WO2022063869A2

WO2022063869A2 - Compounds for the treatment of viral infections

Info

Publication number: WO2022063869A2
Application number: PCT/EP2021/076142
Authority: WO
Inventors: Ulrich Betz; Gordon Philipp Otto
Original assignee: Merck Patent Gmbh
Priority date: 2020-09-24
Filing date: 2021-09-23
Publication date: 2022-03-31
Also published as: WO2022063869A3

Abstract

The present invention encompasses cMET inhibitors for use in the treatment of viral infections, including coronavirus infections such as COVID-19, alone or in combination with one or more additional therapeutic agents.

Description

COMPOUNDS FOR THE TREATMENT OF VIRAL INFECTIONS

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention provides for the use of inhibitors of the receptor tyrosine kinase (TKIs) mesenchymal-epithelial transition factor (cMET) in the treatment of viral infections. The cMET inhibitors can be particularly used in the treatment of coronavirus infections, including SARS-CoV infections such as COVID-19.

BACKGROUND OF THE INVENTION cMET inhibitors

[0002] The mesenchymal-epithelial transition factor (c-Met) has emerged as a promising target in the development of anti-cancer therapeutics because of its low level of expression in normal tissues and its aberrant activation in many human cancers. The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase cMET promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials. See e.g., van der Stee, et al. (2016) J Thoracic One 11(9): 1423. As for selectivity, there is a distinction between type I and II class c-Met inhibitors depending on the binding site on the kinase. Type I inhibitors can be further divided into type la and type lb, with type lb inhibitors being more highly specific for MET and having fewer off-target effects when compared with type la inhibitors. Type II inhibitors inhibit non-activated MET and generally exhibit more off-target effects of other protein kinases, which can cause serious toxic effects.

Coronaviruses

[0003] Coronaviruses (CoVs) are positive-sense, single-stranded RNA (ssRNA) viruses of the order Nidovirales, in the family Coronaviridae. There are four sub-types of coronaviruses - alpha, beta, gamma and delta - with the Alphacoronaviruses and Betacoronaviruses infecting mostly mammals, including humans. Over the last two decades, three significant novel coronaviruses have emerged which jumped from a non-human mammal hosts to infect humans: the severe acute respiratory syndrome (SARS-CoV-1) which appeared in 2002, Middle East respiratory syndrome (MERS-CoV) which appeared in 2012, and COVID-19 (SARS-CoV-2) which appeared in late 2019. By mid- June of 2020, over 7.8 million people are known to have been infected, and over 432,000 people have died. Both numbers likely represent a significant undercount of the devastation wrought by the disease.

COVID-19

[0004] SARS-CoV-2 closely resembles SARS-CoV-1, the causative agent of SARS epidemic of2002-03 (Fung, et al, Annu. Rev. Microbiol. 2019. 73:529-57). Severe disease has been reported in approximately 15% of patients infected with SARS-CoV-2, of which one third progress to critical disease (e.g., respiratory failure, shock, or multiorgan dysfunction (Siddiqi, et al, J. Heart and Lung Trans. (2020); doi: https://doi.Org/10.1016/j.healun.2020.03.012, Zhou, et al, Lancet 2020; 395: 1054-62; https://doi.org/10.1016/S0140-6736(20)30566-3). Fully understanding the mechanism of viral pathogenesis and immune responses triggered by SARS-CoV-2 would be extremely important in rational design of therapeutic interventions beyond antiviral treatments and supportive care. Much is still being discovered about the various ways that COVID-19 impacts the health of the people that develop it.

[0005] Severe acute respiratory syndrome (SARS)-Corona Virus-2 (CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has caused a pandemic affecting almost eight million people worldwide with a case fatality rate of 2-4% as of June 2020. The virus has a high transmission rate, likely linked to high early viral loads and lack of pre-existing immunity (He, et al., Nat Med 2020; https://doi.org/10.1038/s41591-020-0869-5). It causes severe disease especially in the elderly and in individuals with comorbidities. The global burden of COVID-19 is immense, and therapeutic approaches are increasingly necessary to tackle the disease. Intuitive anti-viral approaches including those developed for enveloped RNA viruses like HIV-1 (lopinavir plus ritonavir) and Ebola virus (remdesivir) have been implemented in testing as investigational drugs (Grein et al., NEJM 2020; https://doi.org/10.1056/NEJMoa2007016; Cao, et al., NEJM 2020 DOI: 10.1056/NEJMoa2001282). But given that many patients with severe disease present with immunopathology, host-directed immunomodulatory approaches are also being considered, either in a staged approach or concomitantly with antivirals (Metha, et al., The Lancet 2020; 395(10229); DOI: https://doi.org/10.1016/S0140-6736(20)30628-0, Stebbing, et al., Lancet Infect Dis 2020; https://doi.org/10.1016/S1473-3099(20)30132-8). [0006] While there are many therapies being considered for use in treatment of COVID-19, there are yet no approved medications to treat the disease, and no vaccine available. To date, treatment typically consists only of the available clinical mainstays of symptomatic management, oxygen therapy, with mechanical ventilation for patients with respiratory failure. Thus, there is an urgent need for novel therapies to address the different stages of the SARS-CoV-2 infectious cycle (Siddiqi, et al.). Similarly, there is an urgent need for novel therapies to address further viral infections.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 shows the following: (A) Representative images from dimethyl sulfoxide (DMSO)-, remdesivir-treated wells. Infected (arrow) and uninfected (arrowhead) cells are indicated; 500 pm and 50 pm scale bars are shown in the composite and magnified images, respectively. Raw and normalized (Norm.) values calculated from the images is shown. (B) Box and whiskers plot of SARS-CoV-2 assay control EC₅₀s obtained from independent biological experiments with mean indicated with a bar and all data points shown. Whiskers indicate minimums and maximums. (C) Representative SARS-CoV-2 EC₅₀ (blue), infected HeLa-ACE2 EC₅₀ (orange) and uninfected HeLa-ACE2 CC₅₀ (magenta) dose response curves for the remdesivir, apilimod and puromycin control compounds ran as part of hit reconfirmation.

[0008] Figure 2 shows SARS-CoV-2 EC₅₀ (blue), infected HeLa-ACE2 EC₅₀ (orange) and uninfected HeLa-ACE2 CC₅₀ (magenta) dose response curves for the compound (A) tepotinib hydrochloride monohydrate (cMET inhibitor) and (B) capmatinib (cMET inhibitor).

[0009] Figure 3 shows effects of tepotinib on viral replication in Vero cells infected with (A) SARS-CoV-2, (B) SARS-CoV-1 or (C) MERS.

[0010] Figure 4 shows neutralization effects (IC₅₀) of the compound IVAVT #9 (a.k.a. compound MSC’428) in a CPE inhibition assay using Vero cells infected with (A) ADV (4 dpi), (B) HSV-1 (3 dpi), and (C) HSV-2 (3 dpi). Data points displayed in a box were manually knocked out for better curve fitting.

[0011] Figure 5 shows the cytotoxic effect of the compound IVAVT #9 (a.k.a. compound MSC’428) in Vero cells (3 dpi).

SUMMARY OF THE INVENTION [0012] In a first aspect, the invention provides cMET inhibitors for use in the treatment of viral infections in a subject in need thereof. In one aspect of this embodiment, the viral infection is a single-strand RNA viral infection. In another aspect of this embodiment, the viral infection is a coronavirus infection, adenovirus infection, or herpes simplex virus infection. In another aspect of this embodiment, the viral infection is a coronavirus infection. In a further aspect of this embodiment, the viral infection is a SARS-CoV 1 , MERS-CoV, or SARS-CoV-2 infection. In a final aspect of this embodiment, the viral infection is a SARS-CoV-2 infection.

[0013] A second aspect is a method of treating a viral infection in a subject in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt thereof, to the subject, which is infected with a coronavirus, adenovirus, or herpes simplex virus. One aspect of this embodiment is a method of treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt thereof, to the subject. In one aspect of this embodiment, the administration of the cMET inhibitor reduces the viral load in the subject. In one aspect of this embodiment, the cMET inhibitor is administered prior to COVID-19 pneumonia development. In another aspect of this embodiment, the cMET inhibitor is administered prior to the subject developing a severe cytokine storm. In a further aspect of this embodiment, the subject has a mild to moderate SARS-CoV-2 infection. In an additional aspect of this embodiment, the subject is asymptomatic at the start of the administration regimen.

