WO2021204423A1

WO2021204423A1 - Use of 15-membered azalides as active agents in the treatment of viral infections

Info

Publication number: WO2021204423A1
Application number: PCT/EP2021/025124
Authority: WO
Inventors: Mihaela Peric; Mirjana BUKVIC
Original assignee: University of Zagreb School of Medicine
Priority date: 2020-04-05
Filing date: 2021-04-03
Publication date: 2021-10-14

Abstract

The present invention relates to 15-membered azalides of formulae (I), (II) or (III) or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate, pharmaceutical compositions comprising the same, and methods for the prophylaxis and/or treatment using the same, for use in prophylaxis and/or therapeutic treatment of diseases caused by viruses belonging to the family of Coronaviridae. Such treatment comprises administering to the subject a therapeutically effective amount of compound of the invention or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier for the prophylaxis and /or treatment of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses.

Description

USE OF 15-MEMBERED AZALIDES AS ACTIVE AGENTS IN THE TREATMENT OF VIRAL INFECTIONS FIELD OF THE INVENTION

The present invention relates to a 15-membered azalides for use in the prevention and/or treatment of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses. Specifically, the present invention relates to an 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a- aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A azalides and their pharmaceutically acceptable derivatives for use in the treatment and/or prevention of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses. Furthermore, the present invention relates to a corresponding method of therapeutic or prophylactic treatment of diseases caused by viruses belonging to the family of Coronaviridae in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a-aza-9-deoxo- 9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A azalides and their pharmaceutically acceptable derivatives.

TECHNICAL PROBLEM

The invention is directed to agents with antiviral effects and effects on diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses not heretofore used to treat viruses belonging to the family of Coronaviridae, in particular coronavirus caused infections.

BACKGROUND OF THE INVENTION

Coronaviruses are a group of viruses that are causing various diseases in mammals and birds. In humans, coronaviruses cause respiratory tract infections that can vary from mild, such as some cases of the common cold, to lethal, such as SARS, MERS, and COVID-19. In animals symptoms may differ: in chickens, they cause upper respiratory tract diseases, while in cows and pigs they usually cause diarrhea. Coronaviruses belongs to the family of Coronaviridae that is composed of four genuses: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus.

Human coronavirus infections represent a serious threat to human health with some of the infection proven as very severe (up to 30% mortality in MERS patients) (Liu et al., 2017). Coronaviruses can cause pneumonia (either direct viral pneumonia or a secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or a secondary bacterial bronchitis) (Forgie and Marrie, 2009). The human coronavirus discovered in 2003, SARS-CoV, which causes severe acute respiratory syndrome (SARS), has a unique pathogenesis because it causes both upper and lower respiratory tract infections (Forgie and Marrie, 2009).

Seven strains of coronaviruses that infect humans are currently known. Four strains produce generally mild symptoms (similar to common cold): 1) human coronavirus OC43 (FICoV-OC43), 2) human coronavirus FIKU1, 3) human coronavirus NL63 (FICoV-NL63, New Flaven coronavirus), 4) human coronavirus 229E (FICoV-229E). For the other three belonging to the Betacoronavirus genus, the symptoms they cause are potentially severe and can be lethal: 1) middle East respiratory syndrome- related coronavirus (MERS-CoV), previously known as novel coronavirus 2012 and FICoV-EMC, 2) severe acute respiratory syndrome coronavirus (SARS-CoV or "SARS-classic"), 3) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019-nCoV or "novel coronavirus 2019" (Fehr and Perlman, 2015;He et al., 2020). The coronaviruses FICoV-229E, -NL63, - OC43, and -FIKU1 continually circulate in the human population and cause respiratory infections in adults and children world-wide (Corman et al., 2018).

