WO2022029275A1

WO2022029275A1 - Combination of nicotinamide mononucleotide derivatives and other therapeutic agents for use in the treatment of coronavirus infections and covid-19

Info

Publication number: WO2022029275A1
Application number: PCT/EP2021/071959
Authority: WO
Inventors: Guillaume BERMOND; Laurent GARCON
Original assignee: Nuvamid Sa
Priority date: 2020-08-06
Filing date: 2021-08-05
Publication date: 2022-02-10

Abstract

The present disclosure relates to the combination of remdesivir and nicotinamide mononucleotide derivatives of formula (I) or of formula (la) for use in the treatment and/or prevention of Coronavirus infections and/or respiratory and/or extra-respiratory complications caused by a Coronavirus infection, as well as pharmaceutical compositions and kit of parts comprising the same.

Description

COMBINATION OF NICOTINAMIDE MONONUCLEOTIDE DERIVATIVES AND OTHER THERAPEUTIC AGENTS FOR USE IN THE TREATMENT OF CORONAVIRUS INFECTIONS AND COVID-19

TECHNICAL FIELD

[0001] The present invention relates to combinations of Nicotinamide mononucleotide derivatives compounds and at least remdesivir for use in the treatment and/or prevention of Coronavirus infections as well as respiratory and/or extra-respiratory complications caused by Coronavirus infections.

BACKGROUND

[0002] The defense against diseases is critical for the survival of all animals, and the mechanism employed for this purpose is the animal immune system. With two main divisions involved being (i) innate immunity and (ii) adaptive immunity, the immune system is very complex. The innate immune system includes the cells and mechanisms that defend the host from infection by invading organisms, in a non-specific manner. Leukocytes, which are involved with the innate system, include inter alia phagocytic cells, such as macrophages, neutrophils and dendritic cells. The innate system is fully functional before a pathogen enters the host.

[0003] In contrast, the adaptive system is only initiated after the pathogen has entered the host cells, at which point it develops a pathogen-specific defense. The main cell types of the adaptive immune system are called lymphocytes, the two main categories of which are B cells and T Cells. B cells are involved in the creation of neutralizing antibodies that circulate in blood plasma and lymph and form part of the humoral immune response. T cells play a role in both the humoral immune response and the cell-mediated immunity. There are several subsets of activator or effector T cells, including cytotoxic T cells (CD8+) and “helper” T cells (CD4+), of which there are two main types known as Type 1 helper T cells (Thl) and Type 2 helper T cell (Th2).

[0004] Thl cells promote a cell-mediated adaptive immune response, which involves the activation of macrophages and stimulates the release of various cytokines, such as IFNy, TNF- a and IL- 12, in response to an antigen. These cytokines influence the function of other cells in the adaptive and innate immune responses, and result in the destruction of micro-organisms. [0005] Generally, Thl responses are more effective against intracellular pathogens, such as viruses and bacteria present inside host cells, while a Th2 responses are more effective against extracellular pathogens, such as parasites and toxins located outside host cells.

[0006] Most respiratory infections, especially those of the upper respiratory tract, are mild and not incapacitating. Upper respiratory tract infections often cause rhinorrhea or pharyngitis. Lower respiratory tract infections can be more severe and are more likely than upper respiratory tract infections to cause fever, dyspnea, chest pain or pneumonia. Cough is often present in either upper or lower respiratory tract infections.

[0007] In December 2019, a new highly contagious viral pneumonia (R0 ~ 2.2) emerged, and the epidemic was quickly qualified by the World Health Organization (WHO) as a threat to global public health. The first patients with this unexplained pneumonia appeared in Wuhan, China. A few days later, the virus was identified as a new beta coronavirus, a single-stranded RNA- positive virus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is the seventh coronavirus affecting the human population and the third highly pathogenic coronavirus after the coronaviruses outbreak of severe acute respiratory syndrome (SARS-CoV-2002) first identified in 2003 and Middle East respiratory syndrome (MERS- CoV-2012) first identified in 2012.

[0008] Currently, the incidence of disease associated with SARS-CoV-2, is found in more than 200 countries and territories worldwide and according to WHO data (22 April 2020), the number of confirmed cases worldwide has reached more than 2 million individuals including 162,956 deaths. Not all people exposed to SARS-CoV-2 are infected and not all infected patients develop severe respiratory disease. According to a study of more than 1000 patients in Wuhan, SARS-CoV-2 infects all age groups equally, although children and adolescents appear to be less affected and rarely develop severe forms. This protection to infection could only be relative since the number of cases of infection identified in the youngest age groups increases considerably, probably because of the increased frequency of performed screening.

[0009] CO VID- 19 is a respiratory illness generally first presenting with symptoms including headache, muscle pain, and/or fatigue/tiredness followed by fever and respiratory symptoms (such as a dry cough, shortness of breath, and/or chest tightness). While the symptoms remain mild in the majority of subjects, in others they may progress to pneumonia (referred herein as CO VID- 19 associated pneumonia or COVID-19 pneumonia) and/or to multi-organ failure. Complications of CO VID-19 include acute respiratory distress syndrome (ARDS), RNAaemia, acute cardiac injury and secondary infections (Huang el al., Lancet. 2020;395(10223):497-506). It is estimated that about 20% of subjects suffering from COVID- 19 require hospitalization and about 5% require admission to intensive care unit (ICU). CO VID-19 causes substantial morbidity and mortality and may place unprecedented strain on many health systems.

[0010] Despite the provision of vaccines, antiviral drug, or other specific treatment available, treatment of COVID-19 remains supportive, especially given the current vaccines are not 100% effective in fighting against all emerging variants. Over 175 treatments and vaccines clinical trials are currently registered and current therapeutic strategies include antiviral agents, notably remdesivir (a nucleotide analog), the combination of lopinavir/ritonavir (a antiretroviral therapy notably used for the treatment of human immunodeficiency virus 1 (HIV- 1)), chloroquine or hydroxychloroquine, and 11-6 inhibitors immunomodulatory agents such as tocilizumab. However, there is currently neither any vaccine to prevent and/or treat COVID- 19 or asymptomatic infection with SARS-CoV-2 against all its variants, notably the deltavariant, nor any therapeutic agent with a proven efficacy for preventing and/or treating CO VID-19, CO VID-19 associated pneumonia or CO VID-19 associated acute respiratory distress syndrome (ARDS).

[0011] Therefore, there is an urgent need for effective and safe prophylactic and/or therapeutic treatments for coronavirus infections, in particular coronavirus respiratory infections causing diseases such as SARS, MERS, COVID-19 and in particular COVID-19 associated pneumonia and CO VID-19 associated acute respiratory distress syndrome (ARDS).

[0012] Nicotinamide mononucleotide (NMN) is a nucleotide that is already known.

[0013] The purpose of the present invention is thus to provide an alternative to current treatments by providing Nicotinamide mononucleotide and derivatives thereof for use in the treatment and/or prevention of a viral infections, in particular of respiratory infections, caused by a Coronavirus infection. [0014] The Applicant surprisingly found that the Nicotinamide mononucleotide derivatives according to the invention in combination with a further therapeutic agent, in particular nucleoside analogs such as remdesivir, are potent agents to treat and/or prevent a Coronavirus infection, in particular respiratory and/or extra-respiratory complications caused by a Coronavirus infection, and are well tolerated. SUMMARY [0015] This invention relates to the combination of at least one active ingredient and a Compound of Formula (I),

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C= CH₂; R1 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)( C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHRAANH₂ ; wherein RAA is a side chain selected from a proteinogenic amino acid; R6 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R₉R₁₀, P(S)R₉R₁₀ and

; wherein: R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C₁-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R12; wherein: R₁₁ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)_nC(O)(C₁-C₁₅)alkyl, - (CH₂)_nOC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)_nSC(O)(C₁-C₁₅)alkyl, - (CH₂)nC(O)O(C₁-C₁₅)alkyl and -(CH₂)nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; R₁₂ is selected from hydrogen, C_1-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_1-C₁₀ haloalkyl, C_3- C₁₀ cycloalkyl, C₃-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C1-C4 alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₁₃ and R₁₄ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Rα and Rα’ are independently selected from an hydrogen, C₁-C₁₀ alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C_3-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C_1-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅- C₁₂ aryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6-membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C₅-C₆ aryl and C₅-C₆ heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; or R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein –R9−R10− represents –O-CH₂-CH₂-CHR-O−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; R₈ is selected from H, OR, NHR₁₃, NR₁₃R₁₄, NH-NHR₁₃, SH, CN, N₃ and halogen; wherein R₁₃ and R14 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R₁,

or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: X’₁ and X’₂ are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; R’₁ and R’₁₃ are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C₁-C₁₂ thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1-C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1-C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; R’₆ and R’₈ are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’7 and R’14 are independently selected from H, OR, NHR, NRR’ , NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; Y’₁ and Y’₂ are independently selected from CH, CH₂, C(CH₃)₂ or CCH₃; M’ is selected from H or a suitable counterion; represents a single or a double bound depending on Y’₁ and Y’₂; and represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃, for use in the treatment and/or prevention of a Coronavirus infection. [0016] The invention also relates to a combination of at least one active ingredient and compound of Formula (I) comprising:

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R₁ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHRAANH2 ; wherein RAA is a side chain selected from a proteinogenic amino acid; R₆ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R₉R₁₀, P(S)R₉R₁₀ and ; wherein:

R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C₁-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R12; wherein: R₁₁ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)_nC(O)(C₁-C₁₅)alkyl, - (CH₂)nOC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)nSC(O)(C₁-C₁₅)alkyl, - (CH₂)_nC(O)O(C₁-C₁₅)alkyl and -(CH₂)_nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; R12 is selected from hydrogen, C₁-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₁₀ haloalkyl, C3- C10 cycloalkyl, C₃-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C1-C4 alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₁₃ and R₁₄ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; R_α and R_α’ are independently selected from an hydrogen, C_1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C_3-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C_1-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅- C12 aryl, -(CH₂)3NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6-membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C₅-C₆ aryl and C₅-C₆ heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₈ is selected from H, OR, NHR₁₅, NR₁₅R₁₆, NH-NHR₁₃, SH, CN, N₃ and halogen; wherein R₁₅ and R₁₆ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R₁, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: X’1 and X’2 are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; R’1 and R’13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1-C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1-C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; R’6 and R’8 are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’₇ and R’₁₄ are independently selected from H, OR, NHR, NRR’ , NH-NHR, SH, CN, N₃ and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; Y’₁ and Y’₂ are independently selected from CH, CH₂, C(CH₃)₂ or CCH₃; M’ is selected from H or a suitable counterion; represents a single or a double bound depending on Y’₁ and Y’₂; and represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃, for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. [0017] According to one embodiment, X represent an oxygen. [0018] According to one embodiment, R₁ and R₆ each independently represents a hydrogen. [0019] According to one embodiment, R₂, R₃, R₄ and R₅ each independently represents a hydrogen. [0020] According to one embodiment, R₂, R₃, R₄ and R₅ each independently represents a OH. [0021] According to one embodiment, Y represents a CH or a CH₂. [0022] According to one embodiment, R₇ represents P(O)R9R10, wherein R9 and R10 are as described herein. [0023] According to one embodiment, R₇ represents described in herein.

[0024] According to one embodiment, R₇ is not H. [0025] According to an embodiment: ● X represents an oxygen; and/or ● R1 and R6 each independently represents a hydrogen; and/or ● R₂, R₃, R₄ and R₅ each independently represents a hydrogen, or R₂, R₃, R₄ and R₅ each independently represents a OH; and/or ● Y represents a CH or a CH₂; and/or ● R₇ represents P(O)R₉R₁₀, and wherein R₉ and R₁₀ are independently selected from OH, OR11, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C₁-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R₁₂. [0026] According to one embodiment, the compound for use according to the invention is selected from compounds I-A to I-J or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof.

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof, preferably I-A to I-F and even more preferably I-A or I-B. [0027] According to one embodiment, X’₁ and X’₂ each independently represents an oxygen. [0028] According to one embodiment, R’₇ and R’₁₄ each independently represents a NH₂. [0029] According to one embodiment, R’₁ and/or R’₁₃ each independently represents a hydrogen. [0030] According to one embodiment, R’₆ and/or R’₈ each independently represents a hydrogen. [0031] According to one embodiment, R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁ and R’₁₂ each independently represents a hydrogen. [0032] According to one embodiment, R’2, R’3, R’4, R’5, R’9, R’10, R’11 and R’12 each independently represents a OH. [0033] According to one embodiment, Y’₁ and Y’₂ each independently represents a CH. [0034] According to one embodiment, Y’₁ andY’₂ each independently represents a CH₂. [0035] According to one embodiment, the compound according to the invention is selected from compounds of formula Ia-A to Ia-I:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof. [0036] According to one embodiment, the Coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2. [0037] According to one preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19). [0038] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated pneumonia.

[0039] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID- 19 associated acute respiratory distress syndrome (ARDS).

[0040] According to an embodiment, the combination is for use in the treatment and/or prevention of pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure.

[0041] According to an embodiment, the combination is for use in the treatment and/or prevention of pneumonia and/or acute respiratory syndromes associated with CO VID-19.

[0042] According to one embodiment, said at least one active ingredient can be selected from a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose-derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti-inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, statins, aspirin, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, aviptadil, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

[0043] According to one embodiment, the at least one active ingredient is a plasma of a convalescent patient. Preferably, said convalescent patient has been infected by SARS-CoV- 2.

[0044] According to one embodiment, the at least one active ingredient is an antiviral agent.

[0045] According to one embodiment, the antiviral agent is chosen amongst a nucleoside analog, a nucleotide analog, favilavir, avifavir, umifenovir, favipiravir, an HIV-protease inhibitor, EIDD 2801(MK4482, molnupiravir), a dihydroorotate dehydrogenase inhibitor and their combinations.

[0046] According to one embodiment, said antiviral agent is a nucleoside analog.

[0047] According to a preferred embodiment, said nucleoside analog can be selected amongst: deoxyadenosine analogues such as didanosine and vidarabine; adenosine analogues such as galidesivir and remdesivir; deoxycytidine analogues such as cytarabine, gemcitabine, emtricitabine, lamivudine, zalcitabine ; guanosine and deoxyguanosine analogues such as abacavir, acyclovir and entecavir; thymidine and deoxythymidine analogues such as stavudine, telbivudine, zidovudine; and deoxyuridine analogues such as idoxuridine and trifluridine.

[0048] Preferably, said nucleoside analogue is remdesivir.

[0049] According to one embodiment, the alkaloid is selected amongst berberine, canadine, colchicine, ophiocarpine, mecambridine, corydaline, preferably berberine.

[0050] According to one embodiment, the macrolide is selected from the group consisting of azithromycin, clarithromycin, erythromycin, spiramycin, telithromycin and their combination.

[0051] According to one embodiment, said histamine H2 receptor antagonist is chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine, preferably famotidine.

[0052] According to one embodiment, the HIV protease inhibitor is chosen amongst lopinavir, ritonavir, nelfinavir, indinavir, atazanavir, saquinavir, darunavir, fosamprenavir, amprenavir, tipranavir, asunaprevir, TMC-310911, JE-2147, L-756423 and their combinations.

[0053] According to one embodiment, the SARS-CoV-2 vaccine can be a DNA-, RNA or mRNA- based vaccine coding for SARS-CoV-2 antigens chosen amongst PrEP-001 , mRNA 1273, GX- 19, BNT-162, ZyCoV-D, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA, CvnCoV that can be formulated in lipid nanoparticles (CvnCoV vaccine), in plasmids (INO-4800 DNA vaccine) or in lentiviral vector systems (aAPC vaccine) or in dendritic cells (AV-COVID-19 vaccine).

[0054] According to one embodiment, the SARS-CoV-2 vaccine can be heat inactivated plasma from patients who had Covid-19 such as V-SARS.

[0055] According to one embodiment, the SARS-CoV-2 vaccine can be a stabilised and/or recombinant SARS-CoV-2 spike protein or protein receptor binding domain chosen amongst NVX-CoV237, Clover vaccine or a bacterium expressing the SARS-CoV-2 spike protein such as bacTRL-Spike.