[0014] A third aspect relates to the use of a cMET inhibitor for the manufacture of a medicament for the treatment of viral infections.

DETAILED DESCRIPTION

[0015] At the initial antiviral response phase, when the virus primarily infects ACE2- expressing specialized epithelial cells (type II pneumocytes) in the lung alveoli, direct anti-viral or immune-enhancing therapy (e.g., IFN-I, including Rebif) may prove to be of benefit in minimizing contagion and preventing progression to severe disease (Hoffmann, et al., Cell 2020; DOI: https://doi.Org/10.1016/j.cell.2020.02.052; Sungnak, et al., Qbio preprint; arXiv:2003.06122 [q- bio.CB]; Zou, et al., Front Med 2020; https://doi.org/10.1007/s11684-020-0754-0; Zhao, et al., BioRxv preprint; https://doi.org/10T 101/2020.01.26.919985;_Qi, et al., BBRC 2020; https://doi.org/10.1016/j.bbrc.2020.03.044; Taccone, et al., Lancet Resp. Med. (2020); https://doi.org/10.1016/S2213-2600(20)30172-7).

[0016] Recent papers have suggested a correlation between SARS-CoV-2 viral load, symptom severity and viral shedding (He, et al.; Liu, et al., Lancet Infect Dis 2020; https://doi.org/10.1016/S1473-3099(20)30232-2). Some antiviral drugs administered at symptom onset to blunt coronavirus replication are in the testing phase (Grein, et al.; Taccone, et al.), but none have shown much promise.

[0017] SARS-CoV-2 directly enters cells expressing ACE2 via receptor-mediated endocytosis (Hoffmann, et al.). Successful viral replication requires host endosome acidification to release the viral genome into the host cytosol. Innate immune cells like monocytes, macrophages and neutrophils do not highly express ACE2, but have abundant Fc receptors (Zou, et al.; Qi, et al.; Lu, et al., Nat. Rev. Imm. 2018; https://doi.org/10.1038/nri.2017.106). In stage II (Fig. 1), antibodies that bind the virus can mediate viral uptake into myeloid cell endosomes via Fc receptors (FcR) or complement receptors (CR) (Lu, et al.; Dandekar, et al., Nat. Rev. Imm. 2005; https://doi.org/10.1038/nri1732). Thus, ACE2, FcR and CR present three mechanisms how SARS-CoV-2 can enter endosomes and trigger hyperinflammation leading to cytokine storm and severe disease. Additionally, ssRNA virus can induce NETosis in neutrophils (Saitoh, et al., Cell Host Microbe (2012), 19;12(1): 109-16) leading to release of DNA and RNA, creating a feed- forward loop to further fuel inflammation (Herster et al., Nat Commun 2020; 11, 105; https://doi.org/10.1038/s41467-019-13756-4), which has been proposed as a driver of severe COVID-19 (Barnes, et al., J Exp med 2020; 217 (6); https://doi.org/10.1084/jem.20200652). SARS-CoV-1 derived ssRNA has been shown to mediate severe lung pathology in animal models and presents as a potential driver of virus-associated cytokine storm (Li, et al., Microbes Infect 2013; 15 (2) 88-95; https://doi.Org/10.1016/j.micinf.2012.10.008). Being able to slow the viral reproduction in the early stages of infection may allow the subject to avoid severe disease.

[0018] Ito, et al. (2015) Am J Physiol Lung Cell Mol Physiol 308: LI 178, studied the cytokine/chemokine induction by recombinant human HGF (rhHGF) and rhTGF-a in human alveolar epithelial cells (AECs) and activation of c-Met and EGFR signaling in AECs during influenza infection. Albeit without specific reference to coronaviruses, it was pointed out that hepatocyte growth factor (HGF)/c-Met signaling regulates IL-8 and GM-CSF by human AECs, which attract neutrophils, and that influenza virus infection to AECs activates the PGE2/HGF/c- Met pathway, which induces IL-8 secretion through c-Met activated by HGF secreted from lung fibroblasts. HGF secretion by fibroblasts was stimulated by AEC production of prostaglandin E2 (PGE2) during influenza infection. A most severe complication is viral pneumonia, which can lead to the acute respiratory distress syndrome (ARDS). A key feature of ARDS is the accumulation of neutrophils in the lung. The release of cytokines and chemokines, including IL- 8, from resident cells is central to the recruitment and activation of neutrophils, which in turn induce damage to the epithelial-endothelial barrier. HGF/c-Met and transforming growth factor- α (TGF-α)/epidermal growth factor receptor (EGFR) regulate repair of damaged alveolar epithelium by stimulating cell migration and proliferation. HGF levels in the lungs are increased in ARDS, and plasma concentrations of HGF are significantly increased in patients with severe influenza infection.

[0019] It is hypothesized that compounds for use according to the invention may advantageously target c-Met to suppress excessive neutrophil accumulation and subsequent inflammation. It is conceivable that HGF/c-Met signaling regulates innate immune responses during respiratory infections, including coronavirus infection. cMET inhibitors may be a potential strategy for treating coronavirus-induced ARDS, e.g., by preventing further invasion. The result of administration of a compound of the invention may also be to reduce viral replication, new virus particle transport and/or virus release, which in turn will reduce viral load, and reduce the severity of disease. Whatever the exact mechanism of action for the antiviral properties of the compounds of the invention, it is proposed that administration thereof may have one or more clinical benefits, as described further herein.

[0020] cMET inhibitor" refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of the gene encoding for cMET and/or the expression of cMET and/or the biological activity of cMET. In one embodiment, the cMET inhibitor specifically binds the cMET kinase. There are two classes of agents with clinical activity against receptor tyrosine kinases: antibodies, which target the extracellular domain of the receptor, and small molecule TKIs, which target the intracellular part by competing with ATP, thus inhibiting the autophosphorylation of the receptor and preventing downstream signaling. Examples of cMET TKIs include tepotinib (a.k.a. MSC’119), GST-HG161, MSC’817, MSC’428, capmatinib (a.k.a. MSC’914), crizotinib, savolitinib, cabozantinib, MGCD265 and merestinib, whereas onartuzumab and ARGX-111 are examples of cMET -targeting antibodies. In one embodiment, the following cMET inhibitors are excluded from the compounds for use in accord with the invention:

[0021] "COVID-19" is the name of the disease which is caused by a SARS-CoV-2 infection. While care was taken to describe both the infection and disease with accurate terminology, “COVID-19” and “SARS-CoV-2 infection” are meant to be roughly equivalent terms.

[0022] As of the writing of this application, the determination and characteristics of the severity of COVID-19 patients/symptoms has not been definitively established. However, in the context of this invention, “mild to moderate” COVID-19 occurs when the subject presents as asymptomatic or with less severe clinical symptoms (e.g., low grade or no fever (<39.1 °C), cough, mild to moderate discomfort) with no evidence of pneumonia, and generally does not require medical attention. When “moderate to severe” infection is referred to, generally patients present with more severe clinical symptoms (e.g., fever >39.1 °C, shortness of breath, persistent cough, pneumonia, etc.). As used herein “moderate to severe” infection typically requires medical intervention, including hospitalization. During the progression of disease, a subject can transition from “mild to moderate” to “moderate to severe” and back again in one course of bout of infection.

[0023] Treatment of COVID-19 using the methods of this invention include administration of an effective amount of a cMET inhibitor of the invention at any stage of the infection to prevent or reduce the symptoms associated therewith. Typically, subjects will be administered an effective amount of a cMET inhibitor of the invention after definitive diagnosis and presentation with symptoms consistent with a SARS-CoV2 infection, and administration will reduce the severity of the infection and/or prevent progression of the infection to a more severe state. The clinical benefits upon such administration are described in more detail in the sections below. [0024] It has been surprisingly found that no COVID-19 infection is observed in the VISION clinical trial, in which Tepotinib is being investigated in patients with non-small cell lung cancer (NSCLC), although having a highly sensible patient population and a reasonable number of patients in the effected regions (status end of June 2020).

1. Compounds and Definitions

[0025] One embodiment is a compound according to the following formula (MSC’119):

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for use in the treatment of a viral infection. The compound MSC’ 119 is a highly selective and potent cMET inhibitor.

