Nicotinamide mononucleotide and nicotinamide riboside derivatives and their use in the treatment of viral infections and respiratory complications, in particular caused by influenza virus or coronavirus

Abstract

The present invention relates to nicotinamide mononucleotide derivatives of formula (I) or (Ia) for the treatment and / or prevention of viral infections such as respiratory tract infections. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or (Ia) for the treatment and / or prevention of viral infections.

Description

Technical Field

[0001] The present invention relates to nicotinamide mononucleotide derivative compounds for the treatment and / or prevention of viral infections. Background Art

[0002] Defending against diseases is crucial for the survival of all animals, and the mechanism adopted for this purpose is the animal immune system. The immune system is very complex due to involving two main parts, namely (i) innate immunity and (ii) adaptive immunity. The innate immune system includes cells and mechanisms that protect the host from infection by invading organisms in a non-specific manner. White blood cells related to the innate system particularly include phagocytes such as macrophages, neutrophils, and dendritic cells. The innate system is fully functional before the pathogen enters the host.

[0003] In contrast, the adaptive system is only initiated after the pathogen enters the host cell, at which time it forms a pathogen-specific defense. The main cell types of the adaptive immune system are called lymphocytes, which are mainly divided into two major categories: B cells and T cells. B cells are involved in the production of neutralizing antibodies that circulate in plasma and lymph and form part of the humoral immune response. T cells play a role in both the humoral immune response and cell-mediated immunity. There are several subsets of activated or effector T cells, including cytotoxic T cells (CD8+) and "helper" T cells (CD4+), among which there are mainly two types, called type 1 helper T cells (Th1) and type 2 helper T cells (Th2).

[0004] Th1 cells promote the cell-mediated adaptive immune response, which involves activating macrophages and stimulating the release of various cytokines such as IFNγ, TNF-α, and IL-12 in response to an antigen. These cytokines affect the functions of other cells in the adaptive and innate immune responses and lead to the destruction of microorganisms. Generally, the Th1 response is more effective against intracellular pathogens such as viruses and bacteria present within host cells, while the Th2 response is more effective against extracellular pathogens such as parasites and toxins located outside host cells.

[0005] In viral infections, acute viral infections are the most difficult to control when no vaccine is available. As can be seen from the frequent outbreaks of influenza, measles, or norovirus gastroenteritis, which affect millions of people every year, antiviral treatment is usually ineffective if not administered early in the infection.

[0006] In acute viral infections, respiratory infections are the most common type in humans; pathogens include rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, human metapneumovirus, measles, mumps, adenovirus, and coronavirus.

[0007] Most respiratory tract infections, especially upper respiratory tract infections, are mild and do not lead to incapacity. Upper respiratory tract infections often cause nasal discharge 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 usually occurs in both upper and lower respiratory tract infections.

[0008] Typical influenza in adults is characterized by the sudden onset of chills, fever, prostration, cough, and generalized myalgia (especially in the back and legs). Headache is prominent and often accompanied by photophobia and retrobulbar pain. Respiratory symptoms may initially be mild, with hoarseness, retrosternal burning, dry cough, and sometimes rhinitis. Later, lower respiratory tract disease predominates; the cough can be persistent, harsh, and frequent and may progress to pneumonia.

[0009] Although most patients usually recover completely within 1 to 2 weeks, influenza and influenza-associated pneumonia are important causes of morbidity or death in high-risk patients. In France, seasonal influenza affects 2 to 8 million people and causes 10,000 to 15,000 deaths each year.

[0010] To date, the treatment of influenza is symptomatic, with hygiene measures to limit transmission and may also involve specific antiviral treatment. The antiviral drug available in France is oseltamivir, a neuraminidase inhibitor active against both influenza A and B viruses, in oral form. If taken early, i.e., within 48 hours of the onset of symptoms, it can reduce the duration of the disease and the severity of symptoms. It also reduces the risk of complications and death. In cases of resistance to intravenous oseltamivir, another neuraminidase inhibitor, zanamivir is available on prescription in hospitals. In addition to hygiene measures, annual influenza vaccination remains the most effective way of self-protection. It helps to reduce severe forms of influenza.

[0011] However, resistance can develop during treatment. In some severe cases (pneumonia or hospitalization) receiving antiviral treatment, recurrence of symptoms has also been observed after one day or less of treatment.

[0012] Therefore, there is still a need for effective and safe prophylactic and / or therapeutic treatments for viral infections, especially acute viral infections such as respiratory tract infections.

[0013] In December 2019, a novel highly contagious viral pneumonia (R0≈2.2) emerged, and the epidemic was soon characterized by the World Health Organization (WHO) as a threat to global public health. A few days later, the virus was identified as a new β-coronavirus, a single-stranded RNA positive virus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-Cov-2 is the seventh coronavirus to affect humans and the third highly pathogenic coronavirus after the coronavirus outbreaks of severe acute respiratory syndrome (SARS-CoV-2002) first identified in 2003 and Middle East respiratory syndrome (MERS-CoV-2012) first identified in 2012.

[0014] Currently, the occurrence of diseases associated with SARS-Cov-2 has been detected in more than 200 countries and regions around the world. According to WHO data (April 22, 2020), the number of confirmed cases globally has exceeded 2 million, with 162,956 deaths. Not all people who have been exposed to SARS-CoV-2 will be infected, nor will all infected patients develop severe respiratory diseases. According to a study of more than 1,000 patients in Wuhan, SARS-CoV-2 infects all age groups equally, although children and adolescents seem to be less affected and rarely develop into severe forms. This protection against infection can only be relative, as the number of infected cases found in the youngest age groups has increased significantly, which may be due to the increased frequency of screening.

[0015] COVID-19 is a respiratory disease, and the symptoms that usually appear first include headache, muscle pain and / or fatigue / tiredness, followed by fever and respiratory symptoms (such as dry cough, shortness of breath and / or chest tightness). Although the symptoms of most subjects remain mild, in other subjects, they may develop into pneumonia (referred to as novel coronavirus infection in this article) and / or multiple organ failure. The complications of COVID-19 include acute respiratory distress syndrome (ARDS), RNAemia, acute cardiac injury and secondary infection (Huang et al., Lancet. 2020; 395(10223): 497-506). It is estimated that about 20% of COVID-19 patients need hospitalization, and about 5% need to be admitted to the intensive care unit (ICU). COVID-19 causes a large number of morbidity and mortality and may bring unprecedented pressure to many health systems.

[0016] Due to the unavailability of vaccines, antiviral drugs, or other specific treatments, the treatment of COVID-19 remains supportive. Currently, over 175 treatment and vaccine clinical trials are registered, and current treatment strategies include antiviral agents, particularly remdesivir (a nucleotide analogue), lopinavir / ritonavir (an antiretroviral therapy mainly used to treat human immunodeficiency virus 1 (HIV-1)), chloroquine or hydroxychloroquine, and Il-6 inhibitor immunomodulators such as tocilizumab. However, there are currently no vaccines that can prevent and / or treat COVID-19 or asymptomatic infections with SARS-CoV-2, nor are there any therapeutic agents that have been proven effective in preventing and / or treating COVID-19, novel coronavirus infections, or COVID-19-related acute respiratory distress syndrome (ARDS).

[0017] Therefore, there is an urgent need for effective and safe prophylactic and / or therapeutic treatments for coronavirus infections, particularly for coronavirus respiratory infections that cause diseases such as SARS, MERS, COVID-19, especially novel coronavirus infections and COVID-19-related acute respiratory distress syndrome (ARDS).

[0018] Nicotinamide mononucleotide (NMN) is a known nucleotide.

[0019] Therefore, the object of the present invention is to provide an alternative to current treatments by providing nicotinamide mononucleotide and its derivatives for the treatment and / or prevention of viral infections, particularly respiratory infections such as influenza virus or coronavirus.

[0020] The applicant has surprisingly found that the nicotinamide mononucleotide derivatives according to the present invention are effective agents for the treatment and / or prevention of viral infections and are well tolerated. Summary of the Invention

[0021] Therefore, the present invention relates to a compound of formula (I),

[0022]

[0023] or a pharmaceutically acceptable salt or solvate or prodrug thereof;

[0024] wherein:

[0025] X is selected from O, CH2, S, Se, CHF, CF2, and C=CH2;

[0026] R1 is selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein, R is selected from H and C1-C8 alkyl;

[0027] R2, R3, R4, and R5 are independently selected from H, halogen, azide, cyano, hydroxy, C1-C 12 alkyl, C1-C 12 thioalkyl, C1-C 12 heteroalkyl, C1-C 12 haloalkyl, and OR; wherein R is selected from H, C1-C 12 alkyl, C(O)(C1-C 12 )alkyl, C(O)NH(C1-C 12 )alkyl, C(O)O(C1-C 12 )alkyl, C(O)aryl, C(O)(C1-C 12 )alkylaryl, C(O)NH(C1-C 12 )alkylaryl, C(O)O(C1-C 12 )alkylaryl, and C(O)CHR AA NH2; wherein R AA is a side chain selected from protein amino acids;

[0028] R6 is selected from H, azide, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein R is selected from H and C1-C8 alkyl;

[0029] R7 is selected from P(O)R9R 10 、P(S)R9R 10 and wherein n is an integer selected from 1 or 3; wherein:

[0030] R9 and R 10 are independently selected from OH, OR 11 、NHR 13 、NR 13 R 14 、C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 cycloalkyl, C5-C 12 aryl, C1-C8 arylalkyl, C1-C8 alkylaryl, C1-C8 heteroalkyl, C1-C8 heterocycloalkyl, heteroaryl, and NHCRαRα’C(O)R 12 ; wherein:

[0031] -R 11 is selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, C5-C 12 aryl, C1-C 10 alkylaryl, substituted C5-C 12 aryl, C1-C 10 heteroalkyl, C1-C10 Halogenoalkyl, -(CH2) n C(O)(C1-C 15 )alkyl, -(CH2) n OC(O)(C1-C 15 )alkyl, -(CH2) n OC(O)O(C1-C 15 )alkyl, -(CH2) n SC(O)(C1-C 15 )alkyl, -(CH2) n C(O)O(C1-C 15 )alkyl and -(CH2) n C(O)O(C1-C 15 )alkylaryl; 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(R 11a )2, C1-C6 amido, -COR 11b , -OCOR 11b ; NHSO2(C1-C6 alkyl), -SO2N(R 11a )2SO2, wherein, each R 11a is independently selected from H and (C1-C6) alkyl, and R 11b is independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2;

[0032] -R 12 is selected from hydrogen, C1-C 10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 halogenoalkyl, C3-C 10 cycloalkyl, C3-C 10 cycloheteroalkyl, C5-C 12 aryl, C1-C4 alkylaryl and C5-C 12 heteroaryl; wherein, the aryl or heteroaryl may optionally be substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano;

[0033] -R 13 and R 14 are independently selected from H, C1-C8 alkyl and C1-C8 alkyl-aryl;

[0034] -Rα and Rα’ are independently selected from hydrogen, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C10 cycloalkyl, C1-C 10 thioalkyl, C1-C 10 hydroxyalkyl, C1-C 10 alkylaryl and C5-C 12 aryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and side chains selected from proteinogenic or non-proteinogenic amino acids; wherein said aryl is optionally substituted with a group selected from hydroxy, C1-C 10 alkyl, C1-C6 alkoxy, halogen, nitro and cyano; or

[0035] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 - represents -CH2-CH2-CHR-; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; or

[0036] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano;

[0037] R8 is selected from H, OR, NHR 15 、NR 15 R 16 、NH-NHR 13 、SH、CN、N3 and halogen; wherein R 15 and R 16independently selected from H, C1-C8 alkyl, and C1-C8 alkylaryl; and -CRBRC-C(O)-ORD, wherein RB and RC are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, benzyl, indolyl, or imidazolyl, where the C1-C6 alkyl and C1-C6 alkoxy may optionally and independently of each other be substituted by one or more of halogen, amino, amido, guanidino, hydroxy, mercapto, or carboxy, and benzyl is optionally substituted by one or more of halogen or hydroxy, or RB and RC together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, the C3-C6 cycloalkyl being optionally substituted by one or more of halogen, amino, amido, guanidino, hydroxy, mercapto, and carboxy, and RD is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;

[0038] Y is selected from CH, CH2, C(CH3)2, and CCH3;

[0039] represents a single bond or a double bond according to Y; and

[0040] represents an α or β endo isomer depending on the position of R1,

[0041] or a compound of formula (Ia)

[0042]

[0043] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein:

[0044] -X’1 and X’2 are independently selected from O, CH2, S, Se, CHF, CF2, and C═CH2;

[0045] -R’1 and R’ 13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; where R is selected from H and C1-C8 alkyl;

[0046] -R’2, R’3, R’4, R’5, R’9, R’ 10 、R’ 11 、R’ 12 are independently selected from H, halogen, azido, cyano, hydroxy, C1-C 12 alkyl, C1-C 12 thioalkyl, C1-C 12 heteroalkyl, C1-C 12 haloalkyl, and OR; where R is selected from H, C1-C 12 alkyl, C(O)(C1-C 12)alkyl, C(O)NH(C1-C 12 )alkyl, C(O)O(C1-C 12 )alkyl, C(O)aryl, C(O)(C1-C 12 )alkylaryl, C(O)NH(C1-C 12 )alkylaryl, C(O)O(C1-C 12 )alkylaryl or C(O)CHR AA NH2, wherein R AA is the side chain of a protein amino acid;

[0047] -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;

[0048] -R’7 and R’ 14 are independently selected from H, OR, NHR, NRR’, NH-NHR, SH, CN, N3, and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkylaryl;

[0049] -Y’1 and Y’2 are independently selected from CH, CH2, C(CH3)2, or CCH3;

[0050] -M’ is selected from H or a suitable counterion;

[0051] - represents a single bond or a double bond depending on Y'1 and Y'2; and

[0052] - represents an α or β anomeric isomer depending on the R'1 and R' 13 position,

[0053] The compound is applied to the treatment and / or prevention of viral infections.

[0054] According to one embodiment, X represents oxygen.

[0055] According to one embodiment, R1 and R6 each independently represent hydrogen.

[0056] According to one embodiment, R2, R3, R4, and R5 each independently represent hydrogen.

[0057] According to one embodiment, R2, R3, R4, and R5 each independently represent OH.

[0058] According to one embodiment, Y represents CH or CH2.

[0059] According to one embodiment, R7 represents P(O)R9R 10 wherein, R9 and R10 As described herein.

[0060] According to one embodiment, the compounds used according to the present invention are selected from Compounds I-A to I-J listed in Table 1 below, or pharmaceutically acceptable salts and solvates or prodrugs thereof.

[0061]

[0062]

[0063] Advantageously, the preferred compounds of the present invention are Compounds I-A to I-F or pharmaceutically acceptable salts or solvates thereof, more preferably IB, ID or IF.

[0064] Advantageously, the compound of formula (I) is dihydro-nicotinamide mononucleotide (NMN-H) of the following formula:

[0065]

[0066] According to one embodiment, X'1 and X'2 each independently represent oxygen.

[0067] According to one embodiment, R'7 and R' 14 each independently represent NH2.

[0068] According to one embodiment, R'1 and / or R' 13 each independently represent hydrogen.

[0069] According to one embodiment, R'6 and / or R'8 each independently represent hydrogen.

[0070] According to one embodiment, R'2, R'3, R'4, R'5, R'9, R' 10 , R' 11 and R' 12 each independently represent hydrogen.

[0071] According to one embodiment, R'2, R'3, R'4, R'5, R'9, R' 10 , R' 11 and R' 12 each independently represent OH.

[0072] According to one embodiment, Y'1 and Y'2 each independently represent CH.

[0073] According to one embodiment, Y'1 and Y'2 each independently represent CH2.

[0074] According to one embodiment, the compounds according to the invention are selected from the compounds of formulae Ia-A to Ia-I listed in Table 2, or pharmaceutically acceptable salts and solvates or prodrugs thereof:

[0075] [Table 2]

[0076]

[0077] Advantageously, the preferred compounds of the invention are the compounds of formula Ia-C or Ia-F or Ia-I.

[0078] Advantageously, the preferred compounds of the invention are the compounds of formula Ia-B or Ia-E or Ia-H.

[0079] According to one embodiment, the application comprises the step of administering at least one other active ingredient sequentially, simultaneously and / or separately, the active ingredient being selected from antiviral agents, neuraminidase inhibitors, M2 proton channel blockers, anti-interleukin 6, JAK inhibitors, interferons, macrolides, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brequinar, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelimycin, nicotine, histamine H2 receptor antagonists and mixtures thereof. According to one embodiment, the histamine H2 receptor antagonist is selected from famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavotidine, niperotidine, preferably famotidine.

