Patent Publication Number: US-2023150984-A1

Title: Nicotinamide mononucleotide and nicotinamide riboside derivatives and use thereof in the treatment of viral infections and respiratory complications, in particular caused by influenzavirus or coronavirus

Description:
FIELD OF INVENTION 
     The present invention relates to Nicotinamide mononucleotide derivatives compounds for use in the treatment and/or prevention of viral infections. 
     BACKGROUND OF INVENTION 
     The defense against diseases is critical for the survival of all animals, and the mechanism employed for this purpose is the animal immune system. With two main divisions involved being (i) innate immunity and (ii) adaptive immunity, the immune system is very complex. The innate immune system includes the cells and mechanisms that defend the host from infection by invading organisms, in a non-specific manner. Leukocytes, which are involved with the innate system, include inter alia phagocytic cells, such as macrophages, neutrophils and dendritic cells. The innate system is fully functional before a pathogen enters the host. 
     In contrast, the adaptive system is only initiated after the pathogen has entered the host cells, at which point it develops a pathogen-specific defense. The main cell types of the adaptive immune system are called lymphocytes, the two main categories of which are B cells and T Cells. B cells are involved in the creation of neutralizing antibodies that circulate in blood plasma and lymph and form part of the humoral immune response. T cells play a role in both the humoral immune response and the cell-mediated immunity. There are several subsets of activator or effector T cells, including cytotoxic T cells (CD8+) and “helper” T cells (CD4+), of which there are two main types known as Type 1 helper T cells (Th1) and Type 2 helper T cell (Th2). 
     Th1 cells promote a cell-mediated adaptive immune response, which involves the activation of macrophages and stimulates the release of various cytokines, such as IFNγ, TNF-α and IL-12, in response to an antigen. These cytokines influence the function of other cells in the adaptive and innate immune responses, and result in the destruction of micro-organisms. Generally, Th1 responses are more effective against intracellular pathogens, such as viruses and bacteria present inside host cells, while a Th2 responses are more effective against extracellular pathogens, such as parasites and toxins located outside host cells. 
     Amongst viral infections, acute viral infections are the most difficult to control when vaccines are not available. Antiviral therapy is often not effective if not given early in infection, as seen with influenza, measle or the frequent outbreak of norovirus gastroenteritis, which affect millions of people each year. 
     Amongst acute viral infections, respiratory infection is the most common type in people; causative agents including rhinoviruses, respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, measles, mumps, adenovirus and coronaviruses. 
     Most respiratory infections, especially those of the upper respiratory tract, are mild and not incapacitating. Upper respiratory tract infections often cause rhinorrhea or pharyngitis. Lower respiratory tract infections can be more severe and are more likely than upper respiratory tract infections to cause fever, dyspnea, chest pain or pneumonia. Cough is often present in either upper or lower respiratory tract infections. 
     Typical influenza in adults is characterized by sudden onset of chills, fever, prostration, cough, and generalized aches and pains (especially in the back and legs). Headache is prominent, often with photophobia and retrobulbar aching. Respiratory symptoms may be mild at first, with scratchy sore throat, substernal burning, nonproductive cough and sometimes coryza. Later, lower respiratory tract illness becomes dominant; cough can be persistent, raspy and productive and may evolve in pneumonia. 
     While most patients recover fully often after 1 to 2 weeks, influenza and influenza-related pneumonia are important causes of morbidity or mortality in high-risk patients. In France, seasonal influenza affects 2 to 8 million people and is responsible for 10,000 to 15,000 deaths each year. 
     To date, treatment of influenza is symptomatic, with the application of sanitary measures to limit transmission, and may also involve specific antiviral treatment. The antivirals available in France are neuraminidase inhibitors, oseltamivir (Tamiflu®), which is active on types A and B viruses, is available in oral form. It reduces the duration of the disease and the severity of symptoms if taken early, i.e. within 48 hours of the onset of symptoms. It also reduces the risk of complications and mortality. Another neuraminidase inhibitor, zanamivir (Relenza®) can be prescribed in hospital in case of resistance to intravenous oseltamivir. Apart from sanitary measures, the annual flu vaccination remains the most effective way to protect oneself. It helps to reduce severe forms of influenza. 
     However, the emergence of resistance under treatment may occur. A recurrence of symptoms after one day or less of treatment has also been observed in some serious cases (pneumonia or hospitalization) with antivirals treatment. 
     Therefore, there is still a need for effective and safe prophylactic and/or therapeutic treatments of viral infections, in particular acute viral infections, such as respiratory infections. 
     In December 2019, a new highly contagious viral pneumonia (R0≈2.2) emerged, and the epidemic was quickly qualified by the World Health Organization (WHO) as a threat to global public health. The first patients with this unexplained pneumonia appeared in Wuhan, China. A few days later, the virus was identified as a new beta coronavirus, a single-stranded RNA-positive virus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-Cov-2 is the seventh coronavirus affecting the human population and the third highly pathogenic coronavirus after the coronaviruses outbreak of severe acute respiratory syndrome (SARS-CoV-2002) first identified in 2003 and Middle East respiratory syndrome (MERS-CoV-2012) first identified in 2012. 
     Currently, the incidence of disease associated with SARS-Cov-2, is found in more than 200 countries and territories worldwide and according to WHO data (22 Apr. 2020), the number of confirmed cases worldwide has reached more than 2 million individuals including 162,956 deaths. Not all people exposed to SARS-CoV-2 are infected and not all infected patients develop severe respiratory disease. According to a study of more than 1000 patients in Wuhan, SARS-CoV-2 infects all age groups equally, although children and adolescents appear to be less affected and rarely develop severe forms. This protection to infection could only be relative since the number of cases of infection identified in the youngest age groups increases considerably, probably as a consequence of the increased frequency of performed screening. 
     COVID-19 is a respiratory illness generally first presenting with symptoms including headache, muscle pain, and/or fatigue/tiredness followed by fever and respiratory symptoms (such as a dry cough, shortness of breath, and/or chest tightness). While the symptoms remain mild in the majority of subjects, in others they may progress to pneumonia (referred herein as COVID-19 associated pneumonia or COVID-19 pneumonia) and/or to multi-organ failure. Complications of COVID-19 include acute respiratory distress syndrome (ARDS), RNAaemia, acute cardiac injury and secondary infections (Huang et al., Lancet. 2020; 395(10223):497-506). It is estimated that about 20% of subjects suffering from COVID-19 require hospitalization and about 5% require admission to intensive care unit (ICU). COVID-19 causes substantial morbidity and mortality and may place unprecedented strain on many health systems. 
     With no vaccine, antiviral drug, or other specific treatment available, treatment of COVID-19 remains supportive. Over 175 treatments and vaccines clinical trials are currently registered and current therapeutic strategies include antiviral agents, notably remdesivir (a nucleotide analog), lopinavir/ritonavir (a antiretroviral therapy notably used for the treatment of human immunodeficiency virus 1 (HIV-1)), chloroquine or hydroxychloroquine, and Il-6 inhibitors immunomodulatory agents such as tocilizumab. However, there is currently neither any vaccine to prevent and/or treat COVID-19 or asymptomatic infection with SARS-CoV-2, nor any therapeutic agent with a proven efficacy for preventing and/or treating COVID-19, COVID-19 associated pneumonia or COVID-19 associated acute respiratory distress syndrome (ARDS). 
     Therefore, there is an urgent need for effective and safe prophylactic and/or therapeutic treatments for coronavirus infections, in particular coronavirus respiratory infections causing diseases such as SARS, MERS, COVID-19 and in particular COVID-19 associated pneumonia and COVID-19 associated acute respiratory distress syndrome (ARDS). 
     Nicotinamide mononucleotide (NMN) is a nucleotide that is already known. 
     The purpose of the present invention is thus to provide an alternative to current treatments by providing Nicotinamide mononucleotide and derivatives thereof for use in the treatment and/or prevention of a viral infections, in particular of respiratory infections, such as influenza virus or coronavirus. 
     The Applicant surprisingly found that the Nicotinamide mononucleotide derivatives according to the invention are potent agents to treat and/or prevent viral infections, and are well tolerated. 
     SUMMARY 
     This invention thus relates to a Compound of Formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof;
 
wherein:
 
X is selected from O, CH 2 , S, Se, CHF, CF 2  et C═CH 2 ;
 
R 1  is selected from H, azido, cyano, C 1 -C 8  alkyl, C 1 -C 8  thio-alkyl, C 1 -C 8  heteroalkyl and OR; wherein R is selected from H and C 1 -C 8  alkyl;
 
R 2 , R 3 , R 4  et R 5  are independently selected from H, halogen, azido, cyano, hydroxyl, C 1 -C 12  alkyl, C 1 -C 12  thioalkyl, C 1 -C 12  heteroalkyl, C 1 -C 12  haloalkyl and OR; wherein R is selected from H, C 1 -C 12  alkyl, C(O)(C 1 -C 12 )alkyl, C(O)NH(C 1 -C 12 )alkyl, C(O)O(C 1 -C 12 )alkyl, C(O)aryl, C(O)(C 1 -C 12 )alkyl aryl, C(O)NH(C 1 -C 12 )alkyl aryl, C(O)O(C 1 -C 12 )alkyl aryl and C(O)CHR AA NH 2 ; wherein R AA  is a side chain selected from a proteinogenic amino acid;
 
R 6  is selected from H, azido, cyano, C 1 -C 8  alkyl, C 1 -C 8  thio-alkyl, C 1 -C 8  heteroalkyl and OR; wherein R is selected from H and C 1 -C 8  alkyl;
 
R 7  is selected from P(O)R9R10, P(S)R9R10 and
 
     
       
         
         
             
             
         
       
     
     wherein n is an integer chosen amongst 1 or 3; wherein:
         R 9  and R 10  are independently selected from OH, OR 11 , NHR 13 , NR 13 R 14 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 5 -C 12  aryl, C 1 -C 8  arylalkyl, C 1 -C 8  alkylaryl, C 1 -C 8  heteroalkyl, C 1 -C 8  heterocycloalkyl, heteroaryl and NHCR α R α′ C(O)R 12 ; wherein:
           R 11  is selected from C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, C 5 -C 12  aryl, C 1 -C 10  alkylaryl, substituted C 5 -C 12  aryl, C 1 -C 10  heteroalkyl, C 1 -C 10  haloalkyl, —(CH 2 ) n C(O)(C 1 -C 15 )alkyl, —(CH 2 ) n OC(O)(C 1 -C 15 )alkyl, —(CH 2 ) n OC(O)O(C 1 -C 15 )alkyl, —(CH 2 ) n SC(O)(C 1 -C 15 )alkyl, —(CH 2 ) n C(O)O(C 1 -C 15 )alkyl and —(CH 2 ) n C(O)O(C 1 -C 15 )alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH) 2 ; halogen, nitro, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, —N(R11a)2, C1-C6 acylamino, —COR11b, —OCOR11b; NHSO2(C1-C6 alkyl), —SO2N(R11a)2 S 02  wherein each of R11a is independently selected from H and (C1-C6) alkyl and R11b is independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2;   R 12  is selected from hydrogen, C 1 -C 10  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 1 -C 10  haloalkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloheteroalkyl, C 5 -C 12  aryl, C 1 -C 4  alkylaryl and C 5 -C 12  heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and cyano;   R 13  and R 14  are independently selected from H, C 1 -C 8  alkyl and C 1 -C 8  alkyl-aryl;   R α  and R α′  are independently selected from an hydrogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 1 -C 10  thio-alkyl, C 1 -C 10  hydroxylalkyl, C 1 -C 10  alkylaryl and C 5 -C 12  aryl, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C 1 -C 10  alkyl, C 1 -C 6  alkoxy, halogen, nitro and cyano; or   
           R 9  and R 10  together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R 9 -R 10 — represents —CH 2 —CH 2 —CHR—; wherein R is selected from hydrogen, C 5 -C 6  aryl and C 5 -C 6  heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and cyano; or   R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R9-R10- represents —O—CH2-CH2-CHR—O—; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano;
 
R 8  is selected from H, OR, NHR15, NR15R16, NH—NHR13, SH, CN, N3 and halogen; wherein R15 and R16 are independently selected from H, C1-C8 alkyl and C1-C8 alkyl aryl; and —CRBRC—C(O)—ORD wherein RB and RC are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, benzyl, indolyl or imidazolyl, wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally and independently of each other substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or RB and RC together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group optionally substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol and carboxyl groups and RD is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl;
 
Y is selected from CH, CH 2 , C(CH 3 ) 2  and CCH 3 ;
 
  represents a single or double bond according to Y; and
 
  represents the alpha or beta anomer depending on the position of R 1 ,
   or a compound of formula (Ia)       

     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein:
         X′ 1  and X′ 2  are independently selected from O, CH 2 , S, Se, CHF, CF 2  and C═CH 2 ;   R′ 1  and R′ 13  are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl;   R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11 , R′ 12  are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1-C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1-C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHR AA NH 2 , wherein R AA  is a side chain selected from a proteinogenic amino acid;   R′ 6  and R′ 8  are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl;   R′ 7  and R′ 14  are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N 3  and halogen; wherein R and R′ are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl;   Y′ 1  and Y′ 2  are independently selected from CH, CH 2 , C(CH 3 ) 2  or CCH 3 ;   M′ is selected from H or a suitable counterion;      represents a single or a double bound depending on Y′ 1  and Y′ 2 ; and      represents the alpha or beta anomer depending on the position of R′ 1  and R′ 13 ,
 
for use in the treatment and/or prevention of viral infections.
       

     According to one embodiment, X represent an oxygen. 
     According to one embodiment, R 1  and R 6  each independently represents a hydrogen. 
     According to one embodiment, R 2 , R 3 , R 4  and R 5  each independently represents a hydrogen. 
     According to one embodiment, R 2 , R 3 , R 4  and R 5  each independently represents a OH. 
     According to one embodiment, Y represents a CHI or a CH 2 . 
     According to one embodiment, R 7  represents P(O)R 9 R 10 , wherein R 9  and R 10  are as described in claim  1 . 
     According to one embodiment, the compound for use according to the invention is selected from compounds I-A to I-J, listed in table 1 below, or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof. 
     
       
         
           
               
               
             
               
                   
               
               
                 Compounds 
                   
               
               
                 (anomeres) 
                 Structure 
               
               
                   
               
             
            
               
                 I-A (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-B (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-C (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-D (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-E (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-F (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-G (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-H (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-I (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-J (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Advantageously, preferred compound of the invention are compounds I-A to I-F or a pharmaceutically acceptable salt or solvate thereof, more preferably TB, ID or IF. 
     Advantageously, the compound of formula (I) is dihydro-nicotinamide mononucleotide (NMN-H) of the following formula: 
     
       
         
         
             
             
         
       
     
     According to one embodiment, X′ 1  and X′ 2  each independently represents an oxygen. 
     According to one embodiment, R′ 7  and R′ 14  each independently represents a NH 2 . 
     According to one embodiment, R′ 1  and/or R′ 13  each independently represents a hydrogen. 
     According to one embodiment, R′ 6  and/or R&#39;s each independently represents a hydrogen. 
     According to one embodiment, R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11  and R′ 12  each independently represents a hydrogen. 
     According to one embodiment, R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11  and R′ 12  each independently represents a OH. 
     According to one embodiment, Y′ 1  and Y′ 2  each independently represents a CH. 
     According to one embodiment, Y′ 1  and Y′ 2  each independently represents a CH 2 . 
     According to one embodiment, the compound according to the invention is selected from compounds of formula Ia-A to Ia-I, listed in table 2, or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof. 
     
