Methods for treating influenza and poxvirus infections

Abstract

The present invention relates to methods of treating certain viral infections using compounds with antitubulin or tubulin disrupting activity.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 328,504, filed April 7, 2022, No. 63 / 394,260, filed August 1, 2022, and No. 63 / 456,943, filed April 4, 2023, which are incorporated herein by reference.

[0002] The present invention relates to methods of treating certain viral infections using compounds having cytoskeletal disrupting activity, as well as formulations comprising pharma- ceutically acceptable excipients and / or additional cytoskeletal disrupting compounds. [Background technology]

[0003] Over the past century or two, numerous viral epidemics have posed serious global public health risks, including epidemics and pandemics, in which millions of healthy individuals become infected and die from viral pathogens. Unfortunately, until relatively recently, the development of antiviral drugs has been difficult, and treatment of many viral diseases has been primarily directed at ameliorating symptoms and isolating patients until symptoms resolve. Most notable in recent years is the global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in 2019 and continues to this day. In addition, there are many other families of viruses that are characterized by endemic conditions or episodic / seasonal epidemics and pandemics. The present invention relates to broad spectrum indirect antiviral agents capable of treating not only SARS-CoV-2 (WO2021 / 0203100), but also multiple viral pathogens from the Orthomyxoviridae (Flu viruses, such as Influenza) and Poxviridae (Poxviruses, such as Monkey Pox and Smallpox) virus families. The virology of these two virus families is described below.

[0004] Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus (Influenza A), Betainfluenzavirus (Influenza B), Deltafluenzavirus (Influenza D), Gammainfluenzavirus (Influenza C), Isavirus, Thogotovirus, and Quaranjavirus. The first four genera include viruses that cause influenza in birds and mammals, including humans. Common symptoms of influenza virus infection include fever, headache, and fatigue, which result from the large amount of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced by influenza-infected cells. In contrast to rhinoviruses, which cause the common cold, influenza causes a hyper-reactive inflammatory response, which results in tissue damage. This massive immune response can trigger a life-threatening "cytokine storm" that causes tissue damage, respiratory distress, multiple organ failure, and death. This effect is thought to be responsible for the unusual lethality of both H5N1 avian influenza and the 1918 pandemic H1N1 strain. The 1918 influenza pandemic was truly global, spreading as far as the Arctic and remote islands in the Pacific. The unusually severe disease killed 2-20% of those infected, in contrast to the more common influenza epidemic mortality rate of 0.1%. Another unusual feature of this pandemic was that it primarily killed young adults, with 99% of pandemic influenza deaths being people under 65 years of age, and over half being young adults between 20 and 40 years of age. This is unusual, as influenza is typically most deadly to young children (under 2 years of age) and the elderly (over 70 years of age).The total mortality from the 1918-1919 pandemic is unknown, but it is estimated that it killed 2.5%-5% of the world's population. 25 million people may have died in the first 25 weeks. In contrast, HIV / AIDS killed 25 million people in its first 25 years. Subsequent influenza pandemics have not been as devastating. These include the 1957 Asian influenza (type A, H2N2 strain), the 1968 Hong Kong influenza (type A, H3N2 strain), and the 1977 Russian influenza (type A, H1N1 strain), but even these smaller epidemics killed millions. In subsequent pandemics, antibiotics were available to control secondary infections, which may have helped reduce mortality compared to the 1918 Spanish influenza. Type B influenza does not mutate as rapidly as type A, and therefore does not typically cause pandemic infections, but rather is more often associated with seasonal epidemics. Nevertheless, the costs associated with lost productivity and life associated with annual influenza epidemics are enormous.

[0005] Influenza (flu) infections are typically limited in scope and severity by the immune system of immunocompetent patients, with influenza virus being cleared in 5-10 days. This rapid immune clearance may limit the effectiveness of antiviral agents on the severity of symptoms and length of infection. However, certain patient populations are at risk for complications associated with influenza infection that may lead to hospitalization and death. The most common complication is pneumonia, which may be either primary viral pneumonia, secondary bacterial pneumonia, or a mixture of the two. Other complications may affect the musculoskeletal, cardiac, or nervous systems and may include myocarditis, pericarditis, myositis, rhabdomyolysis, and encephalitis. Those at risk for complications include unvaccinated infants aged 12-24 months, pregnant women in their second or third trimester, those with chronic lung disease such as asthma, cystic fibrosis, or chronic obstructive pulmonary disease, those with hemodynamically significant heart disease, those with vascular disease such as sickle cell anemia, those with immunosuppressive disorders, those with chronic renal dysfunction or cancer, those with neuromuscular, seizure, or cognitive disorders that may interfere with the processing of respiratory secretions, adults over 65 years of age, or residents of long-term care facilities. As a preventive measure, vaccination is recommended for the general population and has been emphasized as being especially important for at-risk populations. However, vaccine efficacy varies for any given influenza season due to antigenic drift from the vaccine strain that is taken into account during vaccine preparation; for example, in the 2014-15 influenza season, the CDC estimated efficacy to be only 23%, although most years have seen vaccine efficacy significantly higher.

[0006] Direct antiviral agents have been approved for influenza. Oseltamivir (Tamiflu®) is an FDA-approved drug used to treat influenza A or B infection. If confirmed within the first 48 hours of symptom onset, oral oseltamivir reduces the severity and length of infection, with greatest benefit when treatment is initiated within the first 24 hours of symptom onset. Oseltamivir is also used for prophylaxis in contacts of influenza patients. Oseltamivir is an inhibitor of influenza virus release from infected cells and acts by inhibiting neuraminidase, one of the major surface proteins of influenza virus, thereby reducing the virus' ability to infect other respiratory cells. Members of the neuraminidase inhibitor (NAI) family include oral oseltamivir, inhaled zanamivir, and intravenous peramivir. The emergence of NAI resistance is of concern due to limited influenza treatment options, as demonstrated by the global spread of NAI-resistant H1N1 viruses in the 2008-2009 influenza season. Oral baloxavir marboxil (Xofluza), another antiviral approved in 2018, is a polymerase acid (PA) endonuclease inhibitor indicated for the treatment of acute uncomplicated influenza in patients aged 12 years or older who have been symptomatic for 48 hours or less. It is not an NAI agent, but instead inhibits the PA protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. In a randomized controlled trial, baloxavir was more effective than oseltamivir in adolescents and adults with influenza B virus infection. As with the use of NAIs, the emergence of resistance to PA inhibitors has been observed clinically, with resistant viruses harboring mutations in the PA protein. In clinical trials, none of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were identified in viruses from pretreatment respiratory specimens. Amantadine and rimantadine are older classes of drugs approved for the prevention or treatment of influenza A in patients aged 17 years or older.Although poorly understood, these drugs are thought to inhibit the function of the viral M2 protein, thereby blocking an early step in the viral replication cycle. In January 2017, the Centers for Disease Control and Prevention now (and will remain so in 2023) recommends against the use of amantadine and rimantadine for the treatment of influenza A, due to high resistance to currently circulating influenza A viruses. Ribavirin has also been used historically but is no longer recommended. Treatment choice depends on influenza A or B, approved age groups, local resistance patterns, and contraindications.

[0007] These three classes of influenza antiviral agents are each directly targeted antivirals because they exert their effectiveness by binding to viral proteins (NA, PA, or M2, respectively). By binding to viral target proteins, direct antiviral agents are susceptible to the emergence of resistance based on viral mutations in response to the selective pressure of antiviral use. Indirect antiviral agents, such as the colchicine binding site inhibitors (CBSIs) of tubulin of the present invention, bind to host target proteins whose functions are conserved. Generally, and certainly with the CBSIs of the present invention, mutant host cells are unlikely to survive, and thus indirect antiviral agents are less susceptible to selective pressures that lead to direct antiviral resistance. Furthermore, because indirect antiviral agents competitively bind or otherwise antagonize the effectiveness of direct antiviral agents, the use of indirect antiviral agents is not contraindicated with the use of existing antiviral agents.

[0008] Influenza infection causes symptoms through lung inflammation, but anti-inflammatory agents that lack antiviral activity, such as corticosteroids, are of limited utility. Most studies report that corticosteroid therapy adversely affects influenza-related outcomes. For example, during the 2009 influenza pandemic, 37%–55% of patients admitted to ICUs in Europe received corticosteroids (e.g., dexamethasone) as part of their treatment. Nevertheless, a recent meta-analysis reported that evidence from observational studies suggests that corticosteroid therapy for presumed influenza-related complications is associated with increased mortality.

[0009] The Poxviridae family is a family of double-stranded DNA viruses that includes pathogens such as smallpox (Variola). Since smallpox has been declared eradicated worldwide, smallpox vaccination has declined and, correspondingly, there has been a recent increase in various non-variola orthopoxvirus infections, such as monkeypox, also known as Mpox. Orthopoxviruses (OPXVs) belonging to the Poxviridae family that infect humans are Variola virus (smallpox), Vaccinia virus (Cowpox) (the virus in the smallpox vaccine called ACAM2000 and the smallpox / monkeypox vaccine called Jynneos), Monkeypox, Horsepox, Camelpox, Akhmeta virus, and Alaskapox virus. Variola virus, the causative agent of smallpox, is the only one that only affects humans; the others are zoonotic diseases that can be transmitted from person to person. Poxvirus infections can be localized to the skin or disseminated. The initial site of infection can be the skin, mucosal surfaces, or the respiratory tract.

[0010] Monkeypox virus belongs to the Orthopoxvirus genus of the Poxviridae family. Orthopoxviruses such as monkeypox can also cause severe clinical disease, including but not limited to encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymphadenopathy with or without airway and / or swallowing disorders, extensive skin lesions during the rash, and / or other septic syndromes. Since the global eradication of smallpox, other orthopoxvirus or non-variola orthopoxvirus (NV-OPXV) infections have emerged as a growing public health concern, especially among previously unvaccinated people, given the potential for spread through international travel and delayed recognition of NV-OPXV infections by health care workers who may be less familiar with these infections.

[0011] Recent cases of human monkeypox (MPox) in countries outside of West and Central Africa highlight the risk of MPox spreading beyond its usual endemic areas and the potential for sustained local transmission. Monkeypox is a disease of global public health importance as it affects not only West and Central African countries but also the rest of the world. In 2003, the first monkeypox outbreak outside of Africa occurred in the United States, which was linked to contact with infected pet prairie dogs. These pets were kept together with Gambian pouched rats and dormice imported from Ghana. This outbreak led to over 70 monkeypox cases in the United States. Monkeypox has also been reported in travelers who visited Israel from Nigeria in September 2018, the United Kingdom in September 2018, December 2019, May 2021, and May 2022, Singapore in May 2019, and the United States in July and November 2021. In May 2022, multiple cases of monkeypox were confirmed in several non-endemic countries. Research is currently underway to further understand the epidemiology, source, and transmission patterns. Prior to April 2022, monkeypox virus infections in humans had rarely been reported outside of Africa, where it is endemic. Cases are now occurring worldwide.

[0012] Mpox pathology is characterized by an incubation period (the interval between infection and the onset of symptoms) that is usually 6–13 days, but can range from 5–21 days. Infection can be divided into two periods: (1) the invasive period (lasting 0–5 days) characterized by fever, intense headache, lymphadenopathy (swollen lymph nodes), back pain, myalgia (muscle pain), and intense asthenia (lack of energy). Lymphadenopathy is a distinctive feature of MPox compared to other diseases (chickenpox, measles, smallpox) that may appear similar in the early stages; (2) the rash period usually begins within 1–3 days after the onset of fever. The rash tends to be more concentrated on the face and extremities than on the trunk. It affects the face (95% of cases), palms, and soles (75% of cases). It also affects the oral mucosa (70% of cases), genitals (30%), conjunctiva (20%), and cornea. The rash evolves sequentially from macules (lesions with a flat base), to papules (slightly raised, firm lesions), to vesicles (lesions filled with clear fluid), to pustules (lesions filled with yellowish fluid), and to dry, sloughing skin. The number of lesions can vary from a few to thousands. In severe cases, the lesions may coalesce and large portions of the skin may fall off. The case fatality rate for MPox cases has historically ranged from 0-11% in the general population, and is higher among young children. More recently, the case fatality rate has been around 3-6%.

[0013] Clinical care for MPox needs to be fully optimized to alleviate symptoms, manage complications, and prevent long-term sequelae. Patients should be provided with fluids and food to maintain adequate nutritional status. Secondary bacterial infections should be treated as indicated. An antiviral agent known as tecovirimat, developed for smallpox, was also approved for monkeypox by the European Medicines Agency (EMA) in 2022 based on data from animal and human studies. It is still not widely used. Tecovirimat inhibits the function of a key envelope protein required for the production of extracellular virus. The drug prevents the virus from exiting the infected cell and impedes the spread of the virus in the body. Although the efficacy of tecovirimat in treating human non-variola orthopoxvirus infections, including MPox, has not been evaluated, it may be reasonable to predict potential therapeutic efficacy based on the animal efficacy data supporting FDA approval for smallpox treatment, and the limited clinical use of tecovirimat in treating NV-OPXV-infected individuals to date. Tecovirimat has been shown to be effective against a variety of orthopoxviruses in multiple animal challenge models. Tecovirimat is approved for smallpox under FDA animal regulations, which allow efficacy findings from appropriate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct efficacy studies in humans. Given the lack of adequately tested drug therapies for non-variola orthopoxvirus infections, including Mpox, and their increasing incidence worldwide, including in non-endemic regions, there is a compelling need to discover new drug therapies for these non-variola orthopoxvirus infections.

[0014] Viruses have efficient mechanisms to control the host cellular machinery to replicate, assemble, and egress from the cell, spreading infectious virus. Considering the spatial distance between the virion entry point at the cell membrane to the intracellular location where DNA or RNA replication (nucleus) and viral assembly occurs in the endoplasmic reticulum and Golgi apparatus, and that the newly generated virions must return to the cell membrane for egress from the cell, it is not surprising that the virus' most important first task is to hijack the host's internal transport system, the cytoskeleton. The cytoskeleton is composed of three main types of protein filaments: microfilaments (actin), microtubules (tubulin), and intermediate filaments. The main ones involved in viral replication and transport are the two main filament systems involved in intracellular transport, microtubules and microfilaments.