[0080] According to one embodiment, the viral infection is caused by at least one virus selected from the genera: Influenza virus, Coronavirus, Respiratory virus, Pneumovirus, Metapneumovirus, Adenovirus, Enterovirus, Rhinovirus, Hepacivirus, Equine rhinitis virus, Aphthovirus, Norovirus, Alphavirus, Rubivirus, Flavivirus, Hepatovirus, Pestivirus, Ebola-like virus, Measles virus, Mumps virus, Henipavirus, Arenavirus, Orthobunyavirus, Phlebovirus, Rotavirus, Herpes simplex virus, Varicella zoster virus or Cytomegalovirus.

[0081] According to one embodiment, the viral infection is a respiratory infection caused by at least one virus selected from the genera: Influenza virus, Coronavirus, Rhinovirus, Respiratory virus, Pneumovirus or Metapneumovirus.

[0082] According to one embodiment, the viral infection is a respiratory infection caused by the genus Influenza virus, preferably influenza A or influenza B.

[0083] 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.

[0084] 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 selected from MERS-CoV, SARS-CoV-1, and SARS-CoV-2.

[0085] According to one embodiment, the coronavirus infection is an SARS-CoV-2 infection that causes coronavirus disease 2019 (COVID-19).

[0086] According to one embodiment, the coronavirus infection is an SARS-CoV-2 infection that causes novel coronavirus infection.

[0087] According to one embodiment, the coronavirus infection is an SARS-CoV-2 infection that causes COVID-19-related acute respiratory distress syndrome (ARDS).

[0088] The present invention also relates to a pharmaceutical composition for treating and / or preventing viral infection, which comprises at least one compound used according to the present invention and at least one pharmaceutically acceptable carrier.

[0089] According to one embodiment, in addition to at least one compound used according to the present invention, the pharmaceutical composition used further comprises at least one active ingredient selected from antiviral agents, neuraminidase inhibitors, M2 proton channel blockers, anti-interleukin 6, JAK inhibitors, interferons, and mixtures thereof, and / or at least another active ingredient selected from antiviral agents, neuraminidase inhibitors, M2 proton channel blockers, anti-interleukin 6, JAK inhibitors, interferons, and mixtures thereof, and / or at least another active ingredient selected from antiviral agents; anti-interleukin 6 (anti-IL6) reagents; Janus-associated kinase (JAK) inhibitors; interferons; macrolides, preferably selected from azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin, and another active ingredient selected from BXT 25, chloroquine, hydroxychloroquine, brequinar, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelesimycin, nicotine, histamine H2 receptor antagonists, and mixtures thereof.

[0090] In one embodiment, in addition to at least one compound used according to the present invention, the pharmaceutical composition used further comprises a histamine H2 receptor antagonist.

[0091] According to one embodiment, the histamine H2 receptor antagonist is selected from famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavulotide, niperotidine, preferably famotidine.

[0092] The present invention also relates to a method for preparing a compound of formula Ia, which comprises the following steps:

[0093] 1) Monophosphorylation of a compound of formula Xa

[0094]

[0095] wherein:

[0096] X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and as defined herein, to obtain a compound of formula XIa

[0097]

[0098] wherein:

[0099] X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and as defined herein;

[0100] 2) Hydrolyzing the compound of formula XIa obtained in step 1) to obtain a compound of formula XIIa

[0101]

[0102] wherein:

[0103] X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and as defined herein;

[0104] 3) Reacting the compound of formula XIIa obtained in step 2) with a compound of formula XIIIa

[0105]

[0106] obtained as described in step 1), wherein:

[0107] X’2, R’8, R’9, R’10 、 R' 11 、 R' 12 、 R' 13 、 R' 14 、 Y'2、 and as defined herein

[0108] to obtain a compound of formula Ia.

[0109] According to one embodiment, the method further comprises the step of reducing the compound of formula Ia obtained in step 3) to obtain a compound of formula Ia, wherein Y'1 and Y'2 each independently represent CH2.

[0110] Definition

[0111] The following definitions and explanations apply to the terms used throughout the application including the specification and claims.

[0112] When describing the compounds of the present invention, unless otherwise specified, the terms used will be construed according to the following definitions.

[0113] Unless otherwise specified, the nomenclature for substituents not specifically defined is obtained by naming the adjacent functional group closest to the point of attachment, followed by the terminal portion of the functional group. For example, the substituent "arylalkyl" refers to the group -(aryl)-(alkyl).

[0114] In the present invention, the following terms have the following meanings:

[0115] The term "alkyl" by itself or as part of another substituent refers to the formula C n H 2n+1a hydrocarbyl group, wherein n is a number greater than or equal to 1. Generally, the alkyl groups of the present invention contain from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 2 carbon atoms. The alkyl groups can be straight-chain or branched-chain and can be substituted as shown herein. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl) and hexyl and its isomers (e.g., n-hexyl, isohexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched-chain alkyl groups include but are not 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-dimethylpentyl, 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.

[0116] Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), hexyl and its isomers (e.g., n-hexyl, isohexyl), heptyl and its isomers (e.g., heptyl-heptyl, isoheptyl), octyl and its isomers (e.g., n-octyl, isooctyl), nonyl and its isomers (e.g., n-nonyl, isononyl), decyl and its isomers (e.g., n-decyl, isodecyl), undecyl and its isomers, dodecyl and its isomers. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Cx-Cy-alkyl means an alkyl group containing from x to y carbon atoms.

[0117] When the suffix "ene" ("alkylene") is used in combination with an alkyl group, it means an alkyl group defined as having two single bonds as the connection points to other groups. The term "alkylene" includes methylene, ethylene, methylethylene, propylene, ethyl ethylene, and 1,2-dimethylethylene.

[0118] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group, which can be straight-chain or branched-chain and contains one or more carbon-carbon double bonds. Suitable alkenyl groups contain 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Examples of alkenyl groups are vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, etc.

[0119] As used herein, the term "alkynyl" refers to a class of monovalent unsaturated hydrocarbon groups in which the unsaturation is caused by the presence of one or more carbon-carbon triple bonds. Alkynyl groups generally and preferably have the same number of carbon atoms as described above for 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, etc.

[0120] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon group having a single ring (i.e., phenyl), or multiple aromatic rings fused together (such as naphthyl), or covalently linked, usually containing 5 to 12 atoms; preferably 6 to 10, with at least one ring being aromatic. The aromatic rings may optionally include one or two additional rings (cycloalkyl, heterocyclic or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems listed therein. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylene, 5- or 6-tetrahydronaphthyl, 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-cyclopentadienyl, 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.

[0121] As used herein, the term "cycloalkyl" is a cyclic alkyl group, i.e., a monovalent saturated or unsaturated hydrocarbon group having 1 or 2 cyclic structures. Cycloalkyl groups include monocyclic or bicyclic hydrocarbon groups. Cycloalkyl groups can contain more than 3 carbon atoms in the ring and generally contain 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6 carbon atoms according to the present invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopropyl is particularly preferred.

[0122] The term "halogen" or "halogens" refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine.

[0123] The term "haloalkyl", alone or in combination, refers to an alkyl residue having the meaning defined above, wherein one or more hydrogens are replaced by a halogen as defined above. Non-limiting examples of such haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, etc. Cx-Cy-haloalkyl and Cx-Cy-alkyl are alkyls containing from x to y carbon atoms. Preferred haloalkyls are difluoromethyl and trifluoromethyl.

[0124] When at least one carbon atom in an aryl group is replaced by a heteroatom, the resulting ring is called a heteroaryl ring.

[0125] The term "heteroalkyl" refers to an alkyl as defined above, wherein one or more carbon atoms are replaced by heteroatoms selected from oxygen, nitrogen and sulfur atoms. In a heteroalkyl, the heteroatoms are connected only to carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom. However, nitrogen and sulfur heteroatoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. 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 contained in the heteroalkyl.

[0126] As used herein, the term "heteroaryl", used alone or as part of another group, refers to, but is not limited to, an aromatic ring of 5 to 12 carbon atoms or a ring system containing 1 to 2 rings fused together or covalently linked, usually containing 5 to 6 atoms; at least one of which is aromatic, and one or more of the carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms can optionally be quaternized. Such rings can be fused to aryl, cycloalkyl, heteroaryl or heterocyclic rings. Non-limiting examples of such heteroaryls include: furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furyl, thieno[3,2-b]thienyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridyl, indolyl, indolizinyl, isoindolyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridyl, purinyl, imidazo[1,2-a]pyridyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-1(2H)-yl, 1,3-benzodioxolane, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0127] When at least one carbon atom in a cycloalkyl is replaced by a heteroatom, the resulting ring is called a "heterocycloalkyl" or "heterocyclic group".

[0128] As used herein, the term "heterocyclyl", "heterocycloalkyl" or "heterocycle", whether used alone or as part of another group, refers to a non-aromatic, fully saturated or partially unsaturated cyclic group having at least one heteroatom in at least one carbon-containing ring (e.g., a 3- to 7-membered monocyclic, 7- to 11-membered bicyclic or a total of 3 to 10 ring atoms). Each ring of the heterocyclic group containing a heteroatom can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. Any carbon atom of the heterocyclyl can be substituted with oxo (e.g., piperidone, pyrrolidone). Where valence permits, the heterocyclic group can be attached to any heteroatom or carbon atom of a ring or ring system. The rings of a polycyclic heterocycle can be fused, bridged and / or linked through one or more spiro atoms. Non-limiting exemplary heterocyclic groups include oxetanyl, piperidyl, azetidinyl, 2-imidazolinyl, pyrazolidyl, imidazolidyl, isoxazolinyl, oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, piperidyl, 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-dioxolane, 1,4-dioxanyl, 2,5-dioxoimidazolidyl, 2-oxopiperidyl, 2-oxopyrrolidyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrazinyl, tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl and morpholin-4-yl.

[0129] As used herein, the term "non-protein amino acid" refers to an amino acid that is not naturally encoded or found in the genetic code of a living organism. Non-limiting examples of non-protein amino acids are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, δ-aminolevulinic acid, β-alanine, cystathionine, γ-aminobutyric acid, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, α-aminobutyric acid, 2-aminoisobutyric acid, D-leucine, D-valine, D-alanine or D-glutamic acid.

[0130] As used herein, the term "protein amino acid" refers to an amino acid incorporated into a protein during the process of ribosomal translation of messenger RNA in a living organism, namely alanine (ALA), arginine (ARG), asparagine (ASN), aspartic acid (ASP), cysteine (CYS), 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).

[0131] As used herein, the term "prodrug" refers to a pharmacologically acceptable derivative of a compound of formula (I), such as an ester whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Suitable prodrugs for the purposes of the present invention include carboxylic acid esters, particularly alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolane carboxylic acid esters; ascorbic acid esters.

[0132] The term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced by any desired group that is substantially stable under the reaction conditions in unprotected form or when protected by a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chlorine, iodine, bromine or fluorine); alkyl; alkenyl; alkynyl as described above; hydroxy; alkoxy; nitro; mercapto; thioether; imine; cyano; amido; phosphonic acid; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl, which may be monocyclic or fused or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl), monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuryl); amino (primary, secondary or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and these moieties may also optionally be substituted by a fused ring structure or a bridge, such as -OCH2O-. These substituents may optionally be further substituted by substituents selected from these groups. In certain embodiments, the term "substituent" or the adjective "substituted" means a substituent selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR 11 R 12 、-NR 13 C(O)R 14 、halogen, -OR 13 、cyano, nitro, 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)rR 13 、-NR 13 S(O)rR 14 、-OS(O)rR14 、 S(O)rNR 11 R 12 、 -O, -S, and -N-R 13 where r is 1 or 2; R 11 and R 12 are independently, each time they appear, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 11 and R 12 together with the nitrogen to which they are attached are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 13 and R 14 are independently, each time they appear, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0133] The term "active ingredient" refers to a molecule or substance whose administration to a subject slows or stops the progression, exacerbation, or worsening of one or more symptoms of a disease or disorder; alleviates the symptoms of a disease or disorder; or cures a disease or disorder. According to one embodiment, the therapeutic ingredient is a natural or synthetic small molecule. According to another embodiment, the therapeutic ingredient is a biomolecule such as an oligonucleotide, siRNA, miRNA, DNA fragment, aptamer, antibody, etc.

[0134] "Pharmaceutically acceptable" means that the components of a pharmaceutical composition are compatible with each other and not harmful to its patient.

[0135] The term "pharmaceutically acceptable excipient" or "pharmaceutical carrier" refers to an inert medium or vehicle used as a solvent or diluent in which a pharmaceutically active agent is formulated and / or administered and which, when administered to an animal, preferably a human, does not produce an adverse reaction, allergic reaction, or other reaction. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption blockers, and other similar components. For human administration, the formulation must meet the sterility, general safety, and purity standards required by regulatory agencies such as the FDA or EMA. For the purposes of the present invention, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents, and / or adjuvants.

[0136] The term "pharmaceutically acceptable salts" includes both its acid addition salts and base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hippurate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethylsulfonate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / monohydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0137] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, 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.

[0138] Half salts of acids and bases can also be formed, such as half sulfate and half calcium salts.

[0139] Pharmaceutically acceptable salts of the compound of formula (I) can be prepared by one or more of these methods:

[0140] (i) by reacting the compound of formula (I) with the desired acid;

[0141] (ii) by reacting the compound of formula (I) with the desired base;

[0142] (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 (such as a lactone or lactam) using the desired acid; and / or

[0143] (iv) by converting one salt of the compound of formula (I) to another via reaction with a suitable acid or by passing through a suitable ion exchange column.

[0144] All of these reactions are typically carried out in solution. The salt can be precipitated from the solution and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to almost non-ionized.

[0145] Although generally, with respect to the salts of the compounds of the present invention, pharmaceutically acceptable salts are preferred, it should be noted that the present invention also includes, in its broadest sense, non-pharmaceutically acceptable salts, which can be used, for example, for the separation and / or purification of the compounds of the present invention. For example, salts formed with optically active acids or bases can be used to form diastereomeric salts, which can facilitate the separation of the optically active isomers of the compounds of formula I above.

[0146] The term "solvate" is used to describe a molecular complex containing a compound of the present invention and containing a stoichiometric or sub-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0147] The term "administer" or its variants (e.g., "administering") means providing an active agent or active ingredient, either alone or as part of a pharmaceutically acceptable composition, to a patient to be treated or prevented from a disorder, symptom, or disease.

[0148] The term "human" refers to a subject of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult).

[0149] The term "patient" refers to a warm-blooded animal, more preferably a human, who is waiting to receive, or is receiving, medical care, or who is, or will be, the subject of a medical procedure.

[0150] As used herein, the term "treat" and its various variants are intended to include alleviating, slowing down, or eliminating a disorder or disease and / or its accompanying symptoms.

[0151] As used herein, the term "prevent" and its various variants refer to methods of delaying or hindering the onset of a disorder or disease and / or its accompanying symptoms, preventing a patient from developing a disorder or disease, or reducing the risk of a patient developing a particular disorder or disease.

[0152] As used herein, the term "therapeutically effective amount" (or more simply "effective amount") refers to the amount of an active agent or active ingredient sufficient to achieve the desired therapeutic or prophylactic effect in a patient to whom it is administered.