       
         
           
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Compound  
                 Structure 
               
               
                   
               
             
            
               
                 Ia-A (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-B (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-C (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-D (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-E (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-F (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-G (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-H (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-I (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     Advantageously, preferred compound of the invention is compound of formula Ia-C or Ia-F or Ia-I. 
     Advantageously, preferred compound of the invention is compound of formula Ia-B or Ia-E or Ia-H. 
     According to one embodiment, said use comprising a step of administering sequentially, simultaneously and/or separately at least another active ingredient selected from an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin, another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a histamine H2 receptor antagonist, and a mixture thereof. According to one embodiment, said histamine H2 receptor antagonist is chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, preferably famotidine. 
     According to one embodiment, the viral infection is caused by at least one virus of the genus selected from Influenzavirus, Coronavirus, Respirovirus, Pneumovirus, Metapneumovirus, Adenovirus, Enterovirus, Rhinovirus, Hepatovirus, Erbovirus, Aphtovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepacivirus, Pestivirus, Ebola-like virus, Morbillivirus, Rubulavirus, Henipavirus, Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Simplexvirus, Varicellovirus or Cytomegalovirus. 
     According to one embodiment, the viral infection is a respiratory infection caused by at least one virus of the genus selected from Influenzavirus, Coronavirus, Rhinovirus, Respirovirus, Pneumovirus or Metapneumovirus. 
     According to one embodiment, the viral infection is a respiratory infection caused by Influenzavirus, preferably influenza A or influenza B. 
     According to one embodiment, the viral infection is a respiratory infection selected from H1N1, H3N2, H5N1, B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. 
     According to one embodiment, the coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV—OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2. 
     According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19). 
     According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated pneumonia. 
     According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated acute respiratory distress syndrome (ARDS). 
     The invention also relates to a pharmaceutical composition for use in treatment and/or prevention of viral infections comprising at least one compound for use according to the invention and at least one pharmaceutically acceptable carrier. 
     According to one embodiment, the pharmaceutical composition for use comprises in addition to at least one compound for use according to the invention, at least one active ingredients, selected from an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon and a mixture thereof, and/or at least another active ingredient selected from an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon and a mixture thereof, and/or at least another active ingredient selected from an antiviral agent; an anti-interleukin 6 (anti-IL6) agent; a Janus-associated kinase (JAK) inhibitor; an interferon; a macrolide, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin, another active ingredient selected from BXT 25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a histamine H2 receptor antagonist, and a mixture thereof. 
     In an embodiment, the pharmaceutical composition for use comprises in addition to at least one compound for use according to the invention, a histamine H2 receptor antagonist. 
     According to one embodiment, said histamine H2 receptor antagonist is chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, preferably famotidine. The present invention further relates to a method for preparing compounds of formula Ia, comprising the following steps:
         1) mono-phosphorylation of a compound of formula Xa,       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: 
                 X′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 ,   and   are as defined in claim  1 , 
                 to give compound of formula XIa, 
               
             
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: 
                 X′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 ,   and   are as defined in claim  1 ; 
               
             
             2) hydrolysis of compound of formula XIa obtained in step 1), to give compound of formula XIIa 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein: 
                 X′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 ,   and   are as defined in claim  1 ;    
               
             
             3) reacting compound of formula XIIa obtained in step 2) with compound of formula XIIIa, 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 obtained as described in step 1) and wherein: 
                 X′ 2 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , R′ 13 , R′ 14 , Y′ 2 ,   and   are as defined in claim  1 , 
                 to give compound of formula Ia.    
               
             
           
         
       
    
     According to one embodiment, the method further comprises a step of reducing the compound of formula Ia obtained in step 3), to give the compound of formula Ia, wherein Y′ 1  and Y′ 2  each independently represents a CH 2 . 
     Definitions 
     The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims. 
     When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise. 
     Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the adjacent functionality toward the point of attachment followed by the terminal portion of the functionality. For example, the substituent “arylalkyl” refers to the group -(aryl)-(alkyl). 
     In the present invention, the following terms have the following meanings: 
     The term “alkyl” by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H 2n+1  wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched alkyls include, without being limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl. 
     Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), hexyl and its isomers (e.g. n-hexyl, isohexyl), heptyl and its isomers (e.g. heptyl-heptyl, iso-heptyl), octyl and its isomers (e.g. n-octyl, iso-octyl), nonyl and its isomers (e.g. n-nonyl, iso-nonyl), decyl and its isomers (e.g. n-decyl, iso-decyl), undecyl and its isomers, dodecyl and its isomers. Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Cx-Cy-alkyl refers to alkyl groups which comprise x to y carbon atoms. 
     When the suffix “ene” (“alkylene”) is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term “alkylene” includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1,2-dimethylethylene. 
     The term “alkenyl” as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 12 carbon atoms, preferably between 2 and 8 carbon atoms, still more preferably between 2 and 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like. 
     The term “alkynyl” as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers—and the like. 
     The term “aryl” as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. 
     The term “cycloalkyl” as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred. 
     The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro. 
     The term “haloalkyl” alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoro methyl, 1,1,1-trifluoroethyl and the like. Cx-Cy-haloalkyl and Cx-Cy-alkyl are alkyl groups which comprise x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl. 
     Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring. 
     The term “heteroalkyl” means an alkyl group as defined above in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, the heteroatoms are linked along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from any other heteroatom by at least one carbon atom. However, the nitrogen and sulphur heteroatoms may optionally be oxidised and the nitrogen heteroatoms may optionally be quaternised. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e. the bonding atom is not selected from the heteroatoms included in the heteroalkyl group. 
     The term “heteroaryl” as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl. 
     Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as “heterocycloalkyl” or “heterocyclyl”. 
     The terms “heterocyclyl”, “heterocycloalkyl” or “heterocyclo” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl. 
     The term “non-proteinogenic amino acid” as used herein refers to an amino acid not naturally encoded or found in the genetic code of living organism. Non limiting examples of Non-proteinogenic amino acid are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, δ-aminolevulinic acid, β-alanine, cystathionine, γ-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, α-aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate. 
     The term “proteinogenic amino acid” as used herein refers to an amino acid that is incorporated into proteins during translation of messenger RNA by ribosomes in living organisms, i.e. Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cysteine (CYS), Glutamate (glutamic acid) (GLU), Glutamine (GLN), Glycine (GLY), Histidine (HIS), Isoleucine (ILE), Leucine (LEU), Lysine (LYS), Methionine (MET), Phenylalanine (PHE), Proline (PRO), Pyrrolysine (PYL), Selenocysteine (SEL), Serine (SER), Threonine (THR), Tryptophan (TRP), Tyrosine (TYR) or Valine (VAL). 
     The term “prodrug” as used herein means the pharmacologically acceptable derivatives of compounds of formula (I) such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters. 
     The term “substituent” or “substituted” means that a hydrogen radical on a compound or group is replaced by any desired group which is substantially stable under the reaction conditions in an unprotected form or when protected by a protecting group. Examples of preferred substituents include, without being limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl, as described above; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (—O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO 2 CH 3 ; CONH 2 ; OCH 2 CONH 2 ; NH 2 ; SO 2 NH 2 ; OCHF 2 ; CF 3 ; OCF 3 ; and such moieties may also be optionally substituted by a fused-ring structure or bridge, for example —OCH 2 O—. These substituents may optionally be further substituted with a substituent selected from such groups. In certain embodiments, the term “substituent” or the adjective “substituted” refers to a substituent selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroarylalkyl, a haloalkyl, 
     —C(O)NR 11 R 12 , —NR 13 C(O)R 14 , a halo, —OR 13 , cyano, nitro, a haloalkoxy, —C(O)R 13 , —NR 11 R 12 , —SR 13 , —C(O)OR 13 , —OC(O)R 13 , —NR 13 C(O)NR 11 R 12 , —OC(O)NR 11 R 12 , —NR 13 C(O)OR 14 , —S(O) r R 13 , —NR 13 S(O)rR 14 , —OS(O)rR 14 , S(O)rNR 11 R 12 , —O, —S, and —N—R 13 , wherein r is 1 or 2; R 11  and R 12 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl; or R 11  and R 12  taken together with the nitrogen to which they are attached is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 13  and R 14  for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl. In certain embodiments, the term “substituent” or the adjective “substituted” refers to a solubilizing group. 
     The term “active ingredient” refers to a molecule or a substance whose administration to a subject slows down or stops the progression, aggravation, or deterioration of one or more symptoms of a disease, or condition; alleviates the symptoms of a disease or condition; cures a disease or condition. According to one embodiment, the therapeutic ingredient is a small molecule, either natural or synthetic. According to another the therapeutic ingredient is a biological molecule such as for example an oligonucleotide, a siRNA, a miRNA, a DNA fragment, an aptamer, an antibody and the like. 
     By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof. 
     The term “pharmaceutically acceptable excipient” or “pharmaceutical vehicle” refers to an inert medium or carrier used as a solvent or diluent in which the pharmaceutically active agent is formulated and/or administered, and which does not produce an adverse, allergic or other reaction when administered to an animal, preferably a human being. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retardants and other similar ingredients. For human administration, preparations must meet standards of sterility, general safety and purity as required by regulatory agencies such as the FDA or EMA. For the purposes of the invention, “pharmaceutically acceptable excipient” includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents, and/or adjuvants. 
     The term “pharmaceutically acceptable salts” include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. 
     Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. 
     Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. 
     Pharmaceutically acceptable salts of compounds of Formula (I) may be prepared by one or more of these methods:
         (i) by reacting the compound of Formula (I) with the desired acid;   (ii) by reacting the compound of Formula (I) with the desired base;   (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or   (iv) by converting one salt of the compound of Formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.       

     All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. 
     Although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above. 
     The term “solvate” is used herein to describe a molecular complex comprising a compound of the invention and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, such as ethanol. The term ‘hydrate’ refers to when said solvent is water. 
     The term “administration”, or a variant thereof (e.g., “administering”), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented. 
     The term “human” refers to a subject of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult). 
     The term “patient” refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure. 
     The terms “treat”, “treating” and “treatment”, as used herein, are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms. 
     The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient&#39;s risk of acquiring a condition or disease. 
     The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered. 
     The bonds of an asymmetric carbon can be represented here using a solid triangle ( ), a dashed triangle ( ) or a zigzag line ( ). 
     DETAILED DESCRIPTION 
     Compound for Use in the Treatment and/or Prevention of Viral Infections 
     This invention thus relates to a Compound of Formula (I), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof;
 
wherein:
 
X is selected from O, CH 2 , S, Se, CHF, CF 2  et C═CH 2 ;
 
R 1  is selected from H, azido, cyano, C 1 -C 8  alkyl, C 1 -C 8  thio-alkyl, C 1 -C 8  heteroalkyl and OR; wherein R is selected from H and C 1 -C 8  alkyl;
 
R 2 , R 3 , R 4  et R 5  are independently selected from H, halogen, azido, cyano, hydroxyl, C 1 -C 12  alkyl, C 1 -C 12  thioalkyl, C 1 -C 12  heteroalkyl, C 1 -C 12  haloalkyl and OR; wherein R is selected from H, C 1 -C 12  alkyl, C(O)(C 1 -C 12 )alkyl, C(O)NH(C 1 -C 12 )alkyl, C(O)O(C 1 -C 12 )alkyl, C(O)aryl, C(O)(C 1 -C 12 )alkyl aryl, C(O)NH(C 1 -C 12 )alkyl aryl, C(O)O(C 1 -C 12 )alkyl aryl and C(O)CHR AA NH 2 ; wherein R AA  is a side chain selected from a proteinogenic amino acid;
 
R 6  is selected from H, azido, cyano, C 1 -C 8  alkyl, C 1 -C 8  thio-alkyl, C 1 -C 8  heteroalkyl and OR; wherein R is selected from H and C 1 -C 8  alkyl;
 
R 7  is selected from P(O)R9R10, P(S)R9R10 and
 
     
       
         
         
             
             
         
       
     
     wherein n is an integer chosen amongst 1 or 3; wherein:
         R 9  and R 10  are independently selected from OH, OR 11 , NHR 13 , NR 13 R 14 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 5 -C 12  aryl, C 1 -C 8  arylalkyl, C 1 -C 8  alkylaryl, C 1 -C 8  heteroalkyl, C 1 -C 8  heterocycloalkyl, heteroaryl and NHCR α R α′ C(O)R 12 ; wherein:
           R 11  is selected from C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, C 5 -C 12  aryl, C 1 -C 10  alkylaryl, substituted C 5 -C 12  aryl, C 1 -C 10  heteroalkyl, C 1 -C 10  haloalkyl, —(CH 2 ) n C(O)(C 1 -C 15 )alkyl, —(CH 2 ) n OC(O)(C 1 -C 15 )alkyl, —(CH 2 ) n OC(O)O(C 1 -C 15 )alkyl, —(CH 2 ) n SC(O)(C 1 -C 15 )alkyl, —(CH 2 ) n C(O)O(C 1 -C 15 )alkyl and —(CH 2 ) n C(O)O(C 1 -C 15 )alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH) 2 ; halogen, nitro, cyano, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, —N(R11a)2, C1-C6 acylamino, —COR11b, —OCOR11b; NHSO2(C1-C6 alkyl), —SO2N(R11a)2 SO2 wherein each of R11a is independently selected from H and (C1-C6) alkyl and R11b is independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2;   R 12  is selected from hydrogen, C 1 -C 10  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 1 -C 10  haloalkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloheteroalkyl, C 5 -C 12  aryl, C 1 -C 4  alkylaryl and C 5 -C 12  heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and cyano;   R 13  and R 14  are independently selected from H, C 1 -C 8  alkyl and C 1 -C 8  alkyl-aryl;   R α  and R α′  are independently selected from an hydrogen, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 1 -C 10  thio-alkyl, C 1 -C 10  hydroxylalkyl, C 1 -C 10  alkylaryl and C 5 -C 12  aryl, —(CH 2 ) 3 NHC(═NH)NH 2 , (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C 1 -C 10  alkyl, C 1 -C 6  alkoxy, halogen, nitro and cyano; or   
           R 9  and R 10  together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R 9 —R 10 — represents —CH 2 —CH 2 —CHR—; wherein R is selected from hydrogen, C 5 -C 6  aryl and C 5 -C 6  heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy and cyano; or   R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein —R9-R10- represents —O—CH2-CH2-CHR—O—; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano;
 
R 8  is selected from H, OR, NHR15, NR15R16, NH—NHR13, SH, CN, N3 and halogen; wherein R15 and R16 are independently selected from H, C1-C8 alkyl and C1-C8 alkyl aryl; and —CRBRC—C(O)—ORD wherein RB and RC are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, benzyl, indolyl or imidazolyl, wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally and independently of each other substituted by one or more of halogen, amino, amido, guanidyl, hydroxyl, thiol or carboxyl groups, and the benzyl group is optionally substituted by one or more of the halogen or hydroxyl groups, or RB and RC together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group optionally substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol and carboxyl groups and RD is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl;
       

     Y is selected from CH, CH 2 , C(CH 3 ) 2  and CCH 3 ; 
        represents a single or double bond according to Y; and 
        represents the alpha or beta anomer depending on the position of R 1 , 
     or a compound of formula (Ia) 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein:
         X′ 1  and X′ 2  are independently selected from O, CH 2 , S, Se, CHF, CF 2  and C═CH 2 ;   R′ 1  and R′ 13  are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl;   R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11 , R′ 12  are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1-C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1-C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHR AA NH 2 , wherein R AA  is a side chain selected from a proteinogenic amino acid;   R′ 6  and R′ 8  are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl;   R′ 7  and R′ 14  are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N 3  and halogen; wherein R and R′ are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl;   Y′ 1  and Y′ 2  are independently selected from CH, CH 2 , C(CH 3 ) 2  or CCH 3 ;   M′ is selected from H or a suitable counterion;      represents a single or a double bound depending on Y′ 1  and Y′ 2 ; and      represents the alpha or beta anomer depending on the position of R′ 1  and R′ 13 ,
 
for use in the treatment and/or prevention of viral infections.
       

