health Organization Ordinal Scale for Clinical Improvement, and non-responders were individuals who died before the assessment date or had a grade of 5-8 on the World Health Organization Ordinal Scale for Clinical Improvement on the assessment date.

[0338] Primary endpoint: Compound 17ya reduced the proportion of non-responding patients (i.e., death or respiratory failure) from 35.0% (7 / 20) in the placebo group to 15.8% (3 / 19) in the compound 17ya treatment group on day 15 (P=0.1697), and from 30.0% (6 / 20) in the placebo group to 10.5% (2 / 19) in the compound 17ya treatment group on day 29 (P=0.1322). See Table 2. This means that compared with placebo, the compound 17ya treatment group reduced treatment failure by approximately 55% on day 15 and 65% on day 29.

[0339]

[0340]

[0341] Compound 17ya reduced the proportion of patients who died 60 days after the start of treatment from 30% (6 / 20) in the placebo group to 5% (1 / 19) in the compound 17ya treatment group. This represents an approximately 82% reduction in mortality in the compound 17ya treatment group.

[0342] Compound 17ya reduced the number of days of mechanical ventilation from an average of 5.4 days in the placebo group to 1.6 days in the compound 17ya treatment group. This means that the number of days of mechanical ventilation in the placebo group increased by 3.4 times compared with the compound 17ya treatment group. See Table 3.

[0343] Compound 17ya reduced the number of days in the ICU from an average of 9.6 days in the placebo group to 3.0 days in the compound 17ya treatment group. The number of days in the ICU in the placebo group increased by 3.2 times compared to the compound 17ya treatment group. See Table 3.

[0344]

[0345] Figure 1 The daily mean World Health Organization Ordinal Clinical Improvement Scale (0 = baseline) is shown. The mean area under the curve was 153 in the group treated with compound 17ya and 182 in the placebo group, indicating a higher incidence in the placebo population and suggesting clinical improvement associated with receiving compound 17ya.

[0346] Due to the limited sample size of this study based on FDA comments received during the IND review process, the study sponsor (Veru, Inc.) conducted a post hoc subgroup analysis of the data from this study. The following additional observations were made from this study:

[0347] There was 1 patient in the compound 17ya treatment group who was not compliant with oxygen supplementation. This patient did not meet the standard of care in this study. The primary endpoint analysis excluding this patient from the analysis (MITT population) showed that the failure rate in the compound 17ya treatment group was 5.6% on day 29 (lower than Table 2), compared to a failure rate of 30% in the placebo group (same as Table 2). This represents an 81% reduction in treatment failure.

[0348] It is well known that elderly patients are at higher risk of death and respiratory failure in COVID-19 patients compared to younger patients. In the analysis of treatment failure in patients >60 years of age, it was shown that in this high-risk group, a statistically significant and clinically meaningful reduction in treatment failure was observed in the compound 17ya treatment group compared to placebo.

[0349]

[0350] A risk factor for adverse clinical outcomes in patients with COVID-19 is the severity of the disease that develops. To assess this risk factor, patients with a World Health Organization disease severity score ≥5 at baseline were analyzed. The results of this analysis showed that in this high-risk group, a statistically significant and clinically meaningful reduction in treatment failure was observed in the compound 17ya treatment group compared to placebo. In addition, in this high-risk group, a clinically meaningful reduction in mortality was observed in the compound 17ya treatment group (1 / 10 or 10%) compared to placebo (6 / 13 or 46%) (78%; not shown).

[0351]

[0352] *In the compound 17ya-treated group, one patient was noncompliant with oxygen therapy and was excluded from this modified intention to treat (MITT) analysis.

[0353] Analysis of the number of days in the ICU for evaluable patients showed a statistically significant and clinically meaningful reduction in the number of days in the ICU in the compound 17ya treatment group compared with placebo.

[0354]

[0355] Additionally, the proportion of patients on study who were in the ICU for ≥3 days was statistically significantly higher in the placebo group compared to the compound 17ya-treated group.

[0356]

[0357] In this study, patients were allowed to receive standard of care. At the time of the study, the standard of care included treatment with remdesivir and / or dexamethasone under emergency use authorization. Eleven patients in the study did not receive remdesivir or dexamethasone (6 in the compound 17ya treatment group and 5 in the placebo group). Patients who received recognized standards of care were analyzed. Specifically, the number of days in the ICU and the number of days on mechanical ventilation in the two treatment groups were compared. In this group, among patients receiving the standard of care, no patient treated with compound 17ya required admission to the ICU or mechanical ventilation, and there were no deaths in this patient group. In the placebo group, 53% (8 / 16) required admission to the ICU, with an average of 9.5 days in the ICU, 20% (3 / 15) required mechanical ventilation, with an average of 3.9 days on mechanical ventilation, and 27% (4 / 15) died in the study.

[0358] In summary, the study sponsors suggest that compound 17ya showed strong clinically meaningful results in this small proof-of-concept Phase 2 study, with statistically significant observations of reductions in mortality in the ITT population and in post hoc high-risk subgroup analyses, as well as in the number of days in the ICU. Notably, all parameters measured in the study showed clinically meaningful results for compound 17ya compared with placebo, and no parameter did not suggest a benefit of compound 17ya treatment compared with placebo, although some parameters did not reach statistical significance in this small study.

[0359] Safety: The overall safety conclusions were: (1) no serious adverse events related to treatment were observed in this study; (2) no adverse events related to treatment were observed in this study; and (3) treatment-emergent adverse events observed in at least 2 patients in both treatment groups of this study are presented in Table 4. There was no imbalance in the adverse events observed in this study for compound 17ya.

[0360] Table 4: COVID-19 study: treatment-emergent adverse events observed in ≥2 patients in either treatment group during the preferred period

[0361]

[0362]

[0363] The treatment-emergent serious adverse events observed in the study are presented in Table 5. There was no imbalance in the serious adverse events observed in the study for compound 17ya.

[0364] Table 5: COVID-19 studies: Serious adverse events observed by system organ class and preferred period

[0365]

[0366] In conclusion, compound 17ya was well tolerated in this patient population, with no clinically relevant safety observations in the compound 17ya-treated group.

[0367] All features described herein (including any attached claims, abstracts and drawings) and / or all steps of any method or process so disclosed may be combined with any of the above aspects in any combination, except where at least some of such features and / or steps are mutually exclusive combinations. Although preferred embodiments have been described and described in detail herein, it is apparent to those skilled in the art that various modifications, additions, substitutions, etc. may be made without departing from the spirit of the invention, and therefore, these modifications, additions, substitutions, etc. are considered to be within the scope of the invention as defined by the appended claims.

Claims

1. Use of a therapeutically effective amount of a compound of formula VII, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating coronavirus infection in an individual in need thereof: in X is a key; Q is NH; and A is a phenyl or indolyl ring, which is optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN or NH2.

2. The use according to claim 1, wherein X is a bond.

3. The method of claim 1, wherein X is a bond; Q is NH; and A is an indolyl ring, optionally substituted with at least one of (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN or NH2; or a pharmaceutically acceptable salt thereof.

4. Use of a therapeutically effective amount of a compound of formula VII(c), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating coronavirus infection in an individual in need thereof: in R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, (C1-C4)alkylamino, amino(C1-C4)alkyl, F, Cl, Br, I, CN, -CH2CN or NH2; and n is 1-4.

5. The method of claim 1 , wherein the coronavirus infection is caused by SARS-CoV, MERS-CoV or SARS-CoV-2.

6. The method according to any one of claims 1 to 4, wherein the coronavirus infection is caused by SARS-CoV-2.

7. The use according to claim 6, wherein the individual with SARS-CoV-2 infection is at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS).

8. The use according to claim 6, wherein the medicament reduces mortality compared to a patient population treated with a placebo.

9. The use according to claim 6, wherein the medicament reduces the morbidity compared to a patient population treated with a placebo.

10. The use of claim 9, wherein the drug reduces respiratory failure, days in the ICU, days on a mechanical ventilator, or improves the World Health Organization Clinical Improvement Ordinal Scale compared to a patient population treated with a placebo.

11. The use according to claim 6, wherein the medicament reduces mortality or respiratory failure in individuals aged > 60 years compared to a patient population treated with a placebo.

12. The use according to claim 6, wherein the drug reduces mortality or respiratory failure when administered in combination with remdesivir and / or dexamethasone compared to a patient population treated with a placebo.

13. The use according to claim 6, wherein the medicament further comprises a second therapeutic agent.

14. The use according to claim 13, wherein the second therapeutic agent is remdesivir, dexamethasone or another corticosteroid, or remdesivir plus a corticosteroid.

15. The use according to claim 13, wherein the second therapeutic agent is a drug that modulates the immune system or host cytokines, an IL-6 inhibitor, an interferon, an IL-1 inhibitor, or a kinase inhibitor.

16. The use according to claim 13, wherein the second therapeutic agent is IVIG, or a monoclonal antibody.

17. The use according to claim 13, wherein the second therapeutic agent is a second antiviral agent, and the second antiviral agent is at least one of favipiravir, lopinavir, ritonavir, remdesivir, janus kinase inhibitors, hydroxychloroquine, azithromycin, neuraminidase inhibitors, amantadine, rimantadine, hemagglutinin inhibitors, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscarnet, zidovudine, didanosine, peramivir, zalcitabine, stavudine, famciclovir, oseltamivir, zanamivir or valacyclovir.

18. The use of claim 13, wherein the second therapeutic agent is at least one of vitamin C or D, zinc, famotidine, ivermectin, or an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor binding (ARB) agent.

19. The use according to claim 6, wherein the therapeutically effective amount is 1 to 100 mg.

20. The use according to claim 6, wherein the therapeutically effective amount is 4 mg to 90 mg.

21. The use according to claim 6, wherein the therapeutically effective amount is 4 mg to 45 mg.

22. The use according to any one of claims 1 to 4, wherein the medicament further comprises a pharmaceutically acceptable excipient.

23. The use according to any one of claims 1 to 4, wherein the individual has a World Health Organization score of 5 or higher.

24. The use according to any one of claims 1 to 4, wherein the subject is receiving standard of care.

25. The use according to any one of claims 1 to 4, wherein the individual is a male.

26. The use of claim 15, wherein the second therapeutic agent is dexamethasone or another corticosteroid, tocilizumab, or baricitinib.

27. The use according to claim 16, wherein the second therapeutic agent is high titer COVID-19 convalescent plasma, casprevirumab plus imidevirumab, banivamab, or banivamab plus etasevirumab.

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