[0153] The bonds to the asymmetric carbon can be represented herein using a solid triangle a dashed triangle or a zigzag line to represent. Detailed Description

[0154] Compounds for the treatment and / or prevention of viral infections

[0155] Accordingly, the present invention relates to compounds of formula (I),

[0156]

[0157] or a pharmaceutically acceptable salt or solvate thereof or a prodrug thereof;

[0158] wherein:

[0159] X is selected from O, CH2, S, Se, CHF, CF2, and C═CH2;

[0160] R1 is selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein, R is selected from H and C1-C8 alkyl;

[0161] R2, R3, R4, and R5 are independently selected from H, halogen, azido, cyano, hydroxy, C1-C 12 alkyl, C1-C 12 thioalkyl, C1-C 12 heteroalkyl, C1-C 12 haloalkyl, and OR; wherein, R is selected from H, C1-C 12 alkyl, C(O)(C1-C 12 )alkyl, C(O)NH(C1-C 12 )alkyl, C(O)O(C1-C 12 )alkyl, C(O)aryl, C(O)(C1-C 12 )alkylaryl, C(O)NH(C1-C 12 )alkylaryl, C(O)O(C1-C 12 )alkylaryl, and C(O)CHR AA NH2; wherein, R AA is the side chain of a protein amino acid;

[0162] R6 is selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein, R is selected from H and C1-C8 alkyl;

[0163]

[0164] R7 is selected from P(O)R9R 10 、P(S)R9R 10 and

[0165] wherein, n is an integer selected from 1 or 3; wherein:

[0166] R9 and R 10 are independently selected from OH, OR 11 、NHR 13 、NR 13 R 14 、C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 cycloalkyl, C5-C 12Aryl, C1-C8 arylalkyl, C1-C8 alkylaryl, C1-C8 heteroalkyl, C1-C8 heterocycloalkyl, heteroaryl, and NHCR α R α’ C(O)R 12 ; wherein:

[0167] -R 11 is selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, C5-C 12 aryl, C1-C 10 alkylaryl, substituted C5-C 12 aryl, C1-C 10 heteroalkyl, C1-C 10 haloalkyl, -(CH2) n C(O)(C1-C 15 )alkyl, -(CH2) n OC(O)(C1-C 15 )alkyl, -(CH2) n OC(O)O(C1-C 15 )alkyl, -(CH2) n SC(O)(C1-C 15 )alkyl, -(CH2) n C(O)O(C1-C 15 )alkyl and -(CH2) n C(O)O(C1-C 15 )alkylaryl; 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 amido, -COR11b, -O COR11b; NHSO2(C1-C6 alkyl), -SO2N(R11a)2SO2, wherein each R 11 a is independently selected from H and (C1-C6) alkyl and R 11 b is independently selected from OH, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2;

[0168] -R 12 is selected from hydrogen, C1-C 10 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C 10 haloalkyl, C3-C 10 cycloalkyl, C3-C 10 cycloheteroalkyl, C5-C 12 aryl, C1-C4 alkylaryl, and C5-C 12Heteroaryl; wherein the aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and cyano;

[0169] -R 13 and R 14 are independently selected from H, C1-C8 alkyl, and C1-C8 alkyl-aryl;

[0170] -R α and R α’ are independently selected from hydrogen, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, C1-C 10 thioalkyl, C1-C 10 hydroxyalkyl, C1-C 10 alkylaryl, and C5-C 12 aryl, -(CH2)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, and side chains selected from protein or non-protein amino acids; wherein the aryl is optionally substituted with groups selected from hydroxy, C1-C 10 alkyl, C1-C6 alkoxy, halogen, nitro, and cyano; or

[0171] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 - represents -CH2-CH2-CHR-; wherein R is selected from hydrogen, C5-C6 aryl, and C5-C6 heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and cyano; or

[0172] R9 and R 10 together with the phosphorus atom to which they are attached form a 6-membered ring, wherein -R9-R 10 - represents -O-CH2-CH2-CHR-O-; wherein R is selected from hydrogen, C5-C6 aryl, and C5-C6 heteroaryl, wherein the aryl or heteroaryl is optionally substituted with groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and cyano;

[0173] R8 is selected from H, OR, NHR 15 、NR 15 R 16 、NH-NHR 13 、SH、CN、N3, and halogen; wherein R 15 and R 16independently selected from H, C1-C8 alkyl, and C1-C8 alkylaryl; 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 optionally and independently of each other be substituted with one or more halogen, amino, amido, guanidino, hydroxy, mercapto, or carboxy groups, and the benzyl may optionally be substituted with one or more halogen or hydroxy groups, or RB and RC together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group which may optionally be substituted with one or more halogen, amino, amido, guanidino, hydroxy, mercapto, and carboxy groups, and RD is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl;

[0174] Y is selected from CH, CH2, C(CH3)2, and CCH3;

[0175] represents a single bond or double bond according to Y; and

[0176] represents an α or β endo-isomer depending on the position of R1,

[0177] or a compound of formula (Ia)

[0178]

[0179] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein:

[0180] -X’1 and X’2 are independently selected from O, CH2, S, Se, CHF, CF2, and C=CH2;

[0181] -R’1 and R’ 13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein R is selected from H and C1-C8 alkyl;

[0182] -R’2, R’3, R’4, R’5, R’9, R’ 10 、R’ 11 、R’ 12 are independently selected from H, halogen, azido, cyano, hydroxy, C1-C 12 alkyl, C1-C 12 thioalkyl, C1-C 12 heteroalkyl, C1-C 12 haloalkyl, and OR; wherein R is selected from H, C1-C 12 alkyl, C(O)(C1-C 12 )alkyl, C(O)NH(C1-C12 ) alkyl, C(O)O(C1-C 12 ) alkyl, C(O)aryl, C(O)(C1-C 12 ) alkylaryl, C(O)NH(C1-C 12 ) alkylaryl, C(O)O(C1-C 12 ) alkylaryl or C(O)CHR AA NH2, wherein R AA is the side chain of a protein amino acid;

[0183] -R’6 and R’8 are independently selected from H, azide, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl;

[0184] -R’7 and R’ 14 are independently selected from H, OR, NHR, NRR’, NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkylaryl;

[0185] -Y’1 and Y’2 are independently selected from CH, CH2, C(CH3)2 or CCH3;

[0186] -M’ is selected from H or a suitable counterion;

[0187] - represents a single bond or a double bond depending on Y'1 and Y'2; and

[0188] - represents an α or β anomeric isomer depending on the position of R'1 and R' 13 ;

[0189] The compound is applied to the treatment and / or prevention of viral infections.

[0190] According to one embodiment, X is selected from O, CH2 and S.

[0191] According to one embodiment, R1 is selected from hydrogen or OH. In one embodiment, R1 is hydrogen. In one embodiment, R1 is OH.

[0192] According to one embodiment, R2, R3, R4 and R5 are independently selected from hydrogen, halogen, hydroxy, C1-C 12 alkyl and OR; wherein R is as described above. In a preferred embodiment, R2, R3, R4 and R5 are independently selected from hydrogen, hydroxy and OR; wherein R is as described above. In a more preferred embodiment, R2, R3, R4 and R5 are independently selected from hydrogen or OH.

[0193] According to one embodiment, R2 and R3 are the same. In one embodiment, R2 and R3 are the same and represent OH. In one embodiment, R2 and R3 are the same and represent hydrogen.

[0194] According to one embodiment, R2 and R3 are different. In a preferred embodiment, R2 is hydrogen and R3 is OH. In a more preferred embodiment, R2 is OH and R3 is hydrogen.

[0195] According to one embodiment, R4 and R5 are the same. In one embodiment, R4 and R5 are the same and represent OH. In one embodiment, R4 and R5 are the same and represent hydrogen.

[0196] According to one embodiment, R2 and R3 are different. In a preferred embodiment, R4 is OH and R5 is hydrogen. In a more preferred embodiment, R4 is hydrogen and R5 is OH.

[0197] According to one embodiment, R3 and R4 are different. In one embodiment, R3 is OH and R4 is hydrogen. In one embodiment, R3 is hydrogen and R4 is OH.

[0198] According to one embodiment, R3 and R4 are the same. In a preferred embodiment, R3 and R4 are the same and represent OH. In a more preferred embodiment, R3 and R4 are the same and represent hydrogen.

[0199] According to one embodiment, R2 and R5 are different. In one embodiment, R2 is hydrogen and R5 is OH. In one embodiment, R2 is OH and R5 is hydrogen.

[0200] According to one embodiment, R2 and R5 are the same. In a preferred embodiment, R2 and R5 are the same and represent hydrogen. In a more preferred embodiment, R2 and R5 are the same and represent OH.

[0201] According to one embodiment, R6 is selected from hydrogen or OH. In one embodiment, R6 is OH. In a preferred embodiment, R6 is hydrogen.

[0202] According to one embodiment, R7 is selected from P(O)R9R 10 or P(S)R9R 10 ; wherein, R9 and R 10 are as described above. In a preferred embodiment, R7 is P(O)R9R 10 ; wherein, R9 and R 10 are as described above. In a preferred embodiment, R7 is P(O)(OH)2.

[0203] According to one embodiment, R8 is selected from H, OR, NHR 13 or NR13 R 14 ; wherein, R 13 and R 14 are as described above. In a preferred embodiment, R8 is NHR 13 ; wherein, R 13 and R 14 are as described above.

[0204] According to one embodiment, Y is CH or CH2. In one embodiment, Y is CH. In one embodiment, Y is CH2.

[0205] According to a preferred embodiment, the compound of formula (I) is a compound wherein X is oxygen.

[0206] According to a preferred embodiment, the present invention relates to a compound of general formula (II):

[0207]

[0208] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R1, R2, R3, R4, R5, R6, R7, R8, Y, and are as described for the compound of formula (I) hereinabove.

[0209] According to one embodiment, a preferred compound of formula (I) is a compound wherein R1 is hydrogen.

[0210] According to a preferred embodiment, the present invention relates to a compound of general formula (III):

[0211]

[0212] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R2, R3, R4, R5, R6, R7, R8, Y, and are as described for the compound of formula (I) hereinabove.

[0213] According to one embodiment, a preferred compound of formula (I) is a compound wherein R2 is OH and R3 is hydrogen.

[0214] According to one embodiment, a preferred compound of formula (I) is a compound wherein R4 is hydrogen and R5 is OH.

[0215] According to one embodiment, a preferred compound of formula (I) is a compound wherein R3 and R4 are the same and represent hydrogen.

[0216] According to a preferred embodiment, the present invention relates to a compound of general formula (IV):

[0217]

[0218] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R2, R5, R6, R7, R8, Y, and as described for the compounds of formula (I) hereinabove.

[0219] According to one embodiment, a preferred compound of formula (I) is a compound wherein R2 and R5 are the same and represent OH.

[0220] According to a preferred embodiment, the present invention relates to compounds of general formula (V):

[0221]

[0222] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R6, R7, R8, Y, and as described for the compounds of formula (I) hereinabove.

[0223] According to one embodiment, a preferred compound of formula (I) is a compound wherein R6 is hydrogen.

[0224] According to a preferred embodiment, the present invention relates to compounds of general formula (VI):

[0225]

[0226] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R7, R8, Y, and as described for the compounds of formula (I) hereinabove.

[0227] According to one embodiment, a preferred compound of formula (I) is a compound wherein R8 is NH2.

[0228] According to a preferred embodiment, the present invention relates to compounds of general formula (VII):

[0229]

[0230] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R7, Y, and as described for the compounds of formula (I) hereinabove.

[0231] According to one embodiment, a preferred compound of formula (I) is a compound wherein Y is CH.

[0232] According to a preferred embodiment, the present invention relates to compounds of general formula (VIII):

[0233]

[0234] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R7, and as described for the compounds of formula (I) hereinabove.

[0235] According to one embodiment, a preferred compound of formula (I) is a compound wherein Y is CH2.

[0236] According to a preferred embodiment, the present invention relates to compounds of general formula (IX):

[0237]

[0238] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, R7, and as described for the compounds of formula (I) above.

[0239] According to one embodiment, a preferred compound of formula (I) is a compound wherein R7 is P(O)(OH)2.

[0240] According to a preferred embodiment, the present invention relates to compounds of general formula (X):

[0241]

[0242] or a pharmaceutically acceptable salt or solvate or prodrug thereof; wherein, Y, and as described for the compounds of formula (I) above.

[0243] According to one embodiment, the compounds according to the present invention are selected from Compounds I-A to I-J of Table 1 below or a pharmaceutically acceptable salt or solvate or prodrug thereof:

[0244] [Table 1]

[0245]

[0246]

[0247] According to one embodiment, the preferred compounds of the present invention are Compounds I-A to I-J or a pharmaceutically acceptable salt or solvate or prodrug thereof. According to one embodiment, the more preferred compounds of the present invention are Compound I-A or a pharmaceutically acceptable salt or solvate or prodrug thereof.

[0248] According to one embodiment, preferred compounds of general formula Ia are compounds wherein X’1 and X’2 are independently selected from O, CH2, S.

[0249] According to one embodiment, R'7 and R' 14 are independently selected from H, OR, NHR, and NRR', where R and R' are independently selected from H, C1-C8 alkyl, and C1-C8 alkylaryl. According to one embodiment, R'7 and R' 14 are NHR, where R is selected from H, C1-C8 alkyl, and C1-C8 alkylaryl.

[0250] 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, hydroxy, C1-C 12 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, hydroxy, and OR, where R is as described above.

[0251] According to one embodiment, a preferred compound of general formula Ia is one in which R'2, R'3, R'4, R'5, R'9, R' 10 , R' 11 , R' 12 are independently selected from H and OH.

[0252] According to one embodiment, R'2 and R'3 are the same. According to one embodiment, R'2 and R'3 are the same and each represents OH. According to one embodiment, R'2 and R'3 are the same and each represents hydrogen.

[0253] 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 OH. According to a more preferred embodiment, R'2 is OH and R'3 is hydrogen.

[0254] According to one embodiment, R'4 and R'5 are the same. According to one embodiment, R'4 and R'5 are the same and each represents OH. According to one embodiment, R'4 and R'5 are the same and each represents hydrogen.

[0255] According to a preferred embodiment, R'4 and R'5 are different. According to a preferred embodiment, R'4 is OH and R'5 is hydrogen. According to a more preferred embodiment, R'4 is hydrogen and R'5 is OH.

[0256] According to one embodiment, R'3 and R'4 are the same. According to one embodiment, R'3 and R'4 are the same and each represents OH. According to one embodiment, R'3 and R'4 are the same and each represents hydrogen.

[0257] According to a preferred embodiment, R'3 and R'4 are different. According to a preferred embodiment, R'3 is OH and R'4 is hydrogen. According to a more preferred embodiment, R'3 is hydrogen and R'4 is OH.

[0258] According to one embodiment, R'2 and R'5 are different. According to one embodiment, R'2 is hydrogen and R'5 is OH. According to one embodiment, R'2 is OH and R'5 is hydrogen.

[0259] According to a preferred embodiment, R'2 and R'5 are the same. According to a preferred embodiment, R'2 and R'5 are the same and each represents hydrogen. According to a more preferred embodiment, R'2 and R'5 are the same and each represents OH.

[0260] According to one embodiment, R'9 and R' 10 are the same. According to one embodiment, R'9 and R' 10 are the same and each represents OH. According to one embodiment, R'9 and R' 10 are the same and each represents hydrogen.

[0261] 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 OH. According to a more preferred embodiment, R'9 is OH and R' 10 is hydrogen.

[0262] According to one embodiment, R' 11 and R' 12 are the same. According to one embodiment, R' 11 and R' 12 are the same and each represents OH. According to one embodiment, R' 11 and R' 12 are the same and each represents hydrogen.

[0263] According to a preferred embodiment, R' 11 and R' 12 are different. According to a preferred embodiment, R' 11 is OH and R' 12 is hydrogen. According to a more preferred embodiment, R' 11 is hydrogen and R' 12 is OH.

[0264] According to one embodiment, R' 10 and R' 11 are different. According to one embodiment, R' 10 is hydrogen and R' 11 is OH. According to one embodiment, R' 10 is OH and R' 11 is hydrogen.

[0265] According to a preferred embodiment, R' 10 and R' 11 are the same. According to a preferred embodiment, R' 10 and R' 11 are the same and each represents OH. According to a more preferred embodiment, R' 10 and R' 11 are the same and each represents hydrogen.

[0266] According to one embodiment, R'9 and R' 12 are different. According to one embodiment, R'9 is hydrogen and R' 12 is OH. According to one embodiment, R'9 is OH and R' 12 is hydrogen.

[0267] According to a preferred embodiment, R'9 and R' 12 are the same. According to a preferred embodiment, R'9 and R' 12 are the same and each represents hydrogen.. According to a more preferred embodiment, R'9 and R' 12 are the same and each represents OH.

[0268] According to one embodiment, Y'1 is CH. According to one embodiment, Y'1 is CH2.

[0269] According to one embodiment, Y'2 is CH. According to one embodiment, Y'2 is CH2.

[0270] According to one embodiment, X'1 and X'2 are different and are selected from the groups as described above. According to one embodiment, X'1 and X'2 are the same and are selected from the groups as described above.

[0271] According to one embodiment, a preferred compound of general formula Ia is a compound in which X'1 and X'2 each independently represent oxygen.

[0272] According to one embodiment, a preferred compound of general formula Ia is a compound in which X'1 and X'2 are the same and each represents oxygen.

[0273] According to a preferred embodiment in the compounds of formula Ia, the present invention relates to compounds having the following formula IIa:

[0274]

[0275] or a pharmaceutically acceptable salt and / or solvate or prodrug 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 as described above.

[0276] According to one embodiment, R'7 and R' 14 are different and are selected from the groups as described above. According to one embodiment, R'7 and R' 14 are the same and are selected from the groups as described above.

[0277] According to one embodiment, a preferred compound of formula Ia is a compound wherein R'7 and R' 14 each independently represent NH2.

[0278] According to one embodiment, a preferred compound of formula Ia is a compound wherein R'7 and R' 14 are the same and each represents NH2.