[0015] Microtubules are important for cell shape, transport, movement, and cell division. Microtubules are dynamic long polar fibers / filaments resulting from polymerization of α and β tubulin heterodimer subunits, with their plus ends located at the cell membrane and their minus ends facing the core at the microtubule organizing center (MTOC). From the MTOC, microtubule fibers radiate from the nuclear region towards the periphery of the cell. Microtubules are dynamic network systems, i.e., they undergo rapid polymerization to form growing polymer chains by adding α and β tubulin subunit heterodimers, followed by rapid depolymerization (removal of α and β tubulin subunit heterodimers) to break down and shrink the polymer chains. This "dynamic" ability of microtubules to grow and shrink accommodates the ever-changing transport requirements of the cell. Large macromolecules such as viruses engage specialized motor proteins (kinesins and dyneins). Kinesins and dyneins attach, transport, and move viral cargo like train cars on these microtubule tracks over long distances to reach various compartments within the cell.

[0016] Since many human and other mammalian animal viruses, as well as most eukaryotic cells, contain microtubules, microtubule-dependent coronavirus replication across species appears to be conserved. Furthermore, viruses may have evolved microtubule-binding motifs complementary to motifs in kinesin and dynein or similar amino acid sequences for successful transport interactions. Examples such as Mouse Hepatitis Virus CoV use microtubules for neuronal spread, and Feline Infectious Peritonitis Virus (FIPV) is transported by microtubules toward the MTOC. For Porcine transmissible gastroenteritis virus (TGEV), upregulation of both α and β tubulin subunits occurs after infection. Thus, focusing on the cytoskeletal network as a drug target with the aim of inhibiting intracellular transport and disrupting virus and host interactions may be an effective way to treat viral infections.

[0017] Viruses are obligate intracellular parasites and therefore depend solely on the cellular machinery for membrane trafficking, nuclear import and export, and gene expression. Invading viral particles translocate from the cell surface to intracellular sites of viral transcription and replication. During assembly and release, subviral nucleoprotein complexes and virions are released by translocating backward across the plasma membrane. Because the diffusion of large molecules is severely restricted in the cytoplasm, viruses use host ATP-hydrolyzing molecular motors to navigate along microtubules, the intracellular highway.

[0018] 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 of various antiviral agents. Compounds that can disrupt the intracellular microtubule-tubulin equilibrium are effective in treating viruses, as viruses commonly use microtubules as a transport source within the cell. Other compounds that disrupt the intracellular microtubule-tubulin equilibrium, such as paclitaxel and vinblastine, are limited by their toxicity.

[0019] Drugs that target the cytoskeleton, particularly microtubule components, are important therapeutic agents against cancer and inflammation. The clinical activity of these compounds is determined by the location at which they bind on the α- and β-tubulin heterodimers that make up the microtubule filament. Three major binding sites on the α- and β-tubulin subunits have been identified as the taxane site, the vinca alkaloid site, and the colchicine binding site. Such drugs are generally classified into two major categories: microtubule stabilizers (e.g., taxanes) and microtubule destabilizers or depolymerizers (e.g., vinca alkaloids and colchicine).

[0020] Colchicine has a narrow therapeutic index, with no clear distinction between non-toxic, toxic, and lethal doses. Metabolically, colchicine is cleared via P-glycoprotein (P-gp; also known as multidrug resistance 1 (MDR1) protein). Drug-drug interactions are common to CYP3A4 and P-glycoprotein inhibitors, and can increase colchicine blood concentrations to toxic levels, resulting in colchicine intoxication 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 severe toxicities, including bone marrow suppression, disseminated intravascular coagulation, and cellular damage in the kidney, liver, circulatory system, and central nervous system, have been observed with approved therapeutic doses of colchicine. These observed severe adverse events limit the clinical use of colchicine.

[0021] 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. The major problem with taxanes, as with many biologically active natural products, 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 preparations, which can result in severe hypersensitivity reactions.

[0022] Nocodazole is a synthetic compound identified in screening for anthelmintic drugs. Nocodazole is a microtubule depolymerizing agent because it binds to free tubulin heterodimers and prevents them from being incorporated into microtubules. It is not used clinically due to its poor bioavailability and high toxicity.

[0023] Cells and viruses are organized networks or filaments that contain microtubules to govern intracellular trafficking. Cells require microtubules for long-term normal physiological function, and viruses are obligate intracellular parasites that are entirely dependent on the physiology of the host cell. It is therefore not surprising that the Orthomyxoviridae and Poxviridae virus life cycles require microtubules for efficient replication. Viral binding sites on microtubulin may provide new targets for antiviral therapy. The invention of the present application addresses a novel method of interfering with the microtubules of the cytoskeleton to prevent the intracellular trafficking, replication, and release of Orthomyxoviridae and Poxviridae viruses. Summary of the Invention [Means for solving the problem]

[0024] The present invention provides a method for treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I):

[0025] [ka]

[0026] During the ceremony, A is phenyl, indolyl, or indazolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole or benzimidazole, 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; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0027] In one embodiment of the present invention, the method for treating an Orthomyxoviridae virus infection comprises administering to a patient a compound of formula I: wherein A is phenyl or indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0028] In another embodiment of the invention, the method of treating an Orthomyxoviridae virus infection comprises administering to a patient a compound of formula I: wherein A is phenyl, 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0029] In yet another embodiment of the present invention, the method of treating an Orthomyxoviridae virus infection comprises administering to a patient a compound of formula I: wherein A is 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0030] In an embodiment of the invention, the method of treating an Orthomyxoviridae virus infection comprises administering to a patient a compound of formula I: wherein A is 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond; Y is -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0031] Another embodiment of the present invention is a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII:

[0032] [ka]

[0033] During the ceremony, X is a bond or NH; Q is S or NH; In yet another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment, the method includes a compound of formula VII, wherein Q is S. In another embodiment of the invention, the method includes a compound of formula VII, where X is NH. In yet another embodiment of the invention, the method includes a compound of formula VII, 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, 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, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0034] An embodiment of the invention is a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula VII(c):

[0035] [ka]

[0036] During the ceremony, 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, 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; n is 1 to 4; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0037] Another embodiment of the present invention includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of compound 17ya, as depicted below.

[0038] [ka]

[0039] Yet another embodiment of the present invention encompasses a method of treating an Orthomyxoviridae virus infection, the Orthomyxoviridae virus infection being caused by an influenza virus. In another embodiment, the influenza virus is influenza A. In one of these embodiments, the influenza A virus has serotype H1N1. In one of these embodiments, the influenza A virus has serotype H2N2. In one of these embodiments, the influenza A virus has serotype H3N2. In one of these embodiments, the influenza A virus has serotype H5N1. In one of these embodiments, the influenza A virus has serotype H7N7. In one of these embodiments, the influenza A virus has serotype H7N9. In one of these embodiments, the influenza A virus has serotype H1N2 and infects pigs and humans. In others of these embodiments, the influenza A virus has at least one of H9N2, H7N2, H7N3, H10N7, or other serotypes known by those of skill in the art.

[0040] In another embodiment, the influenza virus is influenza B. In some embodiments, the influenza B virus is further classified into one of two lineages: B / Yamagata and B / Victoria. In one of these embodiments, the influenza B virus is classified as lineage B / Yamagata. In one of these embodiments, the influenza B virus is classified as lineage B / Victoria. In another embodiment, the influenza virus is influenza D. In another embodiment, the influenza virus is influenza C.

[0041] Further embodiments of the invention include methods of treating subjects with influenza infections at risk for influenza complications, such as, for example, unvaccinated infants aged 12-24 months, individuals with chronic lung disease such as asthma, cystic fibrosis, or chronic obstructive pulmonary disease, individuals with hemodynamically significant cardiac disease, individuals with vascular disease such as sickle cell anemia, individuals with immunosuppressive disorders, individuals with chronic renal dysfunction or cancer, individuals with neuromuscular, seizure, or cognitive disorders that may interfere with the processing of respiratory secretions, adults over 65 years of age, or residents of long-term care facilities. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce mortality. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce mortality. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce morbidity. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce morbidity at risk for pneumonia. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce the risk of developing pneumonia. Another embodiment of the invention includes a method of treating a subject with influenza infection having viral pneumonia. Another embodiment of the invention includes a method of reducing mortality or morbidity in subjects over 65 years of age by treating a subject with influenza infection. Another embodiment of the invention includes prophylactic treatment of influenza. In one embodiment, influenza infection is prevented or reduced in severity in close contacts following exposure to an individual with an initial influenza infection.

[0042] In yet another embodiment of the present invention, the method further comprises at least one additional therapy. This embodiment of the method further comprises a second antiviral therapy, such as, for example, a neuraminidase inhibitor, an M2 inhibitor, a PA inhibitor, oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), peramivir, rimantadine, amantadine, baloxavir marboxil (Xofluza), ribavirin, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. One embodiment of the method further comprises an agent that modulates the immune system or host cell factors, such as, for example, dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, an interferon, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib. This embodiment of the method further comprises an additional therapy, such as, for example, an NAI or PA inhibitor, and / or dexamethasone or another corticosteroid. Yet another embodiment of the method includes 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 valacyclovir.

[0043] The present invention relates to a method for treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I):

[0044] [ka] During the ceremony, A is phenyl, indolyl, or indazolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole or benzimidazole, 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; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0045] In one embodiment of the present invention, the method for treating a Poxviridae virus infection comprises administering to a patient a compound of formula I: wherein A is phenyl or indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0046] In another embodiment of the invention, the method for treating a Poxviridae virus infection comprises administering to a patient a compound of formula I: wherein A is phenyl, 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0047] In yet another embodiment of the present invention, the method for treating a Poxviridae virus infection comprises administering to a patient a compound of formula I: wherein A is 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0048] In an embodiment of the invention, the method of treating a Poxviridae virus infection comprises administering to a patient a compound of formula I: wherein A is 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; B is imidazole, optionally substituted with at least one (C1-C4)alkyl; 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)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; X is a bond; Y is -C=O; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0049] Another embodiment of the invention is a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula VII:

[0050] [ka]

[0051] During the ceremony, X is a bond or NH; Q is S or NH; A is a phenyl, indolyl, or indazolyl 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, 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; or a pharmaceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject. In yet another embodiment, the method involves a compound of formula VII, where Q is S. In another embodiment of the invention, the method involves a compound of formula VII, where X is NH. In yet another embodiment of the invention, the method involves 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, 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.

[0052] An embodiment of the invention is a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(c):

[0053] [ka]

[0054] During the ceremony, 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0055] Another embodiment of the present invention includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of compound 17ya, as depicted below.

[0056] [ka]

[0057] Yet another embodiment of the present invention encompasses a method of treating a Poxviridae viral infection, wherein the viral infection is caused by a virus of the Orthopoxvirus genus. In one of these embodiments, the orthopoxvirus is smallpox. In one of these embodiments, the orthopoxvirus is monkeypox. In one of these embodiments, the orthopoxvirus is vaccinia virus. In one of these embodiments, the orthopoxvirus is any one of cowpox virus, horsepox virus, camelpox virus, affeta virus, and alaskapox, or other orthopoxvirus known to one of skill in the art.

[0058] Further embodiments of the present invention include methods of treating symptoms of Poxviridae virus infection, such as, for example, encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymphadenopathy, widespread skin rash, and the severity of septic syndrome.

[0059] In yet another embodiment of the present invention, the method further comprises at least one additional therapy. An embodiment of the method further comprises a second antiviral therapy, such as, for example, a neuraminidase inhibitor, an M2 inhibitor, a PA inhibitor, oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), peramivir, rimantadine, amantadine, baloxavir marboxil (Xofluza), ribavirin, tecovirimat, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. An embodiment of the method further comprises an agent that modulates the immune system or host cell factors, such as, for example, dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, an interferon, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib. An embodiment of the method further comprises an additional therapy, such as tecovirimat. Yet another embodiment of the method includes a second antiviral therapy that is at least one of tecovirimat, 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 valacyclovir.

[0060] One embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 1 mg to about 100 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 4 mg to about 90 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 9 mg to about 18 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 4 mg to about 45 mg. Yet another embodiment of the method includes at least one pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0061] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification, however, the invention, both as to the organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings.

[0062] [Figure 1] 1 shows clinical sign scores over time following H1N1 challenge in mice. [Figure 2A] Figure 2 shows the effect of compound 17ya on weight gain in an H1N1-induced pulmonary inflammation model. Figure 2A shows the effect of compound 17ya on the percentage change in weight several days after H1N1 administration. [Figure 2B] Figure 2B shows the effect of compound 17ya on weight gain in an H1N1-induced pulmonary inflammation model. Figure 2B shows the effect of compound 17ya on body weight (g) several days after H1N1 challenge. [Figure 3A] Figure 3 shows the effect of compound 17ya on BAL (bronchoalveolar lavage) total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3A shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on total cell counts. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; **p<0.01, ***p<0.001 compared to vehicle / H1N1 group. [Figure 3B]Figure 3B shows the effect of compound 17ya on BAL (bronchoalveolar lavage) total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3B shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on neutrophil counts. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; **p<0.01, ***p<0.001 compared to vehicle / H1N1 group. [Figure 3C] Figure 3C shows the effect of compound 17ya on BAL (bronchoalveolar lavage) total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3C shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on mononuclear cells. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; **p<0.01, ***p<0.001 compared to vehicle / H1N1 group. [Figure 3D] Figure 3D shows the effect of compound 17ya on BAL (bronchoalveolar lavage) total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3D shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on lymphocytes. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; **p<0.01, ***p<0.001 compared to vehicle / H1N1 group. [Figure 3E] Figure 3E shows the effect of compound 17ya on BAL (bronchoalveolar lavage) total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3F shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on eosinophils. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; **p<0.01, ***p<0.001 compared to vehicle / H1N1 group. [Figure 4A]Figure 4 shows the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. Figure 4A shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on TNFα (pg / mL). The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; *p<0.05, **p<0.01, ***p<0.001 compared to vehicle / H1N1 challenge group. [Figure 4B] FIG. 4B shows the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. FIG. 4B shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IFN-γ. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; *p<0.05, **p<0.01, ***p<0.001 compared to vehicle / H1N1 challenge group. [Figure 4C] Figure 4C shows the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. Figure 4C shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IL-6. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; *p<0.05, **p<0.01, ***p<0.001 compared to vehicle / H1N1 challenged group. [Figure 4D] Figure 4D shows the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. Figure 4D shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on KC. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; *p<0.05, **p<0.01, ***p<0.001 compared to vehicle / H1N1 challenge group. [Figure 4E]Figure 4E shows the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. Figure 4E shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IP-10. The following abbreviations are used: sem is standard error of the mean; +++p<0.001 compared to vehicle / vehicle group; *p<0.05, **p<0.01, ***p<0.001 compared to vehicle / H1N1 challenge group. [Diagram 5] Figure 1 shows the effect of various concentrations of 17ya hydrochloride on BSC40 cells. BSC40 cells were treated overnight with various concentrations of drugs. The following day, the amount of remaining cells was determined by CellTiterGlo® assay. Results represent the average of three separate wells at each concentration tested and are shown as a percentage of cells treated with DMSO. [Figure 6] Figure 1 shows the effect of 17ya hydrochloride on vaccinia virus replication. Cells were treated with various concentrations of the drug and then infected with a high multiplicity of infection (MOI) of virus. After 24 hours, virus produced in both cells and released into the medium was quantified by plaque assay. Results represent the average of three replicates and are graphed relative to cells treated with DMSO. [Figure 7] Figure 1 shows the effect of 17ya hydrochloride on vaccinia virus spread. Cells were treated with various concentrations of the drug and then infected with a low MOI of virus. After 48 hours, virus produced in the cells was quantified by plaque assay. Results represent the average of three replicates and are graphed relative to cells treated with DMSO. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] Microtubule-based macromolecular intracellular transport is a key aspect of viral replication. With regard to viral infection, expression of viral proteins alters the organization of these microtubule networks to meet their needs for replicating and spreading infectious virions. Not only do microtubules facilitate infection, they are actively manipulated by viruses. Furthermore, cytoskeleton disrupting agents inhibit viral infection. Without being limited by theory, the present invention is based in part on the fact that tubulin interacts with the cytoplasmic domains of Orthomyxoviridae and Poxviridae proteins. Reduction of infectious virus titers can occur by treatment with drugs that cause microtubule depolymerization, primarily because fewer cytoplasmic proteins are present at the assembly site due to impaired cytoplasmic protein microtubule transport, and the process of incorporation of cytoplasmic proteins themselves into virions is tubulin-dependent. Furthermore, disruption of microtubule transport inhibits the release of virions with fewer cytoplasmic proteins and poorly assembled virions out of the cell, reducing their infectivity. Microtubule depolymerizing agents can be effective in treating viral infections by disrupting microtubule transport, which is important for the viral replication cycle.

[0064] The present invention relates to an antiviral therapy against Orthomyxoviridae or Poxviridae virus infections based on the disruption of the cytoskeleton-disrupting activity of the claimed compounds, which block the intracellular microtubule trafficking network. Intending to overcome the shortcomings of the prior art, including but not limited to toxicity, the method is directed to compounds that are specifically activated in cells infected with Orthomyxoviridae or Poxviridae viruses, or preferably in cells targeted by the virus. Without being limited by theory, the present invention is based on the dependence of Orthomyxoviridae or Poxviridae viruses on host cell machinery for successful replication. For example, Orthomyxoviridae or Poxviridae viruses use the host secretory pathway during their replication cycle. Vesicle trafficking on the secretory pathway is mainly mediated by microtubules and corresponding motor proteins. Disruption of microtubules results in reduced replication, reduced amount of infectious particles released, and reduced virus yield. As a result, the amount of virus is reduced, thereby establishing an antiviral therapy. To address the need for novel, rapidly acting antiviral compounds for Orthomyxoviridae and Poxviridae viral infections, the inventors have proposed a method of treating viral infections by administering the compounds described below.

[0065] In certain embodiments, 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 the polymerization of tubulin into microtubules at low nanomolar concentrations. These colchicine binding site inhibitors (CBSIs) have a wide range of structures, but generally have a predominantly indolyl, phenyl, or indazolyl A ring (left-most ring in Formula I), a direct bond or amino linker (X) between the A and B rings, an imidazole, thiazole, or benzimidazole B ring, a predominantly methanone linker (Y) between the B and C rings (right-most ring in Formula I), and a substituted phenyl C ring. The compounds used in the present methods are not substrates of multidrug resistance proteins (MDR), including P-gp, MRP, and BCRP, nor CYP3A4. The compounds used in the present methods also reduce the transcription of βI, βIII, and βIV-tubulin isoforms (Li 2012). Furthermore, the compounds used in the methods of the present invention have good safety as they do not cause significant neurotoxicity, neutropenia, or myelosuppression and are well tolerated.As outlined herein, the CBSIs of the present invention, including compound 17ya, are promising for the treatment of non-variola orthopoxviruses due to their ability to inhibit the microtubule network required for viral cell entry, intracellular trafficking, viral replication, viral release, etc.As outlined herein, the compounds 17ya and CBSIs of the present invention are promising for the treatment of Orthomyxoviridae and Poxviridae virus infections due to their ability to inhibit the microtubule network required for viral cell entry, intracellular trafficking, viral replication, viral release, etc.

[0066] The indirect antiviral agents of the present invention bind to conserved host targets, which also suggests broad antiviral efficacy across diverse viral families, as previously demonstrated with coronaviruses, and now with members of the Orthomyxoviridae and Poxviridae families of pathogenic viruses. The advantage of the indirect antiviral agents in terms of the lack of selective pressure due to their use is effective whether the viral infection is an influenza infection, or other members of the Orthomyxoviridae family, or Mpox or other members of the Poxviridae family, or any other virus that is sensitive to the colchicine binding site inhibitors of the present invention.

[0067] The three classes of FDA-approved influenza antiviral agents are each direct-targeting antivirals because they exert their efficacy by binding to viral proteins (NA, PA, or M2, respectively). By binding to viral target proteins, direct antiviral agents are susceptible to the emergence of resistance based on viral mutations in response to the selective pressure of antiviral use. Indirect antiviral agents, such as the colchicine binding site inhibitors (CBSIs) of tubulin of the present invention, bind to host target proteins whose functions are conserved. Generally, and certainly with the CBSIs of the present invention, mutant host cells are unlikely to survive, and thus indirect antiviral agents are less susceptible to selective pressures that lead to direct antiviral resistance. Furthermore, because indirect antiviral agents competitively bind or otherwise antagonize the efficacy of direct antiviral agents, the use of indirect antiviral agents is not contraindicated with the use of existing antiviral agents.

[0068] Additionally, methods encompassed by the present invention include compounds that can affect microtubule dynamics, such that the compounds can be administered at sub-cytotoxic concentrations as systemic antiviral agents, in stark contrast to colchicine and other tubulin polymerization destabilizing agents that are used as antiviral agents with high systemic toxicity.

[0069] The present invention provides a method for treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I)

[0070] [ka] During the ceremony, A is phenyl, indolyl, or indazolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole, thiazole, or benzimidazole, 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; 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)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; X is a bond, NH, (C1-C4)alkyl, O, or S; Y is a bond, -C=O, -C=S, SO2, SO, or S; m is 1 to 3; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0071] The present invention provides a method for treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (II):

[0072] [ka]

[0073] During the ceremony, B is imidazole, thiazole, or benzimidazole, optionally substituted independently 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; 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)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; X is a bond, NH, or (C1-C4)alkyl; Y is a bond or -C=O; n is 1 to 3; m is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0074] The present invention relates to a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (III):

[0075] [ka]

[0076] During the ceremony, B is imidazole, thiazole, or benzimidazole, optionally substituted independently 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; 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; X is a bond or NH; Y is -C=O; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0077] The present invention relates to a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (IV):

[0078] [ka]

[0079] wherein ring A is 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; B is imidazole or benzimidazole, optionally substituted independently 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; 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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0080] The present invention provides a method of treating an Orthomyxoviridae viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula IV(a):

[0081] [ka]

[0082] B is imidazole or benzimidazole, optionally substituted independently 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; 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, 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; X is a bond or NH; Y is a bond or -C=O; n is 1 to 2; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0083] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (V):

[0084] [ka]

[0085] B is imidazole or benzimidazole, optionally substituted independently 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; 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, 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; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0086] The present invention relates to a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (VI):

[0087] [ka]

[0088] During the ceremony, 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, 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; Q is S or NH; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0089] Preferably, the compound of formula (VI) is a variant in which 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, 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; Q is S, or NH; and n is 1 to 3, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0090] The present invention further encompasses a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of Formula VI of Table 1A below:

[0091] [Table 1]

[0092] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula VII:

[0093] [ka]

[0094] During the ceremony, X is a bond, NH, or S; Q is S or NH; A is a phenyl, indolyl, or indazolyl 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, 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0095] 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).

[0096] Preferably, the compound of formula VII is a variant in which 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, 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, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0097] The present invention provides a method of treating an Orthomyxoviridae viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(a):

[0098] [ka]

[0099] wherein 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0100] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(b):

[0101] [ka]

[0102] wherein 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0103] The present invention provides a method of treating an Orthomyxoviridae viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(c):

[0104] [ka]

[0105] During the ceremony, 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, 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; n is 1 to 4; or a pharma- ceutical acceptable salt, hydrate, polymorph, or isomer thereof to a subject. An example of a compound of formula VII(c) includes, but is not limited to, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0106] The present invention provides a method of treating an Orthomyxoviridae viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(c):

[0107] [ka]

[0108] During the ceremony, R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, F, Cl, Br, I, or CN; n is 1 to 4; or a pharmaceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject. An example of a compound of formula VII(c) includes, but is not limited to, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0109] The invention further includes a method of treating an Orthomyxoviridae viral infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of Formula 17ya.

[0110] [ka]

[0111] The present invention further encompasses a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of the formula of Table 1B below:

[0112] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0113] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIII:

[0114] [ka]

[0115] During the ceremony, Z is O, 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, 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; 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, 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; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0116] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIV:

[0117] [ka]

[0118] During the ceremony, 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, 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; 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, hydroxyl, OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0119] Non-limiting examples of compounds of formula XIV include (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-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12b). (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)-1H-imidazol-4-yl)(3,4,5 -trimethoxyphenyl)methanone (12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12fb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone (12fc), (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 (2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ha), (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb), (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).

[0120] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIVa:

[0121] [ka]

[0122] During the ceremony, 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, 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; 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, 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; R9 is H, linear or branched alkyl, aryl, CH2Ph, benzyl, haloalkyl, aminoalkyl, OCH2Ph, SO2-aryl, -(C=O)-aryl, or OH, and is selected from hydrogen, hydroxyl, aliphatic linear or branched C1-C 10optionally substituted with at least one of hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (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, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C5-C7 cycloalkyl, arylalkyl, and combinations thereof; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0123] Non-limiting examples of compounds of formula XIVa include (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-fluorophenyl)methanone (11jb), (1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12daa), (1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dab), and (4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)methanone (12cba).

[0124] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XV:

[0125] [ka]

[0126] During the ceremony, 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0127] Non-limiting examples of compounds of formula XV include (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-imidazo[pi]-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12b). (2-(4-(dimethylamino)phenyl)-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 (12b), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12c), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12d), (2-(3,4-dimethoxyphenyl)-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 (12ia), 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).

[0128] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XVI:

[0129] [ka]

[0130] During the ceremony, 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, 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; R3 is I, Br, Cl, or F; n is 1 to 4; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0131] Non-limiting examples of compounds of formula XVI include (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- (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gb), and (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb).

[0132] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XVII:

[0133] [ka]

[0134] During the ceremony, 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; 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; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0135] Non-limiting examples of compounds of formula XVII include (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 (12d). (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)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)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12dc), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)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-imidazo (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)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), and (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).

[0136] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XVII, represented by the structure of formula 12fb.

[0137] [ka]

[0138] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XVII, represented by the structure of formula 12cb.

[0139] [ka]

[0140] 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), and 2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

[0141] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIX:

[0142] [ka]

[0143] During the ceremony, W is C=O, C=S, SO2, or S=O; 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, 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; 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, 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; m is 1 to 4; n is 1 to 4; q is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0144] Non-limiting examples of compounds of formula XIX include (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)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11gaa), -(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 (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), and (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gba).

[0145] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XIX, represented by the structure of formula 11cb.

[0146] [ka]

[0147] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XIX, represented by the structure of formula 11fb.

[0148] [ka]

[0149] The present invention relates to a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XX:

[0150] [ka]

[0151] During the ceremony, 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, 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0152] Non-limiting examples of compounds of formula XX include (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)methanone (12f), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12g), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12h), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12i), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ga), (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).

[0153] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XX, represented by the structure of formula 12da.

[0154] [ka]

[0155] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XX, represented by the structure of formula 12fa.

[0156] [ka]

[0157] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXI:

[0158] [ka]

[0159] During the ceremony, A is indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; Q is S or NH; 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, 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; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0160] In one embodiment of this method, the A ring of the compound of formula XXI is 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 include (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 (15xaa), (2-(1H-indol-3-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).

[0161] Particularly preferred methods of treating Orthomyxoviridae virus infections of the present invention include (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 (17ya), In one embodiment, at least one compound of formula XXI is used, which includes (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.

[0162] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXIa:

[0163] [ka]

[0164] During the ceremony, W is C=O, C=S, SO2, or S=O; A is indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; 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, 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; 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, 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; m is 1 to 4; q is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0165] 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) and (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa).

[0166] The present invention provides a method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXII:

[0167] [ka]

[0168] During the ceremony, A is 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0169] In one embodiment of the method, the A ring of the compound of formula XXII is 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).

[0170] The present invention further includes a method of treating an Orthomyxoviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XXI or XXII, represented by the structure of formula 17ya.

[0171] [ka]

[0172] In one embodiment of the method, R4 and R5 of the compound of formula XIII-XVI are hydrogen. Non-limiting examples of the compound of formula XIII-XVI in which R4 and R5 are hydrogen are (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa), (4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab), (3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac), (3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (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).

[0173] In another embodiment of the invention, the invention encompasses a method of treating an Orthomyxoviridae virus infection, the Orthomyxoviridae virus infection being caused by an influenza virus. In another embodiment, the influenza virus is influenza A. In one of these embodiments, the influenza A virus has serotype H1N1. In one of these embodiments, the influenza A virus has serotype H2N2. In one of these embodiments, the influenza A virus has serotype H3N2. In one of these embodiments, the influenza A virus has serotype H5N1. In one of these embodiments, the influenza A virus has serotype H7N7. In one of these embodiments, the influenza A virus has serotype H1N2 and infects pigs and humans. In other of these embodiments, the influenza A virus has at least one of H9N2, H7N2, H7N3, H10N7, or other serotypes known by those of skill in the art.

[0174] In another embodiment, the influenza virus is influenza B. In some embodiments, the influenza B virus is further classified into one of two lineages: B / Yamagata and B / Victoria. In one of these embodiments, the influenza B virus is classified as lineage B / Yamagata. In one of these embodiments, the influenza B virus is classified as lineage B / Victoria. In another embodiment, the influenza virus is influenza D. In another embodiment, the influenza virus is influenza C.

[0175] Further embodiments of the invention include methods of treating subjects with influenza infections at risk for influenza complications. In some embodiments, subjects at risk for influenza complications include unvaccinated infants aged 12-24 months, individuals with chronic lung disease such as asthma, cystic fibrosis, or chronic obstructive pulmonary disease, individuals with hemodynamically significant heart disease, individuals with vascular disease such as sickle cell anemia, individuals with immunosuppressive disorders, individuals with chronic renal dysfunction or cancer, individuals with neuromuscular, seizure, or cognitive disorders that may interfere with the processing of respiratory secretions, adults over 65 years of age, or residents of long-term care facilities. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce mortality. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce mortality. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce morbidity. In another embodiment, the influenza complication is pneumonia. Another embodiment of the invention includes methods of treating subjects with influenza infections to reduce morbidity. Another embodiment of the invention includes a method of treating a subject with an influenza infection to reduce the risk of developing pneumonia. Another embodiment of the invention includes a method of treating a subject with an influenza infection with viral pneumonia. Another embodiment of the invention includes a method of treating a subject with an influenza infection to reduce the risk of complications or mortality in subjects over 65 years of age.

[0176] In yet another embodiment of the present invention, the method further comprises at least one additional therapy. An embodiment of the method further comprises a second antiviral therapy, such as, for example, a neuraminidase inhibitor, an M2 inhibitor, a PA inhibitor, oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), peramivir, rimantadine, amantadine, baloxavir marboxil (Xofluza), ribavirin, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. An embodiment of the method further comprises an agent that modulates the immune system or host cell factors, such as, for example, dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, an interferon, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib. An embodiment of the method further comprises an additional therapy, such as, for example, an NAI or PA inhibitor, and / or dexamethasone or another corticosteroid. Yet another embodiment of the method includes 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 valacyclovir.

[0177] The present invention relates to a method for treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (I):

[0178] [ka]

[0179] During the ceremony, A is phenyl, indolyl, or indazolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole, thiazole, or benzimidazole, 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; 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)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; X is a bond, NH, (C1-C4)alkyl, O, or S; Y is a bond, -C=O, -C=S, SO2, SO, or S; m is 1 to 3; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0180] The present invention relates to a method for treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula (II):

[0181] [ka]

[0182] During the ceremony, B is imidazole, thiazole, or benzimidazole, optionally substituted independently 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; 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)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; X is a bond, NH, or (C1-C4)alkyl; Y is a bond or -C=O; n is 1 to 3; Further included are methods by administering to the subject a formulation comprising m is 1 to 3, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0183] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (III):

[0184] [ka]

[0185] During the ceremony, B is imidazole, thiazole, or benzimidazole, optionally substituted independently 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; 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; X is a bond or NH; Y is -C=O; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0186] The present invention relates to a method for treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (IV):

[0187] [ka]

[0188] During the ceremony, Ring A is indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; B is imidazole or benzimidazole, optionally substituted independently 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; 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; X is a bond or NH; Y is a bond or -C=O; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0189] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula IV(a):

[0190] [ka]

[0191] B is imidazole or benzimidazole, optionally substituted independently 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; 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, 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; X is a bond or NH; Y is a bond or -C=O; n is 1 to 2; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0192] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (V):

[0193] [ka]

[0194] During the ceremony, B is imidazole or benzimidazole, optionally substituted independently 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; 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, 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; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0195] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (VI):

[0196] [ka]

[0197] During the ceremony, 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, 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; Q is S or NH; n is 1 to 3; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0198] Preferably, the compound of formula (VI) is a variant in which 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, 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; Q is S, or NH; and N is 1-3, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0199] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula VI of Table 1A below:

[0200] [Table 3]

[0201] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula VII:

[0202] [ka]

[0203] During the ceremony, X is a bond, NH, or S; Q is S or NH; A is a phenyl, indolyl, or indazolyl 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, 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0204] 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).

[0205] Preferably, the compound of formula VII is a variant in which 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, 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, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof.

[0206] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(a):

[0207] [ka]

[0208] wherein 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0209] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula VII(b):

[0210] [ka]

[0211] During the ceremony, 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0212] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula VII(c):

[0213] [ka]

[0214] During the ceremony, 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, 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; n is 1 to 4; or a pharmaceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject. An example of a compound of formula VII(c) includes, but is not limited to, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0215] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula VII(c):

[0216] [ka]

[0217] During the ceremony, R4 and R5 are independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, O-(C1-C4)alkyl, O-(C1-C4)haloalkyl, F, Cl, Br, I, and CN; n is 1 to 4; or a pharma- ceutical acceptable salt, hydrate, polymorph, or isomer thereof to a subject. An example of a compound of formula VII(c) includes, but is not limited to, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya).

[0218] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula 17ya.

[0219] [ka]

[0220] The present invention further encompasses a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of the formula of Table 1B above:

[0221] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIII:

[0222] [ka]

[0223] During the ceremony, Z is O, 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, 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; 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, 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; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0224] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIV:

[0225] [ka]

[0226] During the ceremony, 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, 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; 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, hydroxyl, OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(C1-C4)alkyl, C(O)H, -C(O)NH2, or NO2; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0227] Non-limiting examples of compounds of formula XIV include (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-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12b). (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)-1H-imidazol-4-yl)(3,4,5 -trimethoxyphenyl)methanone (12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12fb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone (12fc), (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 (2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ha), (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb), (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).

[0228] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIVa:

[0229] [ka]

[0230] During the ceremony, 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, 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; 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, 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; R9 is H, linear or branched alkyl, aryl, CH2Ph, benzyl, haloalkyl, aminoalkyl, OCH2Ph, SO2-aryl, -(C=O)-aryl, or OH, and is selected from hydrogen, hydroxyl, aliphatic linear or branched C1-C 10optionally substituted with at least one of hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo (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, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C5-C7 cycloalkyl, arylalkyl, and combinations thereof; m is an integer from 1 to 4; n is an integer from 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0231] Non-limiting examples of compounds of formula XIVa include (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-fluorophenyl)methanone (11jb), (1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12daa), (1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12dab), and (4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)methanone (12cba).

[0232] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XV:

[0233] [ka]

[0234] During the ceremony, 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, 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; n is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0235] Non-limiting examples of compounds of formula XV include (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-imidazo[pi]-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12b). (2-(4-(dimethylamino)phenyl)-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 (12b), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12c), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12d), (2-(3,4-dimethoxyphenyl)-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 (12ia), 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).

[0236] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XVI:

[0237] [ka]

[0238] During the ceremony, 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, 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; R3 is I, Br, Cl, or F; n is 1 to 4; or a formulation comprising a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0239] Non-limiting examples of compounds of formula XVI include (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- (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gb), and (2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12jb).

[0240] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XVII:

[0241] [ka]

[0242] During the ceremony, 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; 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; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0243] Non-limiting examples of compounds of formula XVII include (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 (12d). (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)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)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12dc), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)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-imidazo (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)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), and (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12pa).

[0244] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XVII, represented by the structure of formula 12fb.

[0245] [ka]

[0246] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XVII, represented by the structure of formula 12cb.

[0247] [ka]

[0248] 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), and 2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

[0249] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XIX:

[0250] [ka]

[0251] During the ceremony, W is C=O, C=S, SO2, or S=O; 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, 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; 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, 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; m is 1 to 4; n is 1 to 4; q is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0252] Non-limiting examples of compounds of formula XIX include (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)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11gaa), -(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 (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), and (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gba).

[0253] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XIX, represented by the structure of formula 11cb.

[0254] [ka]

[0255] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XIX, represented by the structure of formula 11fb.

[0256] [ka]

[0257] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XX:

[0258] [ka]

[0259] During the ceremony, 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, 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0260] Non-limiting examples of compounds of formula XX include (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)methanone (12f), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12g), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12h), (2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12i), (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12ga), (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).

[0261] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XX, represented by the structure of formula 12da.

[0262] [ka]

[0263] The present invention further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XX, represented by the structure of formula 12fa.

[0264] [ka]

[0265] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXI:

[0266] [ka]

[0267] During the ceremony, A is indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; Q is S or NH; 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, 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; m is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0268] In one embodiment of this method, the A ring of the compound of formula XXI is 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 include (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 (15xaa), (2-(1H-indol-3-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).

[0269] Particularly preferred methods of treating Poxviridae virus infections of the present invention include (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 (17ya), (2-(1H-indol-4-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17ya), In one embodiment, at least one compound of formula XXI is used, which includes (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.

[0270] The present invention provides a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXIa:

[0271] [ka]

[0272] During the ceremony, W is C=O, C=S, SO2, or S=O; A is indolyl, optionally substituted with at least one of (C-C)alkyl, halo(C-C)alkyl, O-(C-C)alkyl, O-(C-C)haloalkyl, (C-C)alkylamino, amino(C-C)alkyl, F, Cl, Br, I, CN, -CHCN, NH, hydroxyl, OC(O)CF, -OCHPh, -NHCO-(C-C)alkyl, COOH, -C(O)Ph, C(O)O-(C-C)alkyl, C(O)H, -C(O)NH, or NO; 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, 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; 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, 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; m is 1 to 4; q is 1 to 4; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0273] 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) and (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa).

[0274] The present invention relates to a method of treating a Poxviridae virus infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula XXII:

[0275] [ka]

[0276] During the ceremony, A is 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; or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof to a subject.

[0277] In one embodiment of the method, the A ring of the compound of formula XXII is 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 further includes a method of treating a Poxviridae virus infection in a subject in need thereof by administering to the subject a formulation comprising a therapeutically effective amount of a compound of formula XXI or XXII, represented by the structure of formula 17ya.

[0279] [ka]

[0280] In one embodiment of the method, R4 and R5 of the compound of formula XIII-XVI are hydrogen. Non-limiting examples of the compound of formula XIII-XVI in which R4 and R5 are hydrogen are (2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa), (4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab), (3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac), (3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (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] Yet another embodiment of the present invention encompasses a method of treating a Poxviridae viral infection, wherein the viral infection is caused by an Orthopoxvirus. In one of these embodiments, the Orthopoxvirus is smallpox. In one of these embodiments, the Orthopoxvirus is monkeypox. In one of these embodiments, the Orthopoxvirus is vaccinia virus. In one of these embodiments, the Orthopoxvirus is any one of cowpox virus, horsepox virus, camelpox virus, affeta virus, and alaskapox, or other Orthopoxvirus known to one of skill in the art.

[0282] Further embodiments of the present invention include methods of treating symptoms of Poxviridae virus infection, such as, for example, encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymphadenopathy, widespread skin rash, and the severity of septic syndrome.

[0283] In yet another embodiment of the present invention, the method further comprises at least one additional therapy. An embodiment of the method further comprises a second antiviral therapy, such as, for example, a neuraminidase inhibitor, an M2 inhibitor, a PA inhibitor, oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), peramivir, rimantadine, amantadine, baloxavir marboxil (Xofluza), ribavirin, tecovirimat, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. An embodiment of the method further comprises an agent that modulates the immune system or host cell factors, such as, for example, dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, an interferon, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib. An embodiment of the method further comprises an additional therapy, such as tecovirimat. Yet another embodiment of the method includes a second antiviral therapy that is at least one of tecovirimat, 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 valacyclovir.

[0284] One embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 1 mg to about 100 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 4 mg to about 90 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 9 mg to about 18 mg. Another embodiment of the present invention includes a method in which a compound of the present invention is administered in an amount of about 4 mg to about 45 mg. Yet another embodiment of the method includes at least one pharma- ceutically acceptable excipient.

[0285] In one embodiment of this method, the compound of the invention is the pure (E)-isomer. In another embodiment, the compound of the invention is the pure (Z)-isomer. In another embodiment, the compound of the invention is a mixture of (E) and (Z) isomers. In one embodiment, the compound of the invention is the pure (R)-isomer. In another embodiment, the compound of the invention is the pure (S)-isomer. In another embodiment, the compound of the invention is a mixture of (R) and (S) isomers.

[0286] The compounds of the present invention can also exist in the form of racemic mixtures containing substantially equal amounts of stereoisomers. In another embodiment, the compounds of the present invention can be prepared or otherwise isolated using known procedures to obtain a stereoisomer that is substantially free of its corresponding stereoisomer (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 purity of a stereoisomer can be at least about 98% pure, more preferably at least about 99% pure.

[0287] The compounds of the present invention may also be in the form of hydrates, which means that the compounds further contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0288] The present invention includes "pharmaceutically acceptable salts" of the compounds used in the methods of the present invention, which may be produced by reaction of the compounds of the present invention with an acid or base. Certain compounds, particularly those having acidic or basic groups, may 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 the free base or free acid, which are not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

[0289] Suitable pharma- ceutically acceptable salts of the amines of the compounds used in the method of the present invention may be prepared from inorganic or organic acids. In one embodiment, examples of inorganic salts of amines are hydrogen sulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochloride, 2-hydroxyethylsulfonate (hydroxyethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfonate, halogen-substituted alkylsulfonate, halogen-substituted arylsulfonate), sulfonate, and thiocyanate.

[0290] Exemplary organic salts of amines may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxyl, and sulfone classes of organic acids, examples of which include acetate, arginine, aspartate, ascorbate, adipate, anthranilate, algenate, alkanecarboxylate, substituted alkanecarboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, bitartrate, citrate, camphorate, camphorsulfonate, cyclohexylsulfamate, cyclopentanepropionate, Calcium edetate, camsylate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, dihydrochloride, decanoate, enanthate, ethanesulfonate, edetate, edisylate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, glucorate, glucoheptanoate, glycerophosphate, gluceptate, glycolylarsanilate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate Acid salts, hydroxycarboxylic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorides, lactates, lactobionates, laurates, malates, maleates, methylene bis(beta-oxynaphthoates), malonates, mandelates, mesylates, methanesulfonates, methyl bromides, methyl nitrates, methanesulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N-methylglucamines, oxalates, Octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, phenylacetate, pectinate, phenylpropionate, palmitate, pantothenate, polygalacturonate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, acetate, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, theoclate, trihaloacetate, triethiodide,These include, but are not limited to, tricarboxylates, undecanoates, and valerates.

[0291] Examples of inorganic salts of carboxylic acids or hydroxyls may be selected from alkali metals including ammonium, lithium, sodium, potassium, cesium, alkaline earth metals including calcium, magnesium, aluminum, zinc, barium, choline, quaternary ammonium.

[0292] Examples of organic salts of carboxylic acids or hydroxyls may be selected from arginine, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathine, t-butylamine, betamin (N-benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, meglamine, N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, nicotinamide, organic amines, ornithine, pyridine, picoline, piperazine, procaine, tris(hydroxymethyl)methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine), and urea.

[0293] Exemplary salts include, but are not limited to, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, borate, nitrate, perchlorate, phosphate, sulfate, acetate, citrate, maleate, malate, or mesylate. Preferred salts include hydrofluoride, hydrochloride, hydrobromide, hydroiodide, acetate, citrate, maleate, or mesylate. More preferred salts include hydrochloride, acetate, or maleate.

[0294] The salts may be formed by conventional means, such as reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water, under vacuum, or by lyophilization, or by exchanging the existing salt ion with another ion or with a suitable ion exchange resin, which is removed.

[0295] The compounds used in the methods of the present invention are synthesized using the methodology described in U.S. Patent 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.

[0296] Pharmaceutical Compositions

[0297] The method of the present invention includes the administration of a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and at least one compound described herein. Typically, the pharmaceutical composition may include the compound or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any suitable adjuvant, carrier, excipient, flavoring agent, or stabilizer that can be used in pharmaceutical preparations in either solid or liquid form. Such forms include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0298] The amount of compound used in the method and the dosage regimen for treating a condition will depend on a variety of factors, including the age, weight, sex, medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound used. Thus, dosage regimens can vary widely, but can be routinely determined using standard methods.

[0299] Typically, the composition contains about 0.01 to 99 percent, preferably about 20 to 75 percent, of the active compound, together with the adjuvants, carriers, and / or excipients. While individual needs may vary, the determination of the optimal range of effective amounts of each component is within the skill of the art. Typical daily dosages include about 2 mg to about 200 mg, or about 1 mg to about 100 mg, or about 0.1 mg to about 1000 mg, with preferred daily dosages including about 4 mg to about 90 mg, and most preferred dosages including about 4 mg to about 80 mg of the compound. Other preferred dosages include amounts of about 4 mg to about 45 mg, or 9 mg to about 18 mg of the antiviral compound. Alternatively, dosages of about 0.01 to 150 mg / kg body weight, preferably about 1 mg to about 100 mg / kg body weight, more preferably about 2 to 50 mg / kg body weight may be appropriate. The daily dosage may be administered in 1 to 4 doses per day. Treatment regimens for administration of the compounds of the present invention can also be readily determined by those skilled in the art, i.e., administration frequency and dose size can be established by routine optimization, preferably while minimizing any side effects.

[0300] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, predisposition of the patient to the disease, condition or symptom, and the judgment of the treating physician.

[0301] Once the condition of the subject is improved, a maintenance dose of compound, composition or preparation can be administered as necessary.Then, the dosage or frequency of administration, or both, can be reduced according to symptoms to a level at which the improved condition is maintained when the condition is reduced to a desired level.However, the subject may require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0302] The methods may include "additional therapeutic agents" including, but not limited to, immunotherapy (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytic agents, antimuscarinics, anti-leukotriene agents, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antibacterial and antiviral agents (e.g., ribavirin and amantadine). The methods of the invention may also be used in combination with gene replacement therapy.

[0303] The method of the present invention can be administered in combination with other antiviral therapies, such as combination therapy, to treat infections or diseases associated with viral infections. Suitable antiviral agents contemplated for use in combination with the method of the present invention can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents. 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], beta-L-FD4 (also called beta-L-D4C, also called beta-L-2',3'-dicreoxy-5-fluoro-cytidine), DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane), and rhodenosine (FddA). Exemplary 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 (+)-calanolide A (NSC-675451) and B. Exemplary suitable proteases include Enzyme inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0304] Other antiviral agents include, but are not limited to, neuraminidase inhibitors, hemagglutinin inhibitors, hydroxychloroquine, azithromycin, or agents that modulate immune system or host cell factors. Examples include, but are not limited to, 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, and valacyclovir. An embodiment of the method further comprises additional therapy, such as remdesivir and / or dexamethasone. An embodiment of the method further comprises additional therapy, such as casirivimab + imdevimab. Embodiments of this method further include an additional therapy, such as bamlanivimab.

[0305] The method of treating an Orthomyxoviridae virus infection or a Poxviridae virus 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. The other therapies included in the method are drugs that modulate immune system or host cell factors, 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 casirivimab + imdevimab, bamlanivimab, or bamlanivimab + etesevimab. The method may further include tocilizumab or baricitinib. The method may further include an additional therapy, such as high titer convalescent plasma, IVIG, casirivimab + imdevimab, bamlanivimab, or bamlanivimab + etesevimab, etc. The method may include 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 valacyclovir. The method may include a second line therapy that is at least one of vitamin C or D, zinc, famotidine, ivermectin, or an angiotensin-converting enzyme inhibitor (ACEI), or an angiotensin receptor binding (ARB) agent.

[0306] The solid unit dosage form can be of conventional type. The solid form can be, for example, a capsule of the usual gelatin type that contains the compound and a carrier. The carrier includes, but is not limited to, lubricants and inert fillers, such as castor oil and similar substances, lactose, sucrose, or cornstarch. The preparation is tableted with conventional tablet bases such as lactose, sucrose, or cornstarch combined with binders such as acacia, cornstarch, or gelatin, disintegrants such as cornstarch, potato starch, or alginic acid, and lubricants such as stearic acid or magnesium stearate.

[0307] Tablets, capsules and the like may contain binders such as tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0308] The present invention can be mixed with a liquid carrier such as fatty oil, castor oil, or other similar oil at low, room, or high temperatures to produce tablets, capsules, and the like.

[0309] 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. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0310] For oral therapeutic administration, the formulations may contain excipients and may be used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be from about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Typical compositions according to the invention are prepared so that an oral dosage unit contains from about 1 mg to 100 mg of active compound, with preferred oral compositions containing from 1 mg to 50 mg of active compound.

[0311] The active compounds of the present invention may be administered orally, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in a hard or soft shell capsule, or they may be compressed into tablets, or they may be directly incorporated into the food of the diet.The preferred formulations are oral formulations.

[0312] Suitable pharmaceutical forms for injection use include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and fluid to the extent that easy syringability exists.The form must be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0313] The compounds or pharmaceutical compositions of the present invention may also be administered in injectable doses by solution or suspension of these substances in a physiologically acceptable diluent with pharmaceutical adjuvants, carriers, or excipients.Such adjuvants, carriers, and / or excipients include, but are not limited to, sterile liquids such as water and oils, with or without the addition of surfactants and other pharma-ceutical and physiologically acceptable components.Exemplary oils are oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, or mineral oil.In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

[0314] The preparations may also be administered parenterally. The solutions or suspensions of these preparations may be prepared in water, suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oil. Exemplary oils are oils of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injection solutions. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0315] For use as an aerosol, the formulation in solution or suspension may be packaged in a pressurized aerosol container with a suitable propellant, e.g., a hydrocarbon propellant such as propane, butane, or isobutane, with a conventional adjuvant. The formulation may also be administered in a non-pressurized form, such as in a nebulizer or atomizer.

[0316] When administering the formulation in the method of the present invention, the formulation can be administered systemically or continuously.Accordingly, administration can be achieved by any method that is effective for delivering the compound or pharmaceutical composition to the site of viral infection.Exemplary administration modes include, but are not limited to, administering the compound or composition orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intranasally, intracavity or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes such as nose, throat, and bronchus.

[0317] biological activity

[0318] The present invention relates to methods for treating Orthomyxoviridae and Poxviridae infections, and antiviral formulations using the compounds and formulations described above. The compounds and formulations are useful in treating Orthomyxoviridae and Poxviridae infections by disrupting microtubule polymerization. The formulations may optionally contain additional active ingredients, the activity of which is useful in treating Orthomyxoviridae and Poxviridae infections, treating adverse effects associated with the compound or dose of a particular formulation, and / or delaying or extending the release of the ingredients.

[0319] Specifically, the method of the present invention may be used to treat infections caused by viruses including those of the Orthomyxoviridae and Poxviridae superfamilies. The method of the present invention may also be used to treat infections caused by viruses including influenza viruses including, but not limited to, influenza A virus (IAV) and influenza B virus (IBV). IAV viruses are known to have antigenic drift, a mutation process in which IAVs present as having different serotypes that change from time to time. Serotypes represent antigenically distinct versions of the hemagglutinin (H) and neuraminidase (N) viral surface proteins, which are important for vaccine preparation and correlate with IAV infection behavior. Often, a particular seasonal epidemic is composed primarily of one particular serotype, or only a few serotypes. Preferably, the method of the present invention treats viral infections caused by H1N1.

[0320] The methods of the invention may be used to treat infections caused by orthomyxoviruses, such as IAV serotypes H1N1, H2N2, H5N1, H3N2, and other seasonal variants from this family of influenza viruses. In one of these embodiments, the influenza A virus has serotype H1N1. In one of these embodiments, the influenza A virus has serotype H2N2. In one of these embodiments, the influenza A virus has serotype H3N2. In one of these embodiments, the influenza A virus has serotype H5N1. In one of these embodiments, the influenza A virus has serotype H7N7. In one of these embodiments, the influenza A virus has serotype H7N9. In one of these embodiments, the influenza A virus has serotype H1N2. In other of these embodiments, the influenza A virus has at least one of H9N2, H7N2, H7N3, H10N7, or other serotypes known by those of skill in the art.

[0321] The methods of the invention may also be used to treat infections caused by influenza (influenza) viruses, including influenza A, influenza B, influenza D, or influenza C. Preferably, the methods of the invention may be used to treat influenza B infections. In some embodiments, the influenza B virus is further classified into one of two lineages: B / Yamagata and B / Victoria. In one of these embodiments, the influenza B virus is classified as lineage B / Yamagata. In one of these embodiments, the influenza B virus is classified as lineage B / Victoria. In another embodiment, the influenza virus is influenza D. In another embodiment, the influenza virus is influenza C.

[0322] The method of the present invention can be used to treat subjects with seasonal influenza virus infection.For example, influenza epidemics are typical annual events, and sometimes pandemic.The method of the present invention can also be used to treat subjects with severe influenza virus infection at risk of complications.The method of the present invention can also be used to treat influenza infection complicated with pneumonia.

[0323] The methods of the invention may be used to prevent or treat viral pneumonia caused by influenza infection in patients at risk for complications. The methods of the invention may be used to prevent or treat influenza complications in high-risk influenza patients, such as, for example, unvaccinated infants aged 12-24 months, individuals with chronic lung disease, such as asthma, cystic fibrosis, or chronic obstructive pulmonary disease, individuals with hemodynamically significant heart disease, individuals with vascular disease, such as sickle cell anemia, individuals with immunosuppressive disorders, individuals with chronic renal dysfunction or cancer, individuals with neuromuscular, seizure, or cognitive disorders that may interfere with the processing of respiratory secretions, adults over 65 years of age, or residents of long-term care facilities.