[0056] According to one embodiment, the SARS-CoV-2 vaccine can be a deactivated virus or deactivated bacterium chosen amongst the Corona Vac, the VPM1002 vaccine, the measles- mumps-rubella vaccine, the BCG vaccine.

[0057] According to one embodiment, the SARS-CoV-2 vaccine can be a deactivated adenovirus carrying the SARS-CoV-2 spike protein or receptor binding domain chosen amongst the ChAdOxl nCoV-19, the Ad5-CoV.

[0058] According to one embodiment, the dihydroorotate dehydrogenase inhibitor is chosen amongst PTC299, brequinar, teriflunomide, leflunomide and their combinations.

[0059] According to one embodiment, the recombinant fusion protein can be chosen amongst CD24Fc, recombinant gelsolin, and their combinations.

[0060] According to one embodiment, the MAP kinase inhibitor is lospamimod.

[0061] According to one embodiment, said anti-helminctic is chosen amongst ivermectin, praziquantel, triclabendazole, albendazole, pyrantel, flubendazole, diethylcarbamazine, niclosamide, and their combinations.

[0062] According to one embodiment, the kinase inhibitor is chosen amongst acalabrutinib, adavosertib, afatinib, axitinib, bemcetinib, bosutinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, sunitinib, su6656, tofacitinib, vandetanib, vemurafenib and their combinations. [0063] According to one embodiment, the sodium-glucose transport protein 2 (SGLT2) inhibitor is chosen amongst dapaglifozin, canaglifozin, empaglifozin, ertugliflozin and their combinations.

[0064] According to one embodiment, the corticoid (or corticosteroid) is chosen amongst hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, tixocortol pivalate, preferably methylprednisone and dexamethasone.

[0065] According to one embodiment, the non-steroidal anti-inflammatory is chosen amongst aspirin, aviptadil, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, diclofenac, sulindac, etodolac, ketorolac, aceclofenac, bromfenac, nabumetone, celecoxib, mefenamic acid, etoricoxib, indomethacin, tolmetin, aspirin, salicylic acid, diflunisal, salsalate, piroxicam, rofecoxib, valdecoxib, lumiracoxib meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, parecoxib, etoricoxib, firocoxib, nimesulide, clonixin, licofelone, H-harpagide, and their combinations, preferably aspirin and aviptadil.

[0066] According to one embodiment, the antibody is chosen amongst an anti-VEGF, an anti- TNF, an anti-GM-CSF, GM-CSF antagonist, a CCR₅ antagonist, an anti-SARS-CoV-2 spike protein, an IL-6 receptor antagonist, an anti-ILlbeta, a C5 complement inhibitor and their combinations.

[0067] Preferably, said antibody is chosen amongst bevacizumab, etesivimab, infliximab, mavrilimumab, lenzilumab, leronlimab, gimsilumab, otilimab, JS016, LY-CoV555, REGN10933, REGN10987, sarilumab, canakinumab, ravulizumab, mavrilimumab, tocilizumab, namilumab, adalimumab, MEDI3506, bamlanivimab, AZD7442, casirivimab, imdevimab, sotrovimab, risankizumab, and their combinations, preferably AZD7442, casirivimab, imdevimab, sarilumab, JS016, LY-CoV555, REGN10933 and REGN10987 and their combinations.

[0068] According to one embodiment, the recombinant fusion protein is CD24Fc, recombinant gelsolin, and their combinations.

[0069] According to one embodiment, the anti-interleukine 6 is chosen amongst tocilizumab, sarilumab, siltuximab, levilimab and their combination.

[0070] According to one embodiment, the JAK inhibitor is selected amongst ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, delgocitinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, abrocitinib, deucravacitinib, cucurbitacin I, CHZ868 and their combinations.

[0071] According to one embodiment, the neuraminidase inhibitor is selected amongst laninamivir, oseltamivir, peramivir, zanamivir, cyanidin-3-sambubioside, coptisine, berberine, and their combinations.

[0072] According to one embodiment, the M2 proton channel blocked is selected amongst amantadine, rimantadine and their combination.

[0073] According to one embodiment, the interferon is selected amongst PEGylated interferon alpha, PEGylated interferon alpha 2b, PEGylated interferon alpha 2a, tilorone and their combinations.

[0074] According to one embodiment, the angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers is selected amongst Alacepril, captopril, zefnopril, enalapril, ramipril, quinapril, perindopril, lisinopril, bezanopril, imidapril, trandolapril, cilazapril, fosinopril and their combinations.

[0075] According to one embodiment, the statin is chosen amongst atorvastatin, cerivastatin,

Fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their combinations. [0076] According to one embodiment, the other at least one active ingredient can be selected amongst dimethyl fumarate, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, and their combinations.

[0077] Preferably, the at least one active ingredient is a corticoid (or corticosteroid), a SARS-CoV- 2 vaccine, an antibody, an antiviral agent, and their combinations. More preferably, the at least one active ingredient is remdesivir.

[0078] According to an embodiment, the active ingredient is not at least one of the ingredients chosen amongst betaine, sodium chloride, zinc sulfate, and their combination preferably the active ingredient is not a combination of betaine, sodium chloride and zinc sulfate.

[0079] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is administered to a patient who has already been administered said at least one active ingredient.

[0080] According to an embodiment, the patient who has already been administered said at least one other active ingredient for a period of at least 1-14 days before being administered with compound of formula (I) or of formula (la).

[0081] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is for administration to a patient for a period of 1-14 days, the patient being a said at least one other active ingredient naive patient.

[0082] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is for administration to a patient for a period of 1-90 days before administration of said at least one other active ingredient.

[0083] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is administered separately, simultaneously or sequentially of said at least one other active ingredient.

[0084] The invention also relates to a combination of at least one of compound of Formula (I) selected from:

and/or one compound of formula (la) selected from:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof with remdesivir for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. [0085] In a preferred embodiment, the compound of Formula (I) is compound of formula I-A and/or the compound of formula (I-B) or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof.

[0086] According to an embodiment, the Coronavirus infection is caused by a coronavirus selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0087] According to an embodiment, the respiratory and/or extra-respiratory complications are selected amongst pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure, pneumonia and/or acute respiratory syndromes associated with COVID-19.

[0088] According to one embodiment, the Coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2.

[0089] According to one preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0090] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated pneumonia.

[0091] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID- 19 associated acute respiratory distress syndrome (ARDS).

[0092] According to an embodiment, the combination is for use in the treatment and/or prevention of pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure.

[0093] According to an embodiment, the combination is for use in the treatment and/or prevention of pneumonia and/or acute respiratory syndromes associated with CO VID-19.

[0094] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is administered to a patient who has already been administered remdesivir for a period of at least 1-10 days before being administered with compound of formula (I) or of formula (la).

[0095] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is for administration to a patient for a period of 5-10 days, the patient being a remdesivir naive patient.

[0096] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is for administration to a patient for a period of 1-90 days before administration of remdesivir.

[0097] According to an embodiment, said one compound of formula (I) and/or one compound of formula (la) is administered separately, simultaneously or sequentially of remdesivir.

[0098] According to an embodiment, the combination of the invention can also comprise at least one further active ingredient as disclosed herein.

[0099] According to an embodiment, the combination does not comprise at least one of the ingredients chosen amongst betaine, sodium chloride, zinc sulfate, and their combination preferably the combination does not comprise betaine, sodium chloride and zinc sulfate.

[0100] The invention also relates to a pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection as disclosed herein, comprising at least one compound for use according to the invention, together with at least one active ingredient as disclosed herein, and at least one pharmaceutically acceptable carrier.

[0101] Another object of the invention is a pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, comprising at least one compound of formula (I) and/or formula (la) for use according to the invention, together with at least one other active ingredient, and at least one pharmaceutically acceptable carrier. [0102] The at least one active ingredient and compound of formula (I) and/or formula (la) are as defined herein.

[0103] The invention also covers a pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, comprising at least one compound of formula (I) or (la) and at least one pharmaceutically acceptable carrier for use together with remdesivir, the compound of formula (I) being selected from:

and the compound of formula (la) being selected from:

[0104] Preferably, the compound of formula I is compound I-A or compound I-B.

[0105] According to an embodiment, the pharmaceutical composition the Coronavirus infection is caused by a coronavirus selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV- HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS- CoV-1 and SARS-CoV-2, preferably a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0106] According to an embodiment, the respiratory and/or extra-respiratory complications are selected amongst pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure, pneumonia and/or acute respiratory syndromes associated with COVID-19.

[0107] According to one embodiment, the Coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2.

[0108] According to one preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0109] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated pneumonia.

[0110] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID- 19 associated acute respiratory distress syndrome (ARDS).

[0111] According to an embodiment, the pharmaceutical composition is for use in the treatment and/or prevention of pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure. [0112] According to an embodiment, the pharmaceutical composition is for use in the treatment and/or prevention of pneumonia and/or acute respiratory syndromes associated with COVID- 19.

[0113] According to an embodiment, the pharmaceutical composition is administered sequentially, simultaneously and/or separately of remdesivir.

[0114] According to an embodiment, the pharmaceutical composition is administered to a patient who has already been administered remdesivir for a period of at least 1-10 days before being administered with compound of formula (I) or of formula (la).

[0115] According to an embodiment, the pharmaceutical composition is for administration to a patient for a period of 5-10 days, the patient being a remdesivir naive patient.

[0116] According to an embodiment, the pharmaceutical composition is for administration to a patient for a period of 1-90 days before administration of remdesivir.

[0117] According to an embodiment, the pharmaceutical composition can comprise or be used in association with at least one further active ingredient as disclosed herein.

[0118] According to an embodiment, the pharmaceutical composition does not comprise at least one of the ingredients chosen amongst betaine, sodium chloride, zinc sulfate, and their combination preferably the pharmaceutical composition does not comprise betaine, sodium chloride and zinc sulfate.

[0119] Another aspect of the invention is a kit of parts for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications and/or infections of viral origin comprising, for administration sequentially, simultaneously and/or separately, at least one other active ingredient and a compound of Formula (I) comprising:

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R₁ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHRAANH2 ; wherein RAA is a side chain selected from a proteinogenic amino acid; R6 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R9R10, P(S)R9R10 and

; wherein: R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂- C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C₁-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R12; wherein: - R11 is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)_nC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)_nSC(O)(C₁- C15)alkyl, -(CH₂)nC(O)O(C₁-C₁₅)alkyl and -(CH₂)nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; - R₁₂ is selected from hydrogen, C_1-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_1-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C1-C4 alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; - R₁₃ and R14 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; - R_α and R_α’ are independently selected from an hydrogen, C_1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C_3-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C_1-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅-C₁₂ aryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H- imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non- proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano;; or R9 and R10 together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R₉−R₁₀− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C₅-C₆ aryl and C₅-C₆ heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R8 is selected from H, OR, NHR₁₅, NR₁₅R16, NH-NHR₁₃, SH, CN, N3 and halogen; wherein R₁₅ and R16 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃;

represents a single or double bond according to Y; and

represents the alpha or beta anomer depending on the position of R₁, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: - X’1 and X’2 are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; - R’₁ and R’₁₃ are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio- alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1- C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1- C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; - R’₆ and R’₈ are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’7 and R’14 are independently selected from H, OR, NHR, NRR^’, NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; - Y’₁ and Y’₂ are independently selected from CH, CH₂, C(CH₃)₂ or CCH₃; - M’ is selected from H or a suitable counterion; - represents a single or a double bound depending on Y’₁ and Y’₂; and - represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃. [0120] According to this aspect, said at least one other active ingredient is as defined above. [0121] According to this aspect, said infection of viral origin is as defined above. [0122] According to this aspect, compound I is as defined above. [0123] According to this aspect, compound Ia is as defined above. [0124] The invention also relates to a kit of parts for use in the treatment of a Coronavirus infection and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection comprising, for administration sequentially, simultaneously and/or separately, at least remdesivir and at least one of compound of Formula (I) selected from:

or one compound of formula (la) selected from:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof.

[0125] Preferably, the compound is compound I-A or compound I-B or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof.

[0126] According to an embodiment, the Coronavirus infection is caused by a coronavirus selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0127] According to an embodiment, the respiratory and/or extra-respiratory complications are selected amongst pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure, pneumonia and/or acute respiratory syndromes associated with COVID-19. [0128] According to one embodiment, the Coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2.

[0129] According to one preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0130] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated pneumonia.

[0131] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing COVID-19 associated acute respiratory distress syndrome (ARDS).

[0132] According to an embodiment, the kit of parts is for use in the treatment and/or prevention of pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure.

[0133] According to an embodiment, the kit of parts is for use in the treatment and/or prevention of pneumonia and/or acute respiratory syndromes associated with CO VID-19.

[0134] According to an embodiment, the compounds of formula I and/or formula la is administered to a patient who has already been administered remdesivir for a period of at least 1-10 days before being administered with compound of formula (I) or of formula (la).

[0135] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 5-10 days, the patient being a remdesivir naive patient.

[0136] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1-90 days before administration of remdesivir.

[0137] According to an embodiment, the kit of parts comprises at least one further active ingredient as disclosed herein.

[0138] According to an embodiment, the kit of parts does not comprise at least one of the ingredients chosen amongst betaine, sodium chloride, zinc sulfate, and their combination preferably the kit of parts does not comprise betaine, sodium chloride and zinc sulfate. [0139] The present invention further relates to a method for preparing compounds of formula Ia, comprising the following steps: mono-phosphorylation of a compound of formula Xa,

wherein: X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and are as defined herein, to give compound of formula XIa,

wherein: X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and are as defined herein ; hydrolysis of compound of formula XIa obtained in step 1), to give compound of formula XIIa

wherein: X’₁, R’₁, R’₂, R’₃, R’₄, R’₅, R’₆, R’₇, Y’₁, and are as defined herein ; 38 reacting compound of formula XIIa obtained in step 2) with compound of formula XIIIa,

( ), obtained as described in step 1) and wherein: X’₂, R’₈, R’₉, R’₁₀, R’₁₁, R’₁₂, R’₁₃, R’₁₄, Y’₂, and are as defined herein , to give compound of formula Ia. [0140] According to one embodiment, the method further comprises a step of reducing the compound of formula Ia obtained in step 3), to give the compound of formula Ia, wherein Y’1 and Y’2 each independently represents a CH₂. DEFINITIONS [0141] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims. [0142] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise. [0143] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the adjacent functionality toward the point of attachment followed by the terminal portion of the functionality. For example, the substituent "arylalkyl" refers to the group -(aryl)-(alkyl). [0144] In the present invention, the following terms have the following meanings: [0145] The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C_nH_2n+1 wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably 1 to 2 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Saturated branched alkyls include, without being limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2- methylbutyl, 3 -methylbutyl, 2-methylpentyl,

3 -methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl, 4-methylhexyl,

5-methylhexyl, 2,3 -dimethylbutyl, 2,3-dimethylpentyl, 2.4-dimethylpentyl.

2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylpentyl.

2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3 ,3 -dimethylhexyl, 4.4-dimethylhexyl.

2-ethylpentyl, 3 -ethylpentyl, 2-ethylhexyl, 3 -ethylhexyl, 4-ethylhexyl,

2-methyl-2-ethylpentyl, 2-methyl-3 -ethylpentyl, 2-methyl-4-ethylpentyl,

2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3- diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl.

[0146] Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), hexyl and its isomers (e.g. n-hexyl, isohexyl), heptyl and its isomers (e.g. heptyl-heptyl, iso-heptyl), octyl and its isomers (e.g. n- octyl, iso-octyl), nonyl and its isomers (e.g. n-nonyl, iso-nonyl), decyl and its isomers (e.g. n- decyl, iso-decyl), undecyl and its isomers, dodecyl and its isomers. Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Cx-Cy-alkyl refers to alkyl groups which comprise x to y carbon atoms.

[0147] When the suffix "ene" ("alkylene") is used in conjunction with an alkyl group, this is intended to mean the alkyl group as defined herein having two single bonds as points of attachment to other groups. The term "alkylene" includes methylene, ethylene, methylmethylene, propylene, ethylethylene, and 1 ,2- dimethylethylene.