In December 2019, an outbreak of an unknown disease called pneumonia of unknown cause was reported in Wuhan, Hubei Province, China (Fie et al., 2020). The causative agent of this pneumonia was identified as a novel coronavirus. World Hea Ith Organization has termed the virus as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease as coronavirus disease 2019 (COVID- 19). The epidemic has spread across China and many other countries very fast (Lai et al., 2020;Wang et al., 2020). Up to end of March 2020, more than 600.000 cases of the disease and more than 27.000 deaths have been reported worldwide (www.who.int). The World Hea Ith Organization on March 12 declared the novel coronavirus outbreak a pandemic as the COVID-19 spreads and becomes a global health threat. It is estimated that most of the population worldwide will be infected with SARS-CoV-2.

COVID-19 produces an acute viral infection in humans with median incubation period 3.0 days, which is similar to the SARS with an incubation period ranging from 2-10 days (Wang et al., 2020). The common clinical symptoms of COVID-19 infection are fever (87.9%), cough (67.7%), fatigue (38.1%), while diarrhea (3.7%) and vomiting (5.0%) are rare, which were similar to others coronavirus. Most patients also present dyspnoea at presentation, because the time from onset of symptoms to the development of acute respiratory distress syndrome (ARDS) is 9 days among the initial patients with COVID-19 infection. Moreover, severe patients present a variety of complications, including acute respiratory distress syndrome, acute heart injury and secondary infection. There are already some evidences that SARS-CoV-2 can cause damage to tissues and organs causing neurological manifestations, arrhythmia, acute heart injury, impaired renal function, and abnormal liver function.

According to the Chinese epidemiology data, about 80% of patients present with mild disease and the overall case-fatality rate is about 2.3% but reaches 8.0% in patients aged 70 to 79 years and 14.8% in those aged >80 years (Wu and McGoogan, 2020). However, as an important number of asymptomatic carriers exists in the population, the mortality rate is probably overemphasized. Europe and USA are now facing the COVID-19 wave with daily increase in new cases and mortalities counted in thousands.

Further, because there is little to no pre-existing immunity against the new virus, it spreads worldwide. The virus that causes COVID-19 is infecting people and spreading easily from person-to-person. Cases have been detected in most countries worldwide, and therefore, there is an urgent need to develop an effective remedy.

In the last days several reports indicated that chloroquine, hydroxychloroquine and azithromycin have potential for prophylactic as well as therapeutic use against COVID-19 (Gautret et al., 2020;Pang et al., 2020). The French scientists reported the preliminary results of the ongoing clinical trial showing that hydroxychloroquine treatment is associated with significant viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin (Gautret et al., 2020). Additionally, Hu et al. reported the potential molecular mechanism behind chloroquine efficacy against SARS-CoV-2: inhibition of pH-dependent viral fusion/replication and prevention of viral envelope glycoprotein as well as host receptor protein glycosylation, inhibition of viral clathrin-mediated endocytosis, prevention of endosome-lysosome fusion, inhibition of endosomal acidification, and inhibition of virion assembly in endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-like structures. In addition, effects on the host, like attenuation the pro-inflammatory factors and receptors inducing acute respiratory distress syndrome, could primarily be responsible for alleviating coronavirus- associated mortality (Hu et al., 2020).

Currently, there are more than 180 vaccines at various stages of development. Because there are valid concerns related to the effectiveness of the available vaccines against current and future outbreaks of the new virus variants, there is an urgent need for an effective prevention and/or treatment of the disease. The idea of combining chloroquinoline derivatives and azithromycin scaffold for treating malaria has already proven successful as active new entities were obtained with improved characteristics over parent compounds (Peric et al., 2012;Pesic et al., 2012; Starcevic et al., 2012). It is know from before that critical molecular property for cellular accumulation and retention of a basic macrolide are its lipophilicity and charge (Stepanic et al., 2011), we propose that for these new azalides the increased number of positively charged centres and the introduced aromatic rings in the scaffold, increase the alkaline (positive charge) as well as lipophilic properties compared to azithromycin and enhance their ability to cross cellular membranes and be retained within cells. Additionally, pH gradient between cytosolic pH and pH of plasma could lead these cationic amphiphilic compounds towards cytosol as well as acidic cellular compartments and entrap them inside (Kaufmann and Krise, 2007). Expanding the use of these compounds for the benefit in preventing and treating the novel infectious global health threats in the form of coronaviruses seems a valid and a necessary effort.