[0324] Treating a subject with an influenza infection may reduce mortality. The methods of the invention include methods of reducing mortality by treating a subject with an influenza infection. The methods of the invention further include treating a subject with an influenza infection at risk for complications that increase mortality. Another embodiment of the invention includes methods of reducing morbidity by treating a subject with an influenza infection. Another embodiment of the invention includes methods of reducing morbidity by treating a subject with an influenza infection at risk for pneumonia. Another embodiment of the invention includes methods of reducing the risk of developing pneumonia by treating a subject with an influenza infection. Another embodiment of the invention includes methods of reducing the risk of developing pneumonia and mortality by treating a subject with an influenza infection with risk factors for developing complications of the infection. Another embodiment of the invention includes methods of treating a subject with an influenza infection with viral pneumonia. Another embodiment of the invention includes methods of reducing mortality or complications in subjects over 65 years of age by treating a subject with an influenza infection. Another embodiment of the invention encompasses a method of treating a subject with an influenza infection to reduce mortality or respiratory failure when administered in combination with influenza standard of care antivirals such as neuraminidase inhibitors, PA inhibitors, amantadine, rimantadine, ribavirin, corticosteroids, etc. Another embodiment of the invention encompasses a method of treating a subject with an influenza infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) to reduce mortality or respiratory failure.Another embodiment of the invention encompasses a method of treating a subject having an influenza infection at high risk for acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) thereby reducing mortality or respiratory failure when administered in combination with Rapivab (peramivir), Relenza (zanamivir), Tamiflu (oseltamivir phosphate, also available generically), Xofluza (baloxavir marboxil), amantadine, rimantadine, ribavirin, corticosteroids, and / or antibiotics.

[0325] The method of the present invention can be used to treat infections caused by enveloped double-stranded DNA viruses from the Poxviridae family. The method of the present invention can also be used prophylactically to prevent infections in subjects who have come into contact with a subject infected with a virus from the Poxviridae family. Preferably, the method of the present invention treats viral infections caused by viruses belonging to the Orthopoxvirus genus of the Poxviridae family. Diseases associated with the Orthopoxvirus genus include smallpox, cowpox, horsepox, camelpox, and monkeypox. Preferably, the method of the present invention can be used to treat monkeypox (Mpox). The method of the present invention can be used to treat smallpox viruses, such as smallpox, vaccinia virus, or non-smallpox orthopoxviruses.

[0326] The methods of the invention may be used to prevent or treat symptoms of Poxviridae virus infection, such as, for example, encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymphadenopathy, widespread skin rash, and septic syndrome.

[0327] In yet another embodiment of the present invention, the method further comprises at least one additional therapy. An embodiment of the method further comprises a second antiviral therapy, such as, for example, a neuraminidase inhibitor, an M2 inhibitor, a PA inhibitor, oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), peramivir, rimantadine, amantadine, baloxavir marboxil (Xofluza), ribavirin, tecovirimat, remdesivir, hydroxychloroquine, azithromycin, or a hemagglutinin inhibitor. An embodiment of the method further comprises an agent that modulates the immune system or host cell factors, such as, for example, dexamethasone or another corticosteroid, an IL-6 inhibitor such as tocilizumab, an interferon, an IL-1 inhibitor, or a kinase inhibitor such as baricitinib. An embodiment of the method further comprises an additional therapy, such as tecovirimat. Yet another embodiment of the method includes a second antiviral therapy that is at least one of tecovirimat, 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 valacyclovir.

[0328] The present invention encompasses a method of treating Orthomyxoviridae and Poxviridae virus infections in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a formulation comprising a compound described herein, or a pharma-ceutically acceptable salt, hydrate, polymorph, or isomer thereof, to treat the viral infection. The method comprises 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 certain methods, the method comprises compound 17ya.

[0329] As used herein, the term "subject" or "patient" refers to any mammalian subject, including, but not limited to, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, bats, and other rodents, unless otherwise specified. In particular, a subject may be human, or may be exclusively male or exclusively female.

[0330] When administering the compounds and formulations described herein, the formulations can be administered systemically or directly to the specific site where the viral infection is present. Thus, administration can be accomplished by any method effective to deliver the compound or pharmaceutical composition to the site of viral infection. Methods of administration include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavity or intravesical infusion, intraocular, intraarterial, intralesional, or application to mucous membranes. Mucous membranes include those found in the nose, throat, and / or bronchi, among others. Preferably, the formulations are administered orally. Administration can be simultaneous or sequential with additional antiviral compounds or formulations, or treatments used to address side effects associated with the compounds or dosages.

[0331] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention, but they should in no way be construed as limiting the broad scope of the invention. EXAMPLES

[0332] The examples set forth below are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0333] Materials and Methods

[0334] In vitro tubulin polymerization assay. Bovine brain tubulin (0.4 mg, >97% purity) (Cytoskeleton, Denver, CO) was mixed with 10 μM of test compound and incubated in 100 μL of common 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 minute for 20 minutes by a SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, VT). The spectrophotometer was set at 37° C. for tubulin polymerization. Compounds of the present invention have demonstrated tubulin inhibition in this assay and other assays known to those skilled in the art.

[0335] Example 1 Compound 17ya significantly reduced key cytokines involved in acute respiratory distress syndrome (ARDS) in a mouse model of H1N1 influenza-induced lung inflammation

[0336] We have completed an animal study aimed at evaluating the efficacy of compound 17ya in influenza H1N1 lung inflammation mouse ARDS model.Details of materials and methods are reported in Example 2 below, as well as the results and statistical significance, while this summary adds some further analysis of these results.2 hours before starting treatment, mice were administered H1N1 or saline via intranasal route to induce viral infection and inflammatory response in the lungs, followed by daily treatment with saline, compound 17ya, dexamethasone (anti-inflammatory control), or oseltamivir (direct antiviral control).

[0337] Clinical signs and longitudinal pulmonary function (Penh) were measured, bronchoalveolar lavage fluid (BAL) was collected from the lungs to determine both the amount of inflammatory cells and the levels of cytokines, and lung histopathology was performed to assess inflammation.

[0338] Preclinical study highlights:

[0339] Compound 17ya treatment resulted in a statistically significant reduction in the total number of inflammatory cells in the BAL fluid (-53%) (p<0.01), including a statistically significant reduction in both innate and adaptive immune cells. Additionally, compound 17ya treatment demonstrated a statistically significant reduction in key cytokines and chemokines in the BAL fluid that are part of the cytokine storm that causes acute lung injury: keratinocyte-derived chemokine (KC) (-38%; p<0.01), interleukin-6 (IL-6) (-74%; p<0.001), TNF-α (-36%; p<0.05), interferon-γ (INF-γ) (-84%; p<0.001), and CXCL-10 (-60%; p<0.001). In contrast, dexamethasone treatment did not demonstrate a statistically significant reduction in the total number of inflammatory cells in the BAL fluid. Dexamethasone also had a different effect than compound 17ya on cytokine production in BAL fluid: dexamethasone treatment produced statistically significant reductions in IL-6 (-52%; p<0.01) and INF-γ (-81%; p<0.001), but no statistically significant changes in KC (+20%), TNF-α (-13%), or CXCL-10 (-8%).

[0340] Clinically, compound 17ya treatment resulted in a reduction in the severity of pulmonary inflammation (by histopathology) and a dose-dependent improvement in pulmonary function (lower Penh versus untreated H1N1 infection). Oral administration of 2 mg / kg compound 17ya resulted in a reduction in clinical signs and weight loss associated with H1N1 infection. From day 11 onwards, 4 of 7 animals showed no clinical signs associated with induction of H1N1 infection. Meanwhile, oral administration of 1 mg / kg dexamethasone did not result in a reduction in clinical signs or weight loss associated with H1N1 infection.

[0341] These data suggest that compound 17ya may be an effective treatment for hospitalized influenza patients at high risk for ARDS and death. The morbidity and mortality of hospitalized influenza-ARDS patients is similar to COVID-19-associated ARDS, representing a high unmet need with very limited treatment options. According to the CDC, the estimated burden of influenza in the United States was up to 630,000 hospitalizations and up to 55,000 deaths in the past six months. Therefore, Veru is planning a double-blind, randomized, placebo-controlled Phase 3 clinical trial to evaluate compound 17ya in hospitalized adult influenza patients at high risk for ARDS.

[0342] "Virus-induced acute respiratory distress syndrome is the leading cause of death in patients with COVID-19 and influenza and continues to be an unmet medical need worldwide," said Mitchell Steiner, MD, Chairman, President and CEO of Veru. Compound 17ya, as a host-targeted antiviral and broad-spectrum anti-inflammatory agent, has the potential to address the two most common causes of virus-induced ARDS: COVID-19 and influenza. Based on the preclinical data highlighted here, we plan to initiate a Phase 3 study of compound 17ya in influenza patients who are at high risk for ARDS and increased likelihood of death.

[0343] Example 2 Evaluation of compound 17ya using influenza model

[0344] This study evaluated the efficacy of compound 17ya in a mouse H1N1 lung inflammation model. Intranasal administration of H1N1 successfully induced lung inflammation in female Balb / c mice. Vehicle, compound 17ya, dexamethasone, and oseltamivir were administered orally for comparison. Table 2 shows the treatment groups and doses.

[0345] [Table 4]

[0346] Groups 1 and 2 were administered a vehicle of 5% DMSO in PBS. Groups 3 and 4 were administered either 0.22 mg / mL (Group 2) or 0.88 mg / mL (Group 3) of Compound 17ya HCl salt in 5% DMSO in PBS. Group 5 was administered dexamethasone (0.1 mg / mL) in 0.5% HPMC / 0.1% Tween 80 in distilled water. Group 6 was administered oseltamivir (3 mg / mL) in water for injection.

[0347] Female Balb / C mice were acclimated for 14 days prior to day 0, where they were randomized into test groups such that the mean weights of the groups were approximately equal. Mice were fed a Teklad 2014C pellet diet, which was unrestricted except during study procedures.

[0348] On day 0, under reversible anesthesia (isoflurane / oxygen mixture), animals were inoculated intranasally with PBS (group 1) or H1N1 (PR8) (groups 2-6). All animals (1-90) received a fixed volume of 50 μL. From day 1, all animals were weighed daily until termination, their temperature was assessed twice daily, and all animals in cohort 2 (49-90) had pulmonary function assessed by non-invasive whole-body plethysmography for minute ventilation (MV), tidal volume (TV), respiratory rate (RR), and enhanced pause (penh).

[0349] On day 5, animals 1-48 were terminated and bronchoalveolar lavage (BAL) samples were collected. From the samples, cell pellets were formed and then resuspended in 0.5 mL PBS and stored on wet ice before total and differential cell counts were performed using an XT 2000iV (Sysmex UK Ltd). Total and differential cell counts (including neutrophils, lymphocytes, eosinophils, and mononuclear cells (monocytes and macrophages)) were reported as cell numbers per animal. Lungs were then excised and weighed. Whole lungs were then infused with 10% neutral buffered formalin for a minimum of 24 hours and tissues were processed into paraffin blocks. The levels of cytokines interferon-γ (IFN-γ), interleukin-6 (IL-6), interferon-gamma-inducible protein of 10 kDa (IP-10), chemokine receptor CXCR2 ligand (KC; a neutrophil attractant), and tumor necrosis factor-alpha (TNF-α) in BAL fluid were analyzed in singlets using a multiplex system (ELISA).

[0350] Starting on day -1, animals 49-90 were assessed for weight, temperature, and clinical signs. On day 14, any surviving animals were assessed for clinical signs (including weight and temperature) in the morning and culled and discarded without further necropsy.

[0351] For data evaluation, weight, temperature, and clinical observations were reported. For longitudinal pulmonary function, respiratory rate (PR), tidal volume (TV), minute ventilation (MV), and penh (PENH) were reported from days 1, 3, and 5. Respiratory parameters were reported at 0, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 min after the start of recording.

[0352] Total and differential cell counts of BAL fluid (BALF) were reported. Cells were classified as neutrophils, lymphocytes, eosinophils, and mononuclear cells (including monocytes and macrophages). The number of each cell type was recorded as million / animal. BALF cytokine levels were expressed as pg / mL.

[0353] Statistical Analysis: Body temperature, longitudinal lung function parameters (RR, TV, MV, and PENH), BAL total and differential cell counts, BAL cytokines (IFN-γ, IL-6, IP-10, KC, and TNF-α), and wet lung weights were analyzed separately for each parameter and time point using one-way analysis of variance (ANOVA). Rank transformation was applied to BAL total and differential cell counts and BAL cytokine data before analysis. Group comparisons were made with group 2 (infected but treated with vehicle) for groups 1, 3, 4, 5, and 6. For BAL total and differential cell counts, BAL cytokines, and wet lung weights, these tests were interpreted with a one-sided risk of a decreased response from group 2 (note, a decreased response in group 1 from group 2 is equivalent to an increased response in group 2 from group 1). For all other parameters, these tests were interpreted with a two-sided risk.

[0354] result

[0355] Clinical Signs. Intranasal administration of H1N1 resulted in adverse clinical signs, which were observed beginning in the afternoon of the second day. These increased in incidence and severity throughout the experiment. Clinical signs included rapid breathing, piloerection, and hunched posture. No clinical signs were observed in the vehicle negative control group. Clinical sign scores following H1N1 administration are shown in Figure 1 for each treatment group.

[0356] Oral administration of compound 17ya at 2 mg / kg once a day resulted in attenuation of clinical signs associated with H1N1 infection, and only mild clinical signs were observed in only 3 out of 7 animals starting from day 2 and day 11. Once-daily oral administration of compound 17ya at 8 mg / kg resulted in exacerbation of clinical signs associated with H1N1 infection starting from day 10. One out of 7 animals in this group had to be culled for welfare reasons on day 12. Once-daily oral administration of 1 mg / kg of dexamethasone did not result in attenuation of clinical signs associated with H1N1 infection. Two out of 7 animals in this group had to be culled for welfare reasons on day 11. Twice-daily oral administration of 30 mg / kg of oseltamivir resulted in attenuation of clinical signs associated with H1N1 infection, and only mild clinical signs were observed (Figure 1).

[0357] Weight gain. Intranasal administration of H1N1 resulted in a statistically significantly lower (<p0.01) weight gain from day 7 to day 11 compared to the vehicle control group. Once-daily oral administration of compound 17ya at 2 mg / kg resulted in a statistically significantly higher (<p0.05) weight gain from day 8 to day 10 compared to the H1N1 vehicle control group. Once-daily oral administration of compound 17ya at 8 mg / kg resulted in a statistically significantly lower (<p0.05) weight on day 11 compared to the H1N1 vehicle control group. Once-daily oral administration of 1 mg / kg of dexamethasone resulted in a statistically significantly lower (<p0.05) weight on day 11 compared to the H1N1 vehicle control group. Twice-daily oral administration of 30 mg / kg of oseltamivir resulted in a statistically significantly higher (p<0.01) weight gain from day 6 to day 11 compared to the H1N1 vehicle control group. Figures 2A and 2B show the effect of compound 17ya on weight gain in the H1N1-induced pulmonary inflammation model.