[0026] The first compound may also be referred to as 3-(1-{3-[5-(1-methyl-piperidin-4- ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (INN: tepotinib). It is disclosed and further characterized as compound “A257” in WO 2009/006959. In an exemplary embodiment, a hydrochloride hydrate form of this first compound is used, which is referred to as 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate. In another exemplary embodiment, a hydrochloride monohydrate form of this first compound is used, which is referred to as 3-(1-{3- [5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3- yl)-benzonitrile hydrochloride monohydrate. It is disclosed and further characterized as compound “A7” in WO 2009/007074. In an exemplary embodiment, the crystalline form H2 of the hydrochloride monohydrate of this first compound is used, which is referred to as crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo- 1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. It is disclosed and further characterized in Example 12 in WO 2010/078897.

[0027] Any reference to the first compound in the following shall be read as including a reference to 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate, 3-(1-{3-[5-(1-methyl-piperidin-4- ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, and crystalline modification H2 of 3-(1-{3-[5-(1-Methyl-piperidin- 4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. All the compounds described above are highly selective and potent cMET inhibitors.

[0028] One embodiment is a compound according to the following formula (GST-HG161):

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for use in the treatment of a viral infection. The cMET inhibitor GST-HG-161 is disclosed and further characterized as “embodiment 1-2” in EP 3 533 787.

[0029] One embodiment is a compound according to the following formula (MSC’817):

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for use in the treatment of a viral infection. The compound MSC’817 is a highly selective and potent cMET inhibitor.

[0030] One embodiment is a compound according to the following formula (MSC’428):

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for use in the treatment of a viral infection. The compound MSC’428 (a.k.a. IVAVT #9) is a highly selective and potent cMET inhibitor.

[0031] In one aspect of this embodiment, the compound MSC’428 is used for the treatment of a coronavirus infection, an adenovirus infection, or a herpes simplex virus infection. In a preferred aspect of this embodiment, the compound MSC’817 is used for the treatment of an adenovirus infection or a herpes simplex virus infection, such as a herpes simplex virus subtype 1 (HSV-1) infection or herpes simplex virus subtype 2 (HSV-2) infection.

[0032] One embodiment is a compound according to the following formula (MSC’914):

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for use in the treatment of a viral infection. The compound MSC’914 (capmatinib) is a highly selective and potent cMET inhibitor.

[0033] In a preferred embodiment, all the compounds described above are used in the treatment of a coronavirus infection.

[0034] The above compounds may either be used in their free forms or as pharmaceutically acceptable salts. The free compounds may be converted into the associated acid-addition salt by reaction with an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as, for example, ethanol, and subsequent evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts, such as, for example, hydrogen halides (for example hydrogen chloride, hydrogen bromide or hydrogen iodide), other mineral acids and corresponding salts thereof (for example sulfate, nitrate or phosphate and the like), alkyl- and monoaryl sulfonates (for example ethanedisulfonate (edisylate), toluene sulfonate, nap thalene-2-sulfonate (napsylate), benzenesulfonate) and other organic acids and corresponding salts thereof (for example fumarate, oxalate, acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.

[0035] An exemplary embodiment of pharmaceutically acceptable salts of the first compound (MSC’ 119) comprises the hydrochloride salt (MSC’ 119J), as described above.

[0036] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0037] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. In some embodiments, the group comprises one or more deuterium atoms.

2. Uses, Formulation and Administration

[0038] The term “patient” or “subject”, as used herein, means an animal, preferably a human. However, “subject” can include companion animals such as dogs and cats. In one embodiment, the subject is an adult human patient. In another embodiment, the subject is a pediatric patient. Pediatric patients include any human which is under the age of 18 at the start of treatment. Adult patients include any human which is age 18 and above at the start of treatment. In one embodiment, the subject is a member of a high-risk group, such as being over 65 years of age, immunocompromised humans of any age, humans with chronic lung conditions (such as, asthma, COPD, cystic fibrosis, etc.), and humans with other co-morbidities. In one aspect of this embodiment, the other co-morbidity is obesity, diabetes, and/or hypertension. [0039] Compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Preferably, the compositions are administered orally. In one embodiment, the oral formulation of a compound of the invention is a tablet or capsule form. In another embodiment, the oral formulation is a solution or suspension which may be given to a subject in need thereof via mouth or nasogastric tube. Any oral formulations of the invention may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0040] Pharmaceutically acceptable compositions of this invention are orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents are optionally also added.

[0041] The amount of compounds of the present invention that are optionally combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, and the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.

[0042] The pharmaceutical composition is in the form of one or more dosage units, which is provided either as a single dose per day or in a series of doses of two or more per day so that the total daily dose would be the same as for the single dose per day. In certain embodiments, the cMET inhibitor is administered in a dosage strength of about 15 mg, 25 mg, 100 mg, 215 mg, 225 mg, 250 mg, 300 mg, 450 mg, 500 mg, or 1000 mg, preferably about 15 mg, 25 mg, 100 mg, 225 mg, 250 mg, 450 mg, or 500 mg, more preferably about 225 mg or 250 mg.

[0043] In certain embodiments, the total amount of cMET inhibitor administered to the subject in need thereof is between about 0.5 mg to about 1400 mg per day, preferably between about 300 mg to about 1400 mg per day. In certain embodiments, the total amount of cMET inhibitor administered to the subject in need thereof is between about 1 mg and 1000 mg per day, more preferably between about 1 mg and 700 mg per day, most preferably between about 100 mg and 500 mg per day, highly preferably between about 225 mg and 500 mg per day. In one embodiment, the total amount of cMET inhibitor administered to the subject in need thereof is between about 225 mg and 450 mg per day. In one embodiment, the total amount of cMET inhibitor administered to the subject in need thereof is between about 250 mg and 500 mg per day. In certain embodiments, the total amount of cMET inhibitor administered to the subject in need thereof is between about 30 mg and 400 mg per day, more preferably between about 30 mg to 230 mg per day. In one embodiment, the total amount of cMET inhibitor administered to the subject in need thereof is between about 60 mg to 315 mg per day.

[0044] In any of the above embodiments, the cMET inhibitor is administered daily. In any of the above embodiments, the cMET inhibitor is administered via oral administration. In any of the above embodiments, the cMET inhibitor is administered daily and via oral administration.

[0045] In any of the above embodiments, the cMET inhibitor is administered once a day. In one embodiment, the cMET inhibitor is administered in a dosage strength of about 450 mg to 500 mg once a day. In one embodiment, the dosage of tepotinib is 450 mg (equivalent to 500 mg tepotinib hydrochloride hydrate) orally once daily. In one embodiment, the dosage of tepotinib is 225 mg orally once daily. 225 mg tepotinib is equivalent to 250 mg tepotinib hydrochloride hydrate.

[0046] In any of the above embodiments, the cMET inhibitor is administered twice a day. In one embodiment, the cMET inhibitor is administered in a dosage strength of 250 mg twice a day.

[0047] In any of the above embodiments, the cMET inhibitor is administered three times a day. In one embodiment, the cMET inhibitor is administered in a dosage strength of about 100 mg three times a day.

[0048] In any of the above embodiments, the cMET inhibitor is administered three times a week. In one embodiment, the cMET inhibitor is administered in a dosage strength between about 60 mg and 315 mg three times a week. [0049] In any of the above embodiments, the cMET inhibitor is administered for a period of about 7 days to about 28 days. In one aspect of any of the above embodiments, the cMET inhibitor is administered for a period of about 7 days to about 21 days. In one aspect of any of the above embodiments, the cMET inhibitor is administered for a period of about 14 days to about 21 days.

[0050] In another aspect of any of the above embodiments, the cMET inhibitor is administered for about 14 days. In one embodiment, the cMET inhibitor is administered in a dosage strength between about 30 mg and 400 mg per day for about 14 days. In one embodiment, the cMET inhibitor is administered in a dosage strength between about 30 mg to 230 mg per day for about 14 days.

[0051] In another aspect of any of the above embodiments, the cMET inhibitor is administered for about 21 days. In one embodiment, the cMET inhibitor is administered in a dosage strength of about 300 mg to 1400 mg once a day for about 21 days. In one embodiment, the cMET inhibitor is administered in a dosage strength of about 450 mg to 500 mg once a day for about 21 days. In one embodiment, the cMET inhibitor is administered in a dosage strength of about 500 mg once a day for about 21 days.