     According to one embodiment, X is selected from O, CH 2  and S. 
     According to one embodiment, R 1  is selected from hydrogen or OH. In one embodiment, R 1  is hydrogen. In one embodiment, R 1  is OH. 
     According to one embodiment, R 2 , R 3 , R 4  and R 5  are independently selected from hydrogen, halogen, hydroxyl, C 1 -C 12  alkyl and OR; wherein R is as described herein above. In a preferred embodiment, R 2 , R 3 , R 4  and R 5  are independently selected from hydrogen, hydroxyl and OR; wherein R is as described herein above. In a more preferred embodiment R 2 , R 3 , R 4  and R 5  are independently selected from hydrogen or OH. 
     According to one embodiment, R 2  and R 3  are identical. In one embodiment, R 2  and R 3  are identical and represent OH. In one embodiment, R 2  and R 3  are identical and represent hydrogen. 
     According to one embodiment, R 2  and R 3  are different. In a preferred embodiment, R 2  is hydrogen and R 3  is OH. In a more preferred embodiment, R 2  is OH and R 3  is hydrogen. 
     According to one embodiment, R 4  and R 5  are identical. In one embodiment, R 4  and R 5  are identical and represent OH. In one embodiment, R 4  and R 5  are identical and represent hydrogen. 
     According to one embodiment, R 2  and R 3  are different. In a preferred embodiment, R 4  is OH and R 5  is hydrogen. In a more preferred embodiment, R 4  is hydrogen and R 5  is OH. 
     According to one embodiment, R 3  and R 4  are different. In one embodiment, R 3  is OH and R 4  is hydrogen. In one embodiment, R 3  is hydrogen and R 4  is OH. 
     According to one embodiment, R 3  and R 4  are identical. In a preferred embodiment, R 3  and R 4  are identical and represent OH. In a more preferred embodiment, R 3  and R 4  are identical and represent hydrogen. 
     According to one embodiment, R 2  and R 5  are different. In one embodiment, R 2  is hydrogen and R 5  is OH. In one embodiment, R 2  is OH and R 5  is hydrogen. 
     According to one embodiment, R 2  and R 5  are identical. In a preferred embodiment, R 2  and R 5  are identical and represent hydrogen. In a more preferred embodiment, R 2  and R 5  are identical and represent OH. 
     According to one embodiment, R 6  is selected from hydrogen or OH. In one embodiment, R 6  is OH. In a preferred embodiment, R 6  is hydrogen. 
     According to one embodiment, R 7  is selected from P(O)R 9 R 10  or P(S)R 9 R 10 ; wherein R 9  and R 10  are as described herein above. In a preferred embodiment, R 7  is P(O)R 9 R 10 ; wherein R 9  and R 10  are as described herein above. In a preferred embodiment, R 7  is P(O)(OH) 2 . 
     According to one embodiment, R 8  is selected from H, OR, NHR 13  or NR 13 R 14 ; wherein R 13  and R 14  are as described herein above. In a preferred embodiment, R 8  is NHR 13 ; wherein R 13  and R 14  are as described herein above. 
     According to one embodiment, Y is a CH or CH 2 . In one embodiment, Y is a CH. In one embodiment, Y is a CH 2 . 
     According to one preferred embodiment, compounds of formula (I) are those wherein X is an oxygen. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (II): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 1  is hydrogen. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (III): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 2  is OH and R 3  is hydrogen. 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 4  is hydrogen and R 5  is OH. 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 3  and R 4  are identical and represent hydrogen. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (IV): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 2 , R 5 , R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 2  and R 5  are identical and represent OH. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (V): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 6  is hydrogen. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (VI): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 8  is NH 2 . 
     According to a preferred embodiment, the invention relates to compounds of general Formula (VII): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof, wherein R 7 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein Y is CH. 
     According to a preferred embodiment, the invention relates to compounds of general Formula (VIII): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 7 ,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein Y is CH 2 . 
     According to a preferred embodiment, the invention relates to compounds of general Formula (IX): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R 7 ,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, preferred compounds of formula (I) are those wherein R 7  is P(O)(OH) 2 . 
     According to a preferred embodiment, the invention relates to compounds of general formula (X): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, the compound according to the invention is selected from compounds I-A to I-J from Table 1 below or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof: 
     
       
         
           
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Compounds 
                   
               
               
                 (anomeres) 
                 Structure 
               
               
                   
               
             
            
               
                 I-A (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-B (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-C (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-D (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-E (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-F (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-G (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-H (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-I (beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 I-J (alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     According to one embodiment, preferred compound of the invention are compounds I-A to I-J or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof. According to one embodiment, more preferred compound of the invention is compounds I-A or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein X′ 1  and X′ 2  are independently selected from O, CH 2 , S. 
     According to one embodiment, R′ 7  and R′ 14  are independently selected from H, OR, NHR and NRR′ wherein R and R′ are independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl. According to one embodiment, R′ 7  and R′ 14  are NHR wherein R is selected from H, C1-C8 alkyl, C1-C8 alkyl aryl. 
     According to one embodiment, R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11 , R′ 12  are independently selected from H, halogen, hydroxyl, C1-C12 alkyl and OR. According to a preferred embodiment, R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11 , R′ 12  are independently selected from H, hydroxyl and OR, wherein R is as described herein above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein, R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 9 , R′ 10 , R′ 11 , R′ 12  are independently selected from H and OH. 
     According to one embodiment, R′ 2  and R′ 3  are identical. According to one embodiment, R′ 2  and R′ 3  are identical and represent each a OH. According to one embodiment, R′ 2  and R′ 3  are identical and represent each hydrogen. 
     According to a preferred embodiment, R′ 2  and R′ 3  are different. According to a preferred embodiment, R′ 2  is hydrogen and R′ 3  is a OH. According to a more preferred embodiment, R′ 2  is a OH and R′ 3  is hydrogen. 
     According to one embodiment, R′ 4  and R′ 5  are identical. According to one embodiment, R′ 4  and R′ 5  are identical and represent each a OH. According to one embodiment, R′ 4  and R′ 5  are identical and represent each hydrogen. 
     According to a preferred embodiment, R′ 4  and R′ 5  are different. According to a preferred embodiment, R′ 4  is a OH and R′ 5  is hydrogen. According to a more preferred embodiment, R′ 4  is hydrogen and R′ 5  is a OH. 
     According to one embodiment, R′ 3  and R′ 4  are identical. According to one embodiment, R′ 3  and R′4 are identical and represent each a OH. According to one embodiment, R′ 3  and R′ 4  are identical and represent each hydrogen. 
     According to a preferred embodiment, R′ 3  and R′ 4  are different. According to a preferred embodiment, R′ 3  is a OH and R′ 4  is hydrogen. According to a more preferred embodiment, R′ 3  is hydrogen and R′ 4  is a OH According to one embodiment, R′ 2  and R′ 5  are different. According to one embodiment, R′ 2  is hydrogen and R′ 5  is a OH. According to one embodiment, R′ 2  is a OH and R′ 5  is hydrogen. 
     According to a preferred embodiment, R′ 2  and R′ 5  are identical. According to a preferred embodiment, R′ 2  and R′ 5  are identical and represent each hydrogen. According to a more preferred embodiment, R′ 2  and R′ 5  are identical and represent each a OH. 
     According to one embodiment, R′ 9  and R′ 10  are identical. According to one embodiment, R′ 9  and R′ 10  are identical and represent each a OH. According to one embodiment, R′ 9  and R′ 10  are identical and represent each hydrogen. 
     According to a preferred embodiment, R′ 9  and R′ 10  are different. According to a preferred embodiment, R′ 9  is hydrogen and R′ 10  is a OH. According to a more preferred embodiment, R′ 9  is a OH and R′ 10  is hydrogen. 
     According to one embodiment, R′ 11  and R′ 12  are identical. According to one embodiment, R′ 11  and R′ 12  are identical and represent each a OH. According to one embodiment, R′ 11  and R′ 12  are identical and represent each hydrogen. 
     According to a preferred embodiment, R′ 11  and R′ 12  are different. According to a preferred embodiment, R′ 11  is a OH and R′ 12  is hydrogen. According to a more preferred embodiment, R′ 11  is hydrogen and R′ 12  is a OH. 
     According to one embodiment, R′ 10  and R′ 11  are different. According to one embodiment, R′ 10  is hydrogen and R′ 11  is a OH. According to one embodiment, R′ 10  is a OH and R′ 11  is hydrogen. 
     According to a preferred embodiment, R′ 10  and R′ 11  are identical. According to a preferred embodiment, R′ 10  and R′ 11  are identical and represent each a OH. According to a more preferred embodiment, R′ 10  and R′ 11  are identical and represent each hydrogen. 
     According to one embodiment, R′ 9  and R′ 12  are different. According to one embodiment, R′ 9  is hydrogen and R′ 12  is a OH. According to one embodiment, R′ 9  is a OH and R′ 12  is hydrogen. 
     According to a preferred embodiment, R′ 9  and R′ 12  are identical. According to a preferred embodiment, R′ 9  and R′ 12  are identical and represent each hydrogen. According to a more preferred embodiment, R′ 9  and R′ 12  are identical and represent each a OH. 
     According to one embodiment, Y′ 1  is CH. According to one embodiment, Y′ 1  is CH 2 . 
     According to one embodiment, Y′ 2  is CH. According to one embodiment, Y′ 2  is CH 2 . 
     According to one embodiment, X′ 1  and X′ 2  are different and are selected from the group as described above. According to one embodiment, X′ 1  and X′ 2  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein X′ 1  and X′ 2  each independently represents an Oxygen. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein X′ 1  and X′ 2  are identical and represent each an Oxygen. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IIa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , R′ 9 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , R′ 13 , R′ 14 , Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, R′ 7  and R′ 14  are different and are selected from the group as described above. According to one embodiment, R′ 7  and R′ 14  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 7  and R′ 14  each independently represents a NH 2 . 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 7  and R′ 14  are identical and represent each a NH 2 . 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IIIa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , R′ 13 , Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, R′ 1  and R′ 13  are different and are selected from the group as described above. According to one embodiment, R′ 1  and R′ 13  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 1  and R′ 13  each independently represents a hydrogen. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 1  and R′ 13  are identical and represent each a hydrogen. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IVa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, R′ 6  and R′ 8  are different and are selected from the group as described above. According to one embodiment, R′ 6  and R′ 8  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 6  and R′ 8  each independently represents a hydrogen. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 6  and R′ 8  are identical and represent each a hydrogen. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula Va: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 7 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, R′ 3 , R′ 4 , R′ 10  and R′n 11  are different and are selected from the group as described above. According one embodiment, R′ 3 , R′ 4 , R′ 10  and R′ 11  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 3 , R′ 4 , R′ 10  and R′ 11  each independently represents a hydrogen. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 3 , R′ 4 , R′ 10 , R′ 11  are identical and represent each a H. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R′ 2 , R′ 5 , R′ 7 , R′ 9 , R′ 12 , Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, R′ 2 , R′ 5 , R′ 9  and R′ 12  are different and are selected from the group as described above. According one embodiment, R′ 2 , R′ 5 , R′ 9  and R′ 12  are identical and are selected from the group as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 2 , R′ 5 , R′ 9  and R′ 12  each independently represents a OH. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein R′ 2 , R′ 5 , R′ 9 , R′ 12  are identical and represent each a OH. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIIa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein Y′ 1 , Y′ 2 , M′,   and   are as described above. 
     According to one embodiment, Y′ 1  and Y′ 2  are different. According to a preferred embodiment, Y′ 1  and Y′ 2  are identical. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein Y′ 1  and Y′ 2  each independently represents a CH. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein Y′ 1  and Y′ 2  are identical and represent each a CH. 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIIIa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein M′ and   are as described above. 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein Y′ 1  and Y′ 2  each independently represents a CH 2 . 
     According to an embodiment, preferred compounds of general Formula Ia are those wherein Y′ 1  and Y′ 2  are identical and represent each a CH 2 . 
     According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IXa: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein M′ and   are as described above. 
     According to one embodiment, preferred compounds of the invention are compounds Ia-A to Ia-I, listed in table 2: 
     
       
         
           
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Compound 
                 Structure 
               
               
                   
               
             
            
               
                 Ia-A (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-B (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-C (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-D (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-E (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-F (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-G (beta, beta) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-H (beta, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 Ia-I (alpha, alpha) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
         
       
     
     According to one embodiment, preferred compound of the invention is compound of formula Ia-A. 
     According to another embodiment, preferred compound of the invention is compound of formula Ia-D. 
     All references to compounds of Formula (I) or (Ia) include references to salts, solvates, multi-component complexes and liquid crystals thereof. All references to compounds of Formula (I) or (Ia) include references to polymorphs and crystal habits thereof. 
     All references to compounds of Formula (I) or (Ia) include references to pharmaceutically acceptable prodrugs and prodrugs thereof. 
     Pharmaceutical Composition 
     This invention also relates to a pharmaceutical composition for use in the treatment and/or prevention of viral infections, comprising the compound for the use according to the invention, and at least one pharmaceutically acceptable carrier. 
     According to one embodiment, the pharmaceutical composition further comprises at least another active ingredient. 
     In one embodiment, the other active ingredient is selected from:
         an antiviral agent, a neuraminidase inhibitor such as oseltamivir, zanamivir, peramivir or laninamivir; a M2 proton channel blocker such as adamantadine or remantanide; an anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clazakizumab or olokizumab; a JAK inhibitor, such as barcitinib, fedratinib or ruxolitinib; an interferon such as interferon beta-1a (IFN-β-1a), interferon beta-1b (IFN-β-1b) or peginterferon beta-la; a macrolide, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin: another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist, and a mixture thereof.   In an embodiment, the composition of the invention comprises at least one of compound of formula I and/or formula Ia and at least one of histamine H2 receptor.   According to one embodiment, said histamine H2 receptor antagonist is chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, preferably famotidine.       