[0148] The term "alkenyl" as used herein refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 12 carbon atoms, preferably between 2 and 8 carbon atoms, still more preferably between 2 and 6 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4- pentadienyl and the like.

[0149] The term "alkynyl" as used herein refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkenyl groups. Non limiting examples of alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like.

[0150]The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Nonlimiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6- tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5- acenaphtylenyl, 3-, 4- or 5- acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6- , 7- or 8-tetrahydronaphthyl, 1, 2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

[0151] The term "cycloalkyl" as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.

[0152] The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro.

[0153] The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoro methyl, 1 , 1 , 1 -trifluoroethyl and the like. C_x-C_y- haloalkyl and C_x-C_y-alkyl are alkyl groups which comprise x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl and trifluoromethyl.

[0154] Where at least one carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

[0155] The term "heteroalkyl" means an alkyl group as defined above in which one or more carbon atoms are replaced by a heteroatom selected from oxygen, nitrogen and sulfur atoms. In heteroalkyl groups, the heteroatoms are linked along the alkyl chain only to carbon atoms, i.e. each heteroatom is separated from any other heteroatom by at least one carbon atom. However, the nitrogen and sulphur heteroatoms may optionally be oxidised and the nitrogen heteroatoms may optionally be quaternised. A heteroalkyl is bonded to another group or molecule only through a carbon atom, i.e. the bonding atom is not selected from the heteroatoms included in the heteroalkyl group.

[0156] The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2, 1 -b] [ 1 ,3] thiazolyl, thieno [3 ,2-b] furanyl, thieno [3 ,2-b] thiophenyl, thieno[2,3- d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2, 1 -benzisoxazolyl, 1,3- benzothiazolyl, 1,2-benzoisothiazolyl, 2, 1 -benzoisothiazolyl, benzotriazolyl, 1,2,3- benzoxadiazolyl, 2,1,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2, 1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2- oxopyridin- l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3- benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0157] Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocycloalkyl" or "heterocyclyl".

[0158] The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atomcontaining ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multiring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2- imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H- indolyl, indolinyl, isoindolinyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5- dioximidazolidinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1-yl, tetrahydroisoquinolin-2- yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin- 4-ylsulf oxide, thiomorpholin-4-ylsulfone, 1,3- dioxolanyl, 1,4-oxathianyl, IH-pyrrolizinyl, tetrahydro-1, 1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

[0159] The term “non-proteinogenic amino acid” as used herein refers to an amino acid not naturally encoded or found in the genetic code of living organism. Non limiting examples of Non-proteinogenic amino acid are ornithine, citrulline, argininosuccinate, homoserine, homocysteine, cysteine-sulfinic acid, 2-aminomuconic acid, 5-aminolevulinic acid, 0-alanine, cystathionine, y-aminobutyrate, DOPA, 5-hydroxytryptophan, D-serine, ibotenic acid, a- aminobutyrate, 2-aminoisobutyrate, D-leucine, D-valine, D-alanine or D-glutamate .

[0160] The term "proteinogenic amino acid" as used herein refers to an amino acid that is incorporated into proteins during translation of messenger RNA by ribosomes in living organisms, i.e. Alanine (ALA), Arginine (ARG), Asparagine (ASN), Aspartate (ASP), Cysteine (CYS), Glutamate (glutamic acid) (GLU), Glutamine (GLN), Glycine (GLY), Histidine (HIS), Isoleucine (ILE), Leucine (LEU), Lysine (LYS), Methionine (MET), Phenylalanine (PHE), Proline (PRO), Pyrrolysine (PYL), Selenocysteine (SEL), Serine (SER), Threonine (THR), Tryptophan (TRP), Tyrosine (TYR) or Valine (VAL).

[0161] The term "prodrug" as used herein means the pharmacologically acceptable derivatives of compounds of formula (I) such as esters whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

[0162] The term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced by any desired group which is substantially stable under the reaction conditions in an unprotected form or when protected by a protecting group. Examples of preferred substituents include, without being limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl, as described above; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO2CH₃; CONH2; OCH₂CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and such moieties may also be optionally substituted by a fused-ring structure or bridge, for example -OCH₂O-. These substituents may optionally be further substituted with a substituent selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a substituent selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an cycloalkyl, an cycloalkenyl, a heterocycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroarylalkyl, a haloalkyl, -C(O)NR11R12, -NR₁₃C(O)R14, a halo, -OR₁₃, cyano, nitro, a haloalkoxy, -C(O)R₁₃, -NR₁₁R₁₂, -SR₁₃, -C(O)OR₁₃, -OC(O)R₁₃, -NR₁₃C(O)NR₁₁R₁₂, -OC(O)NR₁₁R₁₂, -NR₁₃C(O)OR₁₄, -S(O)rR₁₃, -NR₁₃S(O)rR₁₄, -OS(O)rR₁₄, S(O)rNR₁₁R₁₂, -O, -S, and -N-R₁₃, wherein r is 1 or 2; R₁₁ and R₁₂, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl; or R11 and R12 taken together with the nitrogen to which they are attached is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R₁₃ and R₁₄ for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group. [0163] The term “active ingredient” refers to a molecule or a substance whose administration to a subject slows down or stops the progression, aggravation, or deterioration of one or more symptoms of a disease, or condition; alleviates the symptoms of a disease or condition; cures a disease or condition. According to one embodiment, the therapeutic ingredient is a small molecule, either natural or synthetic. According to another the therapeutic ingredient is a biological molecule such as for example an oligonucleotide, a siRNA, a miRNA, a DNA fragment, an aptamer, an antibody and the like. [0164] By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.

[0165] The term “pharmaceutically acceptable excipient” or “pharmaceutical vehicle” refers to an inert medium or carrier used as a solvent or diluent in which the pharmaceutically active agent is formulated and/or administered, and which does not produce an adverse, allergic or other reaction when administered to an animal, preferably a human being. This includes all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption retardants and other similar ingredients. For human administration, preparations must meet standards of sterility, general safety and purity as required by regulatory agencies such as the FDA or EMA. For the purposes of the invention, "pharmaceutically acceptable excipient" includes all pharmaceutically acceptable excipients as well as all pharmaceutically acceptable carriers, diluents, and/or adjuvants.

[0166] The term “pharmaceutically acceptable salts” include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0167] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts.

[0168] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. [0169] Pharmaceutically acceptable salts of compounds of Formula (I) may be prepared by one or more of these methods:

(i) by reacting the compound of Formula (I) with the desired acid;

(ii) by reacting the compound of Formula (I) with the desired base;

(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or

(iv) by converting one salt of the compound of Formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0170] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0171] Although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.

[0172] The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, such as ethanol. The term 'hydrate' refers to when said solvent is water.

[0173] The term "administration", or a variant thereof (e.g., “administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented. [0174] The term "human" refers to a subject of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult). [0175] The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure. [0176] The terms “treat”, “treating” and “treatment”, as used herein, are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms. [0177] The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease. [0178] The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered. [0179] The bonds of an asymmetric carbon can be represented here using a solid triangle ( ), a dashed triangle ( ) or a zigzag line ( ). DETAILED DESCRIPTION The invention relates to a combination of a compound of formula I or Ia with at least one other active ingredient for the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, pharmaceutical compositions and kit of parts comprising the same as well as a method of treatment comprising the administration of a combination of a compound of formula I or Ia with at least one other active ingredient for the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. In a particular aspect of the invention, the invention relates to a combination of a compound of formula I or Ia, preferably compounds of formula I-A and I-B, with at least remdesivir for the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, pharmaceutical compositions and kit of parts comprising the same as well as a method of treatment comprising the administration of a combination of a compound of formula I or Ia, preferably compounds of formula I-A and I-B, with at least remdesivir for the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. Indeed, the inventors have demonstrated that the use of the invention reduces the inflammation, cytokine storms and cell death caused by a Coronavirus infection as well as the proliferation of the virus. Compounds of formula I or Ia [0180] This invention relates to a combination of at least one active ingredient and a compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R₁ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHR_AANH₂ ; wherein R_AA is a side chain selected from a proteinogenic amino acid; R₆ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R9R10, P(S)R9R10 and ; wherein:

R9 and R10 are independently selected from OH, OR11, NHR₁₃, NR₁₃R14, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C_1-C₈ heterocycloalkyl, heteroaryl and NHCR_αR_α’C(O)R₁₂; wherein: R₁₁ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)nC(O)(C₁-C₁₅)alkyl, - (CH₂)nOC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)nSC(O)(C₁-C₁₅)alkyl, - (CH₂)nC(O)O(C₁-C₁₅)alkyl and -(CH₂)nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; R12 is selected from hydrogen, C₁-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₁₀ haloalkyl, C3- C₁₀ cycloalkyl, C_3-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C₁-C₄ alkylaryl and C₅-C₁₂ heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₁₃ and R14 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Rα and Rα’ are independently selected from an hydrogen, C₁-C₁₀ alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C_3-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C_1-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅- C12 aryl, -(CH₂)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6-membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C₅-C₆ aryl and C₅-C₆ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; or R9 and R10 together with the phosphorus atoms to which they are attached form a 6-membered ring wherein –R9−R10− represents –O-CH₂-CH₂-CHR-O−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano; R8 is selected from H, OR, NHR₁₅, NR₁₅R16, NH-NHR₁₃, SH, CN, N3 and halogen; wherein R₁₅ and R₁₆ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R₁, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: X’1 and X’2 are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; R’1 and R’13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio-alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1-C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1-C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; R’6 and R’8 are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; R’7 and R’14 are independently selected from H, OR, NHR, NRR^’, NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; Y’₁ and Y’₂ are independently selected from CH, CH₂, C(CH₃)₂ or CCH₃; M’ is selected from H or a suitable counterion; represents a single or a double bound depending on Y’1 and Y’2; and represents the alpha or beta anomer depending on the position of R’1 and R’13, for use in the treatment and/or prevention of a Coronavirus infection. [0181] According to an embodiment, the combination of the invention is for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. [0182] According to one embodiment, X is selected from O, CH₂ and S. [0183] According to one embodiment, R₁ is selected from hydrogen or OH. In one embodiment, R₁ is hydrogen. In one embodiment, R₁ is OH. [0184] According to one embodiment, R₂, R₃, R₄ and R₅ are independently selected from hydrogen, halogen, hydroxyl, C₁-C₁₂ alkyl and OR; wherein R is as described herein above. In a preferred embodiment, R₂, R₃, R₄ and R₅ are independently selected from hydrogen, hydroxyl and OR; wherein R is as described herein above. In a more preferred embodiment R₂, R₃, R₄ and R₅ are independently selected from hydrogen or OH. [0185] According to one embodiment, R₂ and R₃ are identical. In one embodiment, R₂ and R₃ are identical and represent OH. In one embodiment, R₂ and R₃ are identical and represent hydrogen.

[0186] 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.

[0187] According to one embodiment, R4 and R₅ are identical. In one embodiment, R4 and R₅ are identical and represent OH. In one embodiment, R4 and R₅ are identical and represent hydrogen.

[0188] 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.

[0189] 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.

[0190] According to one embodiment, R₃ and R4 are identical. In a preferred embodiment, R₃ and R4 are identical and represent OH. In a more preferred embodiment, R₃ and R4 are identical and represent hydrogen.

[0191] 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.

[0192] According to one embodiment, R₂ and R₅ are identical. In a preferred embodiment, R₂ and R₅ are identical and represent hydrogen. In a more preferred embodiment, R₂ and R₅ are identical and represent OH.

[0193] According to one embodiment, R6 is selected from hydrogen or OH. In one embodiment, R6 is OH. In a preferred embodiment, R6 is hydrogen.

[0194] According to one embodiment, R₇ is selected from P(O)R9R10 or P(S)R9R10; wherein R9 and R10 are as described herein above. In a preferred embodiment, R₇ is P(O)R9R10; wherein R9 and R10 are as described herein above. In a preferred embodiment, R₇ is P(O)(OH)₂. [0195] According to one embodiment, R₇ is

[0196] According to one embodument, R₇ is not H. [0197] According to one embodiment, R8 is selected from H, OR, NHR13 or NR13R14; wherein R13 and R14 are as described herein above. In a preferred embodiment, R8 is NHR13; wherein R13 and R14 are as described herein above. [0198] According to one embodiment, Y is a CH or CH₂. In one embodiment, Y is a CH. In one embodiment, Y is a CH₂. [0199] According to one preferred embodiment, compounds of formula (I) are those wherein X is an oxygen. [0200] According to a preferred embodiment, the invention relates to compounds of general Formula (II):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R1, R₂, R3, R4, R5, R6, R7, R8, Y, and are as described herein above for compounds of formula (I). [0201] According to one embodiment, preferred compounds of formula (I) are those wherein R1 is hydrogen. [0202] According to a preferred embodiment, the invention relates to compounds of general Formula (III):

( ) or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₂, R₃, R4, R₅, R6, R₇, R8, Y, and are as described herein above for compounds of formula (I). [0203] According to one embodiment, preferred compounds of formula (I) are those wherein R₂ is OH and R₃ is hydrogen. [0204] According to one embodiment, preferred compounds of formula (I) are those wherein R4 is hydrogen and R₅ is OH. [0205] According to one embodiment, preferred compounds of formula (I) are those wherein R₃ and R4 are identical and represent hydrogen. [0206] According to a preferred embodiment, the invention relates to compounds of general Formula (IV):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₂, R₅, R6, R₇, R8, Y, and are as described herein above for compounds of formula (I). [0207] According to one embodiment, preferred compounds of formula (I) are those wherein R₂ and R₅ are identical and represent OH. [0208] According to a preferred embodiment, the invention relates to compounds of general Formula (V):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R6, R₇, R8, Y, and are as described herein above for compounds of formula (I). [0209] According to one embodiment, preferred compounds of formula (I) are those wherein R6 is hydrogen. [0210] According to a preferred embodiment, the invention relates to compounds of general Formula (VI):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₇, R8, Y, and are as described herein above for compounds of formula (I). [0211] According to one embodiment, preferred compounds of formula (I) are those wherein R8 is NH2. [0212] According to a preferred embodiment, the invention relates to compounds of general Formula (VII):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₇, Y, and are as described herein above for compounds of formula (I). [0213] According to one embodiment, preferred compounds of formula (I) are those wherein Y is CH. [0214] According to a preferred embodiment, the invention relates to compounds of general Formula (VIII):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₇, and are as described herein above for compounds of formula (I). [0215] According to one embodiment, preferred compounds of formula (I) are those wherein Y is CH₂. [0216] According to a preferred embodiment, the invention relates to compounds of general Formula (IX):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein R₇, and are as described herein above for compounds of formula (I). [0217] According to one embodiment, preferred compounds of formula (I) are those wherein R₇ is P(O)(OH)2. [0218] According to a preferred embodiment, the invention relates to compounds of general Formula (X):

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein Y, and are as described herein above for compounds of formula (I). [0219] According to one embodiment, the compound according to the invention is selected from compounds I-A to I-J from Table 2 below or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof: [0220] [Table 2]

[0

221] According to one embodiment, preferred compound of the invention are compounds I-A to I-J or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof, more preferably I-A to I-F and even more preferred compounds of the invention are compounds I-A or I-B, or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof. [0222] In a preferred embodiment, the invention relates to a combination of at least one of compound of Formula (I) selected from:

and/or one compound of formula (la) selected from:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof with remdesivir for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection. [0223] Preferably, the compound of Formula (I) is compound of formula I-A and/or the compound of formula (I-B) or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof. [0224] According to an embodiment, preferred compounds of general Formula Ia are those wherein X’1 and X’2 are independently selected from O, CH₂, S. [0225] According to one embodiment, R’7 and R’14 are independently selected from H, OR, NHR and NRR’ wherein R and R' are independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl. According to one embodiment, R’7 and R’14 are NHR wherein R is selected from H, C1-C8 alkyl, C1-C8 alkyl aryl. [0226] According to one embodiment, R’2, R’3, R’4, R’5, R’9, R’10, R’11, R’12 are independently selected from H, halogen, hydroxyl, C1-C12 alkyl and OR. According to a preferred embodiment, R’2, R’3, R’4, R’5, R’9, R’10, R’11, R’12 are independently selected from H, hydroxyl and OR, wherein R is as described herein above. [0227] According to an embodiment, preferred compounds of general Formula Ia are those wherein, R’2, R’3, R’4, R’5, R’9, R’10, R’11, R’12 are independently selected from H and OH. [0228] According to one embodiment, R’2 and R’3 are identical. According to one embodiment, R’2 and R’3 are identical and represent each a OH. According to one embodiment, R’2 and R’3 are identical and represent each hydrogen. [0229] According to a preferred embodiment, R’2 and R’3 are different. According to a preferred embodiment, R’2 is hydrogen and R’3 is a OH. According to a more preferred embodiment, R’2 is a OH and R’3 is hydrogen. [0230] According to one embodiment, R’4 and R’5 are identical. According to one embodiment, R’4 and R’5 are identical and represent each a OH. According to one embodiment, R’4 and R’5 are identical and represent each hydrogen. [0231] According to a preferred embodiment, R’4 and R’5 are different. According to a preferred embodiment, R’4 is a OH and R’5 is hydrogen. According to a more preferred embodiment, R’4 is hydrogen and R’5 is a OH. [0232] According to one embodiment, R’3 and R’4 are identical. According to one embodiment, R’3 and R’4 are identical and represent each a OH. According to one embodiment, R’3 and R’4 are identical and represent each hydrogen.