SUMMARY OF THE INVENTION

It has been found that 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 5-0- decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A azalides have antiviral activity. These compounds can therefore be used in the treatment and/or prevention of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses.

In a first aspect, the present invention is directed to an 9a-substituted, 3'-N-substituted, 2'-0- substituted 9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9- dihydro-9a-homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9- dihydro-9a-homoerythromycin A azalides selected from compounds having the Formula (I), Formula (II) or Formula (III), wherein a compound of Formula (I) is

wherein

R1 represents H or a a-L-cladinosyl group of formula (a); R2 represents H or a b-D-desosaminyl group of formula (b);

provided that when R2 is H then R1 is also H;

L represents -(Ch j_p-X-Q-;

X represents -NR³, -NHC(=0) or -C(=0)NH;

R³ represents H or linear or branched Ci_₄alkyl;

Q represents a) single bond, b) Ci-₄alkylene linear or branched which is unsubstituted or substituted, c) C - alkenylene; p is an integer from 2 to 4;

A1 represents a) aryl is mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic ring which is unsubstituted or substituted by 1-4 groups selected from unsubstituted or substituted Ci-₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄dialkylamino, C - cycloalkylamino; b) 3-14 membered heterocycle, which is monocyclic, bicyclic or tricyclic ring any of which is saturated, unsaturated or aromatic containing 1 to 4 heteroatoms selected from nitrogen (unsubstituted or substituted by H or Cl-4 alkyl), oxygen and sulphur, unsubstituted or substituted on 1-3 ring carbon atoms by groups independently selected from unsubstituted or substituted Ci_₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄ dialkylamino, C - cycloalkylamino; a compound of Formula (II) is wherein

R1 represents H or a a-L-cladinosyl group of Formula (a);

R4 represents H or CH3;

R5 represents Ll-A, L2-A or L3-A;

LI represents -(CH2)a-Xl-(CH2)b-(NH)_c-;

L2 represents -C(0)-(CH2)b-( N H)_c-;

L3 represents

XI represents -N(R⁶)-, -NHC(O)- or -C(0)NH-;

Y represents -N(R⁷)-;

R⁶ and R⁷ independently represent H or Ci- alkyl;

A is a moiety of Formula (c) or (d):

(C) (d) attached to the rest of the molecule through any available carbon atom;

R⁸ represents FI or halogen or -OCFI3 or -CF3 and is attached to Formula (c) or (d) at any available carbon atom; a is an integer from 2 to 6; b is an integer from 0 to 6; c is 0 or 1; m is an integer from 1 to 4; n is an integer from 1 to 4; provided that when c is 1 then b is an integer from 1 to 6; a compound of Formula (III) is

wherein

R1 represents H or a a-L-cladinosyl group of Formula (a);

R9 represents Ll-A; or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate for use in the treatment and/or prophylaxis of diseases caused by viruses belonging to the family of Coronaviridae.

In an additional aspect, the present invention is directed to methods of treating and/or preventing diseases caused by viruses belonging to the family of Coronaviridae comprising the administration of 9a-substituted 9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo- 9-dihydro-9a-homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9- dihydro-9a-homoerythromycin A azalides selected from compounds having the Formula (I), Formula (II) or Formula (III), wherein a compound of Formula (I) is wherein

R1 represents H or a a-L-cladinosyl group of formula (a);

R2 represents H or a b-D-desosaminyl group of formula (b);

provided that when R2 is H then R1 is also H;

L represents -(Ch jp-X-Q-;

X represents -NR³, -NHC(=0) or -C(=0)NH;

R³ represents H or linear or branched Ci_₄alkyl;

A1 represents a) aryl is mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic ring which is unsubstituted or substituted by 1-4 groups selected from unsubstituted or substituted Ci-₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , C alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄dialkylamino, C - cycloalkylamino; b) 3-14 membered heterocycle, which is monocyclic, bicyclic or tricyclic ring any of which is saturated, