Anti-coronavirus compounds

Abstract

The present disclosure relates to new compounds or compositions comprising thereof useful for the treatment or prophylaxis of a disorder mediated by a coronavirus.

Description

[0001] ANTI-CORONAVIRUS COMPOUNDS FIELD OF THE INVENTION The invention relates to new compounds which are useful for the treatment of coronavirus infections. BACKGROUND OF THE INVENTION In the past two decades, three virulent strains of coronaviruses have emerged from animal reservoirs to cause three outbreaks in 2002 (severe acute respiratory syndrome coronavirus; SARS-CoV), 2012 (Middle East respiratory virus coronavirus; MERS-CoV) and 2019 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2). With globally over 774 million confirmed cases and seven million deaths reported, the Covid- 19 caused by the SARS-CoV-2 remains a major threat to global health.SARS-CoV-2 belongs to the zoonotic Coronaviridae family with the classification of fourgenera including α, β, γ, δ -CoV. α- and β-CoV are responsible for the infection inmammals while γ- and δ -CoV are responsible for the infection of avian species. BeforeSARS-CoV-2, six coronaviruses had been found to infect humans: HCoV-229E, HCoV- OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV. α-CoVs have less fatal effects causing common cold while β -CoVs such as SARS-CoV, MERS-CoV and SARS- CoV-2 can cause severe disease and are potentially lethal. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus with a large genome of about 30,000 nucleotides. In the coronavirus replication cycle, the genomic RNA produces two polyproteins, pp1a and pp1ab which are proteolytically cleaved by two viral cysteine proteases: the main protease or 3CL-protease (nsp5, Mpro, 3CLpro) and the papain-like protease (nsp3, PLpro) to generate 16 nonstructural proteins (nsps), essential for the virus replication. The 3CLpro is a cysteine protease consisting of three domains, active as a homodimer. The substrate-binding site with a catalytic dyad of His41 and Cys145 is located between domains I and domain II. Domain III plays an important role in Mpro dimerization. This viral protease was rapidly reported and validated as a promising target to develop broad- spectrum anti-coronavirus compounds because of its crucial role in the viral replication cycle, its high substrate specificity not found in human proteases and the high degree ofhomology shared with other human coronaviruses, in particular at the level of thecatalytic site. However, despite the massive vaccination of the population and the development of some antiviral treatments, greatly reducing the risk of death, the high prevalence and intrinsic virulence of SARS-CoV-2 continue to cause severe disease and mortality. The development of new oral anti-coronavirus compounds is still essential to fight SARS- CoV-2, to address some issues with current treatments including drug-drug interactions or potential emerging resistance with the constant spread of new variants of concern, and also to prepare for emerging coronavirus-related epidemics. SUMMARY OF THE INVENTIONThe invention relates to a compound of formula (I) as disclosed herein as well ashydrates, solvates, salts or deuterated analogs thereof and to their use in medicine, inparticular for the treatment or prophylaxis of a disorder mediated by a coronavirus.The invention also related to a pharmaceutical or veterinary composition comprising atleast one compound of formula (I) as disclosed herein and one or more excipients andto its use in medicine, in particular for the treatment or prophylaxis of a disorder mediatedby a coronavirus. Further aspects of the invention are as disclosed herein and in the claims. DESCRIPTION OF THE INVENTION Compounds of formula (I)The present invention relates to compounds of formula (I): (I) wherein:R1 is selected from the group consisting of -C1-C6-alkyl; -C1-C6-hydroxalkyl; -C1-C6-haloalkyl; -C1-C6-cyanoalkyl; -O-C1-C6-alkyl; -C(O)ORa wherein Ra is selected from thegroup consisting of hydrogen atom, -C1-C6-alkyl and Li; -C(O)N(Rb)2 wherein Rb isindependently selected from the group consisting of hydrogen atom and C1-C6-alkyl, orthe two Rb form together a 5- or 6-membered non-aromatic ring containing one, two orthree heteroatoms, each independently selected from O, S, and N; 3- to 6-memberednon-aromatic ring containing one, two or three heteroatoms, each independentlyselected from O, S, and N; 5- or 6-membered heteroaryl;-C1-C6-alkyl-SRc wherein Rc isselected from the group consisting of hydrogen atom and -C(O)-C1-C6-alkyl; -C1-C6-alkyl-O-C1-C6-alkyl; -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16; -C1-C6-alkyl-N(Rd)2 wherein Rdis independently selected from the group consisting ofhydrogen atom, C1-C6-alkyl and-C(O)O-C1-C6-alkyl; -C1-C6-alkyl-C(O)ORe wherein Re isselected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); C1-C6-alkyl-C(O)-azetine-(5- or 6-membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl, -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16, -C1-C6-alkoxy andC1-C6-alkyl-N(C1-C6-alkyl)2, or the two Rf form together a 5- to 6-membered non-aromaticring containing one, two or three heteroatoms, each independently selected from O, S,and N; -C1-C6-alkyl-(5- or 6-membered heteroaryl); and -C1-C6-alkyl-NH-C(O)ORgwherein Rg is independently selected from the group consisting of -C1-C6-alkyl and -C1-C6-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl; wherein said5- or 6-membered non-aromatic ring, said 3- to 6-membered non-aromatic ring and said5- or 6-membered heteroaryl may be substituted by one or more substituents selectedfrom the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano,=O, =S, =N—CN, and ═N—OH;R2 is independently selected from the group consisting of -C1-C6-alkyl; -C2-C6-alkynyl; -C1-C6-haloalkyl; -C1-C6-alkoxy; -C1-C6-cyanoalkyl; cyano; phenyl; -C1-C6-alkyl-O-C1-C6-alkyl; -C1-C6-alkylsulfonyl; and -C1-C6-alkyl-N(Rh)2 wherein Rh is independently selectedfrom the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl and -C1-C6-alkyl-O-C1-C6-alkyl-O-C1-C6-alkyl; n1 is 1 or 2;X2 is a halogen atom;X3 is a halogen atom;n2 is 0 or 1; n3 is 0 or 1; or hydrates, solvates, or salts thereof. Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of formula (I). However, the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention. The term “physiologically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of the compound of formula (I). A suitable pharmaceutically acceptable salt of the compound of formula (I) may be, for example, an acid-addition salt of a compound of formula (I), such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3 -hydroxy-2 -naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3- phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethane sulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2- naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example. Solvates in the context of the invention are described as those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. The present invention includes all possible stereoisomers of the compounds of formula (I) as single stereoisomer, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of formula (I) can be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.Examples of non-aromatic 5-membered ring or 6-membered ring include but are notlimited to oxiranyl, aziridinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, imidazolidinyl, oxadiazolidinyl, thiadiazolidinyl, triazolidinyl, oxadiazolidinyl, thiadiazolidinyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, isoxazolinyl, isothiazolinyl, 3dihydropyrazolyl, dihydrooxazolyl, piperidinyl, dioxanyl, tetrahydropyranyl,tetrahydrothienyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl andhexahydrotriazinyl.Examples of aromatic 5-membered ring or 6-membered ring containing one, two or threeheteroatoms, together designated as “heteroaryl”, include but are not limited to thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl and tetrazolyl.The terms “aromatic 5-membered ring” and “aromatic 6-membered ring” (designated“heteroaryl”), “non-aromatic 5-membered ring” and “non-aromatic 6-membered ring” areintended to include both substituted and unsubstituted ring. The “aromatic 5-memberedring”, “aromatic 6-membered ring”, “non-aromatic 5-membered ring” and “non-aromatic6-membered ring” can be substituted with one or more substituents. The expression “one or more substituents” refers to a number of substituents that ranges from one to the maximum number of substituents possible based on the number of available bondingsites, provided that the conditions of stability and chemical feasibility are met. Suchsubstituents can include, but are not limited to, -C1-C6-alkyl, -C1-C6-alkoxy, halogen,hydroxyl, nitro, cyano, =O, =S, =N—CN and ═N—OH. Preferably, the ring is substitutedby a single substituent which is -C1-C6-alkyl, preferably methyl.The term “Cx-Cy” as used herein, e.g. in the context of the definition of “C1-C6-alkyl”,designates a group having a finite number of carbon atoms of x to y, e.g. a C1-C6-alkylhas a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5, or 6 carbon atoms.The term “alkyl” as used herein designates a linear or branched alkyl, e.g. methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, iso-pentyl and hexyl.The term “alkynyl” as used herein designates a straight or branched carbon chain containing one or more triple bonds, e.g. ethynyl; 1-, or 2-propynyl; 1-, 2-, or 3-butynyl, or 1,3-butadiynyl.The term “hydroxyalkyl” as used herein designates an alkyl, as defined supra, substitutedby one or more hydroxyl groups, e.g.2-hydroxy-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl and 6-hydroxy-hexyl.The term “haloalkyl” as used herein designates an alkyl, as defined supra, substitutedby one or more halogen radicals which may be the same or different, e.g. chloromethyl,fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.The term “cyanoalkyl” as used herein designates an alkyl, as defined supra, substitutedby one or more cyano groups.The term “alkylsulfonyl” as used herein designates a group of formula -S(O)2-alkyl.The term “alkoxy” as used herein designates a group of formula -O-alkyl. The term “halogen” as used herein designates chlorine, bromine, iodine and fluorine. In some embodiments, X2and X3are fluorine atoms or chlorine atoms. In some embodiments, n2=n3= 1 and X2and X3are fluorine atoms or chlorine atoms. In some embodiments, n2=0 and n3=1 and X3is a fluorine atom or a chlorine atom. In some embodiments, n2=n3= 0. In some embodiments, the compounds of the present invention present any of the following formulas: (X2)n2n2 n3(Ia) (Ib) (Ic) N N N R1 wherein R1, R2, X2, X3, n1, n2 and n3 are as disclosed herein.In some embodiments, in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), R1 isselected from the group consisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl;-C1-C3-cyanoalkyl; -C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C3-alkyl and Li; -C(O)N(Rb)2wherein Rbis independently selectedfrom the group consisting of hydrogen atom and C1-C3-alkyl, or the two Rb form togethera 5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N; 3- to 6-membered non-aromatic ring containingone, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting of hydrogen atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1- C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 2; -C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and- C(O)O-C1-C3-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the groupconsisting of hydrogen atom, -C1-C3-alkyl and Li; C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); -C1-C3-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16, -C1-C3-alkoxy andC1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 5- to 6-membered non-aromaticring containing one, two or three heteroatoms, each independently selected from O, S, and N; -C1-C3-alkyl-NH-C(O)ORgwherein Rgis independently selected from the groupconsisting of -C1-C4-alkyl and -C1-C3-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl. Preferably, R1 is -C1-C3-alkyl-C(O)N(Rf)2 wherein Rf isindependently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1- C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1to 16, -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 4- to6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N. n1 is preferably 1.In some embodiments, in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), R2 isselected from the group consisting of -C1-C3-alkyl; -C2-C3-alkynyl; -C1-C3-haloalkyl; -C1- C3-alkoxy; -C1-C3-cyanoalkyl; cyano; phenyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3- alkylsulfonyl; -C1-C3-haloalkyl and -C1-C3-alkyl-N(Rh)2wherein Rhis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3- alkyl and -C1-C3-alkyl-O-C1-C3-alkyl-O-C1-C3-alkyl.In some embodiments, in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), R1 isselected from the group consisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl; -C1-C3-cyanoalkyl; -C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C3-alkyl and Li; -C(O)N(Rb)2wherein Rbis independently selected from the group consisting of hydrogen atom and C1-C3-alkyl, or the two Rbform togethera 5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N; 3- to 6-membered non-aromatic ring containingone, two or three heteroatoms, each independently selected from O, S, and N; 5- or 6-membered heteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting of hydrogen atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1- C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 2; -C1-C6-alkyl-N(Rd)2 wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and- C(O)O-C1-C3-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the groupconsisting of hydrogen atom, -C1-C3-alkyl and Li; C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); -C1-C3-alkyl-C(O)N(Rf)2 wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, - C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16, -C1-C3-alkoxy andC1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 4- to 6-membered non-aromaticring containing one, two or three heteroatoms, each independently selected from O, S, and N; -C1-C3-alkyl-NH-C(O)ORgwherein Rgis independently selected from the groupconsisting of -C1-C4-alkyl and -C1-C3-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl, preferably, R1 is -C1-C3-alkyl-C(O)N(Rf)2 wherein Rf isindependently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1- C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1to 16, -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rf form together a 4- to6-membered non-aromatic ring containing one, two or three heteroatoms, eachindependently selected from O, S, and N; and R2 is selected from the group consistingof -C1-C3-alkyl; -C1-C3-alkoxy; -C1-C3-cyanoalkyl; phenyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1- C3-alkylsulfonyl; -C1-C3-haloalkyl and -C1-C3-alkyl-N(Rh)2wherein Rhis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl and -C1-C3-alkyl-O-C1-C3-alkyl-O-C1-C3-alkyl. n1 is preferably 1.The present invention includes any of the compounds of formula (I) disclosed in the“Examples” section (i.e. any of the compounds 1 to 9 disclosed herein as well as theirmixtures). The compounds of formula (I) can be prepared by any methods disclosed in theexamples section, in particular by the general route disclosed in the examples section. In the following, the expression “a compound of formula (I)” refers to a compound of formula (I) as described herein, including any compounds of formula (I) disclosed in the “Examples” section, as well as any salts, hydrates, solvates, isomers, mixtures of isomers in any ratio and any combinations thereof. Therefore, the term “a compound of formula (I)” may refer to a single compound of formula (I) or a combination of two or more compounds of formula (I) or salts, hydrates, solvates, isomers or mixtures of isomers thereof.The compounds of formula (I) have been found to be efficient inhibitors of 3CL protease(3CLproor Mpro). “Inhibitors” refer to molecules that are able to reduce or suppress theactivity of the enzyme. They inhibit coronavirus replication by targeting a key componentof the viral cycle. Resultantly, the compounds of formula (I) may be useful in medicine.In particular, the compounds of formula (I) may be useful for the treatment or prophylaxisof disorders in which 3CL protease is implicated, such as disorders mediated bycoronavirus, in particular disorders mediated by SARS-CoV-2. In other terms, thecompounds of formula (I) may be useful for the treatment or prophylaxis of disordersmediated by coronavirus, in particular disorders mediated by SARS-CoV-2. Thecompounds of the present invention exhibit an antiviral activity.The term “disorder” as used herein refers to a disease, condition or illness.The term "treatment" as used herein refers to combating, alleviating, reducing, relieving, suppressing, repelling, healing or improving the condition of a disorder. The terms "prophylaxis" as used herein refers to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disorder. The treatment or prophylaxis of a disorder may be partial or complete. In one aspect, the present invention relates to a compound of formula (I) for use in medicine. In another aspect, the present invention relates to a compound of formula (I) for use in the treatment or prophylaxis of a disorder mediated by a coronavirus, in particular adisorder mediated by SARS-CoV-2. In other terms, the present invention relates to acompound of formula (I) for use in the treatment or prophylaxis of a coronavirus infection,in particular for use in the treatment or prophylaxis of a SARS-CoV-2 infection.In accordance with a further aspect, the present invention relates a method of treatmentor prophylaxis of disorders mediated by a coronavirus, in particular disorders mediatedby SARS-CoV-2, using a therapeutically effective amount of a compound of formula (I).In other words, the present invention relates to a method of treating disorders mediatedby a coronavirus, in particular disorders mediated by SARS-CoV-2, comprising the stepof administering to a subject in need thereof, that may be human or animal, atherapeutically effective amount of at least one compound of formula (I). A “therapeutically effective amount” as used herein refers to an amount that (i) treats or prevents the particular disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disorder described herein. The amount of a compound which constitutes a therapeutically effective amount will vary depending on many factors, such as for instance the compound and its biological activity, the composition used for administration, the route of administration, the type of disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds, and the age, body weight, general health, sex, and diet of the patient. Such an effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge. In another aspect, the present invention relates to a compound of formula (I) for use in amethod of treating disorders mediated by a coronavirus, in particular disorders mediatedby SARS-CoV-2. In accordance with a further aspect, the present invention relates to the use of acompound of formula (I) for the preparation of a pharmaceutical composition, preferablya medicament, for the prophylaxis or treatment of disorders mediated by a coronavirus,in particular disorders mediated by SARS-CoV-2 The present invention also relates to a pharmaceutical or veterinary composition, inparticular a medicament, comprising a compound of formula (I) as described herein andone or more excipient(s), in particular one or more pharmaceutically or veterinaryacceptable excipient(s) and to their uses for the above-mentioned purposes.Said pharmaceutically or veterinary acceptable excipient(s) is / are selected, according tothe desired dosage form and mode of administration, from the typical excipients knownto persons skilled in the art. In one aspect, the present invention relates to a composition, in particular a medicament, comprising a therapeutically effective amount of a compound of formula (I) and apharmaceutically or veterinary acceptable excipient. The compositions may be useful forthe treatment or prophylaxis of disorders mediated by a coronavirus, in particulardisorders mediated by SARS-CoV-2 or in methods for treating disorders mediated bycoronavirus, in particular disorders mediated by SARS-CoV-2.Pharmaceutically acceptable excipients include fillers and carriers, ointment bases, bases for suppositories, solvents, surfactants, emulsifiers, dispersants or wetting agents, buffers, acids and bases, isotonicity agents, adsorbent, viscosity-increasing agents, gel formers, thickeners and / or binders, disintegrants, coating materials and film formers for films or diffusion membranes, capsule materials, natural or synthetic polymers, plasticizers, penetration enhancers, stabilizers, preservatives, colourants, flavourings,sweeteners, flavour- and / or odour-masking agents.The pharmaceutical or veterinary compositions according to the invention can be administered parenterally (such as intravenously or intradermally), topically, orally or rectally. The term “parenteral” as used herein includes subcutaneous, intravenous or intramuscular techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. For therapeutic purposes, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. Preferably, the compositions of the invention are administered via oral route. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersionof active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets,and pills, the dosage forms can also comprise buffering agents such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. In some embodiments, the pharmaceutical or veterinary composition of the inventionfurther comprises one or more further therapeutic compounds. Examples of therapeuticcompounds that may be used in combination with a compound of formula (I) include, butare not limited to, antimicrobial agents (including antivirals, antibiotics, anti-fungal agents), anti-inflammatory agents, PK enhancers (such as ritonavir or cobicistat). Another aspect of the present invention encompasses a combination of a compound of formula (I) as described above, with one or more other therapeutic compounds. The one or more compounds of formula (I) can be administered in therapeutically effective amounts in a combinational therapy with one or more pharmaceutically active agents (pharmaceutical combinations). The compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially or separately. In one aspect of the invention, a compound of formula (I) is administered to prior to administration of one or more other pharmaceutically active agents. In another aspect of the invention, a compound of formula (I) is administered concomitantly with the administration of one or more other pharmaceutically active agents. In yet another aspect of the invention, a compound of formula (I) of the invention is administered immediately after administration of one or more other pharmaceutically active agents. The single pharmaceutically active agents (compounds of formula (I) and other pharmaceutically active agents) may be packaged in a kit or separately. Embodiments of the present invention will now be described by way of the following examples which are provided for illustrative purposes only, and not intended to limit the scope of the disclosure.