[0233] According to a preferred embodiment, R’3 and R’4 are different. According to a preferred embodiment, R’3 is a OH and R’4 is hydrogen. According to a more preferred embodiment, R’3 is hydrogen and R’4 is a OH

[0234] According to one embodiment, R’2 and R’5 are different. According to one embodiment, R’2 is hydrogen and R’5 is a OH. According to one embodiment, R’2 is a OH and R’5 is hydrogen.

[0235] According to a preferred embodiment, R’2 and R’5 are identical. According to a preferred embodiment, R’2 and R’5 are identical and represent each hydrogen. According to a more preferred embodiment, R’2 and R’5 are identical and represent each a OH.

[0236] According to one embodiment, R’9 and R’ 10 are identical. According to one embodiment, R’9 and R’ 10 are identical and represent each a OH. According to one embodiment, R’9 and R’ 10 are identical and represent each hydrogen.

[0237] According to a preferred embodiment, R’9 and R’10 are different. According to a preferred embodiment, R’9 is hydrogen and R’ 10 is a OH. According to a more preferred embodiment, R’9 is a OH and R’10 is hydrogen.

[0238] According to one embodiment, R’ 11 and R’ 12 are identical. According to one embodiment, R’ 11 and R’ 12 are identical and represent each a OH. According to one embodiment, R’ 11 and R’ 12 are identical and represent each hydrogen.

[0239] According to a preferred embodiment, R’ l l and R’ 12 are different. According to a preferred embodiment, R’l l is a OH and R’ 12 is hydrogen. According to a more preferred embodiment, R’l l is hydrogen and R’ 12 is a OH.

[0240] According to one embodiment, R’ 10 and R’l l are different. According to one embodiment, R’ 10 is hydrogen and R’l l is a OH. According to one embodiment, R’ 10 is a OH and R’l l is hydrogen. [0241] According to a preferred embodiment, R’ 10 and R’ l l are identical. According to a preferred embodiment, R’ 10 and R’l l are identical and represent each a OH. According to a more preferred embodiment, R’ 10 and R’ l l are identical and represent each hydrogen.

[0242] According to one embodiment, R’9 and R’12 are different. According to one embodiment, R’9 is hydrogen and R’12 is a OH. According to one embodiment, R’9 is a OH and R’ 12 is hydrogen.

[0243] According to a preferred embodiment, R’9 and R’12 are identical. According to a preferred embodiment, R’9 and R’12 are identical and represent each hydrogen. According to a more preferred embodiment, R’9 and R’ 12 are identical and represent each a OH.

[0244] According to one embodiment, Y’ 1 is CH. According to one embodiment, Y’ 1 is CH₂.

[0245] According to one embodiment, Y’2 is CH. According to one embodiment, Y’2 is CH₂.

[0246] According to one embodiment, X’l and X’2 are different and are selected from the group as described above. According to one embodiment, X’l and X’2 are identical and are selected from the group as described above.

[0247] According to an embodiment, preferred compounds of general Formula la are those wherein X’ 1 and X’2 each independently represents an Oxygen.

[0248] According to an embodiment, preferred compounds of general Formula la are those wherein X’ 1 and X’2 are identical and represent each an Oxygen.

[0249] According to a preferred embodiment, among the compounds of formula la, the present invention is directed to compounds having the following formula Ila:

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein R’ 1, R’2, R’3, R’4, R’5, R’6, R’7, R’9, R’8, R’9, R’10, R’l l, R’12, R’13, R’14, Y’l, Y’2, M’, — and - are as described above.

[0250] According to one embodiment, R’7 and R’ 14 are different and are selected from the group as described above. According to one embodiment, R’7 and R’14 are identical and are selected from the group as described above.

[0251] According to an embodiment, preferred compounds of general Formula la are those wherein R’7 and R’14 each independently represents a NH2.

[0252] According to an embodiment, preferred compounds of general Formula la are those wherein R’7 and R’ 14 are identical and represent each a NH2.

[0253] According to a preferred embodiment, among the compounds of formula la, the present invention is directed to compounds having the following formula Illa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R’l, R’2, R’3, R’4, R’5, R’6, R’8, R’9, R’10, R’l l, R’ 12, R’13, Y’l, Y’2, M’, —and - are as described above.

[0254] According to one embodiment, R’ 1 and R’ 13 are different and are selected from the group as described above. According to one embodiment, R’ 1 and R’ 13 are identical and are selected from the group as described above.

[0255] According to an embodiment, preferred compounds of general Formula la are those wherein R’ 1 and R’ 13 each independently represents a hydrogen. [0256] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’1 and R’13 are identical and represent each a hydrogen. [0257] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IVa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R’2, R’3, R’4, R’5, R’6, R’7, R’8, R’9, R’10, R’11, R’12, Y’1, Y’2, M’, and are as described above. [0258] According to one embodiment, R’6 and R’8 are different and are selected from the group as described above. According to one embodiment, R’6 and R’8 are identical and are selected from the group as described above. [0259] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’6 and R’8 each independently represents a hydrogen. [0260] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’6 and R’8 are identical and represent each a hydrogen. [0261] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula Va:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R’2, R’3, R’4, R’5, R’7, R’9, R’10, R’11, R’12, Y’1, Y’2, M’, and are as described above. [0262] According to one embodiment, R’3, R’4, R’10 and R’11 are different and are selected from the group as described above. According one embodiment, R’3, R’4, R’10 and R’11 are identical and are selected from the group as described above. [0263] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’3, R’4, R’10 and R’11 each independently represents a hydrogen. [0264] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’3, R’4, R’10, R’11 are identical and represent each a H. [0265] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein R’2, R’5, R’7, R’9, R’12, Y’1, Y’2, M’, and are as described above. [0266] According to one embodiment, R’2, R’5, R’9 and R’12 are different and are selected from the group as described above. According one embodiment, R’2, R’5, R’9 and R’12 are identical and are selected from the group as described above. [0267] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’2, R’5, R’9 and R’12 each independently represents a OH. [0268] According to an embodiment, preferred compounds of general Formula Ia are those wherein R’2, R’5, R’9, R’12 are identical and represent each a OH. [0269] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIIa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein Y’1, Y’2, M’, and are as described above. [0270] According to one embodiment, Y’1 and Y’2 are different. According to a preferred embodiment, Y’1 and Y’2 are identical. [0271] According to an embodiment, preferred compounds of general Formula Ia are those wherein Y’1 and Y’2 each independently represents a CH. [0272] According to an embodiment, preferred compounds of general Formula Ia are those wherein Y’1 and Y’2 are identical and represent each a CH. [0273] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula VIIIa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein M’ and are as described above. [0274] According to an embodiment, preferred compounds of general Formula Ia are those wherein Y’1 and Y’2 each independently represents a CH₂. [0275] According to an embodiment, preferred compounds of general Formula Ia are those wherein Y’1 and Y’2 are identical and represent each a CH₂. [0276] According to a preferred embodiment, among the compounds of formula Ia, the present invention is directed to compounds having the following formula IXa:

or pharmaceutically acceptable salt and/or solvates thereof or prodrugs thereof, wherein M’ and are as described above. [0277] According to one embodiment, preferred compounds of the invention are compounds Ia-A to Ia-F, listed in table 1: Table 1

[0278] According to one embodiment, preferred compound of the invention is compound of formula Ia-A. [0279] According to another embodiment, preferred compound of the invention is compound of formula Ia-D. [0280] All references to compounds of Formula (I) or (Ia) include references to salts, solvates, multi-component complexes and liquid crystals thereof. All references to compounds of Formula (I) or (Ia) include references to polymorphs and crystal habits thereof. [0281] All references to compounds of Formula (I) or (Ia) include references to pharmaceutically acceptable prodrugs and prodrugs thereof. [0282] All references to compounds of Formula (I) or (Ia) and subformulas thereof include references to salts, solvates, multi-component complexes, liquid crystals thereof. All references to compounds of Formula (I) or (Ia) and subformulas thereof include references to polymorphs and crystal habits thereof. All references to compounds of Formula (I) or (Ia) and subformulas thereof include references to pharmaceutically acceptable prodrugs and prodrugs thereof. The nicotinamide mononucleotide derivatives of Formula (I) or (Ia) used in the present invention can be under the form of a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a nicotinamide mononucleotide derivative as defined hereinabove, and at least one pharmaceutically acceptable carrier. Therapeutic active ingredient

[0283] According to one embodiment, the combination for use of the invention, the kit of part of the invention for use of the invention and the pharmaceutical composition for use of the invention comprises, in addition to the at least one compound for use of the invention, at least one additional active ingredient.

[0284] According to one embodiment, the at least one other active ingredient is chosen amongst a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose-derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti-inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

[0285] According to one embodiment, the SARS-CoV-2 vaccine can be a DNA-, RNA or mRNA- based vaccine coding for SARS-CoV-2 antigens chosen amongst PrEP-001 , mRNA 1273, GX- 19, BNT-162, ZyCoV-D, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA, CvnCoV that can be formulated in lipid nanoparticles (CvnCoV vaccine), in plasmids (INO-4800 DNA vaccine) or in lentiviral vector systems (aAPC vaccine) or in dendritic cells (AV-COVID-19 vaccine).

[0286] Non-limiting examples of further antiviral agents include:

Nucleoside analogues, preferably remdesivir, polymerase inhibitors, such as favipiravir, pimodivir, baloxavir, marboxil and sofosbuvir; protease inhibitors, such as boceprevir, simeprevir, fosamprenavir, lopinavir, ritonavir, telaprevir, tipranavir, azatanavir, nelfinavir, indinavir, darunavir, fosamprenavir, amprenavir, asunaprevir, TMC-310911, JE-2147, L-756423 and saquinavir and their combinations; integrase strand transfer inhibitors, such as raltegravir, dolutegravir and elvitegravir;

NS5A inhibitors, such as daclatasvir; nucleoside reverse transcriptase inhibitors (NRTIs), such as lamivudine, adefovir, tenofovir, entecavir and emtricitabine; nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, nevirapine and etravirine; purine nucleosides, such as ribavirin, valacyclovir, acyclovir and famciclovir;

EIDD 2801 (MK4482, molnupiravir), a dihydroorotate dehydrogenase inhibitor such as PTC299, brequinar, teriflunomide, leflunomide and their combinations and mixtures thereof.

[0287] According to one embodiment, said antiviral agent is a nucleoside or nucleotide analog, preferably a nucleoside analog.

[0288] According to a preferred embodiment, said nucleoside analog can be selected amongst: deoxyadenosine analogues such as didanosine and vidarabine; adenosine analogues such as galidesivir and remdesivir; deoxycytidine analogues such as cytarabine, gemcitabine, emtricitabine, lamivudine, zalcitabine ; guanosine and deoxyguanosine analogues such as abacavir, acyclovir and entecavir; thymidine and deoxythymidine analogues such as stavudine, telbivudine, zidovudine; and deoxyuridine analogues such as idoxuridine and trifluridine.

[0289] Preferably, when the combination, kits of parts or pharmaceutical composition of the invention does not already comprise remdesivir, said nucleoside analogue is remdesivir. [0290] According to one embodiment, the SARS-CoV-2 vaccine can be a DNA-, RNA or mRNA- based vaccine coding for SARS-CoV-2 antigens chosen amongst PrEP-001 , mRNA 1273, GX- 19, BNT-162, ZyCoV-D, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA, CvnCoV that can be formulated in lipid nanoparticles (CvnCoV vaccine), in plasmids (INO-4800 DNA vaccine) or in lentiviral vector systems (aAPC vaccine) or in dendritic cells (AV-COVID-19 vaccine).

[0291] According to one embodiment, the SARS-CoV-2 vaccine can be heat inactivated plasma from patients who had Covid-19 such as V-SARS.

[0292] According to one embodiment, the SARS-CoV-2 vaccine can be a stabilised and/or recombinant SARS-CoV-2 spike protein or protein receptor binding domain chosen amongst NVX-CoV237, Clover vaccine or a bacterium expressing the SARS-CoV-2 spike protein such as bacTRL-Spike.

[0293] The histamine H2 receptor antagonist can be chosen amongst famotidine, cimetidine, ranitidine, nizatidine, roxatidine, lafutidine, lavoltidine, niperotidine and their combinations.

[0294] The antibody can be chosen amongst an anti-VEGF, an anti- TNF, an anti-GM-CSF, GM- CSF antagonist, a CCR₅ antagonist, an anti-SARS-CoV-2 spike protein, an IL-6 receptor antagonist, an anti-ILlbeta, a C5 complement inhibitor and their combinations.

[0295] Preferably, said antibody can be chosen amongst bevacizumab, etesivimab, infliximab, mavrilimumab, lenzilumab, leronlimab, gimsilumab, otilimab, JS016, LY-CoV555, REGN10933, REGN10987, sarilumab, canakinumab, ravulizumab, mavrilimumab, tocilizumab, namilumab, adalimumab, MEDI3506, bamlanivimab, AZD7442, casirivimab, imdevimab, sotrovimab, risankizumab, and their combinations, preferably AZD7442, casirivimab, imdevimab, sarilumab, JS016, LY-CoV555, REGN10933 and REGN10987 and their combinations.

[0296] The recombinant fusion protein can be CD24Fc, recombinant gelsolin, and their combinations.

[0297] According to one embodiment, the MAP kinase inhibitor can be lospamimod. [0298] The anti-helminctic can be chosen amongst ivermectin, praziquantel, triclabendazole, albendazole, pyrantel, flubendazole, diethylcarbamazine, niclosamide, and their combinations.

[0299] The kinase inhibitor can be chosen amongst acalabrutinib, adavosertib, afatinib, axitinib, bosutinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, sunitinib, su6656, vandetanib, vemurafenib and their combinations.

[0300] The sodium-glucose transport protein 2 (SGLT2) inhibitor can be chosen amongst dapaglifozin, canaglifozin, empaglifozin, ertugliflozin and their combinations.

[0301] According to one embodiment, the corticosteroid (or corticoid) is chosen amongst hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate, tixocortol pivalate, preferably methylprednisone, hydrocortisone, and dexamethasone.

[0302] According to one embodiment, the non-steroidal anti-inflammatory is chosen amongst aviptadil, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, diclofenac, sulindac, etodolac, ketorolac, aceclofenac, bromfenac, nabumetone, celecoxib, mefenamic acid, etoricoxib, indomethacin, tolmetin, aspirin, salicylic acid, diflunisal, salsalate, piroxicam, rofecoxib, valdecoxib, lumiracoxib, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, parecoxib, etoricoxib, firocoxib, nimesulide, clonixin, licofelone, H-harpagide, and their combinations, preferably aviptadil.