     Non-limiting examples of further antiviral agents include:
         polymerase inhibitors, such as favipiravir, pimodivir, baloxavir, marboxil and sofosbuvir;   protease inhibitors, such as boceprevir, simeprevir, fosamprenavir, lopinavir, ritonavir, telaprevir, tipranavir, azatanavir, nelfinavir, indinavir and saquinavir;   integrase strand transfer inhibitors, such as raltegravir, dolutegravir and elvitegravir;   NS5A inhibitors, such as daclatasvir;   nucleoside reverse transcriptase inhibitors (NRTIs), such as lamivudine, adefovir, tenofovir, entecavir and emtricitabine;   nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, nevirapine and etravirine;   purine nucleosides, such as ribavirin, valacyclovir, acyclovir and famciclovir;
 
and mixtures thereof.
       

     According to an embodiment, the pharmaceutical composition for use in the treatment and/or prevention of viral infections or for use in the treatment and/or prevention of respiratory or extra-respiratory complications and/or infections of viral origin, comprises at least one compound for use according to the invention, together with an histamine H2 receptor antagonist chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, and at least one pharmaceutically acceptable carrier. 
     According to an embodiment, the pharmaceutical composition for use in the treatment and/or prevention of viral infections or for use in the treatment and/or prevention of respiratory or extra-respiratory complications and/or infections of viral origin, comprises at least one compound for use according the invention, with famotidine, and at least one pharmaceutically acceptable carrier. 
     Process 
     According to another aspect, the invention relates to a method for the preparation of the compound of Formula (I) as described above. 
     In particular, the compounds of Formula (I) disclosed herein may be prepared as described below from substrates A-E. It shall be understood by a person skilled in the art that these schemes are in no way limiting and that variations may be made without departing from the spirit and scope of this invention. 
     According to one embodiment, the method involves in a first step the mono-phosphorylation of a compound of formula (A), in the presence of phosphoryl chloride and a trialkyl phosphate, to yield the phophorodichloridate of formula (B), 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     In a second step, the phophorodichloridate of formula (B) is hydrolyzed to yield the phosphate of formula (C), 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, the compound of formula (A) is synthesized using various methods known to the person skilled in the art. According to one embodiment, the compound of formula (A) is synthesized by reacting the pentose of formula (D) with a nitrogen derivative of formula (E), wherein R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Y are as described above for compounds of formula (I), leading to the compound of formula (A-1) which is then selectively deprotected to give the compound of formula (A), 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , Y,   and   are as described herein above for compounds of formula (I). 
     According to one embodiment, R is an appropriate protective group known to the skilled person in the art. In one embodiment, the protecting group is selected from triarylmethyls and/or silyls. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4′-dimethoxytrityl and 4,4′,4″-trimethoxytrityl. Non-limiting examples of silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. 
     According to one embodiment, any hydroxyl group attached to the pentose is protected by an appropriate protective group known to the person skilled in the art. 
     The choice and exchange of protective groups is the responsibility of the person skilled in the art. Protective groups can also be removed by methods well known to the skilled person, for example, with an acid (e.g. mineral or organic acid), base or fluoride source. According to a preferred embodiment, the nitrogen derivative of formula (E) is coupled to the pentose of formula (D) by a reaction in the presence of a Lewis acid leading to the compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF 3 .OEt 2 , TiCl 4  and FeCl 3 . 
     According to one embodiment, the method of the present invention further comprises a step of reducing the compound of formula (A) by various methods well known to the skilled person in the art, leading to the compound of formula (A′) wherein is CH 2  and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , Y,   and   are as defined above for compounds of formula (I). 
     According to a specific embodiment, the present invention relates to a method for the preparation of the compounds of formula I-A to I-F. 
     In a first step, the nicotinamide of formula E is coupled to the ribose tetraacetate of formula D by a coupling reaction in the presence of a Lewis acid, resulting in the compound of formula A-1: 
     
       
         
         
             
             
         
       
     
     In a second step, an ammoniacal treatment of the compound of formula A-1 is carried out, leading to the compound of formula A-2: 
     
       
         
         
             
             
         
       
     
     In a third step, the mono-phosphorylation of the compound of formula A-2, in the presence of phosphoryl chloride and a trialkyl phosphate, leads to the phophorodichloridate of formula A-3: 
     
       
         
         
             
             
         
       
     
     In a fourth step, the phophorodichloridate of formula A-3 is hydrolyzed to yield the compound of formula I-A: 
     
       
         
         
             
             
         
       
     
     According to one embodiment, a step of reducing the compound of formula A-2 is carried out, leading to the compound of formula I-E. 
     The compound of formula I-E is then monophosphorylated as described in step 4 and hydrolyzed to the compound of formula I-C. 
     In another aspect, the invention relates to a method for preparing compounds of formula Ia as described above. 
     In particular, compounds of formula Ia disclosed herein can be prepared as described below from substrates Xa-XIIIa. It will be understood by one ordinary skilled in the art that these schemes are in no way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention. 
     According to one embodiment, the invention relates to a method for preparing the compound of formula I described herein above. 
     The method first involves the mono-phosphorylation of a compound of formula Xa, in the presence of phosphoryl chloride in a trialkyl phosphate, to give the phophorodichloridate compound XIa, 
     
       
         
         
             
             
         
       
     
     wherein X′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 ,   and   described herein for formula Ia. 
     In a second step the hydrolysis of the phophorodichloridate XIa obtained in the first step give the phosphate compound of formula XIIa, 
     
       
         
         
             
             
         
       
     
     wherein X′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 , M′,   and   are as described herein for formula Ia. 
     The phosphate compound of formula XIIa obtained in the second step is then reacted, with a phophorodichloridate compound of formula XIIIa obtained as described in the first step, 
     
       
         
         
             
             
         
       
     
     wherein X′ 2 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , R′ 13 , R′ 14 , Y′ 2 ,   and   are as are as described herein for formula Ia, to give the compound of formula Ia as described herein. 
     According to one embodiment, the method of the invention further comprises a step of reducing the compound of formula Ia, using various methods known to those skilled in the art, to give the compound of formula I′a, wherein Y′ 1  and Y′ 2  are identical and represent each CH 2  and wherein X′1, X′ 2 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , R′ 8 , R′ 9 , R′ 10 , R′ 11 , R′ 12 , R′ 13 , R′ 14 , Y′ 1 , Y′ 2 , M′,   and   are as described herein for formula Ia. 
     According to another embodiment, the compound of formula Xa is synthesized using various methods known to those skilled in the art. According to one embodiment, the compound of formula Xa is synthesized in two steps by first reacting the pentose of formula XIVa with the nitrogenous derivatives of formula XVa, wherein R′ 1 , R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1  and R are as described herein for formula Ia, to give the compound of formula Xa-1, then selectively deprotected to give the compound of formula Xa. 
     
       
         
         
             
             
         
       
     
     wherein X′ 1 , R, R′ 1 , R′ 2 , R′ 3 , R′ 4 , R′ 5 , R′ 6 , R′ 7 , Y′ 1 ,   and   are as described herein for formula Ia. 
     According to one embodiment, R is an appropriate protecting group known to those skilled in the art. Examples of appropriate protecting group includes triarylmethyl and/or silyl groups. Non limiting examples of triarylmethyl includes trityl, monomethoxytrityl, 4,4′-dimethoxytrityl and 4,4′,4″-trimethoxytrityl. Non limiting examples of silyl groups includes trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. 
     According to one embodiment, any hydroxy group attached to the pentose ring is protected with an appropriate protecting group known to those skilled in the art. 
     The selection and exchange of the protecting groups is within the skill to those skilled in the art. Any protecting groups can also be removed by methods known in the art, for example, with an acid (e.g., a mineral or an organic acid), a base or a fluoride source. 
     According to a preferred embodiment, the nitrogenous derivatives of formula XVa is added to the pentose XIVa via a coupling reaction in the presence of a Lewis acid to give the compound of formula Xa-1. Non limiting examples of suitable Lewis acid includes TMSOTf, BF 3 .OEt 2 , TiCl 4  and FeCl 3 . 
     According to a specific embodiment, the invention relates to a method for preparing the compound of formula VIIIa, 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof. 
     In a first step, the nicotinamide of formula XVa, is added to the ribose tetraacetate XIVa, via a coupling reaction in the presence of a Lewis acid, to give the compound of formula Xa-1: 
     
       
         
         
             
             
         
       
     
     In a second step, an ammoniacal treatment of the compound of formula Xa-1 give the compound of formula Xa: 
     
       
         
         
             
             
         
       
     
     In a third step, the mono-phosphorylation of a compound of formula Xa, in the presence of phosphoryl chloride in a trialkyl phosphate, give the phophorodichloridate compound XIa: 
     
       
         
         
             
             
         
       
     
     In a fourth step, the phophorodichloridate compound XIa obtained in the third step is partially hydrolyzed to give the phosphate compound of formula XIIa: 
     
       
         
         
             
             
         
       
     
     In a fifth step, the phosphate compound of formula XIIa obtained in the fourth step is then reacted, with the phophorodichloridate compound of formula XIa obtained as described in the third step, to give the compound of formula VIIIa. 
     According to another specific embodiment, the invention relates to a method for preparing the compound of formula IXa, 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof. 
     According to one embodiment, the compound of formula IXa is obtained from the compound of formula VIIIa, previously synthesized as described above. 
     In this embodiment, the compound of formula IXa is obtained by reducing the compound of formula VIIIa, using a suitable reducing agent known to those skilled in the art, to give the compound of formula IXa. 
     Medical Use and Methods of Treatment 
     This invention thus relates to a compound according to the invention, as described hereinabove, for use in the treatment and/or prevention of viral infections. 
     According to one embodiment, the compound is for use in the treatment and/or prevention of at least one viral infection. 
     According to one embodiment, the viral infection is caused by at least one virus selected from positive-sense ribonucleic acid (RNA) viruses, negative-sense RNA viruses, double-strand RNA viruses, single-strand deoxyribonucleic acid (DNA) viruses or double-strand DNA viruses, 
     According to one embodiment, the viral infection is caused by at least one virus of the genus selected from:
         Enterovirus such as Human Enterovirus (HEV) A, HEV-B, HEV-C or HEV-D;   Rhinovirus such as Human rhinovirus (HRV) A or HRV-B;   Coronavirus such as Human coronavirus;   Hepatovirus such as Hepatitis virus A;   Norovirus such as Norwalk virus;   Hepatite E-like virus such as Hepatitis E virus;   Alphavirus;   Rubivirus such as rubella virus;   Flavivirus such as yellow fever virus, Dengue virus or West Nile virus;   Hepacivirus such as Hepatitis C virus;   Pestivirus such as bovine diarrhea virus;   Ebola-like virus such as Zaire Ebola virus, Cote d&#39;Ivoire Ebola virus, Reston Ebola virus or Sudan Ebola virus;   Respirovirus such as Human parainfluenza virus 1 and 3;   Morbillivirus such as measle virus;   Rubulavirus such as Mumps virus or human parainfluenza virus 2, 4a and 4b;   Henipavirus such as Hendra virus or Nipah virus;   Pneumovirus such as Human respiratory syncytial virus;   Metapneumovirus such as Human metapneumovirus;   Influenzavirus such as Influenza A virus, Influenza B virus or Influenza C virus;   Arenavirus;   Orthobunyavirus such as California encephalitis virus;   Phlebovirus such as Rift Valley fever virus;   Rotavirus such as Human rotavirus A, B or C;   Simplexvirus such as Human herpesvirus 1 and 2;   Varicellovirus such as Human herpesvirus 3;   Cytomegalovirus such as Human herpesvirus 5;   Lymphocryptovirus such as Human herpesvirus 4 and 8;   Adenovirus;   Papillomavirus such as Human papillomavirus; and   Aphtovirus such as Foot-and-mouth disease virus.       