[0002] EXAMPLESI. Chemical synthesisSolvents for synthesis, analysis and purification were purchased as analytical grade from commercial suppliers and used directly without further purification. Chemical reagents were purchased as reagent grade and used without further purification. NMR spectra were recorded on a Bruker DRX-300 spectrometer. Chemical shifts are in parts per million (ppm). The assignments were made using one-dimensional (1D)1H and13C spectra and two-dimensional (2D) HSQC, HMBC and COSY spectra. UPLC-MS Waters system was equipped with a UPLC I SMP MGR-FTN sample manager, an ACQUITY UPLC I-Class eK photodiode array detector (210–400 nm) and an ACQUITY QDa (Performance) detector (scan 30–1250). Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 μm, Waters) was used. The injection volume was 0.5 μL. A mixture of water and acetonitrile was used as mobile phase in gradient-elution. The pH of the mobile phase was adjusted with HCOOH and NH4OH to form a buffer solution at pH 3.8. The analysis time was 5 min (at a flow rate at 600 μL / min), 10 min (at a flow rate at 600 μL / min) or 30 min (at a flow rate at 600 μL / min). Purity (%) was determined using UV detection (215 nm), and all final compounds showed purity greater than 95%. HRMS analysis was performed on a LC-MS system equipped with a LCT Premier XE mass spectrometer (Waters), using a XBridge C18 column (50 mm × 4.6 mm, 3.5 μm, Waters). A gradient starting from 98% H2O 5 mM Ammonium Formate pH 3.8 and reaching 100% CH3CN 5 mM Ammonium Formate pH 3.8 within 3 min at a flow rate of 1 mL / min was used. Flash chromatography purifications were performed with a Puriflash® 430 instrument (Interchim) with UV detection at 254 nm and by ELSD, using prepacked columns (Büchi® FlashPure or Macherey-Nagel® Chromabond flash RS SiOH, 15–40 μm). Reverse flash chromatography was performed using a CombiFlash® C18 Rf200 with C18 silica gel cartridges with UV detection at 215 and 254 nm. Preparative HPLC were performed using a Buchi Pure C-830 system with an OmniSphere 10 μm column C18 Dynamax (250 mm × 41.4 mm, Agilent Technologies) with UV detection at 215 and 254 nm. A gradient starting from 10% MeCN / 90% H2O / 0.1% formic acid and reaching 100% MeCN / 0.1% formic acid at a flow rate of 80 mL / min was used. Structures of the synthetized compounds of formula (I) (examples 1 to 9) are presented herein below in table 1.Examples 1-11 were synthetized as follows (synthetic route A): Example 12 was synthetized as follows (synthetic route B): Compound 1.2-[1-benzhydryl-4-(4-methoxypyridine-3-carbonyl)piperazin-2-yl]-N- methyl-acetamide step 1. tert-butyl 4-benzhydryl-3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate Tert-butyl 3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate hydrochloride (2.0 g, 6.78 mmol, 1.0 eq.) was solubilized in dry ACN (25 mL). [bromo(phenyl)methyl]benzene (2.01 g, 8.14 mmol, 1.2 eq.) and triethylamine (2.1 mL, 14.9 mmol, 2.2 eq.) were added. The reaction mixture was heated at 50°C for two days. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as ayellow oil (1.62 g, 55%). MS (ESI+): m / z = 425 [M+H]+step 2. lithium;2-(1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl)acetate Tert-butyl 4-benzhydryl-3-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate (1.62 g, 3.82 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O (10 mL). Lithium;hydroxide;hydrate (480 mg, 11.4 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a beige solid (1.53 g, 94%). MS (ESI+): m / z = 411 [M+H]+step 3. tert-butyl 4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1- carboxylate Lithium;2-(1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl)acetate (1.00 g, 2.35 mmol, 1.0 eq.) was solubilized in dry DMF (8 mL) under inert atmosphere. N,N- Diisopropylethylamine (1.0 mL, 5.88 mmol, 2.50 eq.), methanamine;hydrochloride (318 mg, 4.71 mmol, 2.0 eq.) and HBTU (1.71 g, 2.82 mmol, 1.20 eq.) were added. The mixture was stirred at rt for 2 hours. A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a sticky pale yellow solid (690 mg, 69%). MS (ESI+): m / z = 424 [M+H]+step 4.2-(1-benzhydrylpiperazin-2-yl)-N-methyl-acetamide dihydrochloride Tert-butyl 4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate (690 mg, 1.63 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (8.0 mL, 32.0 mmol, 20.0 eq.). The mixture was stirred for 1h at rt. Solvents were removed under reduced pressure to give the desired product as an off-white solid (650 mg, quant.). MS (ESI+): m / z = 324 [M + H]+ step 5.2-[1-benzhydryl-4-(4-methoxypyridine-3-carbonyl)piperazin-2-yl]-N-methyl- acetamide 4-methoxypyridine-3-carboxylic acid (33 mg, 0.15 mmol, 1.2 eq.) was solubilized in dry DMF (1 mL) under inert atmosphere. N,N-Diisopropylethylamine (90 µL, 0.51 mmol, 4.0 eq.) and 2-(1-benzhydrylpiperazin-2-yl)-N-methyl-acetamide;dihydrochloride (50 mg, 0.13 mmol, 1.0 eq.) were added. The mixture was stirred at rt for 10 min and and HBTU(57 mg, 0.15 mmol, 1.2 eq.) was added. The reaction mixture was stirred at rt overnight.A 1M aqueous solution of NaOH was added and the product was extracted with EtOAc. The combined organic layers were washed with a 1M aqueous solution of NaOH, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a white solid (36 mg, 62%). MS (ESI+): m / z = 459 [M + H]+, HRMS- ESI+ (m / z) : calcd for C27H31N4O3[M+H]+: 459.2396; found: 459.23991H NMR (300 MHz, CD3CN) mixture of rotamers δ (ppm): 8.47 (d, J = 5.8Hz, 0.5H), 8.42(d, J = 5.8Hz, 0.5H), 8.40-8.11 (m, 1H), 7.55-7.42 (m, 4H), 7.35-7.23 (m, 4H), 7.23-7.12(m, 2H), 6.99 (d, J = 6.0Hz, 0.5H), 6.93 (d, J = 6.0Hz, 0.5H), 6.67-6.35 (m, 0.5H), 6.19(br s, 0.5H), 4.74 (s, 0.5H), 4.71 (0.5H), 4.49-4.32 (m, 1H), 3.99-3.72 (m, 3H), 3.50-3.25 (m, 1H+0.5H), 3.25-3.06 (m, 2H), 3.06-2.92 (m, 0.5H), 2.69-2.53 (m, 2H), 2.53-2.39 (2H+0.5H), 2.39-2.28 (m, 2H+0.5H). Compound 2. 