[0279] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having formula IIIa:

[0280]

[0281] or a pharmaceutically acceptable salt and / or solvate or prodrug 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 as described above.

[0282] According to one embodiment, R'1 and R' 13 are different and are selected from the groups as described above. According to one embodiment, R'1 and R' 13 are the same and are selected from the groups as described above.

[0283] According to one embodiment, a preferred compound of formula Ia is a compound wherein R'1 and R' 13Each independently represents a hydrogen compound.

[0284] According to one embodiment, a preferred compound of general formula Ia is one in which R’1 and R’ 13 are the same and each represents a hydrogen compound.

[0285] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula IVa:

[0286]

[0287] or a pharmaceutically acceptable salt and / or solvate or prodrug 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.

[0288] According to one embodiment, R’6 and R’8 are different and are selected from the groups as described above. According to one embodiment, R’6 and R’8 are the same and are selected from the groups as described above.

[0289] According to one embodiment, a preferred compound of general formula Ia is one in which R’6 and R’8 each independently represents a hydrogen compound.

[0290] According to one embodiment, a preferred compound of general formula Ia is one in which R’6 and R’8 are the same and each represents a hydrogen compound.

[0291] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula Va:

[0292]

[0293] or a pharmaceutically acceptable salt and / or solvate or prodrug 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.

[0294] According to one embodiment, R’3, R’4, R’ 10 and R’ 11 are different and are selected from the groups as described above. According to one embodiment, R’3, R’4, R’ 10 and R’ 11The same and selected from the groups as described above.

[0295] According to one embodiment, a preferred compound of general formula Ia is one in which R'3, R'4, R' 10 and R' 11 each independently represent hydrogen.

[0296] According to one embodiment, a preferred compound of general formula Ia is one in which R'3, R'4, R' 10 , R' 11 are the same and each represents H.

[0297] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula VIa:

[0298]

[0299] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein R'2, R'5, R'7, R'9, R' 12 , Y'1, Y'2, M', and are as described above.

[0300] According to one embodiment, R'2, R'5, R'9 and R' 12 are different and selected from the groups as described above. According to one embodiment, R'2, R'5, R'9 and R' 12 are the same and selected from the groups as described above.

[0301] According to one embodiment, a preferred compound of general formula Ia is one in which R'2, R'5, R'9 and R' 12 each independently represent OH.

[0302] According to one embodiment, a preferred compound of general formula Ia is one in which R'2, R'5, R'9, R' 12 are the same and each represents OH.

[0303] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula VIIa:

[0304]

[0305] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein Y'1, Y'2, M', and are as described above.

[0306] According to one embodiment, Y’1 and Y’2 are different. According to a preferred embodiment, Y’1 and Y’2 are the same.

[0307] According to one embodiment, a preferred compound of formula Ia is a compound in which Y’1 and Y’2 each independently represent CH.

[0308] According to one embodiment, a preferred compound of formula Ia is a compound in which Y’1 and Y’2 are the same and each represents CH.

[0309] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula VIIIa:

[0310]

[0311] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein, M’ and as described above.

[0312] According to one embodiment, a preferred compound of formula Ia is a compound in which Y’1 and Y’2 each independently represent CH2.

[0313] According to one embodiment, a preferred compound of formula Ia is a compound in which Y’1 and Y’2 are the same and each represents CH2.

[0314] According to a preferred embodiment, among the compounds of formula Ia, the present invention relates to compounds having the following formula IXa:

[0315]

[0316] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof, wherein, M’ and as described above.

[0317] According to one embodiment, preferred compounds of the present invention are compounds Ia-A to Ia-I listed in Table 2:

[0318] Table 2

[0319]

[0320] According to one embodiment, a preferred compound of the present invention is the compound of formula Ia-A.

[0321] According to another embodiment, a preferred compound of the present invention is the compound of formula Ia-D.

[0322] All references to compounds of formula (I) or (Ia) include references to their salts, solvates, multicomponent complexes and liquid crystals. All references to compounds of formula (I) or (Ia) include references to their polymorphs and crystal habits.

[0323] All references to compounds of formula (I) or (Ia) include references to pharmaceutically acceptable prodrugs and their prodrugs.

[0324] Pharmaceutical composition

[0325] The present invention also relates to a pharmaceutical composition for the treatment and / or prevention of viral infections, which comprises a compound used according to the present invention and at least one pharmaceutically acceptable carrier.

[0326] According to one embodiment, the pharmaceutical composition further comprises at least one other active ingredient.

[0327] In one embodiment, the other active ingredients are selected from:

[0328] Antiviral agents, neuraminidase inhibitors such as oseltamivir, zanamivir, peramivir or laninamivir; M2 proton channel blockers such as amantadine or remantanide; anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clarazumab or olokizumab; JAK inhibitors such as baricitinib, fedratinib or ruxolitinib; interferons such as interferon β-1a (IFN-β-1a), interferon β-1b (IFN-β-1b) or peginterferon β-1a; macrolides, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin: another active ingredient is selected from BXT-25, chloroquine, hydroxychloroquine, brequinar, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, colistin, nicotine, histamine H2 receptor antagonists, and mixtures thereof.

[0329] In one embodiment, the composition of the present invention comprises at least one compound of formula I and / or formula Ia and at least one histamine H2 receptor.

[0330] According to one embodiment, the histamine H2 receptor antagonists are selected from famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lavulafide, lofutidine, niperotidine, preferably famotidine.

[0331] Non-limiting examples of other antiviral agents include:

[0332] - Polymerase inhibitors, such as favipiravir, pimodivir, baloxavir, marboxil, and sofosbuvir;

[0333] - Protease inhibitors, such as boceprevir, simeprevir, fosamprenavir, lopinavir, ritonavir, telaprevir, tipranavir, atazanavir, nelfinavir, indinavir, and saquinavir;

[0334] - Integrase strand transfer inhibitors, such as raltegravir, dolutegravir, and elvitegravir;

[0335] - NS5A inhibitors, such as daclatasvir;

[0336] - Nucleoside reverse transcriptase inhibitors (NRTIs), such as lamivudine, adefovir, tenofovir, entecavir, and emtricitabine;

[0337] - Non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, nevirapine, and etravirine;

[0338] - Purine nucleosides, such as ribavirin, valacyclovir, acyclovir, and famciclovir; and mixtures thereof.

[0339] According to one embodiment, a pharmaceutical composition for treating and / or preventing viral infections or for treating and / or preventing respiratory or extra-respiratory complications and / or virus-derived infections comprises at least one compound used according to the present invention, a histamine H2 receptor antagonist selected from famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavotidine, and nipetitidine, and at least one pharmaceutically acceptable carrier.

[0340] According to one embodiment, a pharmaceutical composition for treating and / or preventing viral infections or for treating and / or preventing respiratory or extra-respiratory complications and / or virus-derived infections comprises at least one compound used according to the present invention, famotidine, and at least one pharmaceutically acceptable carrier.

[0341] Method

[0342] According to another aspect, the present invention relates to a method for preparing the compound of formula (I) above.

[0343] In particular, the compound of formula (I) as disclosed herein can be prepared from substrates A-E as described below. Those skilled in the art should understand that these schemes are by no means restrictive and can be varied without departing from the spirit and scope of the present invention.

[0344] According to one embodiment, the method involves, in a first step, monophosphorylating a compound of formula (A) in the presence of phosphoryl chloride and a trialkyl phosphate to produce a phosphoryl dichloride of formula (B),

[0345]

[0346] wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and are as described for the compound of formula (I) hereinabove.

[0347] In a second step, the phosphoryl dichloride acid of formula (B) is hydrolyzed to produce a phosphate ester of formula (C)

[0348]

[0349] wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and are as described for the compound of formula (I) hereinabove.

[0350] According to one embodiment, the compound of formula (A) is synthesized using various methods known to those skilled in the art. According to one embodiment, the compound of formula (A) is synthesized by reacting a pentose of formula (D) with a nitrogen derivative of formula (E), where R, R2, R3, R4, R5, R6, R7, Y are as described for the compound of formula (I) above, to obtain a compound of formula (A-1), and then selectively deprotecting to obtain the compound of formula (A),

[0351]

[0352] wherein X, R1, R2, R3, R4, R5, R6, R8, Y, and are as described for the compound of formula (I) above.

[0353] According to one embodiment, R is a suitable protecting group known to those skilled in the art. In one embodiment, the protecting group is selected from triarylmethyl and / or silyl. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl, and 4,4',4''-trimethoxytrityl. Non-limiting examples of silyl include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-isopropylsilyloxymethyl, and [2-(trimethylsilyl)ethoxy]methyl.

[0354] According to one embodiment, any hydroxyl group attached to the pentose is protected with a suitable protecting group known to those skilled in the art.

[0355] The selection and replacement of protecting groups are the responsibility of those skilled in the art. Protecting groups can also be removed by methods well known to those skilled in the art, such as with acids (e.g., inorganic or organic acids), bases, or fluoride sources. According to a preferred embodiment, the nitrogen derivative of formula (E) is coupled with a pentose of formula (D) by reaction in the presence of a Lewis acid to give a compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF3.OEt2, TiCl4, and FeCl3.

[0356] According to one embodiment, the method of the present invention further comprises the step of reducing the compound of formula (A) by various methods well known to those skilled in the art to give a compound of formula (A'), wherein is CH2 and R1, R2, R3, R4, R5, R6, R8, Y, and as described for the compound of formula (I) above.

[0357] According to a specific embodiment, the present invention relates to a method for preparing compounds of formula I-A to I-F.

[0358] In the first step, nicotinamide of formula E is coupled with ribose tetraacetate of formula D by a coupling reaction in the presence of a Lewis acid to give a compound of formula A-1:

[0359]

[0360] In the second step, the compound of formula A-1 is ammoniated to give a compound of formula A-2:

[0361]

[0362] In the third step, monophosphorylation of the compound of formula A-2 in the presence of phosphoryl chloride and trialkyl phosphate gives a phosphoryl dichloride of formula A-3:

[0363]

[0364] In the fourth step, the phosphoryl dichloride of formula A-3 is hydrolyzed to give a compound of formula I-A:

[0365]

[0366] According to one embodiment, the step of reducing the compound of formula A-2 is carried out to give a compound of formula I-E.

[0367] Then the compound of formula I-E is monophosphorylated and hydrolyzed to a compound of formula I-C as described in step 4.

[0368] On the other hand, the present invention relates to a method for preparing the above-mentioned compound of formula Ia.

[0369] In particular, the disclosed compounds of formula Ia can be prepared from substrates Xa-XIIIa as described below. Those of ordinary skill in the art will understand that these schemes are in no way limiting and that details can be varied without departing from the spirit and scope of the invention.

[0370] According to one embodiment, the present invention relates to a method for preparing the compounds of formula I described above herein.

[0371] The method first comprises monophosphorylating a compound of formula Xa in a trialkyl phosphate in the presence of phosphoryl chloride to obtain a phosphoryl dichloride compound XIa,

[0372]

[0373] wherein X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and are as described for formula Ia herein.

[0374] In a second step, the phosphoryl dichloride XIa obtained in the first step is hydrolyzed to obtain a phosphate compound of formula XIIa,

[0375]

[0376] wherein X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, M’, and are as described for formula Ia herein.

[0377] Then the phosphate compound of formula XIIa obtained in the second step is reacted with the phosphoryl dichloride compound of formula XIIIa obtained as described in the first step,

[0378]

[0379] wherein X’2, R’8, R’9, R’ 10 、R’ 11 、R’ 12 、R’ 13 、R’ 14 、Y’2, and are as described for formula Ia herein, to obtain a compound of formula Ia as described herein.

[0380] According to one embodiment, the method of the present invention further comprises the step of reducing the compound of formula Ia to obtain the compound of formula I'a using various methods known to those skilled in the art, wherein Y'1 and Y'2 are the same and each represents CH2 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 in formula Ia herein.

[0381] 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 a pentose of formula XIVa with a nitrogen-containing derivative 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 in formula Ia herein, to obtain a compound of formula Xa-1, and then selectively deprotecting to obtain the compound of formula Xa.

[0382]

[0383] wherein, X'1, R, R'1, R'2, R'3, R'4, R'5, R'6, R'7, Y'1, and are as described in formula Ia herein.

[0384] According to one embodiment, R is a suitable protecting group known to those skilled in the art. Examples of suitable protecting groups include triarylmethyl and / or silyl. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'-dimethoxytrityl and 4,4',4''-trimethoxytrityl. Non-limiting examples of silyl include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl.

[0385] According to one embodiment, any hydroxyl group attached to the pentose ring is protected by a suitable protecting group known to those skilled in the art.

[0386] The selection and replacement of protecting groups are within the skills of those skilled in the art. Any protecting group can also be removed by methods known in the art, such as with an acid (e.g., inorganic or organic acid), a base or a fluoride source.

[0387] According to a preferred embodiment, in the presence of a Lewis acid, a nitrogen-containing derivative of formula XVa is added to pentose XIVa by a coupling reaction to obtain a compound of formula Xa-1. Non-limiting examples of suitable Lewis acids include TMSOTf, BF3.OEt2, TiCl4, and FeCl3.

[0388] According to a specific embodiment, the present invention relates to a method for preparing a compound of formula VIIIa,

[0389]

[0390] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof.

[0391] In the first step, nicotinamide of formula XVa is added to ribose tetraacetate XIVa by a coupling reaction in the presence of a Lewis acid to obtain a compound of formula Xa-1:

[0392]

[0393] In the second step, the compound of formula Xa-1 is treated with ammonia to obtain a compound of formula Xa:

[0394]

[0395] In the third step, the compound of formula Xa is monophosphorylated in trialkyl phosphate in the presence of phosphoryl chloride to obtain a phosphoryl dichloride compound XIa:

[0396]

[0397] In the fourth step, the phosphoryl dichloride compound XIa obtained in the third step is partially hydrolyzed to obtain a phosphate compound of formula XIIa:

[0398]

[0399] In the fifth step, the phosphate compound of formula XIIa obtained in the fourth step is then reacted with the phosphoryl dichloride compound XIa obtained in the third step to obtain a compound of formula VIIIa.

[0400] According to another specific embodiment, the present invention relates to a method for preparing a compound of formula IXa,

[0401]

[0402] or a pharmaceutically acceptable salt and / or solvate or prodrug thereof.

[0403] According to one embodiment, the compound of formula IXa is obtained from the compound of formula VIIIa synthesized previously as described above.

[0404] 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 obtain the compound of formula IXa.

[0405] Medical use and treatment method

[0406] Accordingly, the present invention relates to a compound according to the invention as described above for the treatment and / or prevention of viral infections.

[0407] According to one embodiment, the compound is for the treatment and / or prevention of at least one viral infection.

[0408] According to one embodiment, the viral infection is caused by at least one virus selected from the group consisting of positive-sense ribonucleic acid (RNA) viruses, negative-sense RNA viruses, double-stranded RNA viruses, single-stranded deoxyribonucleic acid (DNA) viruses or double-stranded DNA viruses. According to one embodiment, the viral infection is caused by at least one virus selected from the following genera:

[0409] Enterovirus, such as human enterovirus (HEV) A, HEV-B, HEV-C or HEV-D;

[0410] Rhinovirus, such as human rhinovirus (HRV) A or HRV-B;

[0411] Coronavirus, such as human coronavirus;

[0412] Hepatovirus, such as hepatitis A virus;

[0413] Norovirus, such as Norwalk virus;

[0414] Hepatitis E-like virus, such as hepatitis E virus;

[0415] Alphavirus;

[0416] Rubivirus, such as rubella virus;

[0417] Flavivirus, such as yellow fever virus, dengue virus or West Nile virus;

[0418] Hepacivirus, such as hepatitis C virus;

[0419] Pestivirus, such as bovine diarrhea virus;

[0420] Ebola-like virus, such as Ebola virus Zaire, Ebola virus Cote d'Ivoire, Ebola virus Reston or Ebola virus Sudan;

[0421] Paramyxovirus, such as human parainfluenza virus 1 and 3;

[0422] Morbillivirus, such as measles virus;

[0423] Genus Orthomyxovirus, such as mumps virus or human parainfluenza viruses 2, 4a and 4b;

[0424] Genus Henipavirus, such as Hendra virus or Nipah virus;

[0425] Genus Pneumovirus, such as human respiratory syncytial virus;

[0426] Genus Metapneumovirus, such as human metapneumovirus;

[0427] Genus Influenza virus, such as influenza A virus, influenza B virus or influenza C virus;

[0428] Genus Arenavirus;

[0429] Genus Orthobunyavirus, such as California encephalitis virus;

[0430] Genus Phlebovirus, such as Rift Valley fever virus;

[0431] Genus Rotavirus, such as human rotavirus A, B or C;

[0432] Genus Herpes simplex virus, such as human herpesvirus 1 and 2;

[0433] Genus Varicellovirus, such as human herpesvirus 3;

[0434] Genus Cytomegalovirus, such as human herpesvirus 5;

[0435] Genus Lymphocryptovirus, such as human herpesvirus 4 and 8;

[0436] Genus Adenovirus;

[0437] Genus Papillomavirus, such as human papillomavirus; and

[0438] Genus Aphthovirus, such as foot-and-mouth disease virus.

[0439] According to one embodiment, the viral infection is a respiratory infection caused by at least one virus selected from the group consisting of the genus Influenza virus, genus Rhinovirus, genus Coronavirus, genus Respiratory virus, genus Orthomyxovirus, genus Pneumovirus, genus Adenovirus or genus Metapneumovirus.

[0440] According to a preferred embodiment, the viral infection is a respiratory infection caused by the genus Influenza virus.

[0441] According to one embodiment, the influenza virus is selected from influenza A, influenza B and influenza C. According to a preferred embodiment, the genus Influenza virus is selected from influenza A and influenza B.

[0442] Thus, according to a preferred embodiment, the compound is used for the treatment and / or prevention of influenza A and / or influenza B.

[0443] According to one embodiment, influenza A is selected from H1N1, H1N2, H2N2, H3N2, H5N1, H5N2, H5N9, H7N2, H7N3, H7N7, H7N9, H9N2, and H10N7.

[0444] According to one embodiment, influenza B is selected from B / Yamagata / 16 / 88-like and B / Victoria / 2 / 87-like viruses.

[0445] According to a preferred embodiment, the influenza virus is selected from H1N1, H3N2, H5N1, B / Yamagata / 16 / 88-like, and B / Victoria / 2 / 87-like viruses.

[0446] According to a preferred embodiment, the compound is used for treating and / or preventing H1N1, H3N2, H5N1, B / Yamagata / 16 / 88-like, and B / Victoria / 2 / 87-like viruses.

[0447] According to one embodiment, influenza A and / or influenza B cause respiratory complications such as influenza A and / or influenza B-associated pneumonia.

[0448] According to another embodiment, influenza A and / or influenza B cause extrapulmonary complications such as decompensation of underlying pathology or other extrapulmonary complications such as Reye's syndrome, myocarditis, pericarditis, rhabdomyolysis, Guillain-Barré syndrome, or encephalomyelitis associated with aspirin intake.

[0449] 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.

[0450] According to one embodiment, the alpha coronavirus infection is selected from human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63), sometimes also referred to as HCoV-NH or New Haven human coronavirus.

[0451] 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), formerly 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 2 (SARS-CoV-2), also known as 2019-nCoV or novel coronavirus 2019.

[0452] 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.

[0453] According to a preferred embodiment, the coronavirus infection is SARS-CoV-2 infection.

[0454] According to one embodiment, the coronavirus is MERS-CoV infection that causes Middle East Respiratory Syndrome (MERS). According to one embodiment, the coronavirus is SARS-CoV-1 infection that causes Severe Acute Respiratory Syndrome (SARS).

[0455] According to a preferred embodiment, the coronavirus is SARS-CoV-2 infection, which causes Coronavirus Disease 2019 (COVID-19).

[0456] Thus, according to one embodiment, the compound is used for treating and / or preventing coronavirus infections selected from MERS-CoV, SARS-CoV-1, and SARS-CoV-2.

[0457] According to one embodiment, the compound is used for treating and / or preventing MERS, SARS, and COVID-19.

[0458] According to a preferred embodiment, the compound is used for treating and / or preventing COVID-19.

[0459] According to a preferred embodiment, the compound is used for pre-exposure prophylaxis against viruses, including those cited above, preferably SARS-CoV-2.

[0460] Thus, according to one embodiment, the compound is used for treating and / or preventing respiratory or extra-respiratory complications.

[0461] According to a preferred embodiment, the compound is used for treating and / or preventing influenza A and / or influenza B-related pneumonia.

[0462] According to one embodiment, influenza A and / or influenza B-related pneumonia is viral pneumonia that causes acute respiratory failure.

[0463] According to another embodiment, influenza A and / or influenza B-related pneumonia is bacterial pneumonia caused by bacterial superinfection with bacteria selected from Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.

[0464] According to one embodiment, COVID-19 can cause respiratory complications such as novel coronavirus infection or COVID-19-associated acute respiratory distress syndrome (ARDS).

[0465] According to one embodiment, COVID-19 can cause extrapulmonary complications such as sepsis, septic shock, altered mental status, and / or multiple organ failure.

[0466] According to one embodiment, novel coronavirus infection appears as hazy patches on a lung scan (such as a computed tomography (CT) scan), particularly hazy patches clustered at the outer margins of the lungs. In one embodiment, novel coronavirus infection appears as a radiological finding of ground-glass opacity abnormalities or a mixed pattern radiological finding (a combination of consolidation, ground-glass opacity, and reticular opacity in the presence of structural distortion) in a lung scan.

[0467] According to one embodiment, ARDS is a form of acute lung injury (ALI) and occurs due to severe lung injury that results in non-uniform alveolar injury throughout the lung.

[0468] According to one embodiment, coronavirus infection is SARS-CoV-2 infection, which causes coronavirus disease 2019 (COVID-19).

[0469] Thus, according to one embodiment, the compound is used for treating and / or preventing novel coronavirus infection or COVID-19-associated ARDS.

[0470] 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 selected from MERS-CoV, SARS-CoV-1, and SARS-CoV-2.

[0471] The present invention also relates to a pharmaceutical composition comprising at least one compound for use in the present invention as described above and at least one pharmaceutically acceptable carrier for treating and / or preventing a viral infection as described above.

[0472] According to one embodiment, the pharmaceutical composition for the present invention, in addition to comprising at least one compound for the present invention, further comprises at least one additional active ingredient, for example, an active ingredient selected from: antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukin 6; JAK inhibitors; interferons; macrolides, preferably selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brequinar, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelicamycin, nicotine, histamine H2 receptor antagonists, and mixtures thereof; as described above.

[0473] In a preferred embodiment, the pharmaceutical composition for the present invention, in addition to comprising at least one compound for the present invention, further comprises at least one additional active ingredient selected from antiviral agents, neuraminidase inhibitors such as oseltamivir, zanamivir, peramivir or laninamivir; M2 proton channel blockers such as amantadine or remantanide; anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clazakizumab or olokizumab; JAK inhibitors such as baricitinib, fedratinib or ruxolitinib; interferons such as interferon β-1a (IFN-β-1a), interferon β-1b (IFN-β-1b) or peginterferon β-1a; macrolides selected from azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brequinar, dehydroandrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelicamycin, nicotine, histamine H2 receptor antagonists, and mixtures thereof.

[0474] The compounds of the present invention can be used in monotherapy or combination therapy for subjects in need of therapeutic and / or prophylactic treatment. Thus, according to a first embodiment, the compounds used in the present invention are administered to a subject without any other active ingredients. Thus, according to a second embodiment, the compounds of the present invention are administered to a subject in combination with at least one additional active ingredient, for example, an active ingredient selected from antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukin 6; JAK inhibitors; interferons; macrolides selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brequinar, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelicamycin, nicotine, histamine H2 receptor antagonists, and mixtures thereof; as described above.

[0475] In one embodiment, the compound is administered to a subject sequentially, simultaneously, and / or separately with the other active ingredients as described above.

[0476] According to one embodiment, a subject in need of therapeutic and / or prophylactic treatment is diagnosed by a health professional. In practice, a viral infection is diagnosed by any test routinely performed in a medical setting, including direct diagnosis, i.e., identification of the virus or its components, e.g., from a respiratory specimen, or indirect diagnosis, i.e., detection of antibodies specific to the infection.

[0477] The severity of COVID-19 can be assessed according to the severity criteria of the World Health Organization (WHO) as follows:

[0478] - Mild: The case shows mild clinical symptoms and no signs of pneumonia on imaging examination.

[0479] - Moderate: The case presents with fever and respiratory symptoms (such as cough, shortness of breath, and / or chest tightness), and pneumonia is detected on radiological examination and requires (O2): 3 L / min < oxygen < 5 L / min

[0480] - Severe: Cases meeting any of the following criteria:

[0481] · Respiratory distress (respiratory rate (RR) ≧ 30 breaths / min);

[0482] · Oxygen saturation (SpO2) ≤ 93% at rest in ambient air; or SpO2 ≤ 97% and O2 > 5 L / min;

[0483] · The ratio of arterial oxygen partial pressure to inspired oxygen partial pressure (PaO2 / FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa). In high altitude areas (above 1000 meters above sea level), PaO2 / FiO2 should be corrected by the following formula: PaO2 / FiO2 [multiplied by] [atmospheric pressure (mmHg) / 760]; and / or

[0484] · Chest imaging shows significant lesion progression > 50% within 24 - 48 hours.

[0485] - Critical: Cases meeting any of the following criteria:

[0486] · Respiratory failure, requiring mechanical ventilation;

[0487] · Shock; and / or

[0488] · Multiple organ failure (extrapulmonary organ failure) requiring admission to the intensive care unit (ICU).

[0489] According to one embodiment, the subject has mild COVID-19, moderate COVID-19, severe COVID-19, or critical COVID-19. According to one embodiment, the subject has mild to moderate COVID-19. According to one embodiment, the subject has severe to critical COVID-19.

[0490] According to one embodiment, the subject, especially the subject with mild to moderate COVID-19 or severe to critical COVID-19, is not hospitalized.

[0491] According to one embodiment, the subject, especially the subject with mild to moderate COVID-19 or severe to critical COVID-19, is hospitalized. In one embodiment, the subject is hospitalized but does not need to be admitted to the intensive care unit (ICU). In one embodiment, the subject is hospitalized and needs to be admitted to the ICU.

[0492] According to one embodiment, the subject, especially the subject with mild to moderate COVID-19 or severe to critical COVID-19, needs oxygen therapy. In one embodiment, the subject needs non-invasive ventilation (NIV).

[0493] Severe to critical COVID-19 can also be defined as COVID-19 that requires hospitalization and NIV or high-flow oxygen therapy, rather than being evaluated according to the WHO as described above.

[0494] Preferably, the subject in need of therapeutic and / or prophylactic treatment is a warm-blooded animal, more preferably a human. According to one embodiment, the subject is male. According to one embodiment, the subject is female.

[0495] In the present invention, the subject can be of any age. According to one embodiment, the subject is an adult, i.e., 18 years of age or older. 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., older than one month and less than two years of age. According to one embodiment, the subject is a neonate, i.e., from birth to less than one month of age.

[0496] According to one embodiment, the subject does not suffer from any underlying pathology.

[0497] 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 has influenza A and / or influenza B and is at risk of developing respiratory or extra-respiratory complications.

[0498] 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, a subject with COVID-19 is at risk of developing the above-mentioned respiratory or extra-respiratory complications.

[0499] According to one embodiment, the subject has at least one risk factor, i.e., a pre-existing disease, condition, habit or behavior that may increase the risk of developing a severe or critical disease caused by the above-mentioned coronavirus infection.

[0500] According to one embodiment, the subject is an individual of any age suffering from certain chronic diseases, such as HIV / AIDS, asthma or chronic heart or lung diseases. According to one embodiment, the subject is an adult suffering from chronic heart and / or respiratory diseases. 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 obese (BMI > 35). According to one embodiment, the subject is severely immunocompromised.

[0501] The present invention also relates to the use of the above-mentioned compounds in the treatment and / or prevention of the above-mentioned viral infections.

[0502] The present invention also relates to the use of the above-mentioned compounds in the preparation of a medicament for the treatment and / or prevention of the above-mentioned viral infections.

[0503] The present invention also relates to a method for treating and / or preventing the above-mentioned viral infections in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the above-mentioned compounds.

[0504] Another object of the present invention is a kit, which comprises a first part containing the compound of the present invention as described above, and a second part containing another active ingredient selected from antiviral agents; neuraminidase inhibitors; M2 proton channel blockers; anti-interleukin 6; JAK inhibitors; interferons; macrolides selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brazikumab, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelimycin, nicotine, histamine H2 receptor antagonists and their combinations; as described above.

[0505] In a preferred embodiment, the kit of the present invention comprises a first part containing the compound of the present invention as described above, and a second part containing another active ingredient selected from antiviral agents, neuraminidase inhibitors such as oseltamivir, zanamivir, peramivir or laninamivir; M2 proton channel blockers such as amantadine or lemanid; anti-interleukin 6 such as tocilizumab, siltuximab, sarilumab, sirukumab, clazakizumab or olokizumab; JAK inhibitors such as baricitinib, fedratinib or ruxolitinib; interferons such as interferon β-1a (IFN-β-1a), interferon β-1b (IFN-β-1b) or peginterferon β-1a; another active ingredient selected from BXT-25, chloroquine, hydroxychloroquine, brazikumab, dehydrated andrographolide succinate, APN01, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, kelimycin, nicotine, histamine H2 receptor antagonists, and macrolides selected from the group including azithromycin, clarithromycin, erythromycin, spiramycin and telithromycin, and their mixtures.

[0506] In a preferred embodiment, the kit of the present invention comprises a first part containing the compound of the present invention as described above and a second part containing a histamine H2 receptor antagonist.

[0507] In one embodiment, the kit of the present invention comprises a first part containing the compound of the present invention or a pharmaceutically acceptable salt or solvate or prodrug thereof, and a second part containing another active ingredient such as oseltamivir or azithromycin.

[0508] Administration method

[0509] The compounds of the present invention as described above can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation spray, nasal, rectal, sublingual or topical routes of administration, and can be formulated singly or together in suitable dosage unit formulations which contain conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients appropriate for each route of administration. In addition to treating warm-blooded animals such as mice, rats, horses, cows, sheep, dogs, cats, monkeys, etc., the compounds of the present invention are also effective for human use. The pharmaceutical compositions for administering the compounds of the present invention can conveniently be in dosage unit form and can be prepared by any methods well-known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Generally, 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 content of the active target compound is sufficient to produce the desired effect on the course or symptoms of the disease. As used herein, the term "composition" is intended to cover a product containing the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from the combination of the specified amounts of the specified ingredients.

[0510] The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, such as tablets, lozenges, troches, pills, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0511] Compositions intended for oral use may be prepared by any method known in the art for the preparation 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 to provide pharmaceutically elegant and palatable preparations in that order. Tablets contain a mixture of the active ingredient with non-toxic pharmaceutically acceptable excipients 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 such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia, and lubricating agents such as 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 thus provide a longer lasting action. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by the techniques described in U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Oral preparations may also be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0512] The aqueous suspension contains an active substance mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; the dispersing agent or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide and a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide and a long-chain fatty alcohol such as heptadecaethyleneoxyhexadecanol, or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitan monooleate, or a condensation product of ethylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride such as polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents (such as those mentioned above) and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid. The dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient mixed with a dispersing agent or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are those exemplified above. Other excipients may also be present such as sweetening agents, flavoring agents and colorants.

[0513] Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, preservatives as well as flavoring and coloring agents.

[0514] The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension. Such suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile non-volatile oil is commonly used as a solvent or suspending medium. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. The compounds of the present invention can also be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol. For topical use, creams, ointments, gels, solutions or suspensions containing the compounds of the present invention are used. (For the purposes of this application, topical application shall include mouthwashes and gargles.)

[0515] In the treatment or prevention of viral infections, suitable dosage levels are generally about 0.01 to 500 mg per kilogram of patient body weight per day, which can be administered in a single dose or multiple doses. Preferably, the dosage level is about 0.1 to about 350 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. Suitable dosage levels can 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 can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the composition is 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 symptomatic adjustment of the dosage for the patient to be treated. For example, the dosage range can be from 100 mg / day to 5000 mg / day, preferably 500 mg / day to 1000 mg / day. The compound can be administered according to a regimen of 1 to 4 times per day, preferably 1, 2, or 3 times per day. Three times a day is suitable. The duration of treatment will depend on the patent and be determined by the doctor. It can range from one day to one year or even longer, preferably from one week to three months, more preferably from two weeks to six weeks. However, it should be understood that the specific dosage level, frequency, and duration of administration for any particular patient can vary and depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular disorder, and the host being treated.

[0516] According to one embodiment, the compound of formula I or Ia is administered at a daily dose of 10 mg / kg, at least 500 mg / day and at most 2 g / day.

[0517] According to one embodiment, the compound of formula I or Ia, its salt or prodrug is administered at a daily dose of 10 mg / kg, at least 500 mg / day and at most 1 g / day, for 10 days to 30 days, preferably 14 days to 28 days, more preferably about 21 days.