     According to one embodiment, the viral infections is a respiratory infection caused by at least one virus of the genus selected from Influenzavirus, Rhinovirus, Coronavirus, Respirovirus, Rubulavirus, Pneumovirus, Adenovirus or Metapneumovirus. 
     According to a preferred embodiment, the viral infections is a respiratory infection caused by Influenzavirus. 
     According to one embodiment, Influenzavirus is selected from influenza A, influenza B and influenza C. According to a preferred embodiment, Influenzavirus is selected from influenza A and influenza B. 
     Thus, according to a preferred embodiment, the compound is for use in the treatment and/or prevention of influenza A and/or influenza B. 
     According to one embodiment, influenza A is selected from H1N1, H1N2, H2N2, H3N2, H5N1, H5N2, H5N9, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N7. 
     According to one embodiment, influenza B is selected from B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. 
     According to a preferred embodiment, Influenzavirus is selected from H1N1, H3N2, H5N1, B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. 
     According to a preferred embodiment, the compound is for use in the treatment and/or prevention of H1N1, H3N2, H5N1, B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. 
     According to one embodiment, influenza A and/or influenza B lead to respiratory complications such as influenza A and/or influenza B associated pneumonia. 
     According to another embodiment, influenza A and/or influenza B lead to extra-respiratory complications such as decompensation of underlying pathologies or other extra-pulmonary complications such as Reye&#39;s syndrome associated with aspirin intake, myocarditis, pericarditis, rhabdomyolysis, Guillain Barre syndrome or encephalomyelitis. 
     According to one embodiment, the coronavirus infection is an alpha coronavirus infection or a beta coronavirus infection. In a preferred embodiment, the coronavirus infection is a beta coronavirus infection. 
     According to one embodiment, the alpha coronavirus infection is selected from human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63) also sometimes known as HCoV-NH or New Haven human coronavirus. 
     According to one embodiment, the beta coronavirus infection is selected from human coronavirus OC43 (HCoV—OC43), human coronavirus HKU1 (HCoV-HKU1), Middle East respiratory syndrome-related coronavirus (MERS-CoV) previously known as novel coronavirus 2012 or HCoV-EMC, severe acute respiratory syndrome coronavirus (SARS-CoV) also known as SARS-CoV-1 or SARS-classic, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) also known as 2019-nCoV or novel coronavirus 2019. 
     According to one embodiment, the coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV—OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2. In one embodiment, the coronavirus infection is selected from MERS-CoV, SARS-CoV-1 and SARS-CoV-2. 
     According to a preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection. 
     According to one embodiment, the coronavirus is a MERS-CoV infection causing Middle East respiratory syndrome (MERS). According to one embodiment, the coronavirus is a SARS-CoV-1 infection causing severe acute respiratory syndrome (SARS). 
     According to a preferred embodiment, the coronavirus is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19). 
     Thus, according to one embodiment, the compound is for use in the treatment and/or prevention of a coronavirus infection selected from MERS-CoV, SARS-CoV-1 and SARS-CoV-2. 
     According to one embodiment, the compound is for use in the treatment and/or prevention of MERS, SARS and COVID-19. 
     According to a preferred embodiment, the compound is for use in the treatment and/or prevention of COVID-19. 
     According to a preferred embodiment, the compound is for use in the preexposure prophylaxis to virus, including those cited above, and preferably SARS-CoV-2. 
     Thus, according to one embodiment, the compound is for use in the treatment and/or prevention of respiratory or extra-respiratory complications. 
     According to a preferred embodiment, the compound is for use in the treatment and/or prevention of influenza A and/or influenza B associated pneumonia. 
     According to one embodiment, influenza A and/or influenza B associated pneumonia is a viral pneumonia causing Acute Respiratory Failure. 
     According to another embodiment, influenza A and/or influenza B associated pneumonia is a bacterial pneumonia due to bacterial over-infection with a bacterium of the genus selected from  Streptococcus pneumoniae, Staphylococcus aureus  and  Haemophilus influenzae.    
     According to one embodiment, COVID-19 leads to respiratory complications such as COVID-19 associated pneumonia or COVID-19 associated acute respiratory distress syndrome (ARDS). 
     According to one embodiment, COVID-19 leads to extra-respiratory complications such as sepsis, septic shock, altered consciousness, and/or multi-organ failure. 
     According to one embodiment, COVID-19 associated pneumonia presents on a lung scan (such as computerized tomography (CT) scan) as hazy patches, in particular hazy patches clustering on the outer edges of the lungs. In one embodiment, COVID-19 associated pneumonia presents on a lung scan as radiological finding of ground-glass opacity abnormalities or radiological finding of a mixed pattern (combination of consolidation, ground glass opacity and reticular opacity in the presence of architectural distortion). 
     According to one embodiment, ARDS is a form of acute lung injury (ALI) and occurs as a result of a severe pulmonary injury that causes alveolar damage heterogeneously throughout the lung. 
     According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19). 
     Thus, according to one embodiment, the compound is for use in the treatment and/or prevention of COVID-19 associated pneumonia or COVID-19 associated ARDS. 
     According to one embodiment, the coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV—OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2. 
     The present invention also concerns a pharmaceutical composition comprising at least one compound for use of the invention, as described hereinabove, and at least one pharmaceutically acceptable carrier, for use in the treatment and/or prevention of viral infections as described hereinabove. 
     According to one embodiment, the pharmaceutical composition for use of the invention comprises, in addition to the at least one compound for use of the invention, at least one additional active ingredient, e.g., an active ingredient selected from antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukins 6; JAK inhibitors; interferons; a macrolide, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist, and mixtures thereof; as described hereinabove. 
     In a preferred embodiment, the pharmaceutical composition for use of the invention comprises, in addition to the at least one compound for use of the invention, at least one additional active ingredient selected amongst an antiviral agent, a neuraminidase inhibitor such as oseltamivir, zanamivir, peramivir or laninamivir; a M2 proton channel blocker such as adamantadine or remantanide; an anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clazakizumab or olokizumab; a JAK inhibitor, such as barcitinib, fedratinib or ruxolitinib; an interferon such as interferon beta-1a (IFN-β-1a), interferon beta-1b (IFN-β-1b) or peginterferon beta-1a; macrolides selected from the group comprising azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist, and a mixture thereof. 
     The compounds of the invention may be used in monotherapy or in combination therapy in a subject in need of therapeutic and/or preventive treatment. Thus, according to a first embodiment, the compound for use of the invention is administered to the subject without any other active ingredient. Thus, according to a second embodiment, the compound for use of the invention is administered to the subject in combination with at least one additional active ingredient, e.g., an active ingredient selected from antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukins 6; JAK inhibitors; interferons; macrolides selected from the group comprising azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist, and mixtures thereof; as described hereinabove In one embodiment, the compound is administrated to the subject sequentially, simultaneously and/or separately with the other active ingredient as described hereinabove. 
     According to one embodiment, the subject in need of therapeutic and/or preventive treatment is diagnosed by a health professional. In practice, viral infections are diagnosed by any examination routinely carried out in the medical setting, including direct diagnosis, i.e. identification of the virus or its constituents, for example from a respiratory specimen, or indirect diagnosis, i.e. the detection of antibodies specific to the infection. 
     COVID-19 severity may be assessed according to the World Health Organization (WHO) criteria of severity as follows:
         mild: cases showing mild clinical symptoms with no sign of pneumonia on imaging.   moderate: cases showing fever and respiratory symptoms (such as a cough, shortness of breath, and/or chest tightness) with radiological findings of pneumonia and requiring (O 2 ): 3 L/min&lt;oxygen&lt;5 L/min   severe: cases meeting any of the following criteria:
           respiratory distress (respiratory rate (RR)≥30 breaths/min);   oxygen saturation (SpO 2 )≤93% at rest in ambient air; or SpO 2 ≤97% with O 2 &gt;5 L/min;   ratio of artery partial pressure of oxygen/inspired oxygen fraction (PaO 2 /FiO 2 )≤300 mmHg (1 mmHg=0.133 kPa), PaO 2 /FiO 2  in high-altitude areas (at an altitude of over 1,000 meters above the sea level) shall be corrected by the following formula: PaO 2 /FiO 2  [multiplied by] [Atmospheric pressure (mmHg)/760]; and/or   chest imaging that showed obvious lesion progression within 24-48 hours&gt;50%.   
           critical: cases meeting any of the following criteria:
           respiratory failure and requiring mechanical ventilation;   shock; and/or   multiple organ failure (extra pulmonary organ failure) requiring admission to intensive care unit (ICU).   
               

     According to one embodiment, the subject suffers from mild COVID-19, moderate COVID-19, severe COVID-19 or critical COVID-19. According to one embodiment, the subject suffers from mild-to-moderate COVID-19. According to one embodiment, the subject suffers from severe-to-critical COVID-19. 
     According to one embodiment, the subject, especially the subject suffering from mild-to-moderate COVID-19 or from severe-to-critical COVID-19, is not hospitalized. 
     According to one embodiment, the subject, especially the subject suffering from mild-to-moderate COVID-19 or from severe-to-critical COVID-19, is hospitalized. In one embodiment, the subject is hospitalized but does not require admission to intensive care unit (ICU). In one embodiment, the subject is hospitalized and requires admission to ICU. 
     According to one embodiment, the subject, especially the subject suffering from mild-to-moderate COVID-19 or from severe-to-critical COVID-19, requires oxygen therapy. In one embodiment, the subject requires non-invasive ventilation (NIV). 
     Severe-to-critical COVID-19 may alternatively be defined as COVID-19 requiring hospitalization and either NIV or high flow oxygen therapy, instead of being assessed according to the WHO as described hereinabove. 
     Preferably, the subject in need of therapeutic and/or preventive treatment is a warm-blooded animal, more preferably a human. According to one embodiment, the subject is a male. According to one embodiment, the subject is a female. 
     In the invention, the subject may be of any age. According to one embodiment, the subject is an adult, i.e. over 18 years of age. According to one embodiment, the subject is a child, i.e. under 18 years of age. According to one embodiment, the subject is an infant, i.e. having an age of more than one month and less than two years. According to one embodiment, the subject is a newborn, i.e. having an age from birth to less than one month. 
     According to one embodiment, the subject does not suffer from any underlying pathology. 
     According to one embodiment, the subject is at risk of developing a disease caused by a viral infection. According to one embodiment, the subject is at risk of developing a disease caused by a respiratory infection, such as influenza A and/or influenza B. According to one embodiment, the subject is suffering from influenza A and/or influenza B and is at risk of developing a respiratory or an extra-respiratory complication. 
     According to one embodiment, the subject is at risk of developing a disease caused by a coronavirus infection. According to one embodiment, the subject is at risk of developing a disease caused by SARS-CoV-2 infection, such as COVID-19. According to one embodiment, the subject suffering from COVID-19 is at risk of developing a respiratory or an extra-respiratory complication as described above. 
     According to one embodiment, the subject is suffering from at least one risk factor i.e. a preexisting disease, condition, habit or behavior that may lead to an increased risk of developing a severe or critical form of the disease caused by a coronavirus infection as described above. 
     According to one embodiment, the subject is an individual of any age with certain chronic conditions, such as HIV/AIDS, asthma, or chronic heart or lung disease. According to one embodiment, the subject is an adult with chronic cardiac and/or respiratory pathology. According to one embodiment, the subject is a pregnant woman. According to one embodiment, the subject is an elderly individual. According to one embodiment, the subject is an obese person (BMI&gt;35). 
     According to one embodiment, the subject is profoundly immunocompromised. 
     This invention also relates to the use of a compound as described hereinabove in the treatment and/or prevention of viral infections as described hereinabove. 
     This invention also relates to the use of a compound as described hereinabove in the manufacture of a medicament for the treatment and/or prevention of viral infections as described hereinabove. 
     This invention also relates to a method for the treatment and/or prevention of viral infections as described hereinabove in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound as described hereinabove. 
     Another object of the invention is a kit-of-parts comprising a first part comprising a compound of the invention as described hereinabove, and a second part comprising another active ingredient selected from antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukins 6; JAK inhibitors; interferons; macrolides selected from the group comprising azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist and mixtures thereof; as described hereinabove. 
     In a preferred embodiment, the kit-of-parts of the invention comprises a first part comprising a compound of the invention as described hereinabove, and a second part comprising another active ingredient selected from an antiviral agent, a neuraminidase inhibitor such as oseltamivir, zanamivir, peramivir or laninamivir; a M2 proton channel blocker such as adamantadine or remantanide; an anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clazakizumab or olokizumab; a JAK inhibitor, such as barcitinib, fedratinib or ruxolitinib; an interferon such as interferon beta-1a (IFN-β-1a), interferon beta-1b (IFN-β-1b) or peginterferon beta-1a; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, carrimycin, nicotine, a Histamine H2 receptor antagonist, and macrolides selected from the group comprising azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin, and a mixture thereof. 
     In a preferred embodiment, the kit-of-parts of the invention comprises a first part comprising a compound of the invention as described hereinabove, and a second part comprising a Histamine H2 receptor antagonist. 
     In one embodiment, the kit-of-parts of the invention comprises a first part comprising compound of the invention, or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof, and a second part comprising another active ingredient such as oseltamivir or azythromycin. 
     Methods of Administration 
     The compounds of the invention as describes hereinabove, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. 
     The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 
     Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material, such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. 
     Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example  arachis  oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant, such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. 
     Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. 
     The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) 
     In the treatment or prevention of viral infections, an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 350 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For example the dosage may comprise from 100 mg/day to 5000 mg/day, preferably from 500 mg/day to 1000 mg/day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once, twice or three times per day. Three times per day has been fond suitable. The duration of the treatment will depend from the patent and is determined by the physician. It can be from one day to one year or even longer, preferably from one week to three months, more preferably from two weeks to six weeks. It will be understood, however, that the specific dose level and frequency of dosage and duration for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. 
     According to an embodiment, the compound of formula I or Ia is administered at a daily dose of 10 mg/kg, with a minimum of 500 mg/day and a maximum of 2 g/day. 
     According to an embodiment, the compound of formula I or Ia, its salts or prodrugs, is administered at a daily dose of 10 mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day for a period of 10 days to 30 days, preferably for a period of 14 days to 28 days, more preferably for a period of about 21 days. 
     The first day is the day of diagnosis of a viral infection, preferably caused by Coronavirus, or of the diagnosis of respiratory or extra-respiratory complications and/or infections of viral origin, including pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure. The compound of formula I or Ia can be administered at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21. 
     According to an embodiment, the histamine H2 receptor antagonist is administered as per the current dosage recommended. According to an embodiment, famotiding is administered at a daily dose of 50 mg to 1000 mg, preferably 120 mg to 600 mg, more preferably at a daily dose of about 360 mg. 
     Preferably, famotidine is administered at a daily dose of 10 mg/mL mixed with normal saline is given intravenously at e.g. 120 mg (30% of 400 mg oral dose). The total daily dose proposed is 200 to 500 mh/day, preferably 360 mg/day famotidine, preferably through IV route, for a maximum of 14 days, or hospital discharge, whichever comes first. 
     According to an embodiment, hydroxychloroquine sulfate 200 mg tablets will be administered as a loading dose of 400 mg BID on day 1, followed by 200 mg BID for 4 days, or a loading dose of 800 mg QD on day 1, followed by 400 mg QD for 4 days, as per specific clinical protocol for COVID-19. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    is a histogram showing the survival rate of mice during the fourteen days of experiment according to Example 2. 
         FIG.  2    is a histogram showing the weight ( FIG.  2 A ) and weight loss ( FIG.  2 B ) of mice from DO to D14 according to Example 2. 
         FIG.  3    is a histogram showing the effect of treatments on clinical parameters from DO to D14 according to Example 2. 
         FIG.  4    is a histogram showing the viral load in lung of infected mice 8 days after the infection with 500 PFU of influenza A virus according to Example 2. 
         FIG.  5    are histograms of showing the effect of treatments on T cells levels in blood according to Example 2. 
         FIG.  6    are histograms showing the effect of treatments on recruitment of monocytes-derived macrophages and dendritic cells in lungs according to Example 2. 
         FIG.  7    is a histogram showing the survival rate of mice during the fourteen days of experiment of Example 7. 
         FIG.  8    is a histogram showing the weight evolution of mice from DO to D14 according to Example 7. 
         FIG.  9    is a histogram showing the weight loss of mice from DO to D14 according to Example 7. 
         FIG.  10    is a histogram showing the effect of treatments on respiratory scores from DO to D14 according to Example 7. 
         FIG.  11    is a histogram showing the survival rate of mice during the fourteen days of experiment of Example 8. 
         FIG.  12    is a histogram showing the weight evolution of mice from DO to D14 according to Example 8. 
         FIG.  13    is a histogram showing the weight loss of mice from DO to D14 according to Example 8. 
         FIG.  14    is a histogram showing the effect of treatments on clinical parameters from DO to D14 according to Example 8. 
         FIG.  15    is a histogram showing the effect of treatments on respiratory scores from DO to D14 according to Example 8. 
         FIG.  16    is a histogram showing the viral load in lung of infected mice 8 days after the infection of H1N1 PR/8/34 strain according to Example 8. 
     