[0358] Effect of Compound 17ya on BAL and Differential Cell Counts at Day 5. Five days after induction of inflammation, administration of H1N1 resulted in statistically significant (p<0.001) higher total BAL cells, neutrophils, eosinophils, mononuclear cells (macrophages), and lymphocytes compared to the saline control group. Oral administration of Compound 17ya at a dose of 2 mg / kg once daily did not result in statistically significant changes in BAL cells compared to the H1N1 control group, whereas oral administration of Compound 17ya at a dose of 8 mg / kg once daily resulted in statistically significant (p<0.01) lower BAL total cells, neutrophils, mononuclear cells, lymphocytes, and eosinophils compared to the H1N1 control group. Oral administration of dexamethasone at a dose of 1 mg / kg once daily reduced total BAL cells, neutrophils, eosinophils, mononuclear cells (macrophages), and lymphocytes compared to the H1N1 control group, but this was not statistically significant.Oseltamivir at a dose of 30 mg / kg once daily resulted in statistically significant (p<0.01) lower BAL total cells, neutrophils, eosinophils, lymphocytes, and mononuclear cells compared to the H1N1 control group.

[0359] Figures 3A-3E show the effect of compound 17ya on BAL total and differential cell counts in the H1N1 model of induced pulmonary inflammation at day 5. Figure 3A shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on total cell counts. Figure 3B shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on neutrophil counts. Figure 3C shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on mononuclear cells. Figure 3D shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on lymphocytes. Figure 3E shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on eosinophils. The data are presented in Table 3 below.

[0360] [Table 5]

[0361] Effect of Compound 17ya on BAL cytokine levels. Five days after induction of inflammation, administration of H1N1 resulted in statistically significant (p<0.001) higher TNFα, IFNγ, IL-6, KC, and IP-10 levels compared to the saline control group. Oral administration of Compound 17ya once daily at a dose of 2 mg / kg resulted in statistically significant (p<0.05) lower BAL IL-6 and IP-10 compared to the H1N1 control group. Oral administration of Compound 17ya once daily at a dose of 2 mg / kg did not result in statistically significant changes in TNFα, IFNγ, and KC compared to the H1N1 control group. Oral administration of Compound 17ya once daily at a dose of 8 mg / kg resulted in statistically significant (p<0.05) lower IFNγ, IL-6, IP-10, KC, and TNFα compared to the H1N1 control group. Oral administration of dexamethasone at a dose of 1 mg / kg once daily resulted in statistically significant (p<0.01) lower BAL IL-6, KC, and IFN-γ compared to the H1N1 control group. Oral administration of dexamethasone at a dose of 1 mg / kg once daily did not result in statistically significant changes in TNFα and IP-10 compared to the H1N1 control group. Oral administration of oseltamivir at a dose of 30 mg / kg twice daily resulted in statistically significant (p<0.01) lower TNFα, IFNγ, IL-6, KC, and IP-10 compared to the H1N1 control group.

[0362] Figures 4A-4E show the effect of compound 17ya on BAL cytokine concentrations in the H1N1 model of induced pulmonary inflammation at day 5. Figure 4A shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on TNFα (pg / mL). Figure 4B shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IFN-γ. Figure 4C shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IL-6. Figure 4D shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on KC. Figure 4E shows the effect of compound 17ya, vehicle, dexamethasone, and oseltamivir on IP-10. Table 4 summarizes the data from the study.

[0363] [Table 6]

[0364] Effect of Compound 17ya on Histopathology. Compound 17ya administered at 2 or 8 mg / kg / day to Balb / c mice reduced the severity of lung inflammation thought to be related to H1N1 viral load compared to the viral load vehicle control group. A reduction in the severity of lung inflammation was observed in animals administered dexamethasone compared to the viral load control group. A reduction in the incidence and severity of inflammation was observed in animals administered oseltamivir compared to the viral load control group. Comparing the efficacy of the two compounds, Compound 17ya and Oseltamivir, in reducing lung inflammation, a slightly less efficacy was recorded when Compound 17ya was used at 2 or 8 mg / kg / day compared to Oseltamivir.

[0365] Intranasal administration of H1N1 successfully led to the induction of pulmonary inflammation, as demonstrated by lower body weight gain and lower body temperature compared to saline controls, as well as higher wet lung weights (not shown), total BAL, differential cell counts, and BAL IFNγ, IL-6, IP-10, and KC BAL cytokine levels compared to saline controls. Changes in lung function were also observed, including higher PenH on days 5 and 7 compared to saline controls.

[0366] Oral administration of 2 mg / kg compound 17ya resulted in a reduction in clinical signs and weight loss associated with H1N1 infection. From day 11 onwards, 4 of 7 animals showed no clinical signs associated with induction of H1N1 infection. Oral administration of 8 mg / kg compound 17ya resulted in a slight worsening of clinical signs or weight loss associated with H1N1 infection, and 1 of 7 animals in this group had to be culled for welfare reasons on day 12. No animals in the H1N1 vehicle control group were terminated early.

[0367] Oral administration of 1 mg / kg dexamethasone did not result in attenuation of clinical signs or weight loss associated with H1N1 infection. Three of the seven animals in this group had to be culled for welfare reasons on day 11, primarily as a result of worsening weight loss. Oral administration of 30 mg / kg oseltamivir attenuated clinical signs and weight loss associated with H1N1 infection.

[0368] Intranasal administration of H1N1 did not result in changes in minute ventilation, tidal volume, respiratory rate, or Penh on days 1 or 3. Beginning on day 5, intranasal administration of H1N1 resulted in higher PenH, higher tidal volume and minute ventilation (day 5 only), and lower respiratory rate (day 7 only) compared to saline controls.

[0369] Oral administration of 2 mg / kg of compound 17ya on day 5 resulted in lower PenH compared to the H1N1 control group. Oral administration of 8 mg / kg of compound 17ya once daily on day 7 resulted in lower PenH compared to the H1N1 control group. This effect on PenH appears to be dose-dependent.

[0370] Oral administration of 1 mg / kg dexamethasone on days 5 and 7 resulted in lower PenH and higher tidal volumes (day 7 only) compared to the H1N1 control group. Oral administration of 30 mg / kg oseltamivir completely attenuated H1N1 and induced higher PenH on days 5 and 7.

[0371] Five days after induction of inflammation, administration of H1N1 resulted in higher total BAL cells, neutrophils, eosinophils, monocytes (macrophages), and lymphocytes, as well as higher BAL IFNγ, IL-6, IP-10, KC, and TNFα levels compared to saline controls.

[0372] Oral administration of 2 mg / kg of compound 17ya did not result in changes in BAL cells or TNFα, IFN-γ, and KC compared to the H1N1 control group. However, oral administration of 2 mg / kg of compound 17ya resulted in reduced BAL IL-6 and IP-10. Oral administration of 8 mg / kg of compound 17ya resulted in lower BAL total cells, neutrophils, eosinophils, lymphocytes, mononuclear cells, BAL IFNγ, IL-6, IP-10, KC, and TNFα compared to the H1N1 control group.

[0373] Oral administration of 1 mg / kg dexamethasone reduced total BAL cells, neutrophils, eosinophils, monocytes (macrophages), and lymphocytes compared to H1N1 controls, but the results were not statistically significant.Oral administration of dexamethasone once daily resulted in lower BAL IL-6, KC, and IFN-γ compared to H1N1 controls.

[0374] Oral administration of 30 mg / kg oseltamivir resulted in statistically significant lower BAL total cells, neutrophils, eosinophils, lymphocytes, mononuclear cells, BAL IFNγ, IL-6, IP-10, KC, and TNFα compared to the H1N1 control group.

[0375] Balb / c mice were administered 2 or 8 mg / kg / day of compound 17ya, which reduced the severity of lung inflammation thought to be associated with H1N1 viral load compared to the viral load control group. Reduced severity of lung tissue inflammation was recorded in animals administered dexamethasone compared to the viral load control group. Reduced incidence and severity of lung tissue inflammation was recorded in animals administered oseltamivir compared to the viral load control group.

[0376] Example 3 Preclinical trial results demonstrate that compound 17ya inhibits poxviruses, including inhibiting cellular release and cell-to-cell spread of poxviruses.

[0377] Results of preclinical studies evaluating the effect of compound 17ya against vaccinia poxvirus, a prototypical orthopoxvirus, demonstrated that compound 17ya prevented both the release of poxvirus from infected cells and the spread of poxvirus to healthy cells. Materials and methods are reported in Example 4, and this Abstract discusses the data presented in more detail there. These preclinical results expand the potential use of compound 17ya as a treatment for highly lethal smallpox virus infections in preparation for the occurrence of a global emergency, as well as other infections caused by poxviruses that are significant global public health problems.

[0378] Preclinical Study Background: The objective of this study was to evaluate the mechanism of antiviral effect of compound 17ya, a microtubule-disrupting agent, against a prototype vaccinia poxvirus in cell culture. Vaccinia poxvirus uses host cell microtubules for intracellular transport and propagation, releasing newly formed infectious viral particles, called extracellular enveloped viruses (EEV), from the cell, which then spread to healthy cells causing widespread viral infection.

[0379] Highlights from preclinical studies: Treatment of BSC40 cells (African green monkey kidney cells) with different concentrations of compound 17ya prior to inoculation with vaccinia poxvirus reduced infectious extracellular enveloped virus (EEV) release (R) by 50% and 90% at concentrations of 24.3 nM and 37.8 nM of compound 17ya, respectively. 2 The results showed a drug dose-dependent inhibition of vaccinia poxvirus cell-to-cell spread (R value = 0.9573). To evaluate the ability of compound 17ya to slow or stop cell-to-cell spread of vaccinia poxvirus, BSC40 cells were treated with different concentrations of compound 17ya and then inoculated with vaccinia poxvirus at a low multiplicity of infection. A clear drug dose-dependent inhibition of vaccinia poxvirus cell-to-cell spread was observed with compound 17ya at concentrations of 15.7 nM and 27 nM, with 50% and 90% inhibitory concentrations, respectively (R 2 =0.9464).

[0380] The concentration of compound 17ya required to inhibit vaccinia poxvirus release from infected cells and stop cell-to-cell spread was determined to be approximately 32 nM of compound 17ya in patients orally treated with a daily dose of 9 mg of compound 17ya. 平均 ), and the peak concentration level of compound 17ya of 171 nM (C 最大 ), a daily dose of 9 mg of compound 17ya can be achieved.

[0381] In this study, by disrupting microtubules, compound 17ya was able to prevent the transport and release of infectious vaccinia pox (EEV). These findings are consistent with the mechanism of action of compound 17ya as an indirect antiviral agent, as it targets microtubules, a cellular component that the virus uses to cause infection.

[0382] Compound 17ya, as a host-targeted antiviral and broad-spectrum anti-inflammatory agent, may be useful as a novel treatment not only against smallpox and other pox infections, but also against the exaggerated immune responses caused by poxviruses that cause severe pneumonia, ARDS, multiple organ failure, and death.

[0383] Example 4 Antiviral testing of 17ya hydrochloride against the prototype poxvirus vaccinia.

[0384] Context: Orthopoxviruses remain a significant global public health problem. Although the naturally occurring variola virus, the causative agent of smallpox, has been eradicated, concerns remain about its use as a bioterrorism agent. Monkeypox virus is an emerging infectious disease endemic in Africa. Last year, over 4,000 cases of monkeypox were reported in the Democratic Republic of the Congo with a case fatality rate of approximately 4%. Monkeypox is currently endemic worldwide, with over 30,000 cases and 28 deaths in the United States. In addition to monkeypox, other orthopoxvirus outbreaks have recently occurred. An unknown orthopoxvirus infection was recently discovered in the United States. In Brazil, wild vaccinia virus (VACV) has caused sporadic outbreaks over the past few years, with some infections resulting in hospitalization. Recent cases have occurred in Colombia, Argentina, and Uruguay, suggesting that the virus may be spreading throughout South America and possibly heading toward Central America. These cases highlight the continuing importance of orthopoxviruses to public health and underscore the primary reason why multiple orthopoxviruses are listed as category A priority pathogens and emerging infectious diseases by both NIH / NIAID and WHO. Although the monkeypox outbreak has now subsided, it highlights the pandemic potential of the virus and the need for additional vaccines and antivirals against these viruses.

[0385] Viruses are intracellular pathogens and therefore depend on the host cell for multiple aspects of their replication. Among the many cellular systems hijacked by viruses, the cytoskeleton, which functions as an intracellular trafficking system, is typically involved in two distinct phases of viral replication, entry and egress. Thus, targeting this essential system with indirect antiviral compounds would potentially target both the initiation and termination phases of viral replication. In accordance with this, orthopoxviruses have been shown to engage the microtubule system at the onset of cell infection for transport of particles to the juxtanuclear region where viral replication occurs, and to transport progeny virions out of the cell during morphogenesis. Here, experiments were performed to determine whether the microtubule-targeting drug 17ya could interfere with the replication cycle and spread of the prototypic orthopoxvirus vaccinia.

[0386] method:

[0387] Reagents, cells, and viruses: 17ya hydrochloride was diluted to 8,000 μM in tissue culture grade dimethyl sulfoxide (DMSO), dispensed into 1 mL aliquots, and stored at 4°C. CellTiter-Glo® was obtained from Promega. Prior to first use, CellTiter-Glo® reagent was mixed according to the supplier's instructions, divided into 10 mL aliquots, and frozen at -20°C until use. The African green monkey kidney cell line BSC40 was obtained from ATCC (CRL-2761) and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 8% Cosmic Calf Serum® (Hyclone). A recombinant reporter vaccinia virus (VVEGIR) expressing green fluorescent protein (mNeonGreen) under the early promoter and red fluorescent protein (mKate2) under the middle promoter was generated from the Western Reserve (WR) strain of vaccinia virus.