2-[1-benzhydryl-4-(5-methoxypyridine-3-carbonyl)piperazin-2-yl]-N- methyl-acetamide Step 5. 2-[1-benzhydryl-4-(5-methoxypyridine-3-carbonyl)piperazin-2-yl]-N- methyl-acetamide 5-methoxypyridine-3-carboxylic acid (24.0 mg, 0.16 mmol, 1.0 eq.) was solubilized in dry DMF (0.4 mL) under inert atmosphere. N,N-Diisopropylethylamine (82 µL, 0.47 mmol, 3.0 eq.), 2-(1-benzhydrylpiperazin-2-yl)-N-methyl-acetamide;dihydrochloride (62.1 mg, 0.16 mmol, 1.0 eq.) and HBTU (65.3 mg, 0.17 mmol, 1.1 eq.) were added. After one night at rt with stirring, the crude product was extracted with EtOAc, washed three times with NaOH (1M) solution, rinced with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase flashchromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a whitelyophilizate (47.5 mg, 66%). MS (ESI+): m / z =459 [M+H]+. HRMS (TOF, ES+) m / z[M+H]+: calcd. for C27H31N4O3 m / z= 459.2396, found m / z= 459.2374.1H NMR (300 MHz, CDCl3) δ (ppm) Mixture of rotamers: 8.34 (s, 1H), 8.24 (s, 1H), 7.46(br s, 4H), 7.46-7.17 (m, 7H), 4.72 (s, 1H), 4.52-4.47 (m, 1H), 3.84 (s, 3H), 3.58-3.30 (m, 4H), 2.73-2.48 (m, 5H), 2.36-2.28 (m, 2H).Compound 3.2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamide step 1. tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1- carboxylate Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1 g, 3.67 mmol, 1.0 eq.) was solubilized in dry ACN (15.2 mL). N,N-Diisopropylethylamine (943 µL, 5.51 mmol, 1.5 eq.) was added and the mixture was stirred at room temperature for 15 min. [bromo(phenyl)methyl]benzene (907 mg, 3.67 mmol, 1.0 eq.) was added. The mixture was heated at 50°C for 10 days.0.2 eq of [bromo(phenyl)methyl]benzene and 0.5 eq of N,N-Diisopropylethylamine were added in three times during 7 days. Once the reaction completed, the mixture was diluted with EtOAc and washed with a saturated solution of NaHCO35%. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude obtained was used for the next stage without further purification. step 2.2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetic acid Tert-tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (1610 mg, 3.67 mmol, 1.0 eq.) was solubilized in a 4:1 (v / v) mixture of MeOH / H2O. Lithium hydroxide hydrate (462 mg, 11.01 mmol, 3.0 eq.) was added. The reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by reverse phase chromatography (H2O / ACN 9:1 to 0:1) to afford the desired productas an off-white solid (958 mg, 63%). MS (ESI+): m / z = 411.36 [M+H]+Step 3. tert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1- carboxylate 2-[(2R)-1-benzhydryl-4-tert-butoxycarbonyl-piperazin-2-yl]acetic acid (940 mg, 2.29 mmol, 1.0 eq.) was solubilized in dry DMF (15 mL) under inert atmosphere. N,N- Diisopropylethylamine (1.18mL, 6.870 mmol, 3 eq.), methanamine hydrochloride (186 mg, 2.75 mmol, 1.2 eq.) and HBTU (955 mg, 2.52 mmol, 1.1 eq.) were added. The mixture was stirred at rt overnight and then diluted with ethyl acetate and washed with a 1M aqueous solution of NaOH, dried over MgSO4, filtered and concentrated underreduced pressure. The crude obtained was used for the next stage without furtherpurification. MS (ESI+): m / z = 424.46 [M+H]+ step 4.2-[(2R)-(1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride tert-butyl (3R)-4-benzhydryl-3-[2-(methylamino)-2-oxo-ethyl]piperazine-1-carboxylate(1.02 g 0.78 mmol, 1.0 eq.) was solubilized in a 4M HCl solution in dioxane (4.0 mL,16.0 mmol, 20.0 eq.). The mixture was stirred for 2h at rt. Solvents were removed under reduced pressure to give the desired product as a yellow solid (1.2 g, quant.). step5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochloride (80.0 mg, 0.20 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (138 µL, 0.80 mmol, 3.0 eq.), 5-methylpyridine-3-carboxylic acid (33.2 mg, 024 mmol, 1.2 eq.) and HBTU (82 mg, 0.24 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford compound 4 as a white powder (25 mg, 28%). MS (ESI+): m / z == 443 [M+H]+. HRMS-ESI+ (m / z): calcd for C27H31N4O2[M+H]+: 443.2447; found: 443.2434.1H NMR (500 MHz, CDCl3)δ (ppm): 8.53-8.39 (m, 2H), 7.62-7.27 (m, 7.9H), 7.25-7.11(m, 3.3H), 7.11-7.02 (m, 0.7H), 4.67 (s, 1H), 4.56-4.35 (m, 1H), 3.65-3.51 (m, 1H), 3.50- 3.34 (m, 1.7H), 3.34-3.11 (m, 1.3H), 2.82-2.64 (m, 2.8H), 2.63-2.53 (m, 1.1H), 2.53-2.41(m, 1.5H), 2.40-2.32 (m, 3.3H), 2.32-2.21 (m, 1.9H).Compound 4. 2-[(2R)-1-benzhydryl-4-(5-methoxypyridine-3-carbonyl)piperazin-2- yl]-N-methyl-acetamide step 5.5-methoxypyridine-3-carboxylic acid (30.0 mg, 0.2 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (102 µL, 0.6 mmol, 3.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochloride (93.2 mg, 0.23 mmol, 1.2 eq.) and HBTU (81.5 mg, 0.21 mmol, 1.1 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford compound 5 as a white powder (50 mg, 55%). MS (ESI+): m / z = (= 459 [M+H]+. HRMS-ESI+ (m / z): calcd for C27H31N4O3 [M+H]+: 459.2396; found: 459.2388.1H NMR (300 MHz, 250K, CDCl3) δ (ppm): 8.38-8.27 (m, 1H), 8.27-8.18 (m, 1H), 7.50-7.36 (m, 4H), 7.35-7.18 (m, 7.8H), 7.18-7.13 (m, 0.8H), 4.7-4.58 (m, 1H), 4.52-4.38 (m, 1H), 3.93-3.81 (m, 3H), 3.65-3.33 (m, 2.8H), 3.27-3.09 (1.2H), 2.76-2.67 (m, 2.6H), 2.60- 2.53 (m, 1H), 2.50-2.43 (m, 1.3H), 2.41-2.15 (m, 2.2H).Compound 5. 2-[(2R)-1-benzhydryl-4-(5-cyanopyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamide step 5.5-cyanopyridine-3-carboxylic acid (40.0 mg, 0.27 mmol, 1.0 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (139 µL, 0.81 mmol, 3.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide dihydrochloride (128 mg, 0.32 mmol, 1.2 eq.) and HBTU (123 mg, 0.32 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford compound 6 as a white powder (45 mg, 36%). MS (ESI+): m / z = 454 [M+H]+. HRMS-ESI+ (m / z): calcd for C27H28N5O2[M+H]+: 454.2243; found: 454.2249.1H NMR (300 MHz, CDCl3) δ (ppm): 8.97-8.89 (m, 1H), 8.89-8.84 (m, 1H), 8.15-8.05 (m,1H), 7.51-7.37 (m, 4.2H), 7.36-7.19 (m, 6.3H), 7.19-7.13 (m, 0.7H), 7.01-6.93 (m, 0.6H), 4.67-4.55 (m, 1H), 4.51-4.42 (m, 1H), 3.75 (m, 0.4H), 3.59-3.45 (m, 1.7H), 3.45-3.38 (m, 0.6H), 3.30-3.22 (m, 0.6H), 3.22-3.15 (m, 0.4H), 3.14-3.05 (m, 0.4H), 2.78-2.68 (m, 2.3H), 2.65-2.57 (m, 0.6H), 2.54-2.38 (m, 2.1H), 2.36-2.17 (m, 2H).Compound 6. 2-[(2R)-1-benzhydryl-4-(5-phenylpyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamide step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (70.0 mg, 0.17 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (90.7 µL, 0.53 mmol, 3.0 eq.), 5-phenylpyridine-3-carboxylic acid (42.2 mg, 0.21 mmol, 1.2 eq.) and HBTU (80.4 mg, 0.21 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to afford compound 7 as awhite powder (40mg, 45%). MS (ESI+): m / z = 505 [M+H]+. HRMS-ESI+ (m / z): calcd forC32H33N4O2 [M+H]+: 505.2604; found: 505.2622.1H NMR (300 MHz, 250K, CDCl3) δ (ppm): 8.92-8.82 (m, 1H), 8.67-8.58 (m, 1H), 8.17-7.85 (m, 1H), 7.61-7.54 (m, 2H), 7.53-7.35 (m, 7.2H), 7.35-7.26 (m, 3.1H), 7.25-7.18 (m, 2.5H), 7.17-7.7.12 (m, 0.9H), 4.68-4.58 (m, 1H), 4.57-4.43 (m, 1H), 3.7-3.46 (m, 2H), 3.44-3.36 (m, 0.8H), 3.30-3.15 (m, 1.1H), 2.80-2.67 (m, 2.7H), 2.63-2.52 (m, 1H), 2.52- 2.43 (m, 0.8H), 2.42-2.17 (m, 2.5H).Compound 7. 2-[(2R)-1-benzhydryl-4-(5-isopropoxypyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamide step 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (80.0 mg, 0.20 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (104 µL, 0.60 mmol, 3.0 eq.), 5-isopropoxypyridine-3- carboxylic acid (44 mg, 0.24 mmol, 1.2 eq.) and HBTU (92 mg, 0.24 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN / H2O 10:90 to 100:0) to affordcompound 8 as a white powder (23 mg, 23%). MS (ESI+): m / z = 487 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H36N4O3[M+H]+: 487.2709; found: 487.2727.1H NMR (300 MHz, 250k, CDCl3) δ (ppm): 8.32-8.23 (m, 1H) 8.22-8.15 (m, 1H), 7.51-7.35 (m, 4.1H), 7.35-7.26 (m, 3.2H), 7.25-7.18 (m, 3.3H), 7.17-7.12 (1H), 4.69-4.56 (m, 2H), 4.51-4.39 (m, 1H), 3.66-3.5 (m, 1.2H), 3.49-3.33 (m, 1.7H), 3.28-3.12 (1.2H), 2.76- 2.64 (m, 2.6H), 2.6-2.52 (m, 1H), 2.51-2.33 (m, 1.6H), 2.30-2.17 (m, 1.8H), 1.38-1.24 (m, 6H).Compound 8. 2-[(2R)-1-benzhydryl-4-[5-(2-methoxyethoxy)pyridine-3-carbonyl]piperazin-2-yl]-N-methyl-acetamidestep 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (70.0mg, 0.17 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (91 µL, 0.53 mmol, 3.0 eq.), 5-(2-methoxyethoxy)pyridine-3- carboxylic acid (42 mg, 0.21 mmol, 1.2 eq.) and HBTU (80.4 mg, 0.21 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with NaOH (1M) solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (ACN / H2O 10:90 to 100:0) to affordcompound 9 as a white powder (30 mg, 34%). MS (ESI+): m / z = 503 [M+H]+. HRMS-ESI+ (m / z): calcd for C29H35N4O4 [M+H]+: 503.2658; found: 503.2631.1H NMR (300 MHz, 250K, CDCl3) δ (ppm) : 8.41-8.32 (m, 1H), 8.26-8.2 (m, 1H), 7.49-7.26 (m, 7.9H), 7.25-7.18 (m, 3H), 7.18-7.12 (m, 0.9H), 4.69-4.58 (m, 1H), 4.52-4.37 (m, 1H), 4.22-4.11 (m, 2H), 3.81-3.72 (m, 2H), 3.63-3.5 (m, 1.2H), 3.50-3.41 (m, 3.9H), 3.40- 3.33 (m, 0.9H), 3.26-3.13 (m, 1.2H), 2.77-2.67 (m, 2.7H), 2.60-2.52 (m, 1H), 2.49-2.42 (m, 1.3H), 2.4-2.33 (m, 0.2H), 2.30-2.14 (m, 1.9H).Compound 9.2-[(2R)-1-benzhydryl-4-(5-methylsulfonylpyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamidestep 5. 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (80.0mg, 0.20 mmol, 1.0 eq.) was solubilized in dry DMF (0.5 mL) under inert atmosphere. N,N-Diisopropylethylamine (138 µL, 0.81 mmol, 4.0 eq.), 5-methylsulfonylpyridine-3- carboxylic acid (49 mg, 0.24 mmol, 1.2 eq.) and HBTU (92 mg, 0.24 mmol, 1.2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was dilutedwith EtOAc and washed with NaOH (1M) solution. The organic phase was dried overMgSO4, filtered and concentrated under reduced pressure. The crude product was purified using preparative HPLC (10% CH3CN / 90% H2O / 0.1% formic acid to 100% CH3CN / 0.1% formic acid at a flow rate of 80 mL / min) to afford compound 9 as a whitepowder (30 mg, 29%). MS (ESI+): m / z = 507 [M+H]+. HRMS-ESI+ (m / z): calcd forC27H31N4O4S [M+H]+: 507.2066; found: 507.2038.1H NMR (300 MHz, 250K, CDCl3) δ (ppm) : 9.25-9.09 (m, 1H), 8.98-8.82 (m, 1H), 8.41-8.27 (m, 1H), 7.53-7.37 (m, 4.1H), 7.36-7.7.27 (m, 3H), 7.25-7.13 (m, 2.9H), 6.98-6.89 (m, 0.5H), 4.65-4.54 (m, 1H), 4.52-4.42 (m, 1H), 3.71-3.62 (m, 0.4H), 3.60-3.37 (m, 2.1H), 3.32-3.2 (m, 1.9H), 3.2-3.02 (m, 2.7H), 2.8-2.66 (m, 2.2H), 2.65-2.56 (m, 0.6H), 2.52-2.17 (m, 4.5H).Compound 10. 