    
    
     EXAMPLES 
     The present invention is further illustrated by the following examples. 
     Example 1: Synthesis of Compounds of the Invention 
     Materials and Methods 
     All materials were obtained from commercial suppliers and used without further purification. Thin-layer chromatography was performed on TLC plastic sheets of silica gel 60F254 (layer thickness 0.2 mm) from Merck. Column chromatography purification was carried out on silica gel 60 (70-230 mesh ASTM, Merck). Melting points were determined either on a digital melting point apparatus (Electrothermal IA 8103) and are uncorrected or on a Kofler bench type WME (Wagner &amp; Munz). IR,  1 H,  19 F and  13 C NMR spectra confirmed the structures of all compounds. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer and NMR spectra were recorded, using CDCl 3 , CD 3 CN, D 2 O or DMSO-d 6  as solvent, on a Bruker AC 300, Advance DRX 400 and Advance DRX 500 spectrometers, for  1 H, 75 or 100 MHz for  13 C and 282 or 377 MHz for  19 F spectra. Chemical shifts (δ) were expressed in parts per million relative to the signal indirectly (i) to CHCl 3  (δ 7.27) for  1 H and (ii) to CDCl 3  (δ 77.2) for  13 C and directly (iii) to CFCl 3  (internal standard) (δ 0) for  19 F. Chemical shifts are given in ppm and peak multiplicities are designated as follows: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quadruplet; quint, quintuplet; m, multiplet. The high-resolution mass spectra (HRMS) were obtained from the “Service central d&#39;analyse de Solaize” (Centre national de la recherche scientifique) and were recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF). 
     General Experimental Procedures 
     Step 1: Synthesis of the Compound of Formula A-1 
     The compound of formula D (1.0 equiv.) is dissolved in dichloromethane. Nicotinamide of formula E (1.50 equiv.) and TMSOTf (1.55 equiv.) are added at room temperature. The reaction mixture is heated under reflux and stirred until the reaction is complete. The mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness to give tetraacetate A-1. 
     Step 2: Synthesis of the Compound of Formula A-2 
     Tetraacetate A-1 is dissolved in methanol and cooled to −10° C. Ammonia 4.6 M in methanol (3.0 equivalents) at −10° C. is added and the mixture is stirred at this temperature until the reaction is complete. Dowex HCR (H+) resin is added up to pH 6-7. The reaction mixture is heated to 0° C. and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in the acetonitrile and concentrated to dryness. The residue is dissolved in the acetonitrile to give a solution of the compound of formula A-2. 
     Step 3: Synthesis of the Compound of Formula A-3 
     The solution of the crude compound of formula A-2 in acetonitrile is diluted with trimethyl phosphate (10.0 equivalents). The acetonitrile is distilled under vacuum and the mixture is cooled to −10° C. Phosphorus oxychloride (4.0 equivalents) is added at 10° C. and the mixture is stirred at 10° C. until the reaction is complete. 
     Steps 4 and 5: Synthesis of the Compound of Formula I-A 
     The mixture obtained in step 3 above is hydrolyzed by the addition of a 50/50 mixture of acetonitrile and water, followed by the addition of methyl tert-butyl ether. The mixture is filtered and the solid is dissolved in water. The aqueous solution is neutralised by the addition of sodium bicarbonate and extracted with dichloromethane. The aqueous layer is concentrated to dryness to yield the crude formula I-A compound, which is purified on a DOWEX 50 w×8 column with elution in water followed by a silica gel chromatographic column. 
     Example 2: Evaluation of Compounds of the Invention on a Murine Influenza Virus Pulmonary Infection 
     The purpose of this study is to investigate the effects of an NMN derivative in the progression of a viral infection. 
     In order to directly assess the effects of compound I-A on lethal pulmonary viral infections, an in vivo study of severe pneumonia induced by the H1N1 influenza virus model PR/8/34 (protocol in progress) is undertaken. Mice are infected with a lethal dose (500 PFU/mouse) of the virus and are being treated or not with compound I-A and/or Tamiflu injected by IP route for 14 days. Characteristic clinical parameters (weight, temperature, state of alertness, response to stimulation, quality of respiration) of the animals&#39; health status and mortality are monitored throughout the protocol. At D2 and D8 of infection, the progression of pneumonia (histology of the lung) is evaluated, multi-organ damage (histology of the heart, liver, kidneys, spleen) and pulmonary and systemic inflammatory and immune responses (immuno-phenotyping of pulmonary and blood leukocytes in broncoalveolar washings (BAL) and lymph nodes and determination of cytokines in plasma and BAL). A transcriptome analysis of all cell types presents in the lungs at D2 of the infection by the single cell RNAseq technique complete the study and allow to evaluate the effect of compound I-A on the expression of genes from different populations present in the lungs of animals with severe pneumonia. 
     I. Materials and Methods 
     Material 
     Animals: 
     108 Balb/c male mice, 7-week-old at the arrival are obtained from Janvier Labs, Le Genest St Isle, 53941 St Berthevin, France. Each animal is identified by a unique animal number written on the tail/cage when assigned to the groups. Each cage is numbered. Based on the animal number/cage and number of cage, the animals are assigned of unique number with the name of group and mouse number. 
     The matching cards that are used to identify cages where experimental animals are housed will contain the following information: the name of the experiment, the number of the experiment and the cage number. 
     Compound: 
     The NMN derivative is manufactured according to Example 1 or commercially purchased and stored at +4° C. until use. Vehicle is physiological buffer. 
     Methods 
     1. Preparation of Formulation: 
     The powder of compound I-A is dissolved in vehicle (the solution is used at room temperature for maximum 1 day) at 6 mg/ml. A fresh sample for each administration is prepared every day except the week end (the solution is prepared on Saturday and is used on saturday and sunday). 
     The product is administered intraperitoneally once daily for 15 days. 
     Mice are weighed daily to adapt the volume of compound to be administred. 
     2. Influenza Virus H1N1 PR/8/34 Strain Preparation 
     At Day 0, mice are infected with a lethal dose (500 PFU/mouse) of Influenza virus H1N1 PR/8/34 by intranasal route. 
     3. Experimental Groups 
     Group Description: 
     Group 1: Vehicle (i.p.) 
     Group 2: Tamiflu 1 mg/kg (subactive dose)
 
Group 3: Test compound 185 mg/kg (compound I-A)
 
Group 4: Tamiflu 1 mg/kg+test compound 185 mg/kg
 
     Group Repartition: 
     For each group
         12 mice for survival   5 mice for lung/lymph nodes collection and treatment for cytometry at day 2; blood collection   5 mice for lung/lymph nodes collection and treatment for cytometry at day 8; blood collection   5 mice for lung collection and preparing for single cell RNA sequencing at day 2       

     Each group will involve 27 mice. 
     As set forth in the regulations for Non-clinical Laboratory Studies, test and control animal groups is maintained under identical conditions. The duration of study is 15 days. 
     At D0, mice were infected with 500 PFU/mouse of Influenza virus H1N1 PR/8/34 by intranasal route. 
     Mice were i.p treated during all the experiment (D0 to D14) once per day. Last injection occurred 24 hours before sacrifice. 
     At D2, from 5 mice of each group, blood, lymph nodes and lungs are collected. Blood is collected by retro-orbital sampling. 50 μL is immediately added to 200 μL of perchloric acid 0.1N and thorough mixing is achieved by inverting the tube several times. Another aliquot (300 uL minimum) are sampled for cytometry analysis. The rest of blood is centrifuged, the plasma is collected and frozen until potential shipment to the sponsor. 
     Lungs was also collected from 5 other mice for treatment for RNA sequencing. 
     At D8, from 5 mice of each group, blood, lymph nodes and lungs were collected. Blood is collected by retro-orbital sampling. An aliquot (300 uL minimum) is sampled for cytometry analysis. The rest of blood is centrifuged, the plasma is collected and frozen until potential shipment to the sponsor. 
     The weight loss, the health scores and the mortality are assessed for 15 days (D0 to D14). 
     At D14, lungs from remaining mice are collected. 
     4. Dosing 
     The vehicle (physiological buffer) is administered once a day by intraperitoneal route. 
     The Tamiflu reference is administrated twice a day at 1 mg/kg for group 2 and 4 by oral gavage. 
     Compound I-A is administrated once a day at 185 mg/kg by intraperitoneal route. 
     5. Infection 
     Mice are flash anesthetized with isoflurane and then are intranasally infected with the Influenza virus H1N1 PR/8/34 at 500 PFU/mouse. 
     6. Body Weight, Survival Rate and Clinical Examination 
     The mortality, body weight and clinical signs are recorded every day until the end of the experiment (D14) for 12 mice per groups. 
     The clinical score is established as followed: 
     1: healthy mouse
 
2: mouse showing signs of malaise, including slight piloerection, slightly changed gait and increased ambulation
 
3: mouse showing signs of strong piloerection, constricted abdomen, changed gait, periods of inactivity
 
4: mouse with enhanced characteristics of the previous group, but showing little activity and becoming moribund
 
5: dead mouse
 
     The animal appearance and behavior are assessed at least daily from the start and until the end of the experimental phase. Any abnormal findings are recorded in the raw data. Body weight measurement and clinical examination are also carried out before the animals are split into groups. 
     7. Blood Collection at Day 2 and Day 8 
     Retro-orbital blood collection is performed 48 hours and 8 days after the infection with EDTA anticoagulant. 
     At day 2, 50 μL of blood is mixed with 200 μL of perchloric acid (0.5N) by inverting the tube several times. Samples are stored at −70° C. until shipment to sponsor. 
     At day 2 and 8, a minimum of 300 μL of blood is used for cytometry analysis. 
     The rest of blood is centrifuged to collect plasma and stored at −70° C. until shipment. 
     8. Cell Isolation from Lungs and Draining Lymph Nodes 
     At day 2 and 8, lungs and draining lymph nodes are collected in cold RPMI+10% FCS. 
     Lungs is cut in small pieces and then digested in collagenase solution at 37° C. for 30 minutes. Cell suspension is then filtered on 40 μm cell strainer. 
     Draining lymph nodes is smashed on a 40 μm cell strainer on top of a 50 mL tube with a syringe piston. 
     Cell suspension is centrifuged at 400 g during 5 minutes at 4° C. The pellet is resuspended in 1-5 mL of cold RPMI+10% FCS. 
     Viable cells are then counted and used for cytometry. 
     9. Cytometry Analysis on Whole Blood, Lung and Draining Lymph Nodes 
     Whole blood and cells isolated from lungs and draining lymph nodes are labelled with antibodies. 
     For lung cells, 4 panels are performed: 
     Panel 1: identification of alveolar macrophages
 
Panel 2: identification of T cell subsets and NK cells
 
Panel 3: identification of interstitial macrophages and recruited monocytes
 
Panel 4: identification of dendritic cell subsets and plasmacytoid cells
 
     For draining lymph node cells, 3 panels are performed: 
     Panel 1: identification of T cell subsets and NK cells
 
Panel 2: identification of dendritic cell subsets
 
Panel 3: identification of macrophages and plasmacytoid dendritic cells
 
     For whole blood, 3 panels are performed: 
     Panel 1: identification of TCR αβ +  T cell subsets, NK cells and B cells.
 
Panel 2: identification of TCRγδ +  T cells and regulatory T cells.
 
Panel 3: identification of monocytes, dendritic cells and plasmacytoid dendritic cell.
 
     II. Results and Discussion 
     1. Survival Rate 
       FIG.  1    shows the survival rate of mice during the fourteen days of experiment. 
     It was observed that compared to untreated control animals, compound I-A allows to reduce animal mortality. 
     As shown in  FIG.  1   , 92% of mortality was obtained for mice treated with the vehicle at D14. 
     Compared to untreated control animals, it was observed that treatments with oseltamivir (Tamiflu®) at 1 mg/kg/day or compound I-A, improved greatly mice survival, respectively with a survival rate of 58% and 67% at D14. 
     Interestingly, compound I-A appears to be more effective than oseltamivir (1 mg/kg/day). 
     Remarkably, co-administration of compound I-A and oseltamivir (2 mg/kg/day) protects animals from lethality induced by H1N1 infection with a survival rate of 100% at D14. 
     2. Body Weight 
       FIG.  2    shows the body weight evolution of mice from DO to D14. 
     As shown in  FIG.  2   , from D4 to D9, the mice from vehicle group showed 23% of bodyweight loss on average. 
     Daily treatments with compound I-A or oseltamivir alone allows a slight improvement of this parameter in comparison to vehicle, whereas the combination oseltamivir+compound I-A has significantly contributed to maintained body weight of infected mice. 
     3. Clinical Score 
       FIG.  3    shows the effect of treatments on clinical parameters from DO to D14, as follow: 
     1: healthy mouse
 
2: mouse showing signs of malaise, including slight piloerection, slightly changed gait and increased ambulation
 
3: mouse showing signs of strong piloerection, constricted abdomen, changed gait, periods of inactivity
 
4: mouse with enhanced characteristics of the previous group, but showing little activity and becoming moribund
 