[0388] The proliferation of BSC40 cells was increased by 50% (CC 50 ) and 90% (CC 90The concentration of 17ya that reduces the 1×10 4 BSC40 cells were seeded in a 96-well plate and incubated overnight (o / n) at 37°C. The next day, cell culture medium was removed and replaced with 100 μL of fresh medium. 17ya hydrochloride was diluted in DMEM to a concentration of 800 nM and 100 μL was added to the first row of cells to give a starting concentration of 400 nM. A 1:2 serial dilution was performed in subsequent wells to give concentrations of 200, 100, 50, 25, and 12.5 nM in triplicate. Three wells were added with a concentration of DMSO equal to the concentration found in the 400 nM well. The treated cells were incubated o / n at 37°C. The next day, cells were washed once with phosphate buffered saline (PBS). 100 μL of fresh DMEM was added, followed by 100 μL of CellTiterGlo®. This was shaken for 2 minutes before being transferred to an opaque 96-well plate. Luminescence was read using a luminometer with an integration time of 1 second. Luminescence is directly proportional to the number of viable cells. The assay was repeated twice with triplicates each time. Data was exported to MS Excel for analysis. Wells were averaged and compared to DMSO-treated cells. Linear regression was used to determine the CC 50 and C.C. 90 was calculated.

[0389] Growth curve at high multiplicity of infection (MOI): 5×10 5 BSC40 cells were seeded into each well of two 12-well plates and incubated o / n at 37°C. The next day, the cell culture medium was removed and replaced with 1 mL of fresh medium containing 20, 10, 5, 1, 0.5, 0.25, or 0 nM (DMSO) of 17ya hydrochloride. After 1 h, 2 × 10 6Plaque forming units (PFU) of VVEGIR were added and cells were incubated for 2 h at 37°C. Afterwards, cells were washed once with fresh DMEM and medium containing the original concentration of the drug was added. Cells were incubated o / n at 37°C. The next day, virus released in the supernatant was quantified (titered) by serial dilution and plaque assay on monolayers of BSC40 cells. To quantify virus attached to the cells, infected cells were harvested by scraping and transferred to 1.5 mL screw-cap tubes. Intracellular virus was released by three freeze-thaw cycles and titered as described above. Three days after infection, monolayers were stained with crystal violet and the number of plaques in the wells was counted. Data were analyzed using Microsoft Excel.

[0390] Growth curve at low MOI: 5×10 5 BSC40 cells were seeded into each well of two 12-well plates and incubated o / n at 37°C. The next day, the cell culture medium was removed and replaced with 1 mL of fresh medium containing 30, 25, 20, 15, 10, 5, 1, or 0 nM (DMSO) of 17ya hydrochloride. After 1 h, 1 × 10 3 Plaque forming units (PFU) of VVEGIR were added and cells were incubated at 37°C for 48 h. At 48 h post-infection, cells in each well were harvested by scraping and transferred to a 1.5 mL screw-cap tube. Intracellular virus was released by three freeze-thaw cycles and titrated by serial dilution and plaque assay on monolayers of BSC40 cells. Data were analyzed using Microsoft Excel.

[0391] result:

[0392] Determination of cytotoxicity. Treatment of BSC40 cells with various concentrations of 17ya hydrochloride (17ya HCl) demonstrated a dose response for toxicity. BSC40 cells were treated overnight with various concentrations of drug. The following day, the amount of cells remaining was determined by CellTiterGlo® assay. Results represent the average of three separate wells at each concentration tested and are shown as a percentage of cells treated with DMSO.

[0393] Plotting the relationship between drug concentration and % toxicity compared to DMSO treatment yielded R 2 Responses were obtained with values ​​of 0.9214, 0.8895, and 0.9073 (Figure 5). Using the equations determined for the best-fit line of each test, the 50% toxicity values ​​for tests 1, 2, and 3 were calculated to be 2,046.8, 924.6, and 429.5 nM, respectively. Furthermore, the 90% toxicity for tests 1, 2, and 3 was calculated to be 90,393.9, 26,949,718.9, and 43,356.1 nM, respectively (Figure 5).

[0394] Effect of 17ya hydrochloride on vaccinia virus replication. To determine whether 17ya hydrochloride (17ya HCl) affects vaccinia virus replication, cells were treated with different concentrations of the drug and then inoculated with a high multiplicity of infection (MOI) of vaccinia virus. After inoculation, unbound virus was washed away and medium containing the drug was added. After 24 hours, viral replication was determined by measuring the amount of virus released inside the cells and into the medium (Figure 6). For virus in the medium (culture medium), which represents the extracellular enveloped form (EEV) of the virus, there was a dose-dependent inhibition of virus released in the presence of 17ya HCl, R 2 The IC value was 0.9573. Using linear regression, IC values ​​of 24.3 and 37.8 nM were obtained. 50 and IC 90 For viruses associated with infected cells (cells) that represent the intracellular mature form (IMV) of the virus, there is not a good correlation between the amount of drug and the amount of virus produced.

[0395] Effect of 17ya hydrochloride on vaccinia virus cell-to-cell spread. To investigate the ability of 17ya hydrochloride (17ya HCl) to slow or stop vaccinia virus cell-to-cell spread, cells were treated with different concentrations of the drug and then inoculated with a low multiplicity of infection (MOI) of vaccinia virus. After inoculation, unbound virus was washed away and medium containing the drug was added. After 48 hours, viral replication was determined by measuring the amount of virus within the cells (Figure 7). The amount of virus produced was graphed against the concentration of 17ya HCl, showing a clear dose-dependent response, with R 2 The IC value was 0.9464. Using linear regression, IC values ​​of 15.7 and 27.0 nM were obtained. 50 and IC 90 was calculated.

[0396] Consideration

[0397] Orthopoxviruses, such as vaccinia virus, variola virus, and monkeypox virus, produce two antigenically distinct forms of virus, intracellular mature virus (IMV) and extracellular enveloped virus (EEV). IMVs represent the initial form produced and are retained within the cells in which they are produced. EEVs are derived from IMVs but have an extra membrane derived from the trans-Golgi network (TGN). IMVs typically account for 90-99% of progeny virions, while EEVs account for the remainder. IMVs are retained within the infected cell, whereas EEVs utilize microtubules for active release from infected cells and are necessary for cell-to-cell spread and long-distance propagation of infection. The results presented here show a clear effect of 17ya on the production of EEVs by vaccinia virus. These results on 17ya as a microtubule depolymerizing agent were consistent with previous studies suggesting that depolymerization of microtubules may reduce virus trafficking to cell membranes impeding their release.

[0398] All of the features described in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Although preferred embodiments have been shown and described in detail herein, it will be apparent to those skilled in the art that various modifications, additions, substitutions, and the like, can be made without departing from the spirit of the invention, and therefore are considered to be within the scope of the invention as defined in the following claims.

Claims

1. 1. A method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by Formula I below, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof. During the ceremony, A is phenyl, indolyl, or indazolyl, and optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, thiazole, or benzimidazole, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-halo (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ CN, hydroxyl, or NO ２ is substituted with at least one of R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond, NH, or (C １ -C ４ ) alkyl; Y is a bond or -C=O; m is 1 to 3.

2. 2. The method of claim 1 , A is phenyl or indolyl, and optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

3. 2. The method of claim 1 , A is phenyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

4. 2. The method of claim 1 , A is indolyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

5. 2. The method of claim 1 , A is indolyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond; Y is a bond or -C=O; The method wherein m is 1 to 3.

6. 1. A method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by Formula VII: or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof. During the ceremony, X is a bond or NH; Q is S or NH; A is a phenyl, indolyl, or indazolyl ring, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is replaced with at least one of:

7. 7. The method of claim 6, The method wherein X is a bond.

8. 7. The method of claim 6, The method wherein X is NH.

9. 7. The method of claim 6, X is a bond; Q is NH; A is an indolyl ring, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ The method of claim 1, wherein the aryl group is replaced with at least one of the following:

10. 1. A method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by formula VII(c) below, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof: During the ceremony, R ４ and R ５ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ and n is 1 to 4.

11. 1. A method of treating an Orthomyxoviridae virus infection in a subject in need thereof, comprising: The method comprises the step of administering to the subject a formulation containing a therapeutically effective amount of a compound represented by formula 17ya:

12. A method according to any one of claims 1 to 11, comprising: The method, wherein the Orthomyxoviridae viral infection is caused by an influenza virus.

13. A method according to any one of claims 1 to 11, comprising: The method, wherein the Orthomyxoviridae viral infection is caused by influenza A, influenza B, influenza C, or influenza D.

14. 14. The method of claim 13, The subject suffering from an Orthomyxoviridae virus infection is complicated with symptoms of acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS).

15. 14. The method of claim 13, The method, wherein said influenza A is caused by an H1N1 serotype virus.

16. 14. The method of claim 13, The subject suffering from the Orthomyxoviridae virus infection is at high risk of acute respiratory distress syndrome (ARDS) or death.

17. A method for the prophylactic use of a compound of formula I according to claim 1, comprising the steps of: A method wherein a second influenza infection is prevented or the severity is reduced in a close contact of a subject diagnosed with an influenza infection.

18. 1. A method of treating a Poxviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by Formula I below, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof. During the ceremony, A is phenyl, indolyl, or indazolyl, and optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, thiazole, or benzimidazole, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-halo (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ CN, hydroxyl, or NO ２ is substituted with at least one of R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond, NH, or (C １ -C ４ ) alkyl; Y is a bond or -C=O; m is 1 to 3.

19. 20. The method of claim 18, A is phenyl or indolyl, and optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

20. 20. The method of claim 18, A is phenyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

21. 20. The method of claim 18, A is indolyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond or NH; Y is a bond or -C=O; The method wherein m is 1 to 3.

22. 20. The method of claim 18, A is indolyl, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is substituted with at least one of B is imidazole, optionally １ -C ４ ) substituted with at least one alkyl; R １ , R ２ , and R ３ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ At least one of X is a bond; Y is a bond or -C=O; The method wherein m is 1 to 3.

23. 1. A method of treating a Poxviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by Formula VII: or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof. During the ceremony, X is a bond or NH; Q is S or NH; A is a phenyl, indolyl, or indazolyl ring, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ is replaced with at least one of:

24. 24. The method of claim 23, The method wherein X is a bond.

25. 24. The method of claim 23, The method wherein X is NH.

26. 24. The method of claim 23, X is a bond; Q is NH; A is an indolyl ring, optionally １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ The method of claim 1, wherein the aryl group is replaced with at least one of the following:

27. 1. A method of treating a Poxviridae virus infection in a subject in need thereof, comprising: Administering to the subject a formulation containing a therapeutically effective amount of a compound represented by formula VII(c) below, or a pharma- ceutically acceptable salt, hydrate, polymorph, or isomer thereof: During the ceremony, R ４ and R ５ are each independently hydrogen, (C １ -C ４ ) alkyl, halo (C １ -C ４ ) alkyl, O-(C １ -C ４ ) alkyl, O-(C １ -C ４ ) haloalkyl, (C １ -C ４ ) alkylamino, amino (C １ -C ４ ) Alkyl, F, Cl, Br, I, CN, -CH ２ C.N., N.H. ２ , Hydroxyl, OC(O)CF ３ , -OCH ２ Ph, -NHCO-(C １ -C ４ ) alkyl, COOH, -C(O)Ph, C(O)O-(C １ -C ４ ) alkyl, C(O)H, —C(O)NH ２ , or NO ２ and n is 1 to 4.

28. 1. A method of treating a Poxviridae virus infection in a subject in need thereof, comprising: The method comprises the step of administering to the subject a formulation containing a therapeutically effective amount of a compound represented by formula 17ya:

29. A method according to any one of claims 18 to 28, comprising the steps of: The method, wherein said Poxviridae viral infection is caused by a member of the Orthopoxvirus genus of the Poxviridae family.

30. 30. The method of claim 29, The method, wherein said Poxviridae viral infection is caused by a vaccinia virus.

31. 30. The method of claim 29, The method, wherein said Poxviridae viral infection is caused by monkeypox.

32. 30. The method of claim 29, The method of claim 1, wherein said Poxviridae virus infection is caused by any one of monkeypox virus, cowpox virus, horsepox virus, camelpox virus, affephavirus, or Alaskapox virus.

33. 30. The method of claim 29, The method, wherein said Poxviridae virus infection is caused by smallpox.

34. A method according to any one of claims 29 to 33, comprising the steps of: The method, wherein treating the Poxviridae infection reduces the severity of pneumonia, ARDS, multiple organ failure, or prevents death.

35. A method according to any one of claims 29 to 33, comprising the steps of: The method, wherein treating the Poxviridae virus infection reduces the severity of encephalitis, severe inflammatory response syndrome, respiratory failure, painful head and neck lymphadenopathy, widespread skin rash, or sepsis syndrome.

36. 20. The method of claim 1 or 18, comprising: The method reduces mortality compared to a placebo-treated patient population.

37. 20. The method of claim 1 or 18, comprising: The method reduces morbidity compared to a placebo-treated patient population.

38. 20. The method of claim 1 or 18, comprising: The method further comprises a second line treatment.

39. 39. The method of claim 38, The method, wherein the second line therapy comprises at least one of peramivir, zanamivir, oseltamivir phosphate, baloxavir marboxil, amantadine, rimantadine, or ribavirin.

40. 20. The method of claim 1 or 18, comprising: The method wherein the compound is administered in an amount of about 1 to about 100 mg.

41. 20. The method of claim 1 or 18, comprising: The method wherein the compound is administered in an amount of about 4 mg to about 90 mg.

42. 20. The method of claim 1 or 18, comprising: The method wherein the compound is administered in an amount of about 4 mg to about 45 mg.

43. A method according to any one of claims 40 to 42, comprising the steps of: The method, wherein the formulation further comprises a pharma- ceutically acceptable excipient.

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