[0052] In one embodiment of the invention, the subject is suffering from COVID-19 pneumonia. In one embodiment of this invention, the subject is suffering from one or more symptoms selected from chest congestion, cough, blood oxygen saturation (SpO2) levels below 94%, shortness of breath, difficulty breathing, fever, chills, repeated shaking with chills, muscle pain and/or weakness, headache, sore throat and/or new loss of taste or smell.

[0053] In one embodiment, the subject is suffering from a hyperinflammatory host immune response to a SARS-CoV-2 infection. In one aspect of this embodiment, the hyperinflammatory host immune response is associated with one or more clinical indications selected from 1) reduced levels of lymphocytes, especially natural killer (NK) cells in peripheral blood; 2) high levels of inflammatory parameters (e.g., C reactive protein [CRP], ferritin, d-dimer), and pro-inflammatory cytokines (e.g., IL-6, TNF-alpha, IL-8, and/or IL-1beta; 3) a deteriorating immune system demonstrated by lymphocytopenia and/or atrophy of the spleen and lymph nodes, along with reduced lymphocytes in lymphoid organs; 4) dysfunction of the lung physiology represented by lung lesions infiltrated with monocytes, macrophages, and/or neutrophils, but minimal lymphocytes infiltration resulting in decreased oxygenation of the blood; 5) acute respiratory distress syndrome (ARDS); 6) vasculitis; 7) encephalitis, Guillain-Barre syndrome, and other neurologic disorders; 8) kidney dysfunction and kidney failure; 9) hypercoagulability such as arterial thromboses; and 10) or any combination of above resulting in end-organ damage and death.

[0054] In one embodiment, the subject with COVID-19 is a pediatric patient suffering from vasculitis, including Kawasaki disease (i.e., Kawasaki syndrome) and Kawasaki-like disease.

[0055] In one embodiment of the invention, the subject is being treated inpatient in a hospital setting. In another embodiment, the subject is being treated in an outpatient setting. In another embodiment, the subject is undergoing outpatient treatment. In one aspect of the preceding embodiments, the subject may continue administration of the cMET inhibitor after being transitioned from being treated from an inpatient hospital setting to an outpatient setting.

[0056] In one embodiment, the administration of the cMET inhibitor results in one or more clinical benefit. In one aspect of this embodiment, the one or more clinical benefit is selected from the group comprising: reduction of duration of a hospital stay, reduction of the duration of time in the Intensive Care Unit (ICU), reduction in the likelihood of the subject being admitted to an ICU, reduction in the rate of mortality, reduction in the likelihood of kidney failure requiring dialysis, reduction in the likelihood of being put on non-invasive or invasive mechanical ventilation, reduction of the time to recovery, reduction in the likelihood supplemental oxygen will be needed, improvement or normalization in the peripheral capillary oxygen saturation (SpO₂ levels) without mechanical intervention, reduction of severity of the pneumonia as determined by chest imaging (e.g., CT or chest X ray), reduction in the cytokine production, reduction of the severity of acute respiratory distress syndrome (ARDS), reduction in the likelihood of developing ARDS, clinical resolution of the COVID-19 pneumonia, improvement of the PaO₂/FiO₂ ratio, and reduction of the inflammatory response in the subject.

[0057] In another embodiment, the one or more clinical benefits includes the improvement or normalization in the peripheral capillary oxygen saturation (SpO₂ levels) in the subject without mechanical ventilation or extracorporeal membrane oxygenation.

[0058] In one embodiment, the one or more clinical benefits includes the reduction of the inflammatory response of the subject. In one aspect of this embodiment, the reduction of the inflammatory response in the subject results in the reduction of pro inflammatory cytokine release driven by NF-kappa-B, IL-1b, IL-6, IL-8, IL-12, IL-18, IL-23, or IL-27, alone or in combination with inhibition of cytokine release driven by IRF3/7, such as type I IFNs, including IFN-alpha and/or IFN-beta. In one aspect of this embodiment, the one or more clinical benefits includes the avoidance of a severe cytokine storm in the subject.

[0059] In a further embodiment, the one of more clinical benefits is reduction in the likelihood of being hospitalized, reduction in the likelihood of ICU admission, reduction in the likelihood being intubated (invasive mechanical ventilation), reduction in the likelihood supplemental oxygen will be needed, reduction in the length of hospital stay, reduction in the likelihood of mortality, and/or a reduction in likelihood of relapse, including the likelihood of rehospitalization.

[0060] The invention also provides a method of treating a viral infection in a subject in need thereof comprising administering an effective amount of a compound of the invention to the subject. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control subjects.

[0061] One embodiment of the invention is a method of treating an adenovirus infection in a subject in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt and/or solvate or hydrate thereof to the subject.

[0062] One embodiment of the invention is a method of treating a herpes simplex virus infection in a subject in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt and/or solvate or hydrate thereof to the subject. In one aspect of this embodiment, the subject is infected with herpes simplex virus subtype 1 (HSV- 1) or herpes simplex virus subtype 2 (HSV-2), or both.

[0063] One embodiment of the invention is a method of treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt and/or solvate or hydrate thereof to the subject. In one aspect of this embodiment, the subject is infected with SARS-CoV-2. In another aspect of this embodiment, the administration of the cMET inhibitor results in the reduction of the viral load in the subject. In a further aspect of this embodiment, the administration of the cMET inhibitor reduces the viral load by suppressing neutrophil accumulation and inflammation, and/or preventing further virus invasion. In a further aspect of this embodiment, administration of the cMET inhibitor reduces the viral load by increasing the pH of the endosome, reducing the ability of the virus to enter cells, and/or interfering with the terminal glycosylation of cellular receptor ACE2.

[0064] In one embodiment, the cMET inhibitor is administered prior to COVID-19 pneumonia developing. In one embodiment, the cMET inhibitor is administered prior to the subject developing a cytokine storm. In another embodiment, the subject has a mild to moderate SARS- CoV-2 infection. In a further embodiment, the subject is asymptomatic at the start of the administration regimen. In another embodiment, the subject has had known contact with a patient who has been diagnosed with a SARS-CoV-2 infection. In an additional embodiment, the subject begins administration of the cMET inhibitor prior to being formally diagnosed with COVID-19.

[0065] One embodiment is a method of treating a subject with COVID-19 comprising administration of an effective amount of a cMET inhibitor to the subject. In one aspect of this embodiment, the subject has been previously vaccinated with a SARS-CoV-2 vaccine and develops vaccine-related exacerbation of infection, for example, an antibody-dependent enhancement or related antibody-mediated mechanisms of vaccine/antibody-related exacerbation.

[0066] In any of the above embodiments, the administration of the cMET inhibitor results in one or more clinical benefits to the subject. In one aspect of this embodiment, the one or more clinical benefits is shortening the duration of infection, reduction of the likelihood of hospitalization, reduction in the likelihood of mortality, reduction in the likelihood of ICU admission, reduction in the likelihood being placed on mechanical ventilation, reduction in the likelihood supplemental oxygen will be needed, and/or reduction in the length of hospital stay. In another aspect of this embodiment, the one or more clinical benefits is avoidance of a significant proinflammatory response. In a further aspect of this embodiment, the one or more clinical benefit is the failure of the subject to develop significant symptoms of COVID-19.

[0067] The compounds of the invention can be administered before or following an onset of SARS-CoV-2 infection, or after acute infection has been diagnosed in a subject. The aforementioned compounds and medical products of the inventive use are particularly used for the therapeutic treatment. A therapeutically relevant effect relieves to some extent one or more symptoms of a disorder, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a disease or pathological condition. Monitoring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g., to boost the response and eradicate the pathogens and/or symptoms of the disease. The methods of the invention can also be used to reduce the likelihood of developing a disorder or even prevent the initiation of disorders associated with COVID-19 in advance of the manifestation of mild to moderate disease, or to treat the arising and continuing symptoms of an acute infection.

[0068] Treatment of mild to moderate COVID-19 is typically done in an outpatient setting. Treatment of moderate to severe COVID-19 is typically done inpatient in a hospital setting. Additionally, treatment can continue in an outpatient setting after a subject has been discharged from the hospital.

[0069] The invention furthermore relates to a medicament comprising at least one compound according to the invention or a pharmaceutically salts thereof.