5: dead mouse
 
     As shown Mice treated with vehicle showed signs of malaise, slight piloerection and increased ambulation 5 days following the infection. Strong piloerection appeared on Day 7 with long periods of inactivity. 
     Treatments with oseltamivir or compound I-A significantly improved clinical states of the mice. 
     The combination has limited strong clinical signs and all the mice of this group were recovered on Day 11. 
     4. Viral Load 
       FIG.  4    shows the viral load in lung of infected mice at D8. 
     As shown in  FIG.  4    the treatment with compound I-A and oseltamivir had no impact on viral load in lung, 8 days after the infection with 500 PFU of influenza A virus. 
     However, combination of compound I-A with oseltamivir had significantly reduced the quantity of H1N1 particles in comparison to the vehicle group. 
     5. Cytometry 
       FIG.  5    shows the effect of treatments on lymphopenia at D8 in blood. Compound I-A and compound I-A+oseltamivir (Tamiflu) treatments reduced H1N1 induced lymphopenia in blood. 
       FIG.  6    shows the effect of treatments on leukocytes infiltration in lungs. At D8 post-inoculation, compound I-A reduced the recruitment of monocyte-derived macrophages and dendritic cells and CD8+ T cells in infected lungs. 
     Compound I-A and compound I-A+oseltamivir (Tamiflu) treatments reduced lymphopenia and decreased circulating monocytes at D8 post-inoculation in comparison to vehicle and oseltamivir-treated animals. 
     III. Conclusion 
     This study on H1N1 infection already highlights the efficacy of treatment with compound I-A to prevent mortality during severe pneumonia and the superiority of the association between an antiviral molecule and compound I-A compared to treatment with monotherapies of either the antiviral or compound I-A. 
     This study on H1N1 infection allows also to unequivocally determine the effects of treatment on the progression of the pathology and the onset of acute respiratory disease, focusing on innate and acquired pulmonary and systemic (heart, spleen, liver and kidney) immune responses as well as cytokine storm. 
     Example 3: Evaluation of Compounds of the Invention on a Golden Syrian Hamster SARS-CoV-2 Infection 
     The purpose of this study is to investigate the effects of an NMN derivative in the progression of a coronavirus infection, in particular a SARS-CoV-2 infection. 
     Materials and Methods 
     Material 
     Animals: 
     120 Golden syrian hamsters (6 to 10 weeks old) are obtained for the experiment. Each animal is identified by a unique animal number written on the tail/cage when assigned to the groups. Each cage is numbered. Based on the animal number/cage and number of cages, the animals are assigned of unique number with the name of group and hamster number. 
     The matching cards that are used to identify cages where experimental animals are housed will contain the following information: the name of the experiment, the number of the experiment and the cage number. 
     Compound: 
     The NMN derivative is manufactured according to Example 1 or commercially purchased and stored at +4° C. until use. Vehicle is physiological buffer. 
     Methods 
     10. Preparation of Formulation: 
     The powder of NMN derivative is dissolved in vehicle (the solution is used at room temperature for maximum 1 day). A fresh sample for each administration is prepared every day except the weekend (the solution is prepared on Saturday and is used on Saturday and Sunday). 
     The product is administered intraperitoneally once daily for 15 days. 
     Hamster are weighed every day to adapt the volume of compound to be administered. 
     1. SARS-CoV-2 Strain Preparation 
     The animals are kept in Biosafety Level-2 housing and given access to standard pellet feed and water ad libitum until virus challenge in our Biosafety Level-3 animal facility. Phosphate-buffered saline (PBS) is used to dilute virus stocks to the desired concentration, and inocula are back-titrated to verify the dose given. Dulbecco&#39;s Modified Eagle Medium (DMEM) containing 10 5  plaque-forming units in 100 μl of SARS-CoV-2 is intranasally inoculated at day 0. 
     2. Experimental Groups 
     6 experimental groups are investigated. Compound I-A (114 mg/Kg/day), compound I-E (114 mg/Kg/day), anti-viral (Remdesivir (17 mg/Kg/day) ou hydroxychloroquine (91 mg/Kg/day)) or a combination of compound I-A or compound I-E and Remdesivir or hydroxychloroquine is evaluated for efficacy 20 animal per group to follow the evolution of the pathology under each treatment. The following parameters are investigated:
         Viral load   Histopathology of the organs   Immunohistology to analyse macrophages differenciation, immune cells infiltrations in the selected tissues   qPCR of the genes regulated by the virus (IFN-gamma, IL-4, IL-6, IL-10, IL-13, TNF-alpha, IL-21, TGFbeta1, CCL17, CCL22, CCR4, FOXP3, IL-12p40, gamma-actin)   Circulating cytokines levels (IL-6, IL-10, IFN, TNF-alpha, MIP-1A, MCP-1, IP-10, TGF-beta1)   NAD/NADH ratios in blood and tissues samples       

     These analyses are performed on 5 animals of each group at day 2, day 4, day 7 and day 14 post-infection. Read-outs are performed on blood, lungs, spleen, kidneys, liver and intestines. 
     Example 4: Evaluation of Compounds of the Invention on SARS-CoV-2 Infected Human Epithelial Cells and on Human Immune Cell Activated by SARS-CoV-2 Infected Human Epithelial Cells 
     The purpose of this study is to evaluate the effects of an NMN derivative, especially compound I-A, on the activation and function of coronavirus-infected human lung epithelial cells and macrophages and human dendritic cells in contact with infected cells. 
     Primary type II alveolar epithelial cells cultured in the presence or absence of compound I-A alone or in combination with antiviral treatment (remdesivir or hydroxychloroquine) will be infected with the virus (SARS-CoV-2 or another human pathogenic coronavirus strain). 
     The effect of compound I-A is then evaluated on viral replication and infection as well as activation and release of cytokines by alveolar cells. Gene expression levels (RNAseq) in infected alveolar cells under the different treatment conditions are also analyzed. 
     At the same time, human circulating monocytes are differentiated into macrophages and dendritic cells that may or may not be treated with compound I-A alone or in combination with antiviral treatment (remdesivir or hydroxychloroquine). These immune cells are then brought into contact with coronavirus-infected epithelial cells and their levels of infection, their phagocytosis, cytokine secretion and activation (immunophenotyping) capacities are determined as well as the analysis of their differential gene expressions (RNA seq). 
     Example 5: A Prospective, Multicentric, Randomized, Placebo-Controlled Double-Blind Study in COVID-19 Patients 
     The overall objective of the study is to determine the therapeutic effect and tolerance of compound I-A in 300 patients with moderate, severe pneumonia associated with Coronavirus disease 2019 (COVID-19). The study has multiple Randomized Placebo-Controlled Trials (cmRCT) design. Compound I-A is administered to consenting adult patients hospitalized with COVID-19 either diagnosed with moderate or severe pneumonia. 
     The conditions are as follows: 
     Treatment regimen: 4×250 mg/day of compound I-A vs. Placebo (on top of standard of care) for 28 days 
     Inclusion Criteria: 
     
         
         
           
             18 years or older 
             Hospitalized patient 
             Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay≤4 days before randomization 
             Moderate to severe COVID-19 associated disease 
             For moderate patients: peripheral capillary oxygen saturation (SpO2)&gt;94% on room air at screening and radiographic evidence of pulmonary infiltrates 
             For severe patients: Peripheral capillary oxygen saturation (SpO2)≤94% or requiring supplemental oxygen at screening 
             Willing and able to provide written informed consent prior to performing study procedures 
           
         
       
    
     Exclusion Criteria: 
     
         
         
           
             Participation in any other clinical trial of an experimental treatment for COVID-19 
             Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited&lt;24 hours prior to study medication initiation 
             SOFA&gt;10 
             Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR&lt;30) 
             Pregnant women or women who are breastfeeding 
             Immunocompromised patients taking medication upon screening 
             Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive study treatment 
           
         
       
    
     Outcome Measures 
     Primary Outcome Measures: 
     Percentage of subjects reporting each severity rating on a 7-point ordinal scale [Time Frame: Day 7]
         a. Not hospitalized, no limitations on activities   b. Not hospitalized, limitation on activities;   c. Hospitalized, not requiring supplemental oxygen;   d. Hospitalized, requiring supplemental oxygen;   e. Hospitalized, on non-invasive ventilation or highflow oxygen devices;   f Hospitalized, on invasive mechanical ventilation or ECMO;   g. Death.       

     Secondary Outcome Measures: 
     
         
         
           
             1. Overall Survival [Time Frame: 7, 14, 28 days] 
             2. 7-day, 14-day and 28-day ventilator free-days [Time Frame: 28 days] 
             3. PaO2/FiO2 ratio [Time Frame: day 1 to day 14] evolution of PaO2/FiO2 ratio 
             4. time to oxygen supply independency [Time Frame: 7-day, 14-day and 28-day]time to oxygen supply independency 
             5. duration of hospitalization [Time Frame: 7-day, 14-day and 28-day] duration of hospitalization 
             6. time to negative viral excretion [Time Frame: 7-day, 14-day and 28-day] time to negative viral excretion 
             7. time to ICU discharge [Time Frame: 7-day, 14-day and 28-day] time to ICU discharge 
             8. time to hospital discharge [Time Frame: 7-day, 14-day and 28-day] time to hospital discharge 
           
         
       
    
     Labs/Biomarkers at 7-Day, 14-Day and 28-Day: 
     
         
         
           
             NFS, VS, PCR, Fibrinogene 
             NAD 
             Lymphocyte subpopulation (CD8, CD4, CD16, CD56) eurofins 
             CD57 NK 
             CD19 Lympho B 
             IL-1α and IL_1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, vascular endothelium growthfactor (VEGF), interferon γ, epidermal growthfactor (EGF), monocyte chemoattractant protein type 1 (MCP-1) and TNFα. 
             C3, C4, CH50 
             DDID, AT3, TCK, TP, Proteins S and C 
             CPK, CPKMB, Troponin, BNP, myoglobin, procalcitonin 
             Transaminases, PAL, GGT, LDH, bilirubin, calcium levels 
             Complete ionogram (Na, K, Cl, Ra, protidemie) 
             Ferritinemie 
             Lipase, Aldolase 
           
         
       
    
     Example 6: A Randomized, Double-Blind, Multi-Arm Historical Control, Comparative Trial Double-Blind Study of the Combination of NMN Derivatives According to the Invention, Famotidine and Hydroxychloroquine in COVID-19 Patients 
     The overall objective of the study is to determine the therapeutic effect and tolerance of compound I-A in patients with moderate, severe pneumonia associated with Coronavirus disease 2019 (COVID-19). The study has multiple Randomized Placebo-Controlled Trials (cmRCT) design. Compound I-A is administered to consenting adult patients hospitalized with COVID-19 either diagnosed with moderate or severe pneumonia. 
     The conditions are as follows. 
     The study comprises four arms: 
     Arm No. 1: Compound I-A and intravenous famotidine. Subjects in this study arm will receive a combination of oral compound I-A and intravenous famotidine. Famotidine Injection, 10 mg/mL mixed with Normal Saline is given intravenously at 120 mg (30% of 400 mg oral dose). The total daily dose proposed is 360 mg/day famotidine IV for a maximum of 14 days, or hospital discharge, whichever comes first. Compound I-A will be administered orally. Compound I-a is administered at a dose of 10 mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day.
 
Arm No. 2: compound I-A+intravenous famotidine+hydroxhycloroquine. Subjects in this study arm will receive a combination of oral compound I-A, intravenous famotidine and oral hydroxychloroquine. Famotidine Injection, 10 mg/mL mixed with Normal Saline is given intravenously at 120 mg (30% of 400 mg oral dose). The total daily dose proposed is 360 mg/day famotidine IV for a maximum of 14 days, or hospital discharge, whichever comes first. Compound I-A will be administered orally. Compound I-A is administered at a dose of 10 mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day. Hydroxychloroquine sulfate 200 mg tablets will be administered as per the current clinical protocol for COVID-19; a loading dose of 400 mg BID on day 1, followed by 200 mg BID for 4 days, or a loading dose of 800 mg QD on day 1, followed by 400 mg QD for 4 days, as per site specific clinical protocol for COVID-19.
 
Arm No. 3: Compound I-A and intravenous placebo. Subjects in this arm will receive Compound I-A orally. Compound I-A is administered at a dose of 10 mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day. Placebo (Normal Saline) is administered as infusion three times daily.
         No intervention: historical control: In this trial, historical controls refer to hospitalized patients who were not treated with compound I-A or famotidine during the early stages of the pandemic, between Feb. 1, 2020 and Mar. 26, 2021. This study will instead review data previously collected on patients not treated with Compound I-A to compare to the active treatment arms.       

     Inclusion Criteria: 
     1. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
 
2. Understands and agrees to comply with planned study procedures.
 
3. Male or non-pregnant female adult≥18 years of age at time of enrollment.
 
4. Subject consents to randomization within 24 hours of hospital admission.
 
5. Has radiographic confirmed COVID-19 disease&lt;72 hours prior to randomization.
 
6. Illness of any duration, and at least one of the following:
         Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR   Clinical assessment (evidence of rales/crackles on exam) AND SpO2≤94% on room air, OR   Requiring mechanical ventilation and/or supplemental oxygen.
 
7. Subjects do not require laboratory confirmation of the corona virus SARS-CoV-2 to determine eligibility
 
8. Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study (acceptable methods will be determined by the site).
       

     Exclusion Criteria: 
     1. Mild COVID-19 disease (minor clinical symptoms, imaging does not show signs of lung inflammation)
 
2. Recent history of or any in-hospital exposure to investigational medications targeting COVID-19, including hydroxychloroquine if prescribed in excess of the dose prescribed in this protocol.
 
3. ALT/AST&gt;5 times the upper limit of normal.
 
4. Moderate renal insufficiency (creatinine clearance 30-50 mL/min) OR Stage 4 severe chronic kidney disease OR requiring dialysis (i.e. creatinine clearance&lt;30 mL/min)
 
5. Presence of retinal or visual field changes attributable to any 4-aminoquinoline compound.
 
6. Known hypersensitivity to 4-aminoquinolone compounds
 
7. History of or evidence of QT prolongation on ECG examination
 
8. History of psoriasis or  porphyria  
 
9. Absolute neutrophil count (ANC) is &lt;2000 mm3
 
     10. Pregnancy 
     11. History of hepatic disease, Hepatitis C infection, or alcoholism
 
12. History of G-6-PD (glucose-6-phosphate dehydrogenase) deficiency
 
13. Concomitant use of known hepatotoxic drugs
 
14. Anticipated transfer to another hospital which is not a study site within 72 hours.
 
15. Allergy to any study medication
 
16. Known to be immunocompromised by disease or treatment for existing disease
 
     Outcome Measures 
     Primary Outcome Measures: Mortality [Time Frame: 30 days post hospitalization] 
     Secondary Outcome Measures: 
     Virologic response to study treatment detected in blood [Time Frame: Day 30 relative to admission Day 0]
 
Percent change in PCR copy number from first measurement
 
Virologic clearance in nasal swab and/or lower respiratory secretions [Time Frame: Day 6 and Day 30]
 
Presence or absence of SARS-CoV-2 Viral RNA in Nasopharyngeal swab or lower respiratory secretions
 
Clinical Severity [Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30]
 
measured by 7-point ordinal scale: from (1) death, to (7) not hospitalized, no limit on daily activities
 
Clinical Severity [Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30]
 
measured by National Early Warning Score (NEWS): vital sign based score from 0-20, higher score indicates higher degree of illness
 
Clinical Severity [Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30]
 
measured by duration of use of supplemental oxygen (if applicable)
 
Clinical Severity [Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30] measured by duration of use of mechanical ventilation (if applicable)
 
Clinical Severity [Time Frame: Measured on study Days 3, 5, 8, 11, 15 and 30]
 
measured by duration of hospitalization
 
     Example 7: Evaluation of NMN and NR on Influenza Virus Pulmonary Infection in Mice 
     The compounds I-A and I-G were delivered by intraperitoneal route at 185 mg/kg daily during all the experiment. 72 mice were daily weighed to adapt the volume of compounds. Physiological buffer was used as control and was administrated by i.p once per day during all the experiment. Control animals were orally administrated with Tamiflu at 2 mg/kg during all the experiment. Each animal has been infected with H1N1. The experimental groups are as follows:
         vehicle: H1N1 infection+physiological buffer   Tamiflu: H1N1 infection+Tamiflu (2×1 mg/kg)   Compound I-A: H1N1 infection+NMN (185 mg/kg)   Compound I-G: H1N1 infection+NR (185 mg/kg)   Tamiflu+Compound I-A: H1N1 infection+Tamiflu (2×1 mg/kg)+Compound I-A (185 mg/kg)   Tamiflu+Compound I-G: H1N1 infection+Tamiflu (2×1 mg/kg)+Compound I-G (185 mg/kg)       

     Survival rates, body weight and clinical scores were monitored during all the experiment. 
     Survival rates ( FIG.  7   ): Animals which lost 25% or more bodyweight, were euthanized for ethical reasons and considered as dead. Survival rates were monitored during all the experiment. Animals which lost 25% or more bodyweight, were euthanized for ethical reasons and considered as dead. 
     