[0303] According to one embodiment, the SARS-CoV-2 vaccine can be a DNA-, RNA or mRNA- based vaccine coding for SARS-CoV-2 antigens chosen amongst PrEP-001 , mRNA 1273, GX- 19, BNT-162, ZyCoV-D, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA, CvnCoV that can be formulated in lipid nanoparticles (CvnCoV vaccine), in plasmids (INO-4800 DNA vaccine) or in lentiviral vector systems (aAPC vaccine) or in dendritic cells (AV-COVID-19 vaccine).

[0304] According to one embodiment, the SARS-CoV-2 vaccine can be heat inactivated plasma from patients who had Covid-19 such as V-SARS.

[0305] According to one embodiment, the SARS-CoV-2 vaccine can be a stabilised and/or recombinant SARS-CoV-2 spike protein or protein receptor binding domain chosen amongst NVX-CoV237, Clover vaccine or a bacterium expressing the SARS-CoV-2 spike protein such as bacTRL-Spike.

[0306] According to one embodiment, the anti-interleukine 6 is chosen amongst tocilizumab, sarilumab, siltuximab, levilimab and their combination.

[0307] According to one embodiment, the JAK inhibitor is selected amongst ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, delgocitinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, abrocitinib, deucravacitinib, cucurbitacin I, CHZ868 and their combinations.

[0308] According to one embodiment, the neuraminidase inhibitor is selected amongst laninamivir, oseltamivir, peramivir, zanamivir, cyanidin-3-sambubioside, coptisine, berberine, and their combinations.

[0309] According to one embodiment, the M2 proton channel blocked is selected amongst amantadine, rimantadine and their combination.

[0310] According to one embodiment, the interferon is selected amongst PEGylated interferon alpha, PEGylated interferon alpha 2b, PEGylated interferon alpha 2a, tilorone and their combinations.

[0311 ] According to one embodiment, the angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers is selected amongst alacepril, captopril, zefnopril, enalapril, ramipril, quinapril, perindopril, lisinopril, bezanopril, imidapril, trandolapril, cilazapril, fosinopril and their combinations. [0312] According to one embodiment, the statin is chosen amongst atorvastatin, cerivastatin, Fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their combinations.

[0313] According to one embodiment, the other at least one active ingredient can be selected amongst dimethyl fumarate, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, and their combinations.

[0314] Preferably, the at least one active ingredient is a corticoid (or corticosteroid), a SARS-CoV- 2 vaccine, an antibody, an antiviral agent, and their combinations. More preferably, the at least one active ingredient is remdesivir.

[0315] According to an embodiment, the active ingredient is not at least one of the ingredients chosen amongst betaine, sodium chloride, zinc sulfate, and their combination preferably the active ingredient is not a combination of betaine, sodium chloride and zinc sulfate.

Medical use and methods of treatment

[0316] This invention thus relates to a combination, kit of parts and pharmaceutical composition according to the invention, as described hereinabove, for use in the treatment and/or prevention of a Coronavirus infection.

[0317] According to one embodiment, the combination, kit of parts and pharmaceutical composition is for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection.

[0318] 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.

[0319] According to one embodiment, the alpha coronavirus infection is selected from human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63) also sometimes known as HCoV-NH or New Haven human coronavirus. [0320] According to one embodiment, the beta coronavirus infection is selected from human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKUl), Middle East respiratory syndrome-related coronavirus (MERS-CoV) previously known as novel coronavirus 2012 or HCoV-EMC, severe acute respiratory syndrome coronavirus (SARS- CoV) also known as SARS-CoV-1 or SARS-classic, and severe acute respiratory syndrome coronavirus (SARS-CoV-2) also known as 2019-nCoV or novel coronavirus 2019.

[0321] According to one embodiment, the coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, 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.

[0322] According to a preferred embodiment, the coronavirus infection is a SARS-CoV-2 infection.

[0323] According to one embodiment, the coronavirus is a MERS-CoV infection causing Middle East respiratory syndrome (MERS). According to one embodiment, the coronavirus is a SARS- CoV-1 infection causing severe acute respiratory syndrome (SARS).

[0324] According to a preferred embodiment, the coronavirus is a SARS-CoV-2 infection causing coronavirus disease 2019 (CO VID-19).

[0325] Thus, according to one embodiment, the combination is for use in the treatment and/or prevention of a coronavirus infection selected from MERS-CoV, SARS-CoV-1 and SARS- CoV-2.

[0326] According to one embodiment, the combination is for use in the treatment and/or prevention of MERS, SARS and COVID- 19.

[0327] According to a preferred embodiment, the combination is for use in the treatment and/or prevention of COVID-19.

[0328] According to a preferred embodiment, the combination is for use in the preexposure prophylaxis to virus, including those cited above, and preferably SARS-CoV-2.

[0329] Thus, according to one embodiment, the combination is for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications. [0330] According to one embodiment, CO VID- 19 leads to respiratory complications such as CO VID-19 associated pneumonia or CO VID-19 associated acute respiratory distress syndrome (ARDS).

[0331] According to one embodiment, CO VID-19 leads to extra-respiratory complications such as sepsis, septic shock, altered consciousness, and/or multi-organ failure.

[0332] According to one embodiment, CO VID-19 associated pneumonia presents on a lung scan (such as computerized tomography (CT) scan) as hazy patches, in particular hazy patches clustering on the outer edges of the lungs. In one embodiment, COVID-19 associated pneumonia presents on a lung scan as radiological finding of ground-glass opacity abnormalities or radiological finding of a mixed pattern (combination of consolidation, ground glass opacity and reticular opacity in the presence of architectural distortion).

[0333] According to one embodiment, ARDS is a form of acute lung injury (ALI) and occurs as a result of a severe pulmonary injury that causes alveolar damage heterogeneously throughout the lung.

[0334] According to one embodiment, the coronavirus infection is a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

[0335] Thus, according to one embodiment, the compound is for use in the treatment and/or prevention of COVID-19 associated pneumonia or COVID-19 associated ARDS.

[0336] According to one embodiment, the coronavirus infection is selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKUl, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV-1 and SARS-CoV-2.

[0337] According to one embodiment, the subject in need of therapeutic and/or preventive treatment is diagnosed by a health professional. In practice, Coronavirus infections are diagnosed by any examination routinely carried out in the medical setting, including direct diagnosis, i.e. identification of the virus or its constituents, for example from a respiratory specimen, or indirect diagnosis, i.e. the detection of antibodies specific to the infection, a PCR test, an antigen test or any conventional method for the detection of the Coronavirus infection. [0338] CO VID-19 severity may be assessed according to the World Health Organization (WHO) criteria of severity as follows: mild: cases showing mild clinical symptoms with no sign of pneumonia on imaging. moderate: cases showing fever and respiratory symptoms (such as a cough, shortness of breath, and/or chest tightness) with radiological findings of pneumonia and requiring (02): 3L/min < oxygen < 5L/min severe: cases meeting any of the following criteria: respiratory distress (respiratory rate (RR) = 30 breaths/ min); oxygen saturation (SpO2) < 93% at rest in ambient air; or SpO2 < 97% with 02 > 5L/min; ratio of artery partial pressure of oxygen/inspired oxygen fraction (PaO2/FiO2) ^ 300 mmHg (1 mmHg = 0.133 kPa), PaO2/FiO2 in high-altitude areas (at an altitude of over 1,000 meters above the sea level) shall be corrected by the following formula: PaO2/FiO2 [multiplied by] [Atmospheric pressure (mmHg)/760]; and/or chest imaging that showed obvious lesion progression within 24-48 hours > 50%. critical: cases meeting any of the following criteria: respiratory failure and requiring mechanical ventilation; shock; and/or multiple organ failure (extra pulmonary organ failure) requiring admission to intensive care unit (ICU).

[0339] According to one embodiment, the subject suffers from mild CO VID-19, moderate COVID-19, severe COVID-19 or critical COVID-19. According to one embodiment, the subject suffers from mild-to-moderate COVID-19. According to one embodiment, the subject suffers from severe-to-critical CO VID-19.

[0340] According to one embodiment, the subject, especially the subject suffering from mild-to- moderate COVID-19 or from severe-to-critical COVID-19, is not hospitalized. [0341] According to one embodiment, the subject, especially the subject suffering from mild-to- moderate CO VID- 19 or from severe-to-critical COVID-19, is hospitalized. In one embodiment, the subject is hospitalized but does not require admission to intensive care unit (ICU). In one embodiment, the subject is hospitalized and requires admission to ICU.

[0342] According to one embodiment, the subject, especially the subject suffering from mild-to- moderate COVID-19 or from severe-to-critical CO VID-19, requires oxygen therapy. In one embodiment, the subject requires non-invasive ventilation (NIV).

[0343] Severe-to-critical CO VID-19 may alternatively be defined as CO VID-19 requiring hospitalization and either NIV or high flow oxygen therapy, instead of being assessed according to the WHO as described hereinabove.

[0344] Preferably, the subject in need of therapeutic and/or preventive treatment is a warm-blooded animal, more preferably a human. According to one embodiment, the subject is a male. According to one embodiment, the subject is a female.

[0345] In the invention, the subject may be of any age. According to one embodiment, the subject is an adult, i.e., over 18 years of age. According to one embodiment, the subject is a child, i.e., under 18 years of age. According to one embodiment, the subject is an infant, i.e., having an age of more than one month and less than two years. According to one embodiment, the subject is a new-born, i.e., having an age from birth to less than one month.

[0346] According to one embodiment, the subject does not suffer from any underlying pathology.

[0347] According to one embodiment, the subject is at risk of developing a disease caused by a coronavirus infection. According to one embodiment, the subject is at risk of developing a disease caused by SARS-CoV-2 infection, such as COVID-19. According to one embodiment, the subject suffering from CO VID- 19 is at risk of developing a respiratory or an extra- respiratory complication as described above.

[0348] According to one embodiment, the subject is suffering from at least one risk factor i.e., a pre-existing disease, condition, habit or behaviour that may lead to an increased risk of developing a severe or critical form of the disease caused by a coronavirus infection as described above. [0349] According to one embodiment, the subject is an individual of any age with certain chronic conditions, such as HIV/AIDS, asthma, diabetes, high blood pressure, or chronic heart or lung disease. According to one embodiment, the subject is an adult with chronic cardiac and/or respiratory pathology. According to one embodiment, the subject is a pregnant woman. According to one embodiment, the subject is an elderly individual. According to one embodiment, the subject is an obese person (BMI>35). According to one embodiment, the subject is profoundly immunocompromised.

[0350] This invention also relates to the use of a compound as described hereinabove in the treatment and/or prevention of a Coronavirus infection as well as respiratory and/or extra- respiratory complications caused by a Coronavirus infection as described hereinabove.

[0351] This invention also relates to the use of a compound as described hereinabove in the manufacture of a medicament for the treatment and/or prevention of a Coronavirus infection as well as respiratory and/or extra-respiratory complications caused by a Coronavirus infection as described herein.

[0352] In one embodiment, the compound of formula I or la is administrated to the subject sequentially, simultaneously and/or separately with the at least other active ingredient as described hereinabove.

[0353] In an embodiment, the compound of formula (I) or compound of formula (la) is administered to a patient who has already been administered said at least one other active ingredient.

[0354] In an embodiment, the patient has been administered said at least one other active ingredient for a period of at least 1-14 days before being administered with compound of formula (I) or of formula (la). More specifically, the patient is being administered said at least one other active ingredient for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days with compound of formula (I) or of formula (la).

[0355] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1 -14 days in combination with the at least other active ingredient, the patient being said another active ingredient naive patient. More specifically, the patient has been administered said at least one other active ingredient for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days before being administered with compound of formula (I) or of formula (la).

[0356] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1-90 days before administration of the at least other active ingredient.

[0357] The term “naive patient” as disclosed herein means that the patient has never been treated with any other active ingredient for the treatment of Covid 19 prior to the administration of the combination. The compound of formula I and/or la is administered to the patient in association with the at least one other active ingredient, i.e., the compound of formula I and/or la is administered during the same period of time that the patient receives doses of the at least one other active ingredient. In a preferred embodiment, the compound of formula I and/or la is administered during a period of 1-14 days in association with the at least one other active ingredient.

[0358] According to an embodiment, the compounds of formula I and/or formula la is administered to a patient who has already been administered remdesivir for a period of at least 1-10 days before being administered with compound of formula (I) or of formula (la).

[0359] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 5-10 days, the patient being a remdesivir naive patient.

[0360] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1-90 days before administration of remdesivir.

[0361] The term “remdesivir naive patient” as disclosed herein means that the patient has never been treated with remdesivir prior to the administration of the combination. The compound of formula I and/or la is administered to the patient in association with remdesivir, i.e., the compound of formula I and/or la is administered during the same period of time that the patient receives doses of remdesivir. In a preferred embodiment, the compound of formula I and/or la is administered during a period of 5-10 days in association with remdesivir. [0362] In an embodiment, said at least one other active ingredient and one compound of formula (I) or formula (la) are administered at different times of the day.

[0363] In an embodiment, said at least one other active ingredient and one compound of formula (I) or formula (la) are administered simultaneously, separately or sequentially.

[0364] In an embodiment, the compound of formula (I) or (la) is association with the at least one other active ingredient, i.e., the compound of formula (I) or (la) is administered during the same period of time that the patient receives the at least one other active ingredient.

[0365] In an embodiment, the compound of formula (I) or (la) is administered during a longer period of time that the patient receives the at least one other active ingredient.

[0366] This invention also relates to a method for the treatment and/or prevention of a Coronavirus infection as described hereinabove and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection as described hereinabove in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound of formula I or la as described hereinabove with at least one other active ingredient as disclosed herein.

[0367] In an embodiment, the patient has been administered said at least one other active ingredient for a period of at least 1-14 days before being administered with compound of formula (I) or of formula (la). More specifically, the patient is being administered said at least one other active ingredient for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days with compound of formula (I) or of formula (la).

[0368] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1 -14 days in combination with the at least other active ingredient, the patient being said another active ingredient naive patient. More specifically, the patient has been administered said at least one other active ingredient for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days before being administered with compound of formula (I) or of formula (la). [0369] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1-90 days before administration of the at least other active ingredient.

[0370] This invention also relates to a method for the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection as described hereinabove in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound of formula I and/or la as described hereinabove with at least a therapeutically effective amount of remdesivir as disclosed herein.

[0371] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 5-10 days in combination with the at least other active ingredient, the patient being a remdesivir naive patient. More specifically, the patient is being administered remdesivir for a period of at least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, with compound of formula (I) or of formula (la).

[0372] According to an embodiment, the compounds of formula I and/or formula la is administered to a patient who has already been administered remdesivir for a period of at least 1-10 days before being administered with compound of formula (I) or of formula (la). More specifically, the patient has been administered remdesivir for a period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, before being administered with compound of formula (I) or of formula (la).

[0373] According to an embodiment, the compounds of formula I and/or formula la is for administration to a patient for a period of 1-90 days before administration of the at least other active ingredient.

Kit of parts

[0374] The invention also relates to a kit of parts for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection and/or a Coronavirus infection comprising, for administration sequentially, simultaneously and/or separately, at least one other active ingredient and a compound of Formula (I) comprising:

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R1 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHRAANH2 ; wherein RAA is a side chain selected from a proteinogenic amino acid; R6 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R₉R₁₀, P(S)R₉R₁₀ and wherein:

R9 and R10 are independently selected from OH, OR11, NHR₁₃, NR₁₃R14, C₁-C₈ alkyl, C2- C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C_1-C₈ heterocycloalkyl, heteroaryl and NHCR_αR_α’C(O)R₁₂; wherein: - R11 is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)nC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)_nSC(O)(C₁- C₁₅)alkyl, -(CH₂)_nC(O)O(C₁-C₁₅)alkyl and -(CH₂)_nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)₂; - R₁₂ is selected from hydrogen, C_1-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_1-C₁₀ haloalkyl, C_3-C₁₀ cycloalkyl, C_3-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C₁-C₄ alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; - R₁₃ and R₁₄ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; - R_α and R_α’ are independently selected from an hydrogen, C_1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C2-C10 alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C₁-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅-C₁₂ aryl, -(CH₂)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H- imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non- proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C_1-C₁₀ alkyl, C_1-C₆ alkoxy, halogen, nitro and cyano;; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₈ is selected from H, OR, NHR₁₅, NR₁₅R16, NH-NHR₁₃, SH, CN, N3 and halogen; wherein R₁₅ and R₁₆ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R1, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: - X’₁ and X’₂ are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; - R’1 and R’13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio- alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1- C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1- C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; - R’₆ and R’₈ are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’7 and R’14 are independently selected from H, OR, NHR, NRR^’, NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; - Y’₁ and Y’₂ are independently selected from CH, CH₂, C(CH₃)₂ or CCH₃; - M’ is selected from H or a suitable counterion; - represents a single or a double bound depending on Y’1 and Y’2; and - represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃. [0375] According to this aspect, said at least one other active ingredient is defined as above. [0376] According to this aspect, said infection of viral origin is defined as above. [0377] According to this aspect, compound I is defined as above. [0378] According to this aspect, compound Ia is defined as above. [0379] In a preferred embodiment, the kit of parts for use in the treatment of a Coronavirus infection and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection comprising, for administration sequentially, simultaneously and/or separately, at least remdesivir and at least one of compound of Formula (I) selected from:

or one compound of formula (la) selected from:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof.

[0380] In a more preferred embodiment, the compounds are compounds of formula IA or IB.

[0381] According to an embodiment, the respiratory and/or extra-respiratory complications are selected amongst pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure, pneumonia and/or acute respiratory syndromes associated with COVID-19.

[0382] In a preferred embodiment, the kit-of-parts of the invention comprises a first part comprising a compound of the invention as described hereinabove, and a second part comprising another active ingredient selected from a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose-derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti-inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

[0383] According to one embodiment, the SARS-CoV-2 vaccine can be a DNA-, RNA or mRNA- based vaccine coding for SARS-CoV-2 antigens chosen amongst PrEP-001 , mRNA 1273, GX- 19, BNT-162, ZyCoV-D, aAPC vaccine, LNP-nCoVsaRNA, INO-4800 DNA, CvnCoV that can be formulated in lipid nanoparticles (CvnCoV vaccine), in plasmids (INO-4800 DNA vaccine) or in lentiviral vector systems (aAPC vaccine) or in dendritic cells (AV-COVID-19 vaccine).

[0384] According to one embodiment, the SARS-CoV-2 vaccine can be heat inactivated plasma from patients who had Covid-19 such as V-SARS.

[0385] According to one embodiment, the SARS-CoV-2 vaccine can be a stabilised and/or recombinant SARS-CoV-2 spike protein or protein receptor binding domain chosen amongst NVX-CoV237, Clover vaccine or a bacterium expressing the SARS-CoV-2 spike protein such as bacTRL-Spike. [0386] In one embodiment, the kit-of-parts of the invention comprises a first part comprising compound of the invention, or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof, and a second part comprising another active ingredient such as remdesivir or molnupiravir.

Methods of administration

[0387] In one embodiment, the compound of formula I or la is administrated to the subject sequentially, simultaneously and/or separately with the at least other active ingredient as described hereinabove.

[0388] The compounds and compositions of the invention as describes hereinabove, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation nebulization, aerosolization, nasal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0389] In a preferred embodiment, the compounds of formula (I) or (la) are administered orally or parenterally.

[0390] The other at least one active ingredient is administered as provided for by the manufacturer.

[0391] In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.

[0392] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.

[0393] All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0394] In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Pharmaceutical composition

[0395] This invention also relates to a pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection, comprising at least one other active ingredient and the compound of formula (I) as defined herein or formula (la) as defined herein for the use according to the invention, and at least one pharmaceutically acceptable carrier.

[0396] According to an embodiment, the pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by Coronavirus infection, comprises at least one compound of formula (I) as defined herein or formula (la) as defined herein for use according to the invention, together with at least one active ingredient as disclosed herein, and at least one pharmaceutically acceptable carrier.

[0397] In a preferred embodiment, the pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, comprising at least one compound of formula (I) or (la) and at least one pharmaceutically acceptable carrier for use together with remdesivir, the compound of formula (I) being selected from:

and the compound of formula (la) being selected from:

[0398] According to an even preferred embodiment, the compound of Formula (I) is compound of formula I-A and/or the compound of formula (I-B) or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof. [0399] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0400] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material, such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0401] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol , such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant, such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0402] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.

[0403] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) Dosage [0404] In the treatment or prevention of a Coronavirus infection and/or respiratory and/or extra- respiratory complications caused by a Coronavirus infection, an appropriate dosage level of the compounds of formula (I) or (Ia) will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 350 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. For example, the dosage may comprise from 100mg/day to 5000mg/day, preferably from 500mg/day to 1000mg/day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once, twice or three times per day. Three times per day has been found suitable. The duration of the treatment will depend from the patent and is determined by the physician. It can be from one day to one year or even longer, preferably from one week to three months, more preferably from two weeks to six weeks. It will be understood, however, that the specific dose level and frequency of dosage and duration for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0405] According to an embodiment, the compound of formula I or Ia is administered at a daily dose of 10mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day. [0406] According to an embodiment, the compound of formula I or Ia, its salts or prodrugs, is administered at a daily dose of 10mg/kg, with a minimum of 500 mg/day and a maximum of 1 g/day for a period of 10 days to 30 days, preferably for a period of 14 days to 28 days, more preferably for a period of about 21 days. [0407] The first day is the day of diagnosis of a Coronavirus infection, or of the diagnosis of respiratory and/or extra-respiratory complications caused by a Coronavirus infection, including pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure. The compound of formula I or Ia can be administered at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21. [0408] According to one embodiment, remdesivir is administered on the first day at a dosage of 200mg once a day and then at a dose of 100 mg once a day. Preferably, remdesivir is administered for a duration of at least 5 days. Preferably, remdesivir is administered for a duration which does not exceed 10 days. [0409] According to an embodiment, the histamine H2 receptor antagonist is administered as per the current dosage recommended. According to an 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. [0410] Preferably, famotidine is administered at a daily dose of 10mg/mL mixed with normal saline is given intravenously at e.g., 120mg (30% of 400 mg oral dose). The total daily dose proposed is 200 to 500mg/day, preferably 360mg/day famotidine, preferably through IV route, for a maximum of 14 days, or hospital discharge, whichever comes first. [0411] According to an embodiment, hydroxychloroquine sulfate 200mg tablets will be administered as a loading dose of 400 mg BID on day 1, followed by 200 mg BID for 4 days, or a loading dose of 800 mg QD on day 1, followed by 400 mg QD for 4 days, as per specific clinical protocol for COVID-19. Process of preparation of compounds of formula (I) or (Ia) [0412] According to another aspect, the invention relates to a method for the preparation of the compound of Formula (I) as described above. [0191] In particular, the compounds of Formula (I) disclosed herein may be prepared as described below from substrates A-E. It shall be understood by a person skilled in the art that these schemes are in no way limiting and that variations may be made without departing from the spirit and scope of this invention. [0413] According to one embodiment, the method involves in a first step the mono- phosphorylation of a compound of formula (A), in the presence of phosphoryl chloride and a trialkyl phosphate, to yield the phosphorodichloridate of formula (B),

wherein X, R1, R₂, R₃, R4, R₅, R6, R₇, R8, Y, and are as described herein above for compounds of formula (I). [0414] In a second step, the phosphorodichloridate of formula (B) is hydrolysed to yield the phosphate of formula (C),

wherein X, R1, R2, R3, R4, R5, R6, R7, R8, Y, and are as described herein above for compounds of formula (I). [0415] According to one embodiment, the compound of formula (A) is synthesized using various methods known to the person skilled in the art. According to one embodiment, the compound of formula (A) is synthesized by reacting the pentose of formula (D) with a nitrogen derivative of formula (E), wherein R, R₂, R₃, R4, R₅, R6, R₇, Y are as described above for compounds of formula (I), leading to the compound of formula (A-1) which is then selectively deprotected to give the compound of formula (A),

wherein X, R1, R₂, R₃, R4, R₅, R6, R8, Y, and are as described herein above for compounds of formula (I). [0416] According to one embodiment, R is an appropriate protective group known to the skilled person in the art. In one embodiment, the protecting group is selected from triarylmethyls and/or silyls. Non-limiting examples of triarylmethyl include trityl, monomethoxytrityl, 4,4'- dimethoxytrityl and 4,4',4"-trimethoxytrityl. Non-limiting examples of silyl groups include trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-iso- propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. [0417] According to one embodiment, any hydroxyl group attached to the pentose is protected by an appropriate protective group known to the person skilled in the art. [0418] The choice and exchange of protective groups is the responsibility of the person skilled in the art. Protective groups can also be removed by methods well known to the skilled person, for example, with an acid (e.g. mineral or organic acid), base or fluoride source. According to a preferred embodiment, the nitrogen derivative of formula (E) is coupled to the pentose of formula (D) by a reaction in the presence of a Lewis acid leading to the compound of formula (A-1). Non-limiting examples of Lewis acids include TMSOTf, BF3.OEt2, TiCl4 and FeCl3. [0419] According to one embodiment, the method of the present invention further comprises a step of reducing the compound of formula (A) by various methods well known to the skilled person in the art, leading to the compound of formula (A') wherein is CH₂ and R1, R₂, R₃, R4, R₅, R6, R8, Y, and are as defined above for compounds of formula (I). [0420] According to a specific embodiment, the present invention relates to a method for the preparation of the compounds of formula I-A to I-D. [0421] In a first step, the nicotinamide of formula E is coupled to the ribose tetraacetate of formula D by a coupling reaction in the presence of a Lewis acid, resulting in the compound of formula A-1:

[0422] In a second step, an ammoniacal treatment of the compound of formula A-1 is carried out, leading to the compound of formula A-2:

[0423] In a third step, the mono-phosphorylation of the compound of formula A-2, in the presence of phosphoryl chloride and a trialkyl phosphate, leads to the phophorodichloridate of formula A-3:

[0424] In a fourth step, the phophorodichloridate of formula A-3 is hydrolyzed to yield the compound of formula I-A:

[0425] According to one embodiment, a step of reducing the compound of formula A-2 is carried out, leading to the compound of formula I-E. [0426] The compound of formula I-E is then monophosphorylated as described in step 4 and hydrolyzed to the compound of formula I-C. [0427] In another aspect, the invention relates to a method for preparing compounds of formula Ia as described above. [0428] In particular, compounds of formula Ia disclosed herein can be prepared as described below from substrates Xa-XIIIa. It will be understood by one ordinary skilled in the art that these schemes are in no way limiting and that variations of detail can be made without departing from the spirit and scope of the present invention. [0429] According to one embodiment, the invention relates to a method for preparing the compound of formula I described herein above. [0430] The method first involves the mono-phosphorylation of a compound of formula Xa, in the presence of phosphoryl chloride in a trialkyl phosphate, to give the phophorodichloridate compound XIa,

wherein X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and are as described herein for formula Ia. [0431] In a second step the hydrolysis of the phophorodichloridate XIa obtained in the first step give the phosphate compound of formula XIIa,

wherein X’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, M’, and are as described herein for formula Ia. [0432] The phosphate compound of formula XIIa obtained in the second step is then reacted, with a phophorodichloridate compound of formula XIIIa obtained as described in the first step,

wherein X’2, R’8, R’9, R’10, R’11, R’12, R’13, R’14, Y’2, and are as are as described herein for formula Ia, to give the compound of formula Ia as described herein. [0433] According to one embodiment, the method of the invention further comprises a step of reducing the compound of formula Ia, using various methods known to those skilled in the art, to give the compound of formula I’a, wherein Y’1 and Y’2 are identical and represent each 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 herein for formula Ia. [0434] According to another embodiment, the compound of formula Xa is synthesized using various methods known to those skilled in the art. According to one embodiment, the compound of formula Xa is synthesized in two steps by first reacting the pentose of formula XIVa with the nitrogenous derivatives of formula XVa, wherein R’1, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1 and R are as described herein for formula Ia, to give the compound of formula Xa-1, then selectively deprotected to give the compound of formula Xa.

, wherein X’1, R, R’1, R’2, R’3, R’4, R’5, R’6, R’7, Y’1, and are as described herein for formula Ia. [0435] According to one embodiment, R is an appropriate protecting group known to those skilled in the art. Examples of appropriate protecting group includes triarylmethyl and/or silyl groups. Non limiting examples of triarylmethyl includes trityl, monomethoxytrityl, 4,4’- dimethoxytrityl and 4,4’,4”-trimethoxytrityl. Non limiting examples of silyl groups includes trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri-iso- propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. [0436] According to one embodiment, any hydroxy group attached to the pentose ring is protected with an appropriate protecting group known to those skilled in the art. [0437] The selection and exchange of the protecting groups is within the skill to those skilled in the art. Any protecting groups can also be removed by methods known in the art, for example, with an acid (e.g., a mineral or an organic acid), a base or a fluoride source. [0438] According to a preferred embodiment, the nitrogenous derivatives of formula XVa is added to the pentose XIVa via a coupling reaction in the presence of a Lewis acid to give the compound of formula Xa-1. Non limiting examples of suitable Lewis acid includes TMSOTf, BF3.OEt2, TiCl4 and FeCl3. [0439] According to a specific embodiment, the invention relates to a method for preparing the compound of formula VIIIa,

_O ^O or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof. [0440] In a first step, the nicotinamide of formula XVa, is added to the ribose tetraacetate XIVa, via a coupling reaction in the presence of a Lewis acid, to give the compound of formula Xa-

[0441] In a second step, an ammoniacal treatment of the compound of formula Xa-1 give the compound of formula Xa:

[0442] In a third step, the mono-phosphorylation of a compound of formula Xa, in the presence of phosphoryl chloride in a trialkyl phosphate, give the phosphorodichloridate compound XIa:

[0443] In a fourth step, the phosphorodichloridate compound XIa obtained in the third step is partially hydrolyzed to give the phosphate compound of formula XIIa:

.

[0444] In a fifth step, the phosphate compound of formula XIIa obtained in the fourth step is then reacted, with the phosphorodichloridate compound of formula XIa obtained as described in the third step, to give the compound of formula VIIIa. [0445] According to another specific embodiment, the invention relates to a method for preparing the compound of formula IXa,

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof. [0446] According to one embodiment, the compound of formula IXa is obtained from the compound of formula VIIIa, previously synthesized as described above. [0447] In this embodiment, the compound of formula IXa is obtained by reducing the compound of formula VIIIa, using a suitable reducing agent known to those skilled in the art, to give the compound of formula IXa. FIGURES - Figure 1A shows the results of TEER measures in non-infected cells for compound I-A (beta-NMN or NMN). - Figure 1B shows the results of TEER measures in non-infected cells for compound I-B (alpha-NMN). - Figure 2A shows the results of TEER measures in infected cells for compound I-A (beta- NMN or NMN). - Figure 2B shows the results of TEER measures in infected cells for compound I-B (alpha- NMN). - Figure 3 shows the results of the quantitative PCR of nsp14 in infected cells for compound I-A(beta-NMN or NMN). - Figure 4 shows the results of the quantitative PCR of nsp14 in infected cells for compound I-B (alpha-NMN). - Figure 5 shows the efficacy of the different treatments on IP10/CXCL10 expression in non- infected cells (figure 5A) and infected cells (figure 5B) for compound I-A (beta-NMN or NMN) at T72h. - Figure 6 shows the efficacy of the different treatments on IP10/CXCL10 expression in non- infected cells (figure 6A) and infected cells (figure 6B) for compound I-B (alpha-NMN). - Figure 7 shows the efficacy of the different treatments on IL6 expression in non-infected cells (figure 7A) and infected cells (figure 7B) for compound I-A (beta-NMN or NMN). - Figure 8 shows the efficacy of the different treatments on IL6 expression in non-infected cells (figure 8A) and infected cells (figure 8B) for compound I-B (alpha-NMN). - Figure 9 shows the efficacy of the different treatments on TNFα expression in non-infected cells (figure 9A) and infected cells (figure 9B) for compound I-A (beta-NMN or NMN). - Figure 10 shows the efficacy of the different treatments on TNFα expression in non- infected cells (figure 10A) and infected cells (figure 10B) for compound I-B (alpha-NMN). - Figure 11 shows the efficacy of the different treatments on IL10 expression in non-infected cells (figure 11A) and infected cells (figure 11B) for compound I-A (beta-NMN or NMN). - Figure 12 shows the efficacy of the different treatments on IL10 expression in non-infected cells (figure 12A) and infected cells (figure 12B) for compound I-B (alpha-NMN). EXAMPLES [0448] The present invention is further illustrated by the following examples. Example 1: Synthesis of compounds of the invention Materials and Methods [0449] All materials were obtained from commercial suppliers and used without further purification. Thin-layer chromatography was performed on TLC plastic sheets of silica gel 60F254 (layer thickness 0.2 mm) from Merck. Column chromatography purification was carried out on silica gel 60 (70-230 mesh ASTM, Merck). Melting points were determined either on a digital melting point apparatus (Electrothermal IA 8103) and are uncorrected or on a Kofler bench type WME (Wagner & Munz). IR, 1H, 19F and 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, using CDCl3, CD3CN, D2O or DMSO- d6 as solvent, on a Bruker AC 300, Advance DRX 400 and Advance DRX 500 spectrometers, for 1H, 75 or 100 MHz for 13C and 282 or 377 MHz for 19F spectra. Chemical shifts (δ) were expressed in parts per million relative to the signal indirectly (i) to CHCl3 (δ 7.27) for 1H and (ii) to CDCl3 (δ 77.2) for 13C and directly (iii) to CFCl3 (internal standard) (δ 0) for 19F. Chemical shifts are given in ppm and peak multiplicities are designated as follows: s, singlet; br s, broad singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quadruplet; quint, quintuplet; m, multiplet. The high-resolution mass spectra (HRMS) were obtained from the "Service central d'analyse de Solaize" (Centre national de la recherche scientifique) and were recorded on a Waters spectrometer using electrospray-TOF ionization (ESI-TOF). General experimental procedures Step 1: Synthesis of the compound of formula A-1 [0450] The compound of formula D (1.0 equiv.) is dissolved in dichloromethane. Nicotinamide of formula E (1.50 equiv.) and TMSOTf (1.55 equiv.) are added at room temperature. The reaction mixture is heated under reflux and stirred until the reaction is complete. The mixture is cooled to room temperature and filtered. The filtrate is concentrated to dryness to give tetraacetate A-1. Step 2: Synthesis of the compound of formula A-2 [0451] Tetraacetate A-1 is dissolved in methanol and cooled to -10 °C. Ammonia 4,6 M in methanol (3,0 equivalents) at -10 °C is added and the mixture is stirred at this temperature until the reaction is complete. Dowex HCR (H+) resin is added up to pH 6-7. The reaction mixture is heated to 0 °C and filtered. The resin is washed with a mixture of methanol and acetonitrile. The filtrate is concentrated to dryness. The residue is dissolved in the acetonitrile and concentrated to dryness. The residue is dissolved in the acetonitrile to give a solution of the compound of formula A-2. Step 3: Synthesis of the compound of formula A-3 [0452] The solution of the crude compound of formula A-2 in acetonitrile is diluted with trimethyl phosphate (10.0 equivalents). The acetonitrile is distilled under vacuum and the mixture is cooled to -10 °C. Phosphorus oxychloride (4,0 equivalents) is added at 10 °C and the mixture is stirred at 10 °C until the reaction is complete. Steps 4 and 5: Synthesis of the compound of formula I-A [0453] The mixture obtained in step 3 above is hydrolyzed by the addition of a 50/50 mixture of acetonitrile and water, followed by the addition of methyl tert-butyl ether. The mixture is filtered and the solid is dissolved in water. The aqueous solution is neutralised by the addition of sodium bicarbonate and extracted with dichloromethane. The aqueous layer is concentrated to dryness to yield the crude formula I-A compound, which is purified on a DOWEX 50wx8 column with elution in water followed by a silica gel chromatographic column. Example 2: Efficacy of compounds I-A (β-NMN) and I-A (α-NMN), with or without remdesivir, for the treatment of SARS-CoV2 infection. [0454] The efficacy of compounds I-A (beta-NMN) and I-B (alpha-NMN) for the treatment of an infection caused by SARS-CoV-2 has been tested on healthy human nasal epithelium reconstructed from a pool of 14 donors. [0455] Compounds I-A and I-B have been prepared according to the method disclosed herein and diluted in OptiMEM culture medium + 0.01% DMSO. Remdesivir was purchased from Gilead and diluted in OptiMEM culture medium + 0.01% DMSO. The epithelial cells were cultivated in OptiMEM culture medium according to the instructions of the provider (Epithelix) in Transwells® inserts at 37°C, 5%-10% CO2. Transwell® cell culture inserts are permeable support devices for the study of both anchorage-dependent and anchorage-independent cell lines, such as epithelial cells. They are designed to produce a cell culture environment that closely mimics the in vivo state. [0456] The following conditions have been tested:

Each condition is tested in triplicate. Cells are infected by SARS-CoV-2 (“British variant” strain B.1.1.7) suspended in medium culture +0.01% DMSO administered on the apical side of the cells at T0. For non-infected cells: infection is mimicked by the administration of medium without SARS-CoV-2. The treatments are administered at the basal layer of the cells 1h and 24h post infection (p.i.) for infected cells or post-DMSO treatment (p.t.) for non-infected cells. [0457] TEER assay: The integrity of the epithelial layer is measured by transepithelial/transendothelial electrical resistance (TEER) at T0 before infection or mimicking the infection as well as T48h and T72h after infection / mimicking the infection. Measures of TEER are made before treatment and lysis of cells. The resistance is expressed in .cm². The measurement of resistance is an indication of the integrity of the epithelial layer and cell death: the higher the resistance is, the less damaged the epithelial layer is.

[0458] At T48h and T72h post infection/mimicking infection: Briefly, cell culture supernatants are collected by washing at the basal side of each Transwell 48h or 72h after infection / mimicking the infection for further analysis of cytokines expressed in the culture medium and quantification of Coronavirus non-structural protein 14 (nspl4) by RT-qPCR (Real Time quantitative Polymerase Chain Reaction assay).

[0459] At T72h post infection/mimicking infection: Cells are recovered and lysed in RTL Buffer (Qiagen) at T72h for RNA extraction and the quantification of Coronavirus non-structural protein 14 (nspl4), IL6, IL10, TNF-a, and CXCL10/IP10 by RT-qPCR. Supernatants of apical side and basal side are frozen at -20°C for further quantification of TCID50 and further cytokines.

[0460] Quantification of viral genome by RT-qPCR: Briefly, virus particles are collected by washing at the apical side and viral RNA is extracted (QIAamp viral RNA Kits extraction kit, Qiagen) at T48h and T72h after infection or mimicking the infection. Cells are collected and lysed at T72h after infection or mimicking the infection. Total RNA of cell lysates is extracted, and RT-qPCR is performed as known by the skilled in the art using primers based on the sequence of gene ORFlb-nspl4 (as described by Leo Poon, Daniel Chu et Malik Peiris, Detection of 2019 novel coronavirus (2019-nCoV) in suspected human cases by RT-PCR; School of Public Health, The University of Hong Kong, Hong Kong). The results are normalized using GAPDH.

[0461] Quantification of IL6, IL 10. TNF-a. and CXCL10/IP10 by RT-qPCR: Total RNA of cell lysates is extracted, and RT-qPCR is performed as known by the skilled in the art using primers based on the sequence of each gene (Gene Expression Assay, Thermofisher). The results are normalized using GAPDH. Dosages of IL6, IL10, TNF-a, and CXCL10/IP10 are carried-out as an indication of the severity of the infection by SARS-CoV-2 as these markers of inflammation have been found to be highly expressed by patients infected by SARS-CoV-2 and responsible for the respiratory complications and ARDS associated with Covidl9 (See Yujun Tang et al, Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies, Front Immunol. 2020; 11: 1708; David C. Fajgenbaum, M.D., and Carl H. June, Cytokine storm, M.D. N Engl J Med 2020;383:2255-73. DOI: 10.1056/NEJMra2026131). [0462] TCID50 assay: The number of infectious virus particles is quantified by using the Median Tissue Culture Infectious Dose (TCID50) assay. The assay works by adding a serial dilution of the virus sample to Vero E6 cells (ATCC CRL-1586™) in a 96 well plate format. After an incubation period, the cells are inspected for CPE or cell death and each well is classified as infected or not infected. Colorimetric or fluorometric readouts are also possible, which can increase assay sensitivity. The dilution, at which 50% of the wells show a CPE, is used to calculate the TCID50 of the virus sample. This calculation is done by the Reed-Muench method (Reed, L.J.; Muench, H. (1938). A simple method of estimating fifty percent endpoints. The American Journal of Hygiene.27: 493–497). Virus titer is expressed as TCID50 / ml. The dosage of nsp14 quantifies the infection by SARS-CoV-2. It has been found in the literature that the expression of nsp14 by SARS-CoV-2 is essential to the replication of SARS-CoV-2 (Maria Romano, A Structural View of SARS-CoV-2 RNA Replication Machinery: RNA Synthesis, Proofreading and Final Capping, Cells, 2020 May 20;9(5):1267. doi: 10.3390/cells9051267). [0463] Results obtained by TEER for infected and non-infected cells are shown in the tables below. Table 3 – TEER measurements - Non infected cells

[0464] As shown by Table 3 and Figure 1, the cell integrity of non- infected cells slightly decreases over time in a similar manner for all treatments. The cell death observed is consistent with cell renewal in normal cell culture conditions.

Table 4 - TEER measurements - Cells infected by SARS-CoV-2

[0465] As shown by Table 4 and Figure 2, the cell integrity significantly decreases in 72h for control and DMSO cells. The treatment by remdesivir improves cell survival, as shown at T72h p.i. The treatment by compound I-A (β-NMN) and compound I-B (α-NMN) alone does not improve cell survival, regardless of the dosage. However, the combination of compound I-A or compound I-B with remdesivir significantly improves cell survival in a synergetic manner, especially at T72h p.i.. The lower dosage of 100µM of compound I-A or compound I-B provides a better efficiency than the higher dosage of 1000 µM. [0466] The quantification of intracellular genome of SARS-CoV-2 by qPCR of nsp14 is performed to assess both the infection of cells by SARS-CoV-2 and the efficacy of the treatments on the inhibition of SARS-CoV-2 replication in cells. The results after 48h and 72 post infection are shown at Table 5 and figures 3 and 4. Table 5 – RT-qPCR nsp14

[0467] As shown by Figure 3 (compound I-A) and Figure 4 (compound I-B), the treatments by DMSO and compounds I-B or I-A alone are not efficient to inhibit the intracellular replication of the virus. Treatment by remdesivir reduces the replication of the virus. The treatment by compound I-A (0-NMN) and compound I-B (a-NMN) alone shows no inhibitory effect on the virus replication, the combination of compound I-A or compound I-B with remdesivir significantly inhibits the virus replication in a synergetic manner, at both time points postinfection.

[0468] CXCL10/IP10 expression at T72h post infection in non-infected and infected cells: It has been found that IP10 is overexpressed in Covidl9 patients and its expression seems to be strongly correlated with the severity of the infection and risk of death (J. Wang et al. J Leukoc Biol. 2020;l-25.). As shown by Figures 5A and 6A, the administration of remdesivir alone, compound I-A alone, compound I-B alone or the combination of remdesivir + compound I-A or remdesivir + compound I-B slightly decreases the expression CXCL10 in non-infected cells. As shown by Figure 5B and figure 6B, remdesivir significantly decreases the expression of CXCL10 in infected cells. Compounds I-A and I-B alone have no effect on the expression of CXCL10 in infected cells when compared to non-treated cells and DMSO. However, the combination of remdesivir with compound I-A (figure 5B) or compound I-B (figure 6B) significantly decreases the expression of CXCL10 in a synergetic manner when compared to remdesivir alone.

[0469] IL6 expression at T72h post infection in non-infected and infected cells: IL6 is pro- inflammatory cytokine, notably involved in the differentiation of monocytes into macrophage and the stimulation of IgG production. IL6 is overexpressed in SARS-CoV-2 infection, which seems to be responsible of the over-reaction of the immune system and SARS-CoV-2 related ARDS (J. Wang et al. J Leukoc Biol. 2020;l-25.). As shown by figures 7A and 8A, remdesivir and compound I-A/compound I-B decreases the expression of IL6 in non-infected cells, in a similar manner. The combination of compound I-B and remdesivir further reduces the expression of IL6 in comparison with remdesivir alone or compound I-B in non-infected cells (figure 7A). The same observation can be made with compound I-A (figure 8A). The administration of compound I-A alone (figure 7B) or compound I-B alone (figure 8B) does not inhibit the expression of IL6 in infected cells, in comparison with control cells (non-treated or DMSO). The administration of remdesivir significantly reduces the expression of IL6 in infected cells (figures 7B and 8B). The combination of remdesivir with either compound I-A (figure 7B) or compound I-B (figure 8B) further reduces the expression of IL6 in infected cells.

[0470] TNFa expression at T72h post infection in non-infected and infected cells: TNFa is a pro- inflammatory marker and has been found to be overexpressed in critically ill patients infected by SARS-CoV-2 (J. Wang et al. J Leukoc Biol. 2020;l-25.). As shown by figures 9A and 10A, the administration of compound I-A, compound I-B alone has not effect on the expression of TNFa in non-infected cells. The administration of remdesivir alone, compound I-A 1000 pM or compound I-B alone decreases the expression of TNFa in non-infected cells (figures 9A and 10A). [0471] The administration of remdesivir alone decreases further the expression of TNFa in infected cells (figures 9B and 10B). Its efficiency is improved by the combination with compound I-A 1000 pM in infected cells (figure 9B) or by the co-administration with compound I-B (figure 10B). The administration of either compound I-A or compound I-B alone does not have any effect on the expression of IL 10 in infected cells (figures 9B and 10B).

[0472] IL10 expression at T72h post infection in non-infected and infected cells: IL10 is a pro- inflammatory marker and has been found to be overexpressed in critically ill patients infected by SARS-CoV-2 (J.Wang et al. J Leukoc Biol. 2020;l-25.). As shown by figures 11A and 12A, the administration of remdesivir, compound I-A, compound I-B, compound I-A+ remdesivir, compound I-B + remdesivir has not effect on the expression of IL 10 in noninfected cells. The administration of remdesivir alone decreases the expression of IL10 in infected cells (figures 1 IB and 12B). The administration of either compound I-A or compound I-B alone does not have any effect on the expression of IL10 in infected cells. However, the combination of remdesivir + compound I-A (figure 11 B) or remdesivir + compound I-B (figure 12B) further decreases the expression of IL10 in infected cells in a synergetic manner.

[0473] Conclusion: the combination of the compounds of the invention, in particular compounds I-A and LB, with remdisivir synergistically improves the efficiency of remdisivir and reduces cell death of epithelial pulmonary cells, the replication of SARS-CoV-2 and the expression of pro-inflammatory markers such as IL6, IP10, IL10 and TNFa. The compounds of the invention with an anti-viral agent, in particular a nucleoside analog such as remdesivir, are thus useful for the treatment of a Coronavirus infection and Covid- 19.