[0070] A “medicament” in the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of the invention or preparations thereof (e.g., a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up, or aftercare of patients who suffer from clinical symptoms and/or known exposure to COVID-19.

Combination Treatment

[0071] In various embodiments, the active ingredient may be administered alone or in combination with one or more additional therapeutic agents. A synergistic or augmented effect may be achieved by using more than one compound in the pharmaceutical composition. The active ingredients can be used either simultaneously or sequentially.

[0072] In one embodiment, the cMET inhibitor is administered in combination with one or more additional therapeutic agents. In one aspect of this embodiment, the one or more additional therapeutic agents is selected from anti-inflammatories, antibiotics, anti-coagulants, antiparasitic agent, antiplatelet agents and dual antiplatelet therapy, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, statins and other combination cholesterol lowering agents, specific cytokine inhibitors, complement inhibitors, anti-VEGF treatments, JAK inhibitors, immunomodulators, anti-inflammasome therapies, sphingosine- 1 phosphate receptors binders, N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists, corticosteroids, Granulocyte-macrophage colony-stimulating factor (GM-CSF), anti- GM-CSF, interferons, angiotensin receptor-neprilysin inhibitors, calcium channel blockers, vasodilators, diuretics, muscle relaxants, and antiviral medications.

[0073] In one embodiment, the cMET inhibitor is administered in combination with an antiviral agent. In one aspect of this embodiment, the antiviral agent is remdesivir. In another aspect of this embodiment, the antiviral agent is lopinavir-ritonavir, alone or in combination with ribavirin and interferon-beta.

[0074] In one embodiment, the cMET inhibitor is administrated in combination with a broad- spectrum antibiotic.

[0075] In one embodiment, the cMET inhibitor is administered in combination with chloroquine or hydroxychloroquine. In one aspect of this embodiment, the cMET inhibitor is further combined with azithromycin.

[0076] In one embodiment, the cMET inhibitor is administered in combination with interferon- 1-beta (Rebif®).

[0077] In one embodiment, the cMET inhibitor is administered in combination with one or more additional therapeutic agents selected from hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, virazole, ribavirin, remdesivir, lopinavir-ritonavir, favipiravir, arbidol, leronlimab, interferon- 1 -beta, interferon beta- la, interferon beta- lb, beta-interferon, azithromycin, nitazoxanide, lovastatin, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone, belimumab, rituximab, ocrelizumab, anifrolumab, ravulizumab-cwvz, eculizumab, bevacizumab, heparin, enoxaparin, apremilast, coumadin, baricitinib, ruxolitinib, dapagliflozin, methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolate mofetil, colchicine, fingolimod, ifenprodil, prednisone, cortisol, dexamethasone, methylprednisolone, melatonin, otilimab, ATR-002, APN- 01, camostat mesylate, brilacidin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and solnatide.

[0078] In one embodiment, the cMET inhibitor is administered in combination with one or more anti-inflammatory agent. In one aspect of this embodiment, the anti-inflammatory agent is selected from corticosteroids, steroids, COX-2 inhibitors, and non-steroidal anti-inflammatory drugs (NS AID). In one aspect of this embodiment, the anti-inflammatory agent is diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, prednisone, hydrocortisone, fludrocortisone, betamethasone, prednisolone, triamcinolone, methylprednisone, dexamethasone, fluticasone, and budesonide (alone or in combination with formoterol, salmeterol, or vilanterol).

[0079] In one embodiment, the cMET inhibitor is administered in combination with one or more immune modulators. In one aspect of this embodiment the immune modulator is a calcineurin inhibitor, antimetabolite, or alkylating agent. In another aspect of this embodiment, the immune modulator is selected from azathioprine, mycophenolate mofetil, methotrexate, dapsone, cyclosporine, cyclophosphamide, and the like.

[0080] In one embodiment, the cMET inhibitor is administered in combination with one or more antibiotics. In one aspect of this embodiment, the antibiotic is a broad-spectrum antibiotic. In another aspect of this embodiment, the antibiotic is a penicillin, anti-staphylococcal penicillin, cephalosporin, aminopenicillin (commonly administered with a beta lactamase inhibitor), monobactam, quinoline, aminoglycoside, lincosamide, macrolide, tetracycline, glycopeptide, antimetabolite or nitroimidazole. In a further aspect of this embodiment, the antibiotic is selected from penicillin G, oxacillin, amoxicillin, cefazolin, cephalexin, cephotetan, cefoxitin, ceftriazone, augmentin, amoxicillin, ampicillin (plus sulbactam), piperacillin (plus tazobactam), ertapenem, ciprofloxacin, imipenem, meropenem, levofloxacin, moxifloxacin, amikacin, clindamycin, azithromycin, doxycycline, vancomycin, Bactrim, and metronidazole.

[0081] In one embodiment, the cMET inhibitor is administered in combination with one or more anti-coagulants. In one aspect of this embodiment, the anti-coagulant is selected from apixaban, dabigatran, edoxaban, heparin, rivaroxaban, and warfarin.

[0082] In one embodiment, the cMET inhibitor is administered in combination with one or more antiplatelet agents and/or dual antiplatelet therapy. In one aspect of this embodiment, the antiplatelet agent and/or dual antiplatelet therapy is selected from aspirin, clopidogrel, dipyridamole, prasugrel, and ticagrelor.

[0083] In one embodiment, the cMET inhibitor is administered in combination with one or more ACE inhibitors. In one aspect of this embodiment, the ACE inhibitor is selected from benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

[0084] In one embodiment, the cMET inhibitor is administered in combination with one or more angiotensin II receptor blockers. In one aspect of this embodiment, the angiotensin II receptor blocker is selected from azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

[0085] In one embodiment, the cMET inhibitor is administered in combination with one or more beta-blockers. In one aspect of this embodiment, the beta-blocker is selected from acebutolol, atenolol, betaxolol, bisoprolol/hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, and sotalol.

[0086] In another embodiment, the cMET inhibitor is administered in combination with one or more alpha and beta-blocker. In one aspect of this embodiment, the alpha and/or beta-blocker is carvedilol or labetalol hydrochloride.

[0087] In one embodiment, the cMET inhibitor is administered in combination with one or more interferons.

[0088] In one embodiment, the cMET inhibitor is administered in combination with one or more angiotensin receptor-neprilysin inhibitors. In one aspect of this embodiment, the angiotensin receptor-neprilysin inhibitor is saciibitnl/valsartan.

[0089] In one embodiment, the cMET inhibitor is administered in combination with one or more calcium channel blockers. In one aspect of this embodiment, the calcium channel blocker is selected from amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisoldipine, and verapamil.

[0090] In one embodiment, the cMET inhibitor is administered in combination with one or more vasodilators. In one aspect of this embodiment, the one or more vasodilator is selected from isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, and minoxidil.

[0091] In one embodiment, the cMET inhibitor is administered in combination with one or more diuretics. In one aspect of this embodiment, the one or more diuretics is selected from acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, spironolactone, and torsemide. [0092] In one embodiment, the cMET inhibitor is administered in combination with one or more muscle relaxants. In one aspect of this embodiment, the muscle relaxant is an antispasmodic or antispastic. In another aspect of this embodiment, the one or more muscle relaxants is selected from casisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine, baclofen, dantrolene, and diazepam.

[0093] In one embodiment, the cMET inhibitor is administered in combination with one or more antiviral medications. In one aspect of this embodiment, the antiviral medication is remdesivir.

[0094] In one embodiment, the cMET inhibitor is administered in combination with one or more additional therapeutic agents selected from antiparasitic drugs (including, but not limited to, hydroxychloroquine, chloroquine, ivermectin), antivirals (including, but not limited to, tranexamic acid, nafamostat, virazole [ribavirin], lopinavir-ritonavir, remdesivir, favipiravir, leronlimab, interferon- 1 -beta, interferon beta- la, interferon beta- lb, beta-interferon), antibiotics with intracellular activities (including, but not limited to azithromycin, nitazoxanide), statins and other combination cholesterol lowering and anti-inflammatory drugs (including, but not limited to, lovastatin), specific cytokine inhibitors (including, but not limited to, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone), complement inhibitors (including, but not limited to, ravulizumab-cwvz, eculizumab), anti-VEGF treatments (including, but not limited to, bevacizumab), anti-coagulants (including, but not limited to, heparin, enoxaparin, apremilast, coumadin), JAK inhibitors (including, but not limited to, baricitinib, ruxolitinib, dapagliflozin), anti-inflammasome therapies (including, but not limited to, colchicine), sphingosine- 1 phosphate receptors binders (including, but not limited to, fingolimod), N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists (including, but not limited to, ifenprodil), corticosteroids (including, but not limited to, prednisone, cortisol, dexamethasone, methylprednisolone), GM-CSF, anti-GM-CSF (otilimab), ATR-002, APN-01, camostat mesylate, arbidol, brilacidin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and solnatide.