       
         
           
               
               
            
               
                   
               
               
                   
                 Remaining mice 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Vehicle 
                 Tamiflu 
                 I-A 
                 I-G 
                 Tamiflu + I-A 
                 Tamiflu + I-G 
               
               
                   
               
               
                 Day 11 
                 5/12 
                 8/12 
                 7/12 
                 6/12 
                 12/12 
                 12/12 
               
               
                 Day 14 
                 1/12 
                 6/12 
                 7/12 
                 6/12 
                 12/12 
                 12/12 
               
               
                   
               
            
           
         
       
     
     Treatments with Tamiflu, compound I-A and compound I-G improved mice survival respectively with a rate of 50%, 58% and 50%. Combinations of compound I-A and compound I-G with the Tamiflu had triggered 100% of survival at the end of the experiment. The probability of survival is shown at  FIG.  5   . 
     Evolution of body weight ( FIGS.  8  and  9   ): From D4 to D9, the mice from vehicle group showed 20.4% of bodyweight loss on average. From day 10 to the end of the experiment, the bodyweight of all alive mice increased. Daily treatments with compound I-A, compound I-G or Tamiflu decrease the body weight loss in comparison to vehicle. Interestingly, combinations Tamiflu (2 mg/kg)+compound I-A (185 mg/kg) and Tamiflu (2 mg/kg)+compound I-G (185 mg/kg) had significantly contributed to maintain body weight. 
     Respiratory scoring ( FIG.  10   ): the respiratory scoring was assessed according to the following criteria: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Variable 
                 Score and description 
               
               
                   
                   
               
             
            
               
                   
                 Respiration score 
                 0- normal, rapid mouse respiration 
               
               
                   
                   
                 1- slightly decreased respiration 
               
               
                   
                   
                 2- moderately reduced respiration 
               
               
                   
                   
                 3- severely reduced respiration 
               
               
                   
                   
                 4- asphyxia 
               
               
                   
                   
               
            
           
         
       
     
     According to  FIG.  10   , the combination of compound I-A or compound I-G and Tamiflu maintained a normal respiration rate. 
     Conclusion: In this experiment, a positive effect of the two compounds was observed on survival, body weight loss, clinical scores. For compound I-A, an equivalent efficacy alone and in combination was demonstrated in this experiment. Based on the different observed clinical parameters, compound I-A and compound I-G showed a similar activity. It significantly appeared that the combination of Tamiflu and compound I-A or compound I-G had an impact on morbidity and mortality due to the complementary mode of action of compound I-A/compound I-G and Tamiflu. This led to a complete clinical recovery of these group of mice. This is likely due to the combination of an immune protection by the compounds I-A and I-G and the already described antiviral activity of Tamiflu. 
     Example 8: Evaluation of Compound I-A Dose-Response on Influenza Virus Pulmonary Infection 
     The model consists in intranasal administration of 500 PFU of Influenza virus H1N1 PR/8/34 strain to induce pneumonia. Compound I-A was delivered by intraperitoneal (i.p.) route at 90, 185 or 500 mg/kg immediately after infection and then daily during all the experiment. Mice were daily weighed to adapt the volume of compounds. Physiological buffer was used as control and was administrated by i.p once per day during all the experiment. Each experimental group comprises 22 mice: 12 mice for the survival study, 5 mice of the flow cytometry analysis and 5 mice for the assessment of viral load. 
     The experimental groups are the following:
         Group 1: Vehicle (i.p.)   Group 2: Compound I-A 90 mg/kg   Group 3: Compound I-A 185 mg/kg   Group 4: Compound I-A 500 mg/kg       

     At day 8, 5 mice per group are use to measure the following parameters.
         Blood collection: 3 aliquots (a, b and c)
 
a)+ac. perchlorique (NAD dosage)
 
b) immune cell characterization (cytometry)
 
c) remaining plasma-&gt;freezing
   Lung and lymph nodes collection, cell preparation, counting and immune cell characterization (cytometry)   Remaining cells (if any) from the 2 tissues treated for RNAseq   Viral load in the lungs (5 mice per group)       

     Survival rates, body weight, clinical scores, viral load in lungs and quantification of subsets of immune population in lung, blood and draining lymph node at day 8 post-infection by flow cytometry were monitored during all the experiment. 
     Survival ( FIG.  11   ): Animals which lost 25% or more bodyweight, were euthanized for ethical reasons and considered as dead. Survival rates were monitored during all the experiment. Animals which lost 25% or more bodyweight, were euthanized for ethical reasons and considered as dead. 
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Remaining mice 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Vehicle 
                 I-A 90 mg/kg 
                 I-A 185 mg/kg 
                 I-A 500 mg/kg 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                 Day 10 
                 4/12 
                 8/12 
                 12/12 
                 10/12 
               
               
                 Day 14 
                 1/12 
                 4/12 
                  7/12 
                  9/12 
               
               
                   
               
            
           
         
       
     
     92% of mortality were obtained for mice treated with the vehicle. Treatments with compound I-A at 90, 185 and 500 mg/kg improved mice survival respectively with a rate of 33%, 58% and 75%. The probability of survival is shown at  FIG.  9   . 
     Evolution of body weight ( FIGS.  12  and  13   ): Body weights for the 4 groups were stable for the first days after the infection with H1N1. From D3 to D8, the bodyweight for all the groups decreased. Daily treatments with compound I-A led to a weak improvement of this parameter in comparison to vehicle (D3-D8). 
     Clinical scores ( FIGS.  14  and  15   ): Mice treated with vehicle showed signs of malaise, slight piloerection and increased ambulation 3 days following the infection. Strong piloerection appeared on Day 5 with long periods of inactivity. Compound I-A treatments improved clinical states of the mice compared to vehicle group. 
     Viral load in lungs ( FIG.  16   ): The treatment with compound I-A at 90 and 185 mg/kg had no significative impact on viral load in lung, 8 days after the infection with 500 PFU of influenza A virus. The 500 mg/kg dose had significantly reduced the quantity of H1N1 particles in comparison to the vehicle group. 
     Conclusion: The study confirmed that the destruction of alveolar macrophages due to the infection was reduced with compound I-A treatment. Compound I-A treatment also increased the proportion of CD206+ macrophages suggesting a larger proportion of anti-inflammatory macrophages when mice were treated with compound I-A. These results could explain the improvement of clinical parameters and survival of mice treated with compound I-A. Although the modulation the recruitment of monocyte derived macrophages by was not observed in this experiment, the number of CD11b+DC tended to be reduced in presence of compound I-A. CD11b+ dendritic cells are known to have an important role during the Influenza infection. These cells allow the priming and restimulation of CD4+ T cells in the lung. They do not migrate to the draining lymph nodes. They also produce a large number of cytokines and chemokine leading the recruitment of NKT, NK, CD4+ and CD8+ T cells. Treatment with compound I-A modulated the immune response in the lung by preserving the destruction of alveolar macrophages and decreasing the recruitment of pro-inflammatory cell populations probably leading to a moderate lung inflammation. This effect did not seem to be dose dependent. 
     Example 9: Effects of Compound I-A in the Free Choice Diet-Induced Obese NASH Hamster Infected with SARS-CoV-2 
     The aim of the study is to evaluate the effects of compound I-A compound in the free choice diet-induced obese NASH hamster, a preclinical model that also develops heart failure with preserved ejection fraction (Briand et al., Metabolism 2021), infected with SARS-CoV-2. Compound I-A is evaluated over 25 days with treatment starting at the same time as the SARS-CoV-2 infection. 40 male Golden Syrian Hamster hamsters, 4-week-old are treated for 4 or 25 days with vehicle (n=18) or NMN compound 600 mg/kg (n=18) orally once daily (p.o. QD). Dosing starts 1 hour before SARS-CoV-2 infection. Hamsters are sacrificed at 4 days post infection (groups #1 and 3, n=9 hamsters per group) and at 25 days post infection (groups #2 and 4, n=9 hamsters per group). 
     
       
         
           
               
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 Treat- 
                   
                   
                 Dose 
                 Treatment 
               
               
                 Group# 
                 Diet 
                 n = 
                 ment 
                 Route 
                 Dose 
                 volume 
                 duration 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 Free- 
                 9 
                 vehicle  
                 p.o. QD 
                 / 
                 5 mL/kg 
                 4  
                 days 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 choice 
                   
                 QD 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 2 
                 Free- 
                 9 
                 vehicle  
                 p.o. QD 
                 / 
                 5 mL/kg 
                 25  
                 days 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 choice 
                   
                 QD 
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 3 
                 Free- 
                 9 
                 I-A 
                 p.o. QD 
                 600 
                 5 mL/kg 
                 4  
                 days 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 choice 
                   
                 QD 
                   
                 mg/kg 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 4 
                 Free- 
                 9 
                 I-A 
                 p.o. QD 
                 600 
                 5 mL/kg 
                 25  
                 days 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 choice 
                   
                 QD 
                   
                 mg/kg 
                   
                   
               
               
                   
               
            
           
         
       
     
     After the acclimation period, hamsters (n=40) are put on a free-choice diet (free-choice in the same cage between control chow diet or high fat/cholesterol diet and normal water or 10% fructose enriched water, as described by Briand et al., Metabolism 2021) for up to 20 weeks. Body weight is measured weekly during the diet period. 
     Before transfer to biosafety level 3 facility in the Animal Resource Center at the Lille Pasteur Institute, 36 hamsters are selected based on their plasma ALT, AST, total cholesterol, triglycerides levels and body weight: hamsters are 6-hour fasted at ˜8:00 am then bled at ˜2:00 pm (150 μL/heparin) to isolate plasma and assay plasma ALT, AST, total cholesterol and triglycerides. 
     The 36 selected hamsters are transferred to biosafety level 3 facility in the Animal Resource Center at the Lille Pasteur Institute and maintained on free choice diet. The 4 other hamsters are excluded from the study, bled by retro-orbital bleeding to isolate and store plasma at −80° C. and sacrificed for lungs, liver and heart collection. For each organ, one part is kept stored at −80° C. and the other part fixed in formalin for 24 hours prior to storage in ethanol at 4° C., for eventual analysis. 
     After a 1-week acclimation period, hamsters receive 1st dose of vehicle or compound I-A one hour before intranasally inoculated with SARS-CoV-2 (2×104 PFU) and are treated for 25 days after viral infection with vehicle or compound I-A orally QD for 25 days. Body weight is measured daily, and clinical signs monitored during the 25 days period. 
     At 4 days and 25 days post-infection, hamsters (n=9 vehicle and n=9 NMN compound treated hamsters at each timepoint) are sacrificed for maximal blood volume collection, then lungs, liver and heart are collected and dissected for formalin-fixation or storage at −80° C. for analysis. 
     Viral load in lungs (TCID50 and RT-qPCR) is measured at day 4. 
     Viral RNA and infectious virus are determined by quantitative PCR with reverse transcription (RT-qPCR), in situ hybridization and plaque-forming assays. Briefly, total RNAs in the tissue homogenate are extracted with RNeasy Mini kit (Qiagen). RT-qPCR will be performed according to the manufacturer&#39;s instructions. Quantitation of live infectious virus by median tissue culture infectious dose (TCID50) assay is performed as follows. Half of the lung tissues is weighed and homogenized in 1 ml of DMEM with 1% penicillin/streptomycin using pestle. After centrifugation at 13,000 rpm for 10 min, the clarified supernatant is harvested for live virus titration (TCID50 assay). Aliquots of the homogenates are applied on confluent Vero-E6 cells in 96-well plates for TCID50 assay. Briefly, serial 10-fold dilutions of each sample are inoculated in a Vero-E6 cell monolayer in quadruplicate and cultured in DMEM with 1% FBS and penicillin/streptomcycin. The plates are observed for cytopathic effects for 4 days. Viral titer are calculated with the Reed and Münch endpoint method. One TCID50 are interpreted as the amount of virus that caused cytopathic effects in 50% of inoculated wells. Virus titers are expressed as TCID50/gram of tissue. 
     The following analysis are then performed at 4 days and 25 days post-infection/treatment:
         plasma biochemistry: glucose, ALT, AST, ALP, LDH, TC, TG, FFA, LDL-c, HDL-c, bilirubin, total protein, IL-6 and ACE-2 activity.   lung qPCR (10 selected genes): IL-6, INF-g, Isg15, TNF-α, IL-10, IL-12p40, CXCL10, TGF-b, occluding, cadherin.   Right lung histology (H&amp;E and Sirius Red staining), histopathological scoring (cellular death/necrosis, alveolar and/or perivascular edema, hyaline membrane or fibrin, inflammation, thrombi, congestion, hemorrhage, type II hyperplasia, and syncytia) and % Sirius Red labelling (lung fibrosis)       

     Remaining RNA preparation, plasma samples and fixed liver and cardiac tissues from all animals are kept for additional analysis. Data are analysed with the presentation of mean±standard error. 
     Example 10: Evaluation of Compound I-A in Covid-19-Infected Mice 
     Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus&#39;s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). The B6.Cg-Tg(K18-ACE2)2Prlmn/J (i.e. hACE2) mice are susceptible to Sars-Cov-2 pulmonary infection (Yinda et al., 2020). Compound I-A is administered by i.p administration of the compound once daily for up to 10 days. 
     More specifically, 72 B6.Cg-Tg(K18-ACE2)2Prlmn/J males, 7-week-old at the arrival are obtained from Charles Rivers, BP0109, 69592, L&#39;Arbresle, France. Animals are divided in 6 experimental groups as follows:
         Group 1: 400 pfu+vehicle (n=10)   Group 2: 400 pfu+compound I-A 500 mg/kg (n=12)       

     Pfu means particle forming unit. The duration of the study is 10 days. At DO, all the mice are infected with 25 μL of DMEM containing Sars-Cov-2 (400 PFU/mouse) through intranasal route. Once per day, every day, mice are treated by oral gavage once per day with vehicle or compound I-A at 500 mg/kg. From DO to D10, the bodyweight, survival and clinical scoring of 10 mice per group are monitored. 
     The mortality, body weight and clinical signs are recorded every day until the end of the experiment (D10) for 12 mice per groups. 
     The clinical score is established as followed: 
     1: healthy mouse
 
2: mouse showing signs of malaise, including slight piloerection, slightly changed gait and increased ambulation
 
3: mouse showing signs of strong piloerection, constricted abdomen, changed gait, periods of inactivity
 
4: mouse with enhanced characteristics of the previous group, but showing little activity and becoming moribund
 
5: dead mouse
 
     The animal appearance and behaviour are assessed at least daily from the start and until the end of the experimental phase. Any abnormal finding is recorded in the raw data. Body weight measurement and clinical examination are also carried out before the animals are split into groups. 
     Respiratory score is monitored as follows: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Variable 
                 Score and description 
               
               
                   
                   
               
             
            
               
                   
                 Respiration rate 
                 0- normal, rapid mouse respiration 
               
               
                   
                   
                 1- slightly decreased respiration 
               
               
                   
                   
                 2- moderately reduced respiration 
               
               
                   
                   
                 3- severely reduced respiration 
               
               
                   
                   
                 4- asphyxia