Claims

CLAIMS 1. A combination of at least one other active ingredient and compound of Formula (I) comprising:

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R1 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHRAANH2 ; wherein RAA is a side chain selected from a proteinogenic amino acid; R6 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R₉R₁₀, P(S)R₉R₁₀ and

wherein: R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂- C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C₁-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R12; wherein: - R₁₁ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)_nC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)nSC(O)(C1- C15)alkyl, -(CH₂)nC(O)O(C₁-C₁₅)alkyl and -(CH₂)nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; - R₁₂ is selected from hydrogen, C_1-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_1-C₁₀ haloalkyl, C_3-C₁₀ cycloalkyl, C_3-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C₁-C₄ alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; - R₁₃ and R₁₄ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; - Rα and Rα’ are independently selected from an hydrogen, C₁-C₁₀ alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C₁-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅-C₁₂ aryl, -(CH₂)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H- imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non- proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C_1-C₁₀ alkyl, C_1-C₆ alkoxy, halogen, nitro and cyano;; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R9−R10− represents –O-CH₂-CH₂-CHR-O−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy and cyano R₈ is selected from H, OR, NHR₁₅, NR₁₅R16, NH-NHR₁₃, SH, CN, N3 and halogen; wherein R₁₅ and R16 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: - X’₁ and X’₂ are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; - R’1 and R’13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio- alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1- C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1- C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; - R’₆ and R’₈ are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’7 and R’14 are independently selected from H, OR, NHR, NRR’ , NH-NHR, SH, CN, N3 and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; - Y’1 and Y’2 are independently selected from CH, CH₂, C(CH₃)2 or CCH₃; - M’ is selected from H or a suitable counterion; - represents a single or a double bound depending on Y’₁ and Y’₂; and - represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃, for use in the treatment and/or the prevention of a Coronavirus infection and/or treatment and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection.

2. The combination according to claim 1, wherein the Coronavirus infection is caused by a coronavirus selected from HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1 and SARS-CoV-2, preferably from MERS-CoV, SARS-CoV- 1 and SARS-CoV-2, preferably a SARS-CoV-2 infection causing coronavirus disease 2019 (COVID-19).

3. The combination according to claim 1 or 2 for use in the treatment and/or prevention of pneumonia and/or acute respiratory diseases, acute respiratory distress syndrome (ARDS), acute respiratory failure, pneumonia and/or acute respiratory syndromes associated with COVID-19.

4. The combination for use according to any of the preceding claims wherein the at least one other active ingredient is chosen from a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose- derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti-inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin- converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

5. The combination for use according to claim 4 wherein the at least one other active ingredient is an antiviral agent.

6. The combination for use according to claim 5 wherein the antiviral agent is selected amongst a nucleoside analog, a nucleotide analog, favilavir, avifavir, umifenovir, favipiravir, an HIV-protease inhibitor, EIDD 2801(molnupiravir), a dihydroorotate dehydrogenase inhibitor and their combinations, preferably a nucleoside analog.

7. The combination for use according to claim 6 wherein the nucleoside analogue is selected amongst: - deoxyadenosine analogues preferably didanosine and vidarabine; - adenosine analogues preferably galidesivir and remdesivir; - deoxycytidine analogues preferably cytarabine, gemcitabine, emtricitabine, lamivudine, zalcitabine ; - guanosine and deoxyguanosine analogues preferably abacavir, acyclovir and entecavir; - thymidine and deoxythymidine analogues preferably stavudine, telbivudine, zidovudine; and - deoxyuridine analogues preferably idoxuridine and trifluridine.

8. The combination for use according to claim 7 wherein the nucleoside analogue is remdesivir.

9. The combination for use according to claim 4 wherein the antibody is selected amongst an anti-VEGF, an anti- TNF, an anti-GM-CSF, GM-CSF antagonist, a CCR₅ antagonist, an anti-SARS-CoV-2 spike protein, an IL-6 receptor antagonist, an anti-IL1beta, a C5 complement inhibitor and their combinations.

10. The combination for use according to claim 9 wherein the antibody is selected amongst bevacizumab, etesivimab, infliximab, mavrilimumab, lenzilumab, leronlimab, gimsilumab, otilimab, JS016, LY-CoV555, REGN10933, REGN10987, sarilumab, canakinumab, ravulizumab, mavrilimumab, tocilizumab, namilumab, adalimumab, MEDI3506, bamlanivimab, AZD7442, casirivimab, imdevimab, sotrovimab, risankizumab, and their combinations, preferably AZD7442, casirivimab, imdevimab, sarilumab, JS016, LY-CoV555, REGN10933 and REGN10987 and their combinations.

11. The combination for use according to claim 1 wherein said one compound of formula (I) or one compound of formula (Ia) is administered to a patient who has already been administered said at least one other active ingredient.

12. The combination for use according to claim 1, wherein the patient has been administered said at least one other active ingredient for a period of at least 1-14 days before being administered with compound of formula (I) or of formula (Ia).

13. The combination for use according to claim 1 wherein said at least one other active ingredient and one compound of formula (I) or formula (Ia) are administered at different times of the day.

14. The combination for use according to claim 1 wherein said at least one other active ingredient and one compound of formula (I) or formula (Ia) are administered separately, simultaneously or sequentially.

15. The combination according to any of the preceding claims, wherein the compound of formula (I) has: - X represents oxygen; and/or - R1 and R6 each independently represents a hydrogen; and/or - R₂, R₃, R₄ and R₅ each independently represents a hydrogen, or R₂, R₃, R₄ and R₅ each independently represents a OH; and/or - Y represents a CH or a CH₂; and/or - R₇ represents P(O)R9R10, and wherein R9 and R10 are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅- C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C_1-C₈ heterocycloalkyl, heteroaryl and NHCRαRα’C(O)R12.

16. The combination according to any of the preceding claims, wherein the compound of formula I is selected from:

Or the compound of formula (Ia) is selected from:

or pharmaceutically acceptable salts and solvates thereof or prodrugs thereof, preferably compounds of formula I-A and/or I-B.

17. The combination according to any of claims 1-15, wherein R₇ is not H.

18. A pharmaceutical composition for use in the treatment and/or prevention of a Coronavirus infection and/or for use in the treatment and/or prevention of respiratory and/or extra- respiratory complications caused by a Coronavirus infection together with at least one other active ingredient, comprising at least one a compound of Formula (I) comprising:

or a pharmaceutically acceptable salt or solvate thereof or prodrug thereof; wherein: X is selected from O, CH₂, S, Se, CHF, CF₂ et C=CH₂; R1 is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₂, R₃, R₄ et R₅ are independently selected from H, halogen, azido, cyano, hydroxyl, C₁-C₁₂ alkyl, C₁-C₁₂ thioalkyl, C₁-C₁₂ heteroalkyl, C₁-C₁₂ haloalkyl and OR; wherein R is selected from H, C₁-C₁₂ alkyl, C(O)(C₁-C₁₂)alkyl, C(O)NH(C₁-C₁₂)alkyl, C(O)O(C₁-C₁₂)alkyl, C(O)aryl, C(O)(C₁-C₁₂)alkyl aryl, C(O)NH(C₁-C₁₂)alkyl aryl, C(O)O(C₁-C₁₂)alkyl aryl and C(O)CHR_AANH₂ ; wherein R_AA is a side chain selected from a proteinogenic amino acid; R₆ is selected from H, azido, cyano, C₁-C₈ alkyl, C₁-C₈ thio-alkyl, C₁-C₈ heteroalkyl and OR; wherein R is selected from H and C₁-C₈ alkyl; R₇ is selected from H, P(O)R₉R₁₀, P(S)R₉R₁₀ and

; wherein: R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂- C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C_1-C₈ heterocycloalkyl, heteroaryl and NHCR_αR_α’C(O)R₁₂; wherein: - R11 is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)nC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)(C₁-C₁₅)alkyl, -(CH₂)_nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)_nSC(O)(C₁- C₁₅)alkyl, -(CH₂)_nC(O)O(C₁-C₁₅)alkyl and -(CH₂)_nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)₂; - R12 is selected from hydrogen, C₁-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C1-C4 alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; - R₁₃ and R14 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; - Rα and Rα’ are independently selected from an hydrogen, C₁-C₁₀ alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C₁-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅-C₁₂ aryl, -(CH₂)₃NHC(=NH)NH₂, (1H-indol-3-yl)methyl, (1H- imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non- proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano;; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C₅-C₆ aryl and C₅-C₆ heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R8 is selected from H, OR, NHR₁₅, NR₁₅R16, NH-NHR₁₃, SH, CN, N3 and halogen; wherein R₁₅ and R16 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R₁, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: - X’1 and X’2 are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; - R’₁ and R’₁₃ are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio- alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’2, R’3, R’4, R’5, R’9, R’10, R’11, R’12 are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1- C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1- C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHRAANH2, wherein RAA is a side chain selected from a proteinogenic amino acid ; - R’6 and R’8 are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’₇ and R’₁₄ are independently selected from H, OR, NHR, NRR^’, NH-NHR, SH, CN, N₃ and halogen; wherein R and R' are each independently selected from H, C1-C8 alkyl, C1-C8 alkyl aryl; - Y’1 and Y’2 are independently selected from CH, CH₂, C(CH₃)2 or CCH₃; - M’ is selected from H or a suitable counterion; - represents a single or a double bound depending on Y’1 and Y’2; and - represents the alpha or beta anomer depending on the position of R’₁ and R’₁₃, and at least one pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, further comprising at least one active ingredient selected from a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose- derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti-inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin- converting-enzyme inhibitors/angiotensin II receptor blockers, statins, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

20. A kit of parts for use in the treatment of a Coronavirus infection and/or prevention of respiratory and/or extra-respiratory complications caused by a Coronavirus infection comprising, for administration sequentially, simultaneously and/or separately, at least one other active ingredient and at least one compound of Formula (I):

R₉ and R₁₀ are independently selected from OH, OR₁₁, NHR₁₃, NR₁₃R₁₄, C₁-C₈ alkyl, C₂- C₈ alkenyl, C₂-C₈ alkynyl, C_3-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₈ arylalkyl, C₁-C₈ alkylaryl, C₁-C₈ heteroalkyl, C_1-C₈ heterocycloalkyl, heteroaryl and NHCR_αR_α’C(O)R₁₂; wherein: - R₁₁ is selected from C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkylaryl, substituted C₅-C₁₂ aryl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ haloalkyl, -(CH₂)_nC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)(C₁-C₁₅)alkyl, -(CH₂)nOC(O)O(C₁-C₁₅)alkyl, -(CH₂)nSC(O)(C1- C15)alkyl, -(CH₂)nC(O)O(C₁-C₁₅)alkyl and -(CH₂)nC(O)O(C₁-C₁₅)alkyl aryl; wherein n is an integer selected from 1 to 8; and P(O)(OH)OP(O)(OH)2; - R₁₂ is selected from hydrogen, C_1-C₁₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C_1-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloheteroalkyl, C₅-C₁₂ aryl, C1-C4 alkylaryl and C₅-C₁₂ heteroaryl; wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; - R₁₃ and R14 are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; - Rα and Rα’ are independently selected from an hydrogen, C₁-C₁₀ alkyl, C2-C10 alkenyl, C₂-C₁₀ alkynyl, C_3-C₁₀ cycloalkyl, C₁-C₁₀ thio-alkyl, C_1-C₁₀ hydroxylalkyl, C₁-C₁₀ alkylaryl and C₅-C₁₂ aryl, -(CH₂)3NHC(=NH)NH2, (1H-indol-3-yl)methyl, (1H- imidazol-4-yl)methyl and a side chain selected from a proteinogenic or non- proteinogenic amino acid; wherein said aryl groups are optionally substituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano;; or R₉ and R₁₀ together with the phosphorus atoms to which they are attached form a 6- membered ring wherein –R9−R10− represents –CH₂-CH₂-CHR−; wherein R is selected from hydrogen, C5-C6 aryl and C5-C6 heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted by one or two groups selected from halogen, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy and cyano; R₈ is selected from H, OR, NHR₁₅, NR₁₅R₁₆, NH-NHR₁₃, SH, CN, N₃ and halogen; wherein R₁₅ and R₁₆ are independently selected from H, C₁-C₈ alkyl and C₁-C₈ alkyl-aryl; Y is selected from CH, CH₂, C(CH₃)₂ and CCH₃; represents a single or double bond according to Y; and represents the alpha or beta anomer depending on the position of R1, or a compound of formula (Ia)

or pharmaceutically acceptable salts and/or solvates thereof or prodrugs thereof, wherein: - X’₁ and X’₂ are independently selected from O, CH₂, S, Se, CHF, CF₂ and C=CH₂; - R’₁ and R’₁₃ are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thio- alkyl, C1-C8 heteroalkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’₂, R’₃, R’₄, R’₅, R’₉, R’₁₀, R’₁₁, R’₁₂ are independently selected from H, halogen, azido, cyano, hydroxyl, C1-C12 alkyl, C1-C12 thio-alkyl, C1-C12 heteroalkyl, C1-C12 haloalkyl and OR; wherein R is selected from H, C1-C12 alkyl, C(O)(C1-C12)alkyl, C(O)NH(C1- C12)alkyl, C(O)O(C1-C12)alkyl, C(O)aryl, C(O)(C1-C12)alkyl aryl, C(O)NH(C1- C12)alkyl aryl, C(O)O(C1-C12)alkyl aryl or C(O)CHR_AANH₂, wherein R_AA is a side chain selected from a proteinogenic amino acid ; - R’₆ and R’₈ are independently selected from H, azido, cyano, C1-C8 alkyl and OR; wherein R is selected from H and C1-C8 alkyl; - R’ and R’ are independe ’ 7 14 ntly 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 alkyl aryl; - Y’1 and Y’2 are independently selected from CH, CH₂, C(CH₃)2 or CCH₃; - M’ is selected from H or a suitable counterion; - represents a single or a double bound depending on Y’₁ and Y’₂; and - represents the alpha or beta anomer depending on the position of R’1 and R’13.

21. The kit of parts according to claim 20, further comprising at least one active ingredient selected from a plasma of a convalescent patient, an antibody, a recombinant fusion protein, nitric oxide therapy, a MAP kinase inhibitor, an adipose-derived mesenchymal stem cells, an anthelmintic, a kinase inhibitor, a sodium-glucose transport protein 2 (SGLT2) inhibitor, a SARS-CoV-2 vaccine, a corticoid, a non-steroidal anti- inflammatory drug, a histamine H2 receptor antagonist, ABX464, an antiviral agent, a neuraminidase inhibitor, a M2 proton channel blocker, an anti-interleukin 6, a JAK inhibitor, an interferon, a macrolide, an alkaloid, dimethyl fumarate, angiotensin- converting-enzyme inhibitors/angiotensin II receptor blockers, statins, aspirin, clopidogrel, anticoagulants, bemcentinib, omeprazole, zilucoplan, vitamin C, vitamin D3, aviptadil, tradipitant, fluvoxamine, proxalutamide, ruconest, TRV027, IMU-838, BXT-25, chloroquine, hydroxychloroquine, brilacidin, dehydroandrographolide succinate, APN01, fingolimod, thalidomide, sildenafil citrate, carrimycin, nicotine, cyclosporine A, and a mixture thereof.

22. The kit of parts according to claim 20 or 21 wherein the at least one active ingredient is an antiviral agent selected amongst a nucleoside analog, a nucleotide analog, favilavir, avifavir, umifenovir, favipiravir, an HIV-protease inhibitor, EIDD 2801, a dihydroorotate dehydrogenase inhibitor and their combinations, preferably a nucleoside analog.

23. The kit of parts according to claim 22 wherein the antiviral agent is a nucleoside analog, preferably selected amongst nucleoside analogue is selected amongst: - deoxyadenosine analogues preferably didanosine and vidarabine; - adenosine analogues preferably galidesivir and remdesivir; - deoxycytidine analogues preferably cytarabine, gemcitabine, emtricitabine, lamivudine, zalcitabine ; - guanosine and deoxyguanosine analogues preferably abacavir, acyclovir and entecavir; - thymidine and deoxythymidine analogues preferably stavudine, telbivudine, zidovudine; and - deoxyuridine analogues preferably idoxuridine and trifluridine.

24. The kit of parts of claim 23 wherein the nucleoside analogue is remdesivir.

25. The kit of parts of claim 21 wherein the antibody is selected amongst bevacizumab, etesivimab, infliximab, mavrilimumab, lenzilumab, leronlimab, gimsilumab, otilimab, JS016, LY-CoV555, REGN10933, REGN10987, sarilumab, canakinumab, ravulizumab, mavrilimumab, tocilizumab, namilumab, adalimumab, MEDI3506, bamlanivimab, AZD7442, casirivimab, imdevimab, sotrovimab, risankizumab, and their combinations, preferably AZD7442, casirivimab, imdevimab, sarilumab, JS016, LY-CoV555, REGN10933 and REGN10987 and their combinations.