[0095] In some embodiments, the combination of a cMET inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, dosage volume, dosage concentration, and/or total drug dose administered) of the cMET inhibitor and/or the one or more additional therapeutic agents administered to achieve the same result as compared to the effective amount administered when the cMET inhibitor or the additional therapeutic agent is administered alone. In some embodiments, the combination of a cMET inhibitor with the additional therapeutic agent reduces the total duration of treatment compared to administration of the additional therapeutic agent alone. In some embodiments, the combination of a cMET inhibitor with the additional therapeutic agent reduces the side effects associated with administration of the additional therapeutic agent alone. In some embodiments, the combination of an effective amount of the cMET inhibitor with the additional therapeutic agent is more efficacious compared to an effective amount of the cMET inhibitor or the additional therapeutic agent alone. In one embodiment, the combination of an effective amount of the cMET inhibitor with the one or more additional therapeutic agent results in one or more additional clinical benefits than administration of either agent alone.

[0096] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a viral infection, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., considering a known exposure to an infected person and/or considering comorbidities which are predictors for severe disease, or other susceptibility factors).

EXEMPLIFICATION

[0097] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures.

Example 1: Synthesis

[0098] 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6- dihydro-pyridazin-3-yl)-benzonitrile (free base), referred to as compound “A257” (a.k.a. MSC’119), can be synthesized as described in WO 2009/006959, example 40, and WO 2009/007074, example 3, as follows:

[0099] To a suspension of 13.0 g (56.5 mmol) of 3-(5-hydroxy-pyrimidin-2-yl)-benzoic acid methylester and 13.4 g (62.1 mmol) of N-Boc-piperidinemethanol in 115 ml THF 17.7 g (67.8 mmol) of triphenyl-phosphine are given. The suspension is cooled down to 5° C. To the suspension kept at this temperature 13.3 ml (67.8 mmol) of diisopropylazodicarboxylate are given dropwise under stirring within 45 minutes. The reaction mixture is stirred at room temperature for one hour. Subsequently, further 22.2 g (84.7 mmol) of triphenylphosphine and 16.6 ml (84.7 mmol) of diisopropylazodicarboxylate are added. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo. The resulting solid of 4-[2-(3-methoxycarbonyl-phenyl)- pyrimidin-5-yloxymethyl]-piperidine-l-carbonic acid tert. -butylester is sucked off, washed with diethyl ether and subjected to chromatography (silica gel column and dichloromethane/methanol as eluent/mobile phase).

[00100] To a suspension of 1.71 g (3.99 mmol) of 4-[2-(3-methoxycarbonyl-phenyl)-pyrimidin- 5-yloxymethyl]-piperidine-1-carbonic acid tert. -butylester in 20 ml THF 25 ml (25 mmol) of a 1 M solution of diisobutylaluminiumhydride in THF are given dropwise under nitrogen. The reaction mixture is stirred for one hour at room temperature and mixed with a saturated solution of sodium sulfate. The resulting precipitate is sucked off and washed with THF and hot 2-propanol. The filtrate is concentrated and re-crystallized from tert. -butylmethylether, resulting in {3-[5-(1- methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl] -phenyl} -methanol as beige crystals. [00101] To a solution of 313 mg (1.00 mmol) of {3-[5-(1-methyl-piperidin-4-ylmethoxy)- pyrimidin-2-yl]-phenyl}-methanol in 2 ml THF 264 mg (1.30 mmol) of 3-(6-oxo-1,6-dihydro- pyridazin-3-yl)-benzonitrile and 397 mg (1.5 mmol) triphenylphosphine are added subsequently. The reaction mixture is cooled in an ice bath and 294 pl ( 1.5 mmol) of diisopropylazodicarboxylate are added dropwise. The reaction mixture is stirred at room temperature for 18 hours and then concentrated. The residue is subjected to chromatography (silica gel column and dichloromethane/methanol as eluent/mobile phase). The product containing fractions are pooled, concentrated and the residue of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is decocted with tert. -butylmethylether, sucked off and dried in vacuo.

[00102] By means of salt formation, the hemi sulfate, citrate, tartrate, sulfate, succinate, and hydrochloride can be obtained from compound “A257”.

[00103] Alternatively, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}- 6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) can be synthesized as described in WO 2009/006959, example 43, as follows:

[00104] To a suspension of 4.15 g (20 mmol) of 3-(6-oxo-1,6-dihydro-pyridazin-3-yl)- benzonitrile in 40 ml of 1-methyl-2-pyrrolidon 6.00 g (21 mmol) of 5-bromo-2-(3-chloromethyl- phenyl)-pyrimidine and 2.76 g (341 mmol) of potassium carbonate are given. The reaction mixture is stirred at 80° C for 18 hours. Subsequently, the reaction mixture is given onto 200 ml water. The resulting precipitate of 3-{1-[3-(5-bromopyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3- yl} -benzonitrile is sucked off, washed with water, and dried in vacuo.

[00105] To a solution of solution of 18.0 g (41.0 mmol) of 3-{1-[3-(5-bromopyrimidin-2-yl)- benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile in 85 ml DMF 11.8 g (47 mmol) of bis(pinacolato)diboron and 11.9 g ( 122 mmol) of potassium acetate are given. The reaction mixture is heated up to 80° C under nitrogen. After 15 minutes of stirring at this temperature 273 mg (1.22 mmol) of palladium(II)-acetate are added and the reaction mixture is stirred for 2 hours at 80°C under nitrogen. Subsequently, the reaction mixture is allowed to cool down to room temperature before the addition of water and dichloromethane, filtration over diatomite/kieselguhr and separation of the organic phase. The organic phase is dried over sodium sulphate and concentrated yielding 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]- benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrile as grey solid, which can be used for subsequent reactions without purification.

[00106] To a suspension of 5.33 g (10.9 mmol) of 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrile in 35 ml THF and 35 ml water 4.93 g (49.4 mmol) of sodium perborate are given in portions under ice cooling before it is stirred at room temperature for 2 hours. The reaction mixture is mixed with 300 ml of dichloromethane and 100 ml of saturated ammonium chloride solution. The organic phase is separated, dried over sodium sulphate, and concentrated. The residue of 3-{1-[3-(5- hydroxy-pyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile is re- crystallized from methanol.

[00107] To a suspension of 25 g (65.6 mmol) of 3-{1-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]- 6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile in 250 ml THF 15.6 g (68.8 mmol) of N-Boc-4- piperidine-methanol and 19.1 g (72.1 mmol) of triphenylphosphine are subsequently added. Then, 14.9 ml (72.1 mmol) of diisopropylazodicarboxylate are added dropwise under ice cooling. The resulting solution is stirred at room temperature for 2 hours. The reaction mixture is further mixed with 750 ml of 2-propanol and 13.1 ml of a 0.5 M solution of potassium hydroxide in ethanol. The resulting precipitate of 4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}- pyrimidin-5-yloxymethyl)-piperidine-1-carbonic acid tert. -butylester is sucked off, washed with diethyl ether, and dried in vacuo.

[00108] To a solution of 16.0 g (28.0 mmol) of 4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H- pyridazin-1-ylmethyl]-phenyl}-pyrimidin-5-yloxymethyl)-piperidine-1-carbonic acid tert.- butylester in 80 ml formic acid 6.60 ml of 35% aqueous formaldehyde solution are given. The reaction mixture is stirred at a temperature of 110° C for 2 hours before 300 ml water are added. The reaction mixture is concentrated in vacuo to a volume of 150 ml and is then extracted with 200 ml of dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried over sodium sulphate, and concentrated. The residue of 3-(1-{3-[5-(1-methyl-piperidin-4- ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile is re- crystallized from 2-propanol.

[00109] The compounds MSC’817 and MSC’428 were prepared as described for example compound “A257” (MSC’119) above.