2-[(2R)-1-benzhydryl-4-(5-ethynylpyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamidestep 5.5-ethynylpyridine-3-carboxylic acid (33.2 mg, 0.23 mmol, 1.2eq.) was solubilizedin dry DMF (0.9 mL) under inert atmosphere. HBTU (88.5 mg, 0.23 mmol, 1.3 eq.) andN,N-Diisopropylethylamine (154 µL, 0.88 mmol, 5 eq.) were added. After 15 min, 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (71.4 mg, 0.18 mmol,1eq.) was added. After 2 hours, 1.2 eq of HBTU were added.The mixture was stirred at room temperature overnight. The mixture was diluted withEtOAc and washed with aqueous NaHCO3 (5%). The organic phase was dried overMgSO4, filtered and concentrated under reduced pressure to afford compound 10 as awhite powder (28 mg, 34%). MS (ESI+): m / z = 453 [M+H]+. HRMS-ESI+ (m / z): calcd forC28H29N4O2 [M+H]+: 453.2291; found: 453.2270.1H NMR (300 MHz, CDCl3) δ (ppm): 8.74 (s, 1H), 8.61 (s,1H), 7.84 (s, 1H), 7.47-7.39 (m, 4H), 7.33-7.29 (m, 2.8H), 7.23-7.16 (m, 2.8H), 6.89 (s, 1H), 5.43-5.30 (m, 0.2H), 4.67 (s, 1H), 4.51-4.46 (m, 1H), 3.54-3.21 (m, 5H), 2.72-2.23 (m, 7H).Compound 11. BDM_100543.R SNO24JV8209 2-[(2R)-1-benzhydryl-4-[5-(trifluoromethyl)pyridine-3-carbonyl]piperazin-2-yl]-N-methyl-acetamidestep 5. 4,5-dichloropyridine-3-carboxylic acid (52.3mg, 0.27mmol, 1.5eq.) wassolubilized in dry DMF (0.9 mL) under inert atmosphere. HBTU (85.7mg, 0.23mmol,1.3eq.) and N,N-Diisopropylethylamine (154 µL, 0.88 mmol, 5 eq.) were added. After 15min, 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (70mg,0.177mmol, 1eq.) was added. The mixture was stirred at room temperature overnight.The mixture was diluted with EtOAc and washed with aqueous NaHCO3 (5%). Theorganic phase was dried over MgSO4, filtered and concentrated under reduced pressure The crude product was purified by preparative HPLC to afford the desired product as awhite solid (23mg, 26%). MS (ESI+): m / z = 497 [M+H]+. HRMS-ESI+ (m / z): calcd forC27H28F3N4O2[M+H]+: 497.2164; found: 497.2166.1H NMR (300 MHz, CDCl3) δ (ppm): 8.94-8.86 (m, 2H), 8.03 (s, 1H), 7.45-7.17 (m, 11H),6.80 (s, 0.6H), 5.14 (s, 0.2H), 4.68 (s, 1H), 4.53-4.48 (m, 1H), 2.74-2.25 (m, 7H), 1.62 (s, 2.6H)Compound 12. 2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]-N-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]acetamidestep 1. Tert-butyl (3R)-4-benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate: Tert-butyl (3R)-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (2500 mg, 9.18 mmol, 1.0 eq.) was solubilized in dry ACN (28.5 mL). N,N-Diisopropylethylamine (2.36 mL, 13.8 mmol, 1.5 eq.) was added and the mixture was stirred at rt for 15 min. [bromo(phenyl)methyl]benzene (2269 mg, 9.18 mmol, 1.0 eq.) and sodium;iodide (275 mg, 1.84 mmol, 0.2 eq.) were added. The mixture was heated at 35°C. After 24h, [bromo(phenyl)methyl]benzene (464 mg, 1.84 mmol, 0.2 eq.) and N,N- Diisopropylethylamine (0.47 mL, 2.8 mmol, 0.3 eq.) were added. After 99h, [bromo(phenyl)methyl]benzene (227 mg, 0.92 mmol, 0.1 eq.) and N,N-Diisopropylethylamine (0.30 mL, 1.8 mmol, 0.2 eq.) were added. After a week, themixture was concentrated under reduced pressure. The crude product was solubilized in ethyl acetate and washed with NaHCO3 (saturated solution). The organic layer was dried on MgSO4 and concentrated under reduced pressure. The following step was started without purification. MS (ESI+): m / z [M+H]+=439.step 2. Ethyl 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride:HCl 4M in dioxane (8 eq., 76.1 mmol, 19.1 mL) was added to tert-butyl (3R)-4- benzhydryl-3-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (4026 mg, 9.18 mmol) at 0°C and stirred for 7h at rt. The reaction mixture was concentrated under reducedpressure. The crude product was solubilized in DCM (15 mL) and cyclohexane (300 mL)was added to allow precipitation of the product as pale brown chlorhydrate solid (3690mg, 95%). MS (ESI+): m / z [M+H]+ =339.step 3. Ethyl 2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]acetate: Ethyl 2-[(2R)-1-benzhydrylpiperazin-2-yl]acetate;dihydrochloride (100 mg, 0.24 mmol, 1.0 eq.) was solubilized in dry DMF (1.2 mL) under inert atmosphere. N,N- Diisopropylethylamine (212 µL, 1.22 mmol, 5.0 eq.), 5-methylpyridine-3-carboxylic acid (37.0 mg, 0.27 mmol, 1.1 eq.) and HBTU (101 mg, 0.27 mmol, 1.1 eq.) were added. Afterstirring 3h at rt, the mixture was diluted with EtOAc and washed with NaHCO3 (sat.). Theorganic layer was dried over MgSO4, filtered and concentrated under reduced pressure.The crude product was used in the next step without any further purification (127mg, quantitative). MS (ESI+): m / z [M+H]+ =458.step 4. Lithium;2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]acetate: To a solution of ethyl 2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]acetate (111 mg, 0.24 mmol, 1.0 eq.) in MeOH (0.5 mL), was addedlithium;hydroxide;hydrate (30.6 mg, 0.73 mmol, 3.0 eq.) in water (0.1 mL). The mixture was stirred for 24h at 35°C. The crude product was concentrated under reduced pressure and purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford thedesired product as a white lyophilizate (66 mg, 62%). MS (ESI+): m / z [M+H]+ =430.step 5. 2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]-N-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]acetamide: Lithium;2-[(2R)-1-benzhydryl-4-(5-methylpyridine-3-carbonyl)piperazin-2-yl]acetate (65.0 mg, 0.15 mmol, 1.0 eq.) was solubilized in dry DMF (0.7 mL) under inert atmosphere. N,N-Diisopropylethylamine (104 µL, 0.60 mmol, 4.0 eq.), 2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethanamine (45.0 mg, 0.18 mmol, 1.2 eq.) andHBTU (62.3 mg, 0.16 mmol, 1.1 eq.) were added. After one night at rt with stirring, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (H2O / ACN with 0.1% HCOOH) to afford the desired product as a paleyellow oil (71 mg, 72%). MS (ESI+): m / z [M+H]+ =663. HRMS (TOF, ES+) m / z [M+H]+:calcd. for C37H51N4O7 m / z= 663.3758, found m / z= 663.3788. 1H NMR(500 MHz, CDCl3) δ (ppm) Mixture of rotamers: 8.44 (br s, 2H), 7.58-7.53 (m, 1H), 7.43-7.40 (m, 4H), 7.29-7.28 (m, 2H), 7.19-7.15 (m, 4H), 4.71 (s, 1H), 4.50-4.48 (m, 0.6H), 4.37-4.35 (m, 0.4H), 3.76-3.13 (m, 27H), 2.66-2.26 (m, 7H). Compound 13.2-[(2R)-1-benzhydryl-4-[5-[(2-methoxyethylamino)methyl]pyridine- 3-carbonyl]piperazin-2-yl]-N-methyl-acetamide.step 5. 