[0518] The first day is the day of diagnosis of a viral infection, preferably caused by a coronavirus, or the diagnosis of respiratory or extra-respiratory complications and / or virus-derived infections, 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 on 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.

[0519] According to one embodiment, the amine H2 receptor antagonist is administered at the currently recommended dose. According to one embodiment, famotidine 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.

[0520] Preferably, famotidine is administered at a daily dose of 10 mg / mL, mixed with physiological saline for intravenous injection at, for example, 120 mg (30% of the 400 mg oral dose). The recommended total daily dose is 200 to 500 mg / day, preferably 360 mg / day of famotidine, preferably by the IV route, for up to 14 days, or until discharge, whichever comes first.

[0521] According to one embodiment, according to the specific clinical protocol for COVID-19, hydroxychloroquine sulfate tablets will be administered at a loading dose of 400 mg BID on day 1, followed by 200 mg BID for 4 days, or at a loading dose of 800 mg once daily on day 1, followed by 400 mg once daily for 4 days. Description of the Drawings

[0522] Figure 1 is a bar graph showing the survival rate of mice during the 14-day experiment according to Example 2.

[0523] Figure 2 is a bar graph of the body weight ( Figure 2A ) and weight loss ( Figure 2B ) of mice from day 0 to day 14 of Example 2.

[0524] Figure 3 is a bar graph showing the effect of the treatment according to Example 2 on clinical parameters from day 0 to day 14.

[0525] Figure 4 is a bar graph showing the viral load in the lungs of infected mice 8 days after infection with 500 PFU of influenza A virus according to Example 2.

[0526] Figure 5 is a bar graph showing the effect of the treatment according to Example 2 on the level of T cells in the blood.

[0527] Figure 6 is a bar graph showing the effect of the treatment according to Example 2 on the recruitment of monocyte-derived macrophages and dendritic cells in the lung.

[0528] Figure 7 is a bar graph showing the survival rate of mice during the 14-day experiment of Example 7.

[0529] Figure 8 is a bar graph showing the change in body weight of mice according to Example 7 from Day 0 to Day 14.

[0530] Figure 9 is a bar graph showing the weight loss of mice according to Example 7 from Day 0 to Day 14.

[0531] Figure 10 is a bar graph showing the effect of the treatment according to Example 7 on the respiratory score from Day 0 to Day 14.

[0532] Figure 11 is a bar graph showing the survival rate of mice during the 14-day experiment of Example 8.

[0533] Figure 12 is a bar graph showing the change in body weight of mice according to Example 8 from Day 0 to Day 14.

[0534] Figure 13 is a bar graph showing the weight loss of mice according to Example 8 from Day 0 to Day 14.

[0535] Figure 14 is a bar graph showing the effect of the treatment according to Example 8 on the clinical parameters from Day 0 to Day 14.

[0536] Figure 15 is a bar graph showing the effect of the treatment according to Example 8 on the respiratory score from Day 0 to Day 14.

[0537] Figure 16 is a bar graph showing the viral load in the lungs of infected mice 8 days after infection with the H1N1 PR / 8 / 34 strain according to Example 8.

[0538] Example

[0539] The present invention is further illustrated by the following examples.

[0540] Example 1: Synthesis of the compounds of the present invention

[0541] Materials and Methods

[0542] 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 purification chromatography was performed on silica gel 60 (70 - 230 mesh ASTM, Merck). Melting points were determined on a digital melting point apparatus (Electrothermal IA 8103), uncorrected, or on a Kofler bench type WME (Wagner & Munz). IR, 1 H, 19 F, and 13 13C 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 on Bruker AC 300, Advance DRX400, and Advance DRX 500 spectrometers using CDCl3, CD3CN, D2O, or DMSO-d6 as solvents. For 1 1H, for 13 13C, 75 or 100 MHz, and for 19 19F spectra, 282 or 377 MHz. Chemical shifts (δ) were expressed in parts per million relative to the signal. Indirectly, (i) for 1 1H, relative to CHCl3 (δ 7.27) and (ii) for 13 13C, relative to CDCl3 (δ 77.2), and directly (iii) for 19 19F, relative to CFCl3 (internal standard) (δ 0). Chemical shifts were given in ppm, and peak multiplicities were specified as follows: s, singlet; br s, broad signal; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; quint, quintet; m, multiplet. High resolution mass spectra (HRMS) were obtained from “Service central d'analysis de Solaize” (Centre national de la recherche scientifique) and recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF).

[0543] General experimental procedures

[0544] Step 1: Synthesis of the compound of formula A-1

[0545] The compound of formula D (1.0 equivalent) was dissolved in dichloromethane. Nicotinamide of formula E (1.50 equivalents) and TMSOTf (1.55 equivalents) were added at room temperature. The reaction mixture was heated to reflux and stirred until the reaction was complete. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness to give tetraacetate A-1.

[0546] Step 2: Synthesis of Compound A-2

[0547] Dissolve tetraacetate A-1 in methanol and cool to -10 °C. Add a methanol solution of 4.6 M ammonia (3.0 equivalents) at -10 °C and stir the mixture at this temperature until the reaction is complete. Add Dowex HCR (H+) resin to pH 6 - 7. Heat the reaction mixture to 0 °C and filter. Wash the resin with a mixture of methanol and acetonitrile. Concentrate the filtrate to dryness. Dissolve the residue in acetonitrile and concentrate to dryness. Dissolve the residue in acetonitrile to obtain a solution of Compound A-2.

[0548] Step 3: Synthesis of Compound A-3

[0549] Dilute the acetonitrile solution of crude Compound A-2 with trimethyl phosphate (10.0 equivalents). Distill acetonitrile under vacuum and cool the mixture to -10 °C. Add phosphoryl chloride (4.0 equivalents) at 10 °C and stir the mixture at 10 °C until the reaction is complete.

[0550] Steps 4 and 5: Synthesis of Compound I-A

[0551] Hydrolyze the mixture obtained in Step 3 above by adding a 50 / 50 mixture of acetonitrile and water, and then adding methyl tert-butyl ether. Filter the mixture and dissolve the solid in water. Neutralize the aqueous solution by adding sodium bicarbonate and extract with dichloromethane. Concentrate the aqueous layer to dryness to obtain crude Compound I-A, which is purified on a DOWEX 50wx8 column, eluted with water, and then using a silica gel chromatography column.

[0552] Example 2: Evaluation of the compounds of the present invention on murine influenza virus pulmonary infection

[0553] The purpose of this study is to investigate the role of NMN derivatives in the progression of viral infection.

[0554] To directly evaluate the effect of compound I-A on a lethal pulmonary viral infection, an in vivo study was conducted on severe pneumonia induced by the H1N1 influenza virus model PR / 8 / 34 (protocol in progress). Mice were infected with a lethal dose (500 PFU / mouse) of the virus and received either compound I-A and / or Tamiflu by IP injection for 14 days or not. Characteristic clinical parameters of animal health status and mortality (body weight, temperature, alertness, response to stimuli, respiratory quality) were monitored throughout the protocol. On days 2 and 8 of infection, the progression of pneumonia (lung histology), multi-organ damage (histology of the heart, liver, kidneys, spleen), and pulmonary and systemic inflammatory and immune responses (pulmonary immunophenotype and determination of blood leukocytes in bronchoalveolar lavage fluid (BAL) and lymph nodes, as well as cytokines in plasma and BAL) were evaluated. The study was completed with transcriptome analysis of all cell types in the lungs on day 2 of infection by single-cell RNAseq technology, and allowed the evaluation of the effect of compound I-A on the expression of genes from different populations present in the lungs of animals with severe pneumonia.

[0555] I. Materials and Methods

[0556] Materials

[0557] Animal:

[0558] One hundred and eight male Balb / c mice, 7 weeks old upon arrival, were purchased from Janvier Labs, Le Genest St Isle, 53941 St Berthevin, France. Each animal was identified by a unique animal number written on the tail / cage when assigned to a group. Each cage was numbered. Based on the animal number / cage and the number of cages, a unique number was assigned to the animal, along with the group name and mouse number.

[0559] The matching card used to identify the cage where the experimental animals are located will contain the following information: experiment name, experiment number, and cage number.

[0560] Compound:

[0561] The NMN derivative was manufactured according to Example 1 or purchased commercially and stored at +4 °C until use. The vehicle was physiological buffer.

[0562] Methods

[0563] 1. Preparation of the preparation:

[0564] The powder of compound I-A was dissolved in the vehicle at 6 mg / ml (the solution was used for at most 1 day at room temperature). Fresh samples were prepared daily for each administration except on weekends (the solution was prepared on Saturday and used on Saturday and Sunday).

[0565] The product is administered intraperitoneally once a day for 15 days.

[0566] Mice are weighed daily to accommodate the volume of the compound to be administered.

[0567] 2. Preparation of influenza virus H1N1 PR / 8 / 34 strain

[0568] On day 0, mice are infected intranasally with a lethal dose (500 PFU / mouse) of influenza virus H1N1 PR / 8 / 34.

[0569] 3. Experimental groups

[0570] Group description:

[0571] Group 1: Vehicle (intraperitoneal injection)

[0572] Group 2: Tamiflu 1 mg / kg (subactive dose)

[0573] Group 3: Test compound 185 mg / kg (Compound I-A)

[0574] Group 4: Tamiflu 1 mg / kg + Test compound 185 mg / kg

[0575] Group allocation:

[0576] For each group

[0577] - 12 mice survive

[0578] - 5 mice have their lungs / lymph nodes collected and processed for cell counting on day 2; blood is drawn

[0579] - 5 mice have their lungs / lymph nodes collected and processed for cell counting on day 8; blood is drawn

[0580] - 5 mice are used for lung collection on day 2 and prepared for single-cell RNA sequencing

[0581] Each group will involve 27 mice.

[0582] As described in the non-clinical laboratory study regulations, the test and control animal groups are kept under the same conditions. The study duration is 15 days.

[0583] On day 0, mice are infected intranasally with 500 PFU / mouse of influenza virus H1N1 PR / 8 / 34.

[0584] Mice are given intraperitoneal treatment once a day during all experimental periods (day 0 to day 14). The last injection occurs 24 hours before euthanasia.

[0585] On day 2, blood, lymph nodes, and lungs were collected from 5 mice in each group. Blood was collected by retro-orbital sampling. Immediately, 50 μL was added to 200 μL of 0.1 N perchloric acid, and thorough mixing was achieved by inverting the tube several times. Another aliquot (at least 300 μL) was sampled for cell count analysis. The remaining blood was centrifuged, and the plasma was collected and frozen until possible shipment to the sponsor.

[0586] Lungs were also collected from another 5 mice for RNA sequencing treatment.

[0587] On day 8, blood, lymph nodes, and lungs were collected from 5 mice in each group. Blood was collected by retro-orbital sampling. Aliquots (at least 300 μL) were sampled for cell count analysis. The remaining blood was centrifuged, and the plasma was collected and frozen until possible shipment to the sponsor.

[0588] Body weight loss, health score, and mortality were evaluated for 15 days (day 0 to day 14).

[0589] On day 14, the lungs of the remaining mice were collected.

[0590] 4. Administration

[0591] The vehicle (physiological buffer) was administered once daily via the intraperitoneal route.

[0592] For groups 2 and 4, oseltamivir reference was administered twice daily at a dose of 1 mg / kg by oral gavage.

[0593] Compound I-A was administered once daily at 185 mg / kg via the intraperitoneal route.

[0594] 5. Infection

[0595] Mice were rapidly anesthetized with isoflurane and then infected intranasally with influenza virus H1N1 PR / 8 / 34 at 500 PFU / mouse.

[0596] 6. Body weight, survival rate, and clinical examination

[0597] The mortality, body weight, and clinical symptoms of 12 mice in each group were recorded daily until the end of the experiment (day 14).

[0598] The clinical score was established as follows:

[0599] 1: Healthy mice

[0600] 2: Mice showed signs of discomfort, including slight piloerection, slight gait changes, and increased locomotion

[0601] 3: Mice showed strong signs of piloerection, abdominal contractions, gait changes, and periods of inactivity

[0602] 4: Mice with the previous set of characteristics, but showing little activity and becoming moribund

[0603] 5: Dead mice

[0604] From the start to the end of the experimental phase, the appearance and behavior of the animals were evaluated at least daily. Any abnormal findings were recorded in the raw data. Body weight measurements and clinical examinations were also performed before the animals were grouped.

[0605] 7. Blood collection on the 2nd and 8th days

[0606] Retro-orbital blood collection was performed 48 hours and 8 days after infection with EDTA anticoagulant.

[0607] On day 2, 50 μL of blood was mixed with 200 μL of perchloric acid (0.5 N) by inverting the tube several times. The samples were stored at -70 °C until shipped to the sponsor.

[0608] On days 2 and 8, at least 300 μL of blood was used for cell counting analysis.

[0609] The remaining blood was centrifuged to collect plasma and stored at -70 °C until shipment.

[0610] 8. Isolation of cells from the lung and draining lymph nodes

[0611] On days 2 and 8, lungs and draining lymph nodes were collected in cold RPMI + 10% FCS.

[0612] The lungs were cut into small pieces and then digested in collagenase solution at 37 °C for 30 minutes. The cell suspension was then filtered through a 40-μm cell strainer.

[0613] The draining lymph nodes were disrupted with a syringe plunger on top of a 40-μm cell strainer in a 50-mL tube.

[0614] The cell suspension was centrifuged at 400 g for 5 minutes at 4 °C. The pellet was resuspended in 1 - 5 mL of cold RPMI + 10% FCS.

[0615] Then the live cells were counted and used for cell counting.

[0616] 9. Flow cytometry analysis of whole blood, lung and draining lymph nodes

[0617] Whole blood and cells isolated from the lungs and draining lymph nodes were labeled with antibodies.

[0618] For lung cells, 4 groups were performed:

[0619] Group 1: Identification of alveolar macrophages

[0620] Group 2: Identification of T cell subsets and NK cells

[0621] Group 3: Identification of interstitial macrophages and recruited monocytes

[0622] Group 4: Identification of dendritic cell subsets and plasmacytoid cells

[0623] For draining lymph node cells, 3 groups were performed:

[0624] Group 1: Identification of T cell subsets and NK cells

[0625] Group 2: Identification of dendritic cell subsets

[0626] Group 3: Identification of macrophages and plasmacytoid dendritic cells

[0627] For whole blood, 3 groups were performed:

[0628] Group 1: TCRαβ + Identification of T cell subsets, NK cells and B cells.

[0629] Group 2: TCRγδ + Identification of T cells and regulatory T cells.

[0630] Group 3: Identification of monocytes, dendritic cells and plasmacytoid dendritic cells.

[0631] II. Results and Discussion

[0632] 1. Survival rate

[0633] Figure 1 The survival rate of mice during the 14-day experiment is shown.

[0634] It was observed that compared with untreated control animals, Compound I-A allowed a reduction in animal mortality.

[0635] As Figure 1 shown, mice treated with the vehicle on day 14 had a 92% mortality rate.

[0636] Compared with untreated control animals, it was observed that treatment with oseltamivir at 1 mg / kg / day or Compound I-A significantly increased the survival rate of mice, with survival rates of 58% and 67% on day 14, respectively.

[0637] Interestingly, Compound I-A seems to be more effective than oseltamivir (1 mg / kg / day).

[0638] Notably, co - administration of Compound I - A and oseltamivir (2 mg / kg / day) protected animals from lethality caused by H1N1 infection, with a 100% survival rate on day 14.

[0639] 2. Body weight

[0640] Figure 2 shows the change in body weight of mice from day 0 to day 14.

[0641] As shown in Figure 2, from day 4 to day 9, the average body weight of mice in the vehicle group lost 23%.

[0642] Compared with the excipient, daily treatment with either Compound I - A or oseltamivir alone slightly improved this parameter, while the combination of oseltamivir + Compound I - A significantly helped maintain the body weight of infected mice.

[0643] 3. Clinical score

[0644] Figure 3 Shows the effect of treatment on clinical parameters from day 0 to day 14 as follows:

[0645] 1: Healthy mice

[0646] 2: Mice showed signs of discomfort, including slight piloerection, slight gait changes, and increased walking

[0647] 3: Mice showed strong signs of piloerection, abdominal contraction, gait changes, and periods of inactivity

[0648] 4: Mice with the characteristics of the previous group, but showed little activity and became moribund

[0649] 5: Dead mice

[0650] As shown, mice treated with the vehicle showed signs of discomfort, slight piloerection, and increased walking 5 days after infection. Strong piloerection and prolonged inactivity occurred on day 7.

[0651] Treatment with oseltamivir or Compound I - A significantly improved the clinical status of mice.

[0652] The combination had limited strong clinical symptoms, and all mice in this group recovered on day 11.

[0653] 4. Viral load

[0654] Figure 4 Shows the viral load in the lungs of infected mice on day 8.

[0655] As Figure 4As shown, 8 days after infection with 500 PFU of influenza A virus, treatment with Compound I-A and oseltamivir had no effect on the viral load in the lungs.

[0656] However, compared with the vehicle group, the combination of Compound I-A and oseltamivir significantly reduced the number of H1N1 particles.

[0657] 5. Cell Count

[0658] Figure 5 shows the effect of treatment on lymphopenia in the blood on day 8. Treatment with Compound I-A and Compound I-A + oseltamivir (Tamiflu) reduced H1N1-induced lymphopenia in the blood.

[0659] Figure 6 shows the effect of treatment on leukocyte infiltration in the lungs. On day 8 after inoculation, Compound I-A reduced the recruitment of monocyte-derived macrophages, dendritic cells, and CD8+ T cells in the infected lungs.

[0660] Compared with animals treated with vehicle and oseltamivir, treatment with Compound I-A and Compound I-A + oseltamivir (Tamiflu) on day 8 after inoculation reduced lymphocytes and circulating monocytes.

[0661] III. Conclusions

[0662] This study on H1N1 infection has highlighted the efficacy of treatment with Compound I-A in preventing death during severe pneumonia, as well as the superiority of the association between the antiviral molecule and Compound I-A compared with monotherapy with antiviral drugs or Compound I-A alone.

[0663] This study on H1N1 infection can also clearly determine the effect of treatment on pathological progression and the onset of acute respiratory diseases, focusing on innate and acquired pulmonary and systemic (heart, spleen, liver, and kidney) immune responses and cytokine storms.

[0664] Example 3: Evaluation of the compounds of the present invention on SARS-CoV-2 infection in golden Syrian hamsters

[0665] The aim of this study was to investigate the effect of NMN derivatives on the progression of coronavirus infection, particularly SARS-CoV-2 infection.

[0666] Materials and Methods

[0667] Materials

[0668] Animal:

[0669] For the experiment, 120 golden Syrian hamsters (6 to 10 weeks old) were obtained. When assigned to a group, each animal was identified by a unique animal number written on the tail / cage. Each cage was numbered. Based on the animal number / cage and the number of cages, the animals were assigned a unique number with the group name and hamster number.

[0670] The matching card used to identify the cage where the experimental animals are located will contain the following information: experiment name, experiment number, and cage number.

[0671] Compound:

[0672] The NMN derivative was manufactured according to Example 1 or purchased commercially and stored at +4 °C until use. The vehicle is a physiological buffer.

[0673] Method

[0674] 10. Preparation of the preparation:

[0675] The powder of the NMN derivative was dissolved in the vehicle (the solution was used for up to 1 day at room temperature). Fresh samples were prepared daily for each administration except on weekends (the solution was prepared on Saturday and used on Saturday and Sunday).

[0676] The said product was administered intraperitoneally once a day for 15 days.

[0677] The hamsters were weighed daily to accommodate the volume of the compound to be administered.

[0678] 1. Preparation of SARS-CoV-2 strain

[0679] These animals were housed in a biosafety level 2 holding room and had free access to standard pellet feed and water until challenged with the virus in our biosafety level 3 animal facility. Phosphate-buffered saline (PBS) was used to dilute the virus stock solution to the desired concentration and to retitrate the inoculum to verify the given dose. Intranasal inoculation was performed on day 0 with Dulbecco's modified Eagle's medium (DMEM) containing 10 5 plaque-forming units of SARS-CoV-2 in 100 μl.

[0680] 2. Experimental group

[0681] Six experimental groups were studied. The efficacy of compound I-A (114 mg / Kg / day), compound I-E (114 mg / Kg / day), antiviral drugs (remdesivir (17 mg / Kg / day) or hydroxychloroquine (91 mg / Kg / day)), or the combination of compound I-A or compound I-E and remdesivir or hydroxychloroquine was evaluated, with 20 animals in each group, and the pathological evolution under each treatment was followed. The following parameters were studied:

[0682] ·Viral load

[0683] ·Histopathology of organs

[0684] ·Immunohistological analysis of macrophage differentiation and infiltration of immune cells in selected tissues

[0685] ·qPCR of virus-regulated genes (IFN-γ, IL-4, IL-6, IL-10, IL-13, TNF-α, IL-21, TGFβ1, CCL17, CCL22, CCR4, FOXP3, IL-12p40, γ-actin)

[0686] ·Levels of circulating cytokines (IL-6, IL-10, IFN, TNF-α, MIP-1A, MCP-1, IP-10, TGF-β1)

[0687] ·NAD / NADH ratio in blood and tissue samples

[0688] These analyses were performed on 5 animals per group at 2, 4, 7, and 14 days post-infection. Readings were taken from blood, lung, spleen, kidney, liver, and intestine.

[0689] Example 4: Evaluation of the compounds of the present invention on human epithelial cells infected with SARS-CoV-2 and human immune cells activated by human epithelial cells infected with SARS-CoV-2 Example 5: Prospective, multicenter, randomized, placebo-controlled double-blind study for COVID-19 patients

[0690] The aim of this study was to evaluate the effects of NMN derivatives, especially compound I-A, on the activation and function of coronavirus-infected human lung epithelial cells, macrophages, and human dendritic cells in contact with infected cells.

[0691] Primary type II alveolar epithelial cells cultured in the presence or absence of compound I-A alone or in combination with antiviral therapy (remdesivir or hydroxychloroquine) will be infected with virus (SARS-CoV-2 or another human pathogenic coronavirus strain).

[0692] Then, the effects of compound I-A on virus replication and infection, as well as on the activation and cytokine release of alveolar cells, will be evaluated. The gene expression levels (RNAseq) in infected alveolar cells under different treatment conditions will also be analyzed.

[0693] Meanwhile, human circulating monocytes will be differentiated into macrophages and dendritic cells, which can be treated alone or in combination with compound I-A or antiviral therapy (remdesivir or hydroxychloroquine). These immune cells will then be contacted with coronavirus-infected epithelial cells, and their infection levels, phagocytosis, cytokine secretion, and activation (immunophenotyping) capabilities will be determined, and their differential gene expression (RNAseq) will be analyzed.

[0694] Inclusion criteria:

[0695] The overall objective of the study was to determine the therapeutic efficacy and tolerability of Compound IA in 300 patients with moderate and severe pneumonia associated with coronavirus disease 2019 (COVID-19). The study had a multiple randomized placebo-controlled trial (cmRCT) design. Compound IA was administered to consenting adult patients hospitalized with COVID-19 who were diagnosed with moderate or severe pneumonia.

[0696] The conditions are as follows:

[0697] Treatment regimen: 4x 250 mg / day of Compound IA vs. placebo (on top of standard of care) for 28 days

[0698] Exclusion criteria:

[0699] 18 years and above

[0700] Inpatient

[0701] Laboratory-confirmed diagnosis by PCR or other commercial or public health test ≤ 4 days before randomization

[0702] SARS-CoV-2 infection

[0703] Moderate to severe COVID-19 related illness

[0704] For moderate patients: Peripheral capillary oxygen saturation (SpO2) >94% on room air and pulmonary immersion at screening

[0705] Imaging evidence of

[0706] · For critically ill patients: Peripheral capillary oxygen saturation (SpO2) ≤ 94% or requiring supplemental oxygen at screening · Willing and able to provide written informed consent prior to study procedures

[0707] Primary outcome measure:

[0708] Participating in any other clinical trials of experimental treatments for COVID-19

[0709] Avoid any other medications with actual or potential direct effects on SARS-CoV-2 within 24 hours before starting the study drug

[0710] Concurrent treatment with drugs with antiviral activity

[0711] SOFA>10

[0712] Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30)

[0713] · Pregnant or lactating women

[0714] · Patients with impaired immune function taking medications during screening

[0715] · Subjects whom the investigator deems unsuitable for study treatment for any reason

[0716] Outcome Measures

[0717] Secondary outcome measure:

[0718] Percentage of subjects reporting each severity grade on a 7-point ordinal scale [Time Frame: Day 7]

[0719] a. Not hospitalized, no activity restriction

[0720] b. Not hospitalized, activity restricted;

[0721] c. Hospitalized, no supplemental oxygen required;

[0722] d. Hospitalized, supplemental oxygen required;

[0723] e. Hospitalized, using non-invasive ventilation or high-flow oxygen device;

[0724] f. Hospitalized, receiving invasive mechanical ventilation or ECMO;

[0725] g. Dead.

[0726] Laboratory / biomarkers at 7 days, 14 days and 28 days

[0727] 1. Overall survival [Time Frame: 7, 14, 28 days]

[0728] 2. Days off ventilator at 7 days, 14 days, and 28 days [Time Frame: 28 days]

[0729] 3. PaO2 / FiO2 ratio [Time Frame: Day 1 to Day 14]

[0730] Evolution of PaO2 / FiO2 ratio

[0731] 4. Time to oxygen independence at 7 days, 14 days, and 28 days [Time Frame: 7 days, 14 days, and 28 days]

[0732] Time to oxygen independence

[0733] 5. Length of hospital stay [Time Frame: 7 days, 14 days, 28 days]

[0734] Length of hospital stay

[0735] 6. Time to negative viral excretion at 7 days, 14 days, and 28 days [Time Frame: 7 days, 14 days, and 28 days]

[0736] Time to negative viral excretion

[0737] 7. Time to discharge from the ICU [Time range: 7 days, 14 days, and 28 days]

[0738] Time to discharge from the ICU

[0739] 8. Discharge time [Time range: 7 days, 14 days, and 28 days]

[0740] Discharge time

[0741] Example 6: Randomized, double-blind, multi-group historical control, comparative trial double-blind study of the combination of NMN derivative, famotidine and hydroxychloroquine according to the present invention in COVID-19 patients :

[0742] - NFS, VS, PCR, fibrinogen

[0743] - NAD

[0744] - Lymphocyte subsets (CD8, CD4, CD16, CD56) eurofins up to page 80

[0745] - CD57 NK

[0746] - CD19 lymph B

[0747] - IL-1α and IL-1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, vascular endothelial growth factor (VEGF), interferon γ, epidermal growth factor (EGF), monocyte chemoattractant protein type 1 (MCP-1), and TNFα.

[0748] - C3, C4, CH50

[0749] - DDID, AT3, TCK, TP, protein S, and C

[0750] - CPK, CPKMB, troponin, BNP, myoglobin, procalcitonin

[0751] - Transaminases, PAL, GGT, LDH, bilirubin, calcium level

[0752] - Complete ionogram (Na, K, Cl, Ra, proteinemia)

[0753] - Ferritinemia (Ferritinemie)

[0754] - Lipase, aldolase

[0755] Inclusion criteria: Exclusion criteria:

[0756] The overall objective of this study is to determine the therapeutic efficacy and tolerance of Compound I-A in patients with moderate and severe pneumonia associated with coronavirus disease 2019 (COVID-19). This study has a design of multiple randomized placebo-controlled trials (cmRCT). Compound I-A will be administered to adult patients who have consented to hospitalization for COVID-19 and have been diagnosed with moderate or severe pneumonia.

[0757] The conditions are as follows.

[0758] This study includes four groups:

[0759] Group 1: Compound I-A and intravenous famotidine. Subjects in this study group will receive a combination of oral Compound I-A and intravenous famotidine. Famotidine injection, 10 mg / mL mixed with normal saline, will be administered intravenously at 120 mg (30% of the 400 mg oral dose). The recommended total daily dose is 360 mg / day of famotidine IV for up to 14 days, or until discharge, whichever comes first. Compound I-A will be administered orally. The dose of Compound I-a to be administered is 10 mg / kg, at least 500 mg / day and at most 1 g / day.

[0760] Group 2: Compound I-A + intravenous famotidine + hydroxychloroquine. Subjects in this study group will receive a combination of oral Compound I-A, intravenous famotidine, and oral hydroxychloroquine. Famotidine injection, 10 mg / mL mixed with normal saline, will be administered intravenously at 120 mg (30% of the 400 mg oral dose). The recommended total daily dose is 360 mg / day of famotidine IV for up to 14 days, or until discharge, whichever comes first. Compound I-A will be administered orally. The dose of Compound I-A to be administered is 10 mg / kg, at least 500 mg / day and at most 1 g / day. Hydroxychloroquine sulfate 200 mg tablets will be administered according to the current clinical protocol for COVID-19; according to the specific-site clinical protocol for COVID-1, the loading dose on Day 1 is 400 mg BID, followed by 200 mg BID for 4 days, or the loading dose on Day 1 is 800 mg once daily, followed by 400 mg once daily for 4 days.

[0761] - Group 3: Compound I-A and intravenous placebo. Subjects in this group will receive oral Compound I-A. The dose of Compound I-A to be administered is 10 mg / kg, at least 500 mg / day and at most 1 g / day. Placebo (normal saline) will be infused 3 times a day.

[0762] - No intervention: Historical control: In this trial, the historical control refers to inpatients who did not receive Compound I-A or famotidine during the early stage of the pandemic from February 1, 2020, to March 26, 2021. This study will instead review previously collected data on patients who were not treated with Compound I-A for comparison with the active treatment group.

[0763] Outcome measure

[0764] 1. The subject (or legally authorized representative) provides written informed consent before starting any study procedures.

[0765] 2. Understand and agree to comply with the planned study procedures.

[0766] 3. Adult males or non-pregnant females aged ≥ 18 years at the time of inclusion.

[0767] 4. The subject agrees to randomization within 24 hours after admission.

[0768] 5. COVID-19 disease is radiologically confirmed < 72 hours before randomization.

[0769] 6. Disease of any duration, and at least one of the following:

[0770] o Radiological infiltrates by imaging (chest X-ray, CT scan, etc.), or

[0771] o Clinical assessment (evidence of rales / crackles on examination) and SpO2 ≤ 94% (room air), or

[0772] o Requirement for mechanical ventilation and / or supplemental oxygen.

[0773] 7. The subject does not require laboratory confirmation of the SARS-CoV-2 coronavirus for eligibility determination

[0774] 8. Women of childbearing potential must agree to use at least one primary contraceptive method during the study (acceptable methods will be determined by the study center).

[0775] Example 7: Evaluation of NMN and NR on murine influenza virus pulmonary infection

[0776] 1. Mild COVID-19 disease (mild clinical symptoms, no signs of pulmonary inflammation on imaging)

[0777] 2. Recent or any in-hospital exposure to investigational drugs for COVID-19, including hydroxychloroquine (if prescribed at a dose exceeding that specified in this protocol).

[0778] 3. ALT / AST > 5 times the upper limit of normal.

[0779] 4. Moderate renal insufficiency (creatinine clearance rate 30 - 50 mL / min), or stage 4 severe chronic kidney disease, or requiring dialysis (i.e., creatinine clearance rate < 30 mL / min)

[0780] 5. Presence of retinal or visual field changes attributable to any 4 - aminoquinoline compound.

[0781] 6. Known hypersensitivity to 4 - aminoquinolone compounds

[0782] 7. History or evidence of prolonged QT interval on ECG

[0783] 8. History of psoriasis or porphyria

[0784] 9. Absolute neutrophil count (ANC) < 2000 / mm3

[0785] 10. Pregnancy

[0786] 11. History of liver disease, hepatitis C infection, or alcohol abuse

[0787] 12. History of G - 6 - PD (glucose - 6 - phosphate dehydrogenase) deficiency

[0788] 13. Concomitant use of known hepatotoxic drugs

[0789] 14. Anticipated transfer to another hospital at a non - study site within 72 hours.