[00110] The crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)- pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate can be prepared as described in WO 2010/078897, example 12, as follows:

[00111] Approx. 511 mg of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile were dispersed in 75 mL acetone, and approx. 1.12 mL of 1 N aqueous HCl solution were added. No clear solution was obtained. However, the remaining solid-state residue was removed by filtration to yield a clear solution afterwards. The resulting clear solution was then incubated overnight, whereupon crystals were obtained. The crystals were separated by filtration and dried for 1 h in a vacuum drying cabinet at 65 °C (purification option 1) or the crystals were separated by filtration, washed with acetone, and dried in a vacuum drying cabinet (purification option 2).

[00112] A Powder X-Ray Diffraction pattern of compound “A7” was obtained by standard techniques as described in the European Pharmacopeia 6^th Edition chapter 2.9.33 (Cu-Kα₁ radiation, λ = 1.5406 Å, Stoe StadiP 611 KL diffractometer). Compound “A7” is characterized by the following XRD data:

[00113] Powder X-ray diffractogram peak list (purification option 1):

[00114] Powder X-ray diffractogram peak list (purification option 2):

[00115] Powder X-Ray Diffraction pattern and corresponding XRD data confirmed that compound “A7” is crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)- pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate.

Example 2: Antiviral testing of compounds - SARS-CoV-2/HeLa-ACE2 high-content screening assay

[00116] SARS-CoV-2/HeLa-ACE2 high-content screening assay

[00117] Compounds were acoustically transferred into 384-well μclear-bottom plates (Greiner, Part. No. 781090-2B) and HeLa-ACE2 cells were seeded in the plates in 2% FBS at a density of 1.0x10³ cells per well. Plated cells were transported to the BSL3 facility where SARS-CoV-2 (strain USA-WA1/2020 propagated in Vero E6 cells) diluted in assay media was added to achieve ~30 - 50% infected cells. Plates were incubated for 24 h at 34°C 5% CO₂, and then fixed with 8% formaldehyde. Fixed cells were stained with human polyclonal sera as the primary antibody, goat anti-human H+L conjugated Alexa 488 (Thermo Fisher Scientific Al 1013) as the secondary antibody, and antifade-46-diamidino-2-phenylindole (DAPI; Thermo Fisher Scientific DI 306) to stain DNA, with PBS 0.05% Tween 20 washes in between fixation and subsequent primary and secondary antibody staining.

[00118] Plates were imaged using the ImageXpress Micro Confocal High-Content Imaging System (Molecular Devices) with a 10x objective, with 4 fields imaged per well. Images were analyzed using the Multi-Wavelength Cell Scoring Application Module (MetaXpress), with DAPI staining identifying the host-cell nuclei (the total number of cells in the images) and the SARS- CoV-2 immunofluorescence signal leading to identification of infected cells.

[00119] Uninfected host cell cytotoxicity counter screen

[00120] Compounds were acoustically transferred into 1,536-well μclear plates (Greiner Part. No. 789091). HeLa-ACE2 cells were maintained as described for the infection assay and seeded in the assay-ready plates at 400 cells/well in DM EM with 2% FBS. Plates were incubated for 24 hours at 37°C 5% CO₂. To assess cell viability, the Image-iT DEAD green reagent (Thermo Fisher) was used according to manufacturer instructions. Cells were fixed with 4% paraformaldehyde, and counterstained with DAPI. Fixed cells were imaged using the ImageXpress Micro Confocal High-Content Imaging System (Molecular Devices) with a 10x objective, and total live cells per well quantified in the acquired images using the Live Dead Application Module (MetaXpress).

[00121] Data analysis

[00122] Primary in vitro screen and the host cell cytotoxicity counter screen data were uploaded to Genedata Screener, Version 16.0. Data were normalized to neutral (DMSO) minus inhibitor controls (2.5 μM remdesivir for antiviral effect and 10 μM puromycin for infected host cell toxicity). For the uninfected host cell cytotoxicity counter screen, 40 μM puromycin (Sigma) was used as the positive control. For dose response experiments compounds were tested in technical triplicates on different assay plates and dose curves were fitted with the four parameter Hill Equation. Data for three assay readouts were reported: 1) % infected cells in blue (CoV-2 EC₅₀), 2) total cells per well in the HeLa-ACE2/SARS-CoV-2 infection assay in orange HeLa-ACE2 EC₅₀), and 3) live cells per well in the uninfected HeLa-ACE2 counter-screen cytotoxicity assay in magenta (HeLa-ACE2 CC₅₀). The Selectivity Index (SI) refers to uninfected HeLa-ACE2 CC₅₀ divided by SARS-CoV-2 EC₅₀. Figure 2 contains representative dose response curves for (A) Tepotinib hydrochloride monohydrate and (B) capmatinib.

[00123] Assay validation

[00124] The assay was validated by using compounds with reported activity against Ebola and suspected or previously verified activity against SARS-CoV-2: remdesivir (GS-5734) (EC₅₀ = 194 ± 20 nM; average ± sem of 5 independent experiments) and the PIKfyve inhibitor apilimod (EC₅₀ = 50 ± 11 nM, average ± sem of 4 independent experiments). Compound toxicity was also assessed in the context of infection by quantifying the total cell numbers per well, with cytotoxic protein synthesis inhibitor puromycin serving as a positive control (average EC₅₀ = 547 ± 27 nM, average ± sem of 5 independent experiments; HeLa-ACE2 CC₅₀ = 2.45 ± 0.23 μM, average ± sem of 5 independent experiments). Figure 1 contains (A) images from the assay for DMSO and remdesivir-treated wells, (B) EC₅₀ data for controls from independent experiments, and (C) representative dose response curves.

[00125] Compound testing and results [00126] Using the methods described above, influence of several compounds on SARS-CoV-2 and cell viability was tested (see Table 1).

[00127] Table 1 : Antiviral test results of selected compounds.

[00128] The following cMET inhibitors were negative in the antiviral testing (CoV-2 EC₅₀):

Example 3: Antiviral testing of compounds - CoV/Vero screening assay

[00129] Viral replication kinetics

[00130] Vero cells were seeded in 24-well plates with 1.5x10⁵ cells/ml, 1 ml per well, for 24 hours. The compounds to be tested were diluted in coronavirus (MERS, SARS-CoV-1, or SARS- CoV-2) infection medium to reach the final concentrations. The growth medium was removed from the cells, cells were washed once with 1x PBS (phosphate buffered saline), and subsequently inoculated with coronavirus at a MOI (multiplicity of infection) of 0.01. After attachment of viral particles to the cells for 45 min, the inoculum was removed, cells were washed twice with 1x PBS, and infection medium containing compounds was added (1 ml/well). As coronavirus replication peaks at approximately 48 hours post infection (p.i.), this time point was chosen for all subsequent analyses. At 48 hours p.i., supernatants were collected from infected cells and stored at -80°C. Then, viral titers were determined by plaque test on African green monkey kidney epithelial cells (VeroE6) cells as described below.

[00131] Cell viability assay

[00132] Vero cells were seeded in 96-well plates with 1.5xl0⁵ cells/ml, 100 pl per well, for 24 hours. The compounds to be tested or pure DMSO as positive control were serially diluted in SARS-CoV- 2 infection medium (DMEM, supplemented with 1% L-Glu, 1% P/S and 2% FBS) to obtain 5- fold of the desired final concentrations. The growth medium was removed from the cells and replaced with 80 pl/well of fresh infection medium. Subsequently, 20 pl of the diluted compounds were added in quadruplicates for each concentration (i.e., 5-fold dilution to reach the final concentrations). Cells were incubated for 48 hours at 37°C (5% CO₂, 96 % rH). At 48 hours post treatment, cell viability was measured on a Tecan Safire 2 plate reader using the CellTiter 96® Non-Radioactive Cell Proliferation Assay (MTT) (Promega) according to manufacturer’s instructions.