2-[(2R)-1-benzhydryl-4-(5-formylpyridine-3-carbonyl)piperazin-2-yl]-N-methyl-acetamide: 5-formylpyridine-3-carboxylic acid (57 mg, 0.36 mmol, 1.0 eq.) was solubilized in dry DMF (1.6 mL) under inert atmosphere. N,N-Diisopropylethylamine (250 µL, 1.44 mmol, 4.0 eq.), 2-[(2R)-1-benzhydrylpiperazin-2-yl]-N-methyl-acetamide;dihydrochloride (150 mg, 0.36 mmol, 1.0 eq.) and HBTU (164 mg, 0.43 mmol, 1.2 eq.) were added. Afterstirring overnight at rt, acid (29.9 mg, 0.5 eq.), HBTU (78 mg, 0.5 eq.) and N,N-Diisopropylethylamine (32 µL, 0.5 eq.) were added and the mixture was stirred for 3h. The mixture was then diluted with EtOAc and washed with NaHCO3(5%), filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (H2O / ACN 9:1 to 0:1) to afford the desired product as a whitelyophilizate (110 mg, 67%). MS (ESI+): m / z [M+H]+ =457.step 6. 2-[(2R)-1-benzhydryl-4-[5-[(2-methoxyethylamino)methyl]pyridine-3- carbonyl]piperazin-2-yl]-N-methyl-acetamide: A mixture of 2-[(2R)-1-benzhydryl-4-(5-formylpyridine-3-carbonyl)piperazin-2-yl]-N- methyl-acetamide (85 mg, 0.19 mmol, 1.0 eq.) and 2-methoxyethanamine (14 mg, 0.18 mmol, 1.0 eq.) in 0.6 mL DCM was stirred under argon for 15 minutes. Due to solubility issue, 0.6 mL of MeOH were added. Sodium triacetoxyborohydride (80 mg, 0.37 mmol, 2.0 eq.) was added portion wise at 0°C and the reaction mixture was stirred for 48h at r.t. Sodium triacetoxyborohydride (80 mg, 2.0 eq.) and 2-methoxyethanamine (14 mg, 1.0 eq) were added. After an additional 48h, sodium triacetoxyborohydride (80 mg, 2.0eq.) was added and the reaction mixture was stirred for 24h. The reaction was quenchedwith water and solvents were evaporated under vacuum. The crude product was purified by normal phase flash chromatography (DCM / MeOH 1:0 to 85:15) to afford the desired product as a yellow oil. The product was then solubilized in water and acetonitrile andlyophilized (50 mg, 52%). MS (ESI+): m / z [M+H]+ =516.1H NMR (300 MHz, CDCl3) δ (ppm): 8.60 (br s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.82 (br s,1H), 7.47-7.39 (m, 4H), 7.33-7.28 (m, 2.6H), 7.24-7.15 (m, 3.4H), 7.07 (br s, 0.6 NH), 5.50 (br s, 0.2 NH), 4.66 (s, 1H), 4.51-4.39 (m, 1H), 3.86 (s, 2H), 3.57 (br s, 1H), 3.50 (t,J = 4.9 Hz, 2H), 3.44-3.41 (m, 2H), 3.33 (s, 3H), 3.24-3.20 (m, 1H), 2.80 (t, J = 4.9 Hz,2H), 2.74-2.72 (m, 2H + 0.5H), 2.57-2.45 (m, 2H + 0.5H), 2.33-2.29 (m, 2H).II. Biological dataSARS-CoV-23CLproenzymatic assays. The FRET-based assay was optimized and miniaturized in Corning 384-wells plates (dark, low-binding, low volume). The assay was conducted at room temperature using a reaction volume of 20 µL and a buffer containing 50 mM HEPES, 0.1 mg / mL BSA, 0.01% Triton and 2 mM GSH at pH 7.5. Compounds stored as 10 mM stock solutions in DMSO were dispensed by acoustic nanodispensing with an Echo Liquid Handler (Labcyte).10 µL 3CLprowas added to the tested compounds and preincubated for 30 min before addition of 10 µL FRET-based substrate {Dabcyl}-KTSAVLQSGFRKM-{Glu(Edans)}. Final concentrations were 15 nM and 10 µM for enzyme and substrate respectively. Final concentration of DMSO did not exceed 1%. After 30 min of preincubation, the reaction progress was monitored for 30 minutes to measure the initial velocities used in calculations. The fluorescence intensity was monitored with a Victor 3V instrument (Perkin-Elmer) using excitation and emission wavelengths of 340(25) nm and 535(25) nm. pIC50values were obtained from concentration-response curves by a nonlinear regression analysis of the data using an equation at four parameters (using XL fitTMUnited Kingdom) or GraphPad Prism 7 (San Diego, USA). ^ x ^ A, minimum y value; B, maximum y value; C, LogIC50value; D, slope factor. pIC50values were averages of three independent experiments and were given with their standard deviation (SD). IC50were calculated from the mean pIC50value Results are presented in table 1. Examp le StructureIUPAC name 3CLpro3CLproIC50 (nM)pIC50 + / - SD2-[1-benzhydryl-4-(4- methoxypyridine-3- 1198 6.70 ± 0.03carbonyl)piperazin-2-yl]-N- methyl-acetamide 2-[1-benzhydryl-4-(5- methoxypyridine-3- 2 carbonyl)piperazin-2-yl]-N-106 6.97 ± 0.04methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- methylpyridine-3- 3 carbonyl)piperazin-2-yl]-N-32 7.50 ± 0.05methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- methoxypyridine-3- 4 carbonyl)piperazin-2-yl]-N-120 6.93 ± 0.1methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- cyanopyridine-3- 5 carbonyl)piperazin-2-yl]-N-130 6.89 ± 0.03methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- phenylpyridine-3- carbonyl)piperazin-2-yl]-N-497 6.30 ± 0.14methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- isopropoxypyridine-3- carbonyl)piperazin-2-yl]-N-83 7.08 ± 0.08methyl-acetamide 2-[(2R)-1-benzhydryl-4-[5-(2- methoxyethoxy)pyridine-3- carbonyl]piperazin-2-yl]-N-54 7.26 ± 0.15methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- methylsulfonylpyridine-3- carbonyl)piperazin-2-yl]-N-1400 5.85 ± 0.03methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- ethynylpyridine-3- carbonyl)piperazin-2-yl]-N-47 7.33 ± 0.01methyl-acetamide 2-[(2R)-1-benzhydryl-4-[5- (trifluoromethyl)pyridine-3-94carbonyl]piperazin-2-yl]-N-7.02 ± 0.01methyl-acetamide 2-[(2R)-1-benzhydryl-4-(5- methylpyridine-3- carbonyl)piperazin-2-yl]-N-41 7,38 ± 0,10[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]eth oxy]ethoxy]ethyl]acetamide 6,48 ± 2-[(2R)-1-benzhydryl-4-[5-[(2- methoxyethylamino)methyl]p 330 0,04 yridine-3-carbonyl]piperazin- 2-yl]-N-methyl-acetamide