[0790] 15. Allergy to any study drug

[0791] 16. Known immunocompromise due to disease or treatment of an existing disease

[0792] Figure 7

[0793] Primary Outcome Measure: Mortality [Time Frame: 30 days after hospitalization]

[0794] Secondary Outcome Measures:

[0795] · Detection of virological response to study treatment in the blood [Time Frame: Day 30 relative to Day 0 of admission]

[0796] Percentage change in PCR copy number compared to the first measurement

[0797] · Virological clearance from nasal swabs and / or lower respiratory secretions [Time Frame: Days 6 and 30]

[0798] Presence or absence of SARS - CoV - 2 viral RNA in nasopharyngeal swabs or lower respiratory secretions

[0799] · Clinical severity [Time frame: Measured on days 3, 5, 8, 11, 15, and 30 of the study]

[0800] Measured on a 7-point ordinal scale: ranging from (1) death to (7) not hospitalized, with no restrictions on daily activities

[0801] · Clinical severity [Time frame: Measured on days 3, 5, 8, 11, 15, and 30 of the study]

[0802] Measured by the National Early Warning Score (NEWS): score based on vital signs ranges from 0 - 20, with higher scores indicating greater disease severity

[0803] · Clinical severity [Time frame: Measured on days 3, 5, 8, 11, 15, and 30 of the study]

[0804] Measured by the duration of supplemental oxygen use (if applicable)

[0805] · Clinical severity [Time frame: Measured on days 3, 5, 8, 11, 15, and 30 of the study]

[0806] Measured by the duration of mechanical ventilation use (if applicable)

[0807] · Clinical severity [Time frame: Measured on days 3, 5, 8, 11, 15, and 30 of the study]

[0808] Measured by length of hospital stay

[0809] Body weight change

[0810] During all experiments, Compounds I-A and I-G were delivered via the intraperitoneal route at 185 mg / kg daily. Seventy-two mice were weighed daily to accommodate the volume of the compound. Physiological buffer was used as a control and was injected intraperitoneally once daily during all experiments. During all experiments, control animals were administered Tamiflu orally at 2 mg / kg. Each animal was infected with H1N1. The experimental groups were as follows:

[0811] - Vehicle: H1N1 infection + physiological buffer

[0812] - Tamiflu: H1N1 infection + Tamiflu (2 x 1 mg / kg)

[0813] - Compound I-A: H1N1 infection + NMN (185 mg / kg)

[0814] - Compound I-G: H1N1 infection + NR (185 mg / kg)

[0815] - Tamiflu + Compound I-A: H1N1 infection + Tamiflu (2 x 1 mg / kg) + Compound I-A (185 mg / kg)

[0816] - Oseltamivir + Compound I-G: H1N1 infection + Oseltamivir (2 x 1 mg / kg) + Compound I-G (185 mg / kg)

[0817] Survival rate, body weight and clinical score were monitored during all experiments.

[0818] Survival rate( Figure 8 ) : Animals with more than 25% body weight loss were euthanized for ethical reasons and considered dead. Survival rate was monitored during all experiments. Animals with more than 25% body weight loss were euthanized for ethical reasons and considered dead.

[0819]

[0820] Treatment with oseltamivir, Compound I-A and Compound I-G improved the survival rate of mice at rates of 50%, 58% and 50% respectively. The combination of Compound I-A and Compound I-G with oseltamivir triggered a 100% survival rate at the end of the experiment. The survival rate is shown in Figure 5.

[0821] Respiratory score ( Figure 10 and 9 ): From day 4 to day 9, the average body weight of mice in the vehicle group decreased by 20.4%. From day 10 to the end of the experiment, the body weights of all surviving mice increased. Treatment with Compound I-A, Compound I-G or oseltamivir daily reduced body weight loss compared with the vehicle. Interestingly, the combinations of oseltamivir (2 mg / kg) + Compound I-A (185 mg / kg) and oseltamivir (2 mg / kg) + Compound I-G (185 mg / kg) contributed significantly to maintaining body weight.

[0822] Figure 10 ( Conclusion ): Respiratory score was evaluated according to the following criteria:

[0823]

[0824] According to Example 8: Dose-response evaluation of Compound I-A on influenza virus pulmonary infection , the combination of Compound I-A or Compound I-G with oseltamivir maintained a normal respiratory rate.

[0825] Figure 11: In this experiment, positive effects of two compounds on survival, weight loss, and clinical score were observed. For compound I-A, equivalent efficacy was demonstrated alone and in combination in this experiment. Based on the different clinical parameters observed, compounds I-A and I-G showed similar activities. Due to the complementary mode of action of compound I-A / compound I-G and Tamiflu, the combination of Tamiflu and compound I-A or compound I-G had a significant impact on morbidity and mortality. This led to complete clinical recovery in these groups of mice. This may be due to the combination of the immunoprotective effects of compounds I-A and I-G and the described antiviral activity of Tamiflu.

[0826] Figure 9

[0827] The model included intranasal administration of 500 PFU of influenza virus strain H1N1 PR / 8 / 34 to induce pneumonia. Compound I-A was delivered immediately after infection at 90, 185, or 500 mg / kg via the intraperitoneal (i.p.) route and then daily during all experiments. Mice were weighed daily to adjust the volume of the compound. Physiological buffer was used as a control and administered daily once via intraperitoneal injection during all experiments. Each experimental group consisted of 22 mice: 12 mice for survival studies, 5 mice for flow cytometry analysis, and 5 mice for assessing viral load.

[0828] The experimental groups were as follows:

[0829] - Group 1: Vehicle (i.p.)

[0830] - Group 2: Compound I-A 90 mg / kg

[0831] - Group 3: Compound I-A 185 mg / kg

[0832] - Group 4: Compound I-A 500 mg / kg

[0833] On day 8, 5 mice from each group were used to measure the following parameters.

[0834] · Blood collection: 3 aliquots (a, b, and c)

[0835] a) + ac. Perchloric acid (NAD dose)

[0836] b) Immunocyte characterization (cell counting)

[0837] c) Remaining plasma -> Freeze

[0838] · Lung and lymph node collection, cell preparation, counting, and immunocyte characterization (cell counting)

[0839] · Remaining cells of 2 tissues treated by RNAseq (if any)

[0840] · Lung viral load (5 mice per group)

[0841] During all experiments, the survival rate, body weight, clinical score, viral load in the lungs, and quantification of immune cell subsets in the lungs, blood, and draining lymph nodes (by flow cytometry) were monitored on day 8 post-infection.

[0842] Survival ( Figure 12 ): Animals with more than 25% weight loss were euthanized for ethical reasons and considered dead. The survival rate was monitored during all experiments. Animals with more than 25% weight loss were euthanized for ethical reasons and considered dead.

[0843]

[0844] Mice treated with the vehicle had a 92% mortality rate. Treatment with Compound I-A at 90, 185, and 500 mg / kg improved the survival rate of mice at rates of 33%, 58%, and 75%, respectively. The survival rate is as Figure 14 shown.

[0845] Body weight change ( Figure 16 and 13 ): The body weights of the 4 groups remained stable on the first day after H1N1 infection. From day 3 to day 8, the body weights of all groups decreased. Treatment with Compound I-A daily resulted in a weaker improvement in this parameter compared to the vehicle (D3-D8).

[0846] Clinical score ( Example 9: Effect of Compound I-A in free-choice diet-induced obese NASH hamsters infected with SARS-CoV-2 and 15 ): Mice treated with the vehicle showed signs of discomfort, mild piloerection, and increased locomotion 3 days after infection. Intense piloerection and long periods of inactivity appeared on day 5. Treatment with Compound I-A improved the clinical status of the mice compared to the vehicle group.

[0847] Viral load in the lungs ( Example 10: Evaluation of Compound I-A in mice infected with Covid-19 ): Treatment with Compound I-A at 90 and 185 mg / kg had no significant effect on the viral load in the lungs 8 days after infection with 500 PFU of influenza A virus. The 500 mg / kg dose significantly reduced the number of H1N1 particles compared to the vehicle group.

[0848] Conclusion: This study confirmed that compound I-A treatment reduced alveolar macrophage destruction caused by infection. Compound I-A treatment also increased the proportion of CD206+ macrophages, indicating a greater proportion of anti-inflammatory macrophages when mice were treated with compound I-A. These results could explain the improvement in clinical parameters and survival rate of mice treated with compound I-A. Although no regulation of monocyte-derived macrophage recruitment was observed in this experiment, the number of CD11b+ DCs tended to decrease in the presence of compound I-A. CD11b+ dendritic cells are known to play an important role during 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 large amounts of cytokines and chemokines, leading to the recruitment of NKT, NK, CD4+ and CD8+ T cells. Treatment with compound I-A regulates the immune response in the lung by maintaining alveolar macrophage destruction and reducing the recruitment of pro-inflammatory cell populations that may cause moderate pulmonary inflammation. This effect does not seem to be dose-dependent.

[0849] ​ ​

[0850] The aim of this study was to evaluate the effect of compound I-A in free-choice diet-induced obese NASH hamsters, a preclinical model infected with SARS-coronavirus 2 that also develops heart failure with preserved ejection fraction (Briand et al., Metabolism 2021). Compound I-A was evaluated over 25 days, and treatment started simultaneously with SARS-CoV-2 infection. Forty 4-week-old male golden Syrian hamsters were treated orally once daily (once daily orally) for 4 or 25 days with vehicle (n = 18) or NMN compound 600 mg / kg (n = 18). Administration started 1 hour before SARS-CoV-2 infection. Hamsters were sacrificed 4 days after infection (groups #1 and 3, n = 9 hamsters per group) and 25 days after infection (groups #2 and 4, n = 9 hamsters per group).

[0851]

[0852]

[0853] After the adaptation period, the hamsters (n = 40) were fed a free-choice diet (free to choose between control food or high-fat / cholesterol diet and regular water or 10% fructose-rich water in the same cage, as described by Briand et al., Metabolism 2021) for up to 20 weeks. Body weight was measured weekly during the diet period.

[0854] Before being transferred to the Biosafety Level 3 facility of the Animal Resources Center at the Institut Pasteur de Lille, 36 hamsters were selected based on plasma ALT, AST, total cholesterol, triglyceride levels, and body weight: the hamsters were fasted for 6 hours at 8:00 am and then bled at 2:00 pm (150 μL / heparin) to isolate plasma and measure plasma ALT, AST, total cholesterol, and triglycerides.

[0855] The 36 selected hamsters were transferred to the Biosafety Level 3 facility at the Animal Resources Center of the Institut Pasteur de Lille and maintained on a free-choice diet. Four other hamsters were excluded from the study, and they were bled by retroorbital hemorrhage to isolate and store plasma at -80 °C and sacrificed to collect the lungs, liver, and heart. For each organ, one part was stored at -80 °C and the other part was fixed in formalin for 24 hours and then stored in ethanol at 4 °C for final analysis.

[0856] After a 1-week acclimation period, the hamsters received the first dose of the vehicle or compound I-A one hour before intranasal inoculation with SARS-CoV-2 (2 x 104 PFU) and were treated for 25 days after viral infection, orally with the vehicle or compound I-A once daily for 25 days. Body weight was measured daily, and clinical symptoms were monitored during the 25-day period.

[0857] At 4 days and 25 days post-infection, the hamsters (n = 9 vehicle and n = 9 NMN compound-treated hamsters at each time point) were sacrificed to collect the maximum blood volume, and then the lungs, liver, and heart were collected and dissected for formalin fixation or storage at -80 °C for analysis.

[0858] Viral load in the lungs (TCID50 and RT-qPCR) was measured on day 4.

[0859] Viral RNA and infectious virus were determined by reverse transcription quantitative PCR (RT-qPCR), in situ hybridization, and plaque formation assay. Briefly, total RNA in tissues was extracted and homogenized using an RNeasy Mini Kit (Qiagen). RT-qPCR was performed according to the manufacturer's instructions. Quantification of live infectious virus was performed by median tissue culture infective dose (TCID50) assay as follows. Half of the lung tissue was weighed and homogenized in 1 ml of DMEM containing 1% penicillin / streptomycin using a pestle. After centrifugation at 13,000 rpm for 10 minutes, the clarified supernatant was collected for live virus titration (TCID50 assay). Aliquots of the homogenate were applied to confluent Vero-E6 cells in 96-well plates for TCID50 assay. Briefly, serial 10-fold dilutions of each sample were inoculated in quadruplicate onto a monolayer of Vero-E6 cells and cultured in DMEM containing 1% FBS and penicillin / streptomycin. The cytopathic effect of the plates was observed for 4 days. Virus titers were calculated using the Reed and Münch endpoint method. One TCID50 was interpreted as the amount of virus that caused cytopathic effect in 50% of the inoculated wells. Virus titers were expressed as TCID50 / g of tissue. Then the following analyses were performed at 4 days and 25 days post-infection / treatment:

[0860] · Plasma biochemistry: glucose, ALT, AST, ALP, LDH, TC, TG, FFA, LDL-c, HDL-c, bilirubin, total protein, IL-6, and ACE-2 activity.

[0861] · Lung qPCR (10 selected genes): IL-6, INF-g, Isg15, TNF-a, IL-10, IL-12p40, CXCL10, TGF-b, occludin, cadherin.

[0862] · Right lung histology (H&E and Sirius red staining), histopathological scoring (cell death / necrosis, alveolar and / or perivascular edema, hyaline membrane or fibrin, inflammation, thrombosis, congestion, hemorrhage, type II hyperplasia, and syncytium), and Sirius red percentage labeling (lung fibrosis)

[0863] Remaining RNA preparations, plasma samples, and fixed liver and heart tissues from all animals were retained for further analysis. Data were analyzed as mean ± standard error.

[0864] ​

[0865] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 13,000,000 coronavirus disease (COVID-19) cases with a high mortality rate. Laboratory mice have been the mainstay in the development of treatments and vaccines; however, they do not support SARS-CoV-2 infection because the virus cannot use the murine ortholog of its human entry receptor, angiotensin-converting enzyme 2 (hACE2). 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 was administered by intraperitoneal injection of the compound once daily for up to 10 days.

[0866] More specifically, 72 male B6.Cg-Tg(K18-ACE2)2Prlmn / J, 7-week-old animals upon arrival, were obtained from Charles Rivers, BP0109, 69592, L'Arbresle, France. The animals were divided into the following 6 experimental groups:

[0867] - Group 1: 400 pfu + vehicle (n = 10)

[0868] - Group 2: 400 pfu + Compound I-A 500 mg / kg (n = 12)

[0869] Pfu represents plaque-forming units. The study duration was 10 days. On day 0, all mice were infected intranasally with 25 μL of DMEM containing SARS-CoV-2 (400 PFU / mouse). The mice were treated with vehicle or Compound I-A at 500 mg / kg once daily by oral gavage. From day 0 to day 10, the body weight, survival rate, and clinical score of 10 mice per group were monitored.

[0870] The mortality rate, body weight, and clinical symptoms of 12 mice per group were recorded daily until the end of the experiment (D10).

[0871] The clinical score was established as follows:

[0872] 1: Healthy mice

[0873] 2: Mice showing signs of discomfort, including slight piloerection, slight gait changes, and increased walking

[0874] 3: Mice showing strong piloerection, abdominal contractions, gait changes, and periods of inactivity

[0875] 4: Mice with the characteristics of the previous group but showing little activity and becoming moribund

[0876] 5: Dead mice

[0877] From the start to the end of the experimental phase, the appearance and behavior of the animals were evaluated at least daily. Any abnormal findings were recorded in the raw data. Body weight measurements and clinical examinations were also performed before the animals were grouped. Respiratory scoring was monitored as follows:

[0878]

Claims

1. Use of a compound selected from the following or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prophylaxis of influenza virus infection: or 2. The application according to claim 1, wherein, The viral infection is a respiratory tract infection caused by influenza A or influenza B, wherein the viral infection is a respiratory tract infection selected from H1N1, H3N2, H5N1, B / Yamagata / 16 / 88-like and B / Victoria / 2 / 87-like viruses.

3. The application according to claim 1, wherein, The medicament is for the treatment and / or prophylaxis of respiratory or extrapulmonary complications.

4. The application according to claim 1, wherein The medicament is for the treatment and / or prophylaxis of pneumonia and / or acute respiratory disease.

5. The application according to claim 4, wherein, The medicament is for the treatment and / or prophylaxis of acute respiratory failure.

6. The application according to claim 4, wherein, The medicament is for the treatment and / or prophylaxis of acute respiratory distress syndrome (ARDS).

7. Use of a pharmaceutical composition in the manufacture of a medicament for the treatment and / or prophylaxis of influenza virus infection, the pharmaceutical composition comprising a compound as defined in claim 1 and at least one pharmaceutically acceptable carrier.

8. The use according to claim 7, wherein the pharmaceutical composition further comprises at least one active ingredient selected from: antiviral agents, neuraminidase inhibitors, M2 proton channel blockers, anti-interleukin 6, JAK inhibitors, interferons and mixtures thereof, and / or at least another active ingredient selected from antiviral agents, neuraminidase inhibitors, M2 proton channel blockers, anti-interleukin 6, JAK inhibitors, interferons and mixtures thereof, and / or at least yet another active ingredient selected from the group consisting of: antiviral agents; anti-interleukin 6 (anti-IL6) agents; Janus-associated kinase (JAK) inhibitors; interferons; macrolides selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin; selected from BXT-25, chloroquine, hydroxychloroquine, bruceine, dehydroandrographolide succinate, fingolimod, methylprednisolone, thalidomide, bevacizumab, sildenafil citrate, keliimycin, histamine H2 receptor antagonists, nicotine; and mixtures thereof.

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