[00133] Plaque test

[00134] Viral titers in supernatants collected from infected cells were determined by plaque test on VeroE6 cells. Briefly, VeroE6 cells were seeded in 12-well plates (1:6 dilution of a confluent flask), 1.5 ml/well, for 24 hours. Cell culture supernatants were 10-fold serially diluted in 1x PBS. The growth medium was removed from the cells, cells were washed once with 1x PBS, and diluted supernatants were added (150 μl/well). After 30 min inoculation, an overlay medium (double- concentrated minimal essential medium (MEM; supplemented with 2% L-Glu, 2% P/S, 0.4% bovine serum albumin (BSA)), mixed 1:1 with 2.5% avicel solution (prepared in ddH₂O) was added to the cells (1.5 ml/well). Then, cells were incubated for 72 hours at 37°C. After 72 hours, the overlay medium was removed from the cells, and following a washing step with 1x PBS the cells were fixed with 4% paraformaldehyde (PFA) for at least 30 min at 4°C. Subsequently, the 4% PFA solution was removed, and the cells were counterstained with crystal violet solution to visualize the virus-induced plaques in the cell layer. The number of plaques at a given dilution was used to calculate the viral titers as plaque-forming units (PFU/ml). [00135] Statistics

[00136] All statistical evaluations were performed using GraphPad Prism 8 (v4.8.3). Statistically significant differences in viral titers were determined using a non-parametric t-test (Mann- Whitney Test). IC₅₀ and maximum effect values were obtained by fitting a sigmoidal curve onto the data of an eight-point dose response curve experiment.

[00137] Compound testing and results

[00138] Using the methods described above, influence of tepotinib on viral replication of coronavirus (MERS, SARS-CoV-1, SARS-CoV-2) and on cell viability was tested. Figure 3 shows the results obtained with tepotinib on the viral replication in Vero cells infected with (A) SARS-CoV-2, (B) SARS-CoV-1 or (C) MERS. As apparent from Figure 3, tepotinib led to a dose-dependent inhibition of virus replication of all coronaviruses tested (MERS, SARS-CoV-1, SARS-CoV-2), whereby in each case the cell viability remained nearly unaffected.

Example 4: Antiviral testing against multiple viruses - CPE inhibition assay

[00139] Viruses

[00140] The antiviral effect of the compound MSC’428 (a.k.a. IVAVT #9) was evaluated against the following seven different viruses: Adenovirus (ADV; strain: 5; MOI: 0.030); Herpes simplex virus subtype 1 (HSV-1; strain: MacIntyre; MOI: 0.025); Herpes simplex virus subtype 2 (HSV-2; strain: MS; MOI: 0.020); Chikungunya virus (CHKV; strain: 181/25; MOI: 0.025); Dengue virus serotype 2 (DENV-2; strain: D2Y98P; MOI: 0.020); Influenza virus (INFV; strain: H1N1 A/California/07/09; MOI: 0.030); and Zika Virus (ZIKV; strain: FSS13025; MOI: 0.020).

[00141] Cytopathic effect (CPE) inhibition assay

[00142] The antiviral effect was evaluated as follows: Eight 5-fold serial dilutions of the compound MSC’428 (a.k.a. IVAVT #9) were prepared at a starting concentration of 50 μM and added in triplicate to 1.00E+04 Vero cells seeded in 96-well plates one day prior. Cells and compound MSC’428 were incubated for 1 hour. Each virus was prepared at its specific multiplicity of infection (MOI) and added to the MSC’428/cells mix. Virus only and cells only wells were also added. After the appropriate time of incubation, cells were immuno-stained with a specific antibody (ADV DENV, and INFV) or stained with crystal violet (HSV-1, HSV-2, CHKV, and ZIKV). The optical density was read for calculation of 50% inhibition concentration (IC₅₀) of the compound MSC’428 using the XLfit dose response model. The results are shown in Figure 4, confirming an antiviral effect against (A) ADV (4 dpi), (B) HSV-1 (3 dpi), and (C) HSV- 2 (3 dpi). Some antiviral activity was measured in the assay using DENV-infected cells (4 dpi: IC₅₀ = 47.05), whereas 50% inhibition was not reached and/or could not be extrapolated in the assay using cells infected with CHKV (3 dpi), INFV (3 dpi), and ZIKV (5 dpi) (data not shown).

[00143] Cytotoxicity assay

[00144] The cytotoxic effect was assessed in parallel as follows: Similar MSC’428 dilutions were used for 1-hour incubation with cells seeded in 96-well black plates. Cells only and medium only wells were also added. On 3 dpi and 5 dpi, cells were lysed for evaluation of the ATP content using Promega’s Cell Titer Gio kit. The luciferase luminescence in relative light units (RLU) was read and 50% cytotoxicity concentration (CC₅₀) was calculated using the XLfit dose response model. The result is shown in Figure 5.

Claims

CLAIMS WE CLAIM

1. A method of treating a viral infection in a subj ect in need thereof, comprising administering an effective amount of a cMET inhibitor, or a pharmaceutically acceptable salt thereof, to the subject, which is infected with a coronavirus, adenovirus, or herpes simplex virus.

2. The method of claim 1, wherein the viral infection is a coronavirus infection; wherein, optionally, the coronavirus causes a SARS or MERS infection; preferably a SARS-CoV-1, SARS-CoV-2 or MERS-CoV infection.

3. The method of claim 1 or 2, wherein the coronavirus is SARS-CoV-2.

4. The method of any one of claims 1-3, wherein the cMET inhibitor is selected from the group of:

or a pharmaceutically acceptable salt and/or solvate or hydrate thereof.

5. The method of any of claims 1-4, wherein the cMET inhibitor is selected from the group consisting of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6- oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, 3-(1-{3-[5-(1-methyl-piperidin-4- ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]- benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl)-benxonitrile hydrochloride monohydrate, and crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2- yl]-benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate.

6. The method of any one of claims 1-5, wherein the administration of the cMET inhibitor results in the reduction of the viral load in the subject; wherein, optionally, the administration of the cMET inhibitor reduces the viral load by suppressing neutrophil accumulation and inflammation, and/or preventing further virus invasion.

7. The method of claim 6, wherein the cMET inhibitor is administered prior to COVID-19 pneumonia development or prior to the subject developing a cytokine storm.

8. The method of any one of the preceding claims, wherein the subject is asymptomatic at the start of the administration regimen or has a mild to moderate SARS-CoV-2 infection.

9. The method of any one of the preceding claims, wherein the subject has been previously vaccinated with a SARS-CoV-2 vaccine and develops vaccine-related exacerbation of infection.

10. The method of any one of claims 1-8, wherein the subject begins administration of the cMET inhibitor prior to being formally diagnosed with SARS-CoV-2 infection.

11. The method of any one of the preceding claims, further comprising administration of one or more additional therapeutic agents; wherein, optionally, the one or more additional therapeutic agents is selected from the group of anti-inflammatories, antibiotics, anti-coagulants, antiparasitic agent, antiplatelet agents and dual antiplatelet therapy, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, statins and other combination cholesterol lowering agents, specific cytokine inhibitors, complement inhibitors, anti-VEGF treatments, JAK inhibitors, immunomodulators, anti-inflammasome therapies, sphingosine-1 phosphate receptors binders, N-methyl-d-aspartate (MDMA) receptor glutamate receptor antagonists, corticosteroids, Granulocyte-macrophage colony- stimulating factor (GM-CSF), anti-GM-CSF, interferons, angiotensin receptor-neprilysin inhibitors, calcium channel blockers, vasodilators, diuretics, muscle relaxants, and antiviral medications; preferably an antiviral medication.

12. The method of claim 11, wherein the one or more additional therapeutic agent is selected from the group of hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, virazole, ribavirin, remdesivir, lopinavir-ritonavir, favipiravir, leronlimab, interferon-1-beta, interferon beta-1a, interferon beta-1b, beta-interferon, azithromycin, nitazoxanide, lovastatin, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone, ravulizumab-cwvz, eculizumab, bevacizumab, heparin, enoxaparin, apremilast, coumadin, baricitinib, ruxolitinib, dapagliflozin, colchicine, fingolimod, ifenprodil, prednisone, cortisol, dexamethasone, methylprednisolone, GM-CSF, otilimab, ATR-002, APN-01, camostat mesylate, arbidol, brilacidin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and solnatide; preferably remdesivir, lopinavir-ritonavir, chloroquine, hydroxychloroquine, or interferon- 1-beta.

13. The method of any one of the preceding claims, wherein the cMET inhibitor is administered daily or via oral administration, or both.

14. The method of any one of the preceding claims, wherein the total amount of cMET inhibitor administered is between about 225 mg and about 500 mg per day.

15. The method of any one of the preceding claims, wherein the cMET inhibitor is administered for about 7 days to about 21 days.