Claims

1. CLAIMS1. A compound of formula (I):wherein:R1 is selected from the group consisting of -C1-C6-alkyl; -C1-C6-hydroxalkyl; -C1-C6-haloalkyl; -C1-C6-cyanoalkyl; -O-C1-C6-alkyl; -C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; -C(O)N(Rb)2 wherein Rbis independently selected from the group consisting of hydrogen atom and C1-C6-alkyl, orthe two Rb form together a 5- or 6-membered non-aromatic ring containing one, two orthree heteroatoms, each independently selected from O, S, and N; 3- to 6-memberednon-aromatic ring containing one, two or three heteroatoms, each independentlyselected from O, S, and N; 5- or 6-membered heteroaryl;-C1-C6-alkyl-SRc wherein Rc isselected from the group consisting of hydrogen atom and -C(O)-C1-C6-alkyl; -C1-C6-alkyl- O-C1-C6-alkyl; -C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16; - C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C6-alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group consisting of hydrogen atom, -C1-C6-alkyl and Li; C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); ; C1-C6-alkyl-C(O)-azetine-(5- or 6-membered heteroaryl); -C1-C6-alkyl-C(O)N(Rf)2 wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl, - C1-C6-alkyl-[O-C1-C6-alkyl]n-O-C1-C6-alkyl with n ranging from 1 to 16, -C1-C6-alkoxy andC1-C6-alkyl-N(C1-C6-alkyl)2, or the two Rf form together a 5- to 6-membered non-aromaticring containing one, two or three heteroatoms, each independently selected from O, S,and N; -C1-C6-alkyl-(5- or 6-membered heteroaryl); and -C1-C6-alkyl-NH-C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C6-alkyl and -C1-C6-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl; wherein said5- or 6-membered non-aromatic ring, said 3- to 6-membered non-aromatic ring and said5- or 6-membered heteroaryl may be substituted by one or more substituents selectedfrom the group consisting of -C1-C6-alkyl, -C1-C6-alkoxy, halogen, hydroxyl, nitro, cyano, =O, =S, =N—CN, and ═N—OH;R2 is independently selected from the group consisting of -C1-C6-alkyl; -C2-C6-alkynyl; -C1-C6-haloalkyl; -C1-C6-alkoxy; -C1-C6-cyanoalkyl; cyano; phenyl; -C1-C6-alkyl-O-C1-C6- alkyl; -C1-C6-alkylsulfonyl; and -C1-C6-alkyl-N(Rh)2 wherein Rhis independently selected from the group consisting of hydrogen atom, -C1-C6-alkyl, -C1-C6-alkyl-O-C1-C6-alkyl and -C1-C6-alkyl-O-C1-C6-alkyl-O-C1-C6-alkyl; n1 is 1 or 2;X2 is a halogen atom;X3is a halogen atom; n2is 0 or 1; n3is 0 or 1; or hydrate, solvate, or salt thereof.

2. The compound according to claim 1, wherein R1 is selected from the groupconsisting of -C1-C6-alkyl; -C1-C3-hydroxalkyl; -C1-C3-haloalkyl; -C1-C3-cyanoalkyl; - C(O)ORawherein Rais selected from the group consisting of hydrogen atom, -C1-C3- alkyl and Li; -C(O)N(Rb)2wherein Rbis independently selected from the group consistingof hydrogen atom and C1-C3-alkyl, or the two Rb form together a 5- or 6-membered non-aromatic ring containing one, two or three heteroatoms, each independently selectedfrom O, S, and N; 3- to 6-membered non-aromatic ring containing one, two or threeheteroatoms, each independently selected from O, S, and N; 5- or 6-memberedheteroaryl; -C1-C6-alkyl-SRcwherein Rcis selected from the group consisting of hydrogen atom and -C(O)-C1-C3-alkyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkyl-[O-C1-C3-alkyl]n-O- C1-C3-alkyl with n ranging from 1 to 2; -C1-C6-alkyl-N(Rd)2wherein Rdis independently selected from the group consisting of hydrogen atom, C1-C6-alkyl and-C(O)O-C1-C3- alkyl; -C1-C6-alkyl-C(O)ORewherein Reis selected from the group consisting of hydrogenatom, -C1-C3-alkyl and Li; C1-C6-alkyl-C(O)-azetidine-(5- or 6-membered heteroaryl); -C1-C3-alkyl-C(O)N(Rf)2 wherein Rfis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O- C1-C3-alkyl with n ranging from 1 to 16, -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, orthe two Rf form together a 5- to 6-membered non-aromatic ring containing one, two orthree heteroatoms, each independently selected from O, S, and N; -C1-C3-alkyl-NH- C(O)ORgwherein Rgis independently selected from the group consisting of -C1-C4-alkyland -C1-C3-alkyl-heteroaryl wherein the heteroaryl is a 5- or 6-membered heteroaryl.

3. The compound according to claim 1 or 2 wherein R1 is -C1-C3-alkyl-C(O)N(Rf)2wherein Rfis independently selected from the group consisting of hydrogen atom, -C1- C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl, -C1-C3-alkyl-[O-C1-C3-alkyl]n-O-C1-C3-alkyl with n ranging from 1 to 16, -C1-C3-alkoxy and C1-C3-alkyl-N(C1-C3-alkyl)2, or the two Rfformtogether a 4- to 6-membered non-aromatic ring containing one, two or threeheteroatoms, each independently selected from O, S, and N.

4. The compound according to any one of claims 1 to 3, wherein R2 is selected fromthe group consisting of -C1-C3-alkyl; -C2-C3-alkynyl; -C1-C3-haloalkyl; -C1-C3-alkoxy; -C1- C3-cyanoalkyl; cyano; phenyl; -C1-C3-alkyl-O-C1-C3-alkyl; -C1-C3-alkylsulfonyl; -C1-C3- haloalkyl and -C1-C3-alkyl-N(Rh)2wherein Rhis independently selected from the group consisting of hydrogen atom, -C1-C3-alkyl, -C1-C3-alkyl-O-C1-C3-alkyl and -C1-C3-alkyl-O- C1-C3-alkyl-O-C1-C3-alkyl.

5. The compound according to any one of claims 1 to 4, wherein it has one of thefollowing formulas: n3N N N R1R1, R2, X2, X3, n1, n2 and n3 being as recited in any one of claims 1 to 4.

6. The compound according to any one the preceding claims, which is any of thecompounds 1-13 as listed in table 1.

7. A pharmaceutical or veterinary composition comprising at least one compound offormula (I) according to any one of the preceding claims and one or more excipients.

8. A compound of formula (I) according to any of claims 1 to 6 or a pharmaceuticalcomposition according to claim 7 for use in medicine.

9. A compound of formula (I) according to any of claims 1 to 6 or a pharmaceuticalcomposition according to claim 7 for use in treatment or prophylaxis of a disordermediated by a coronavirus.

10. A compound of formula (I) or a pharmaceutical composition for its use accordingto claim 9, wherein the coronavirus is SARS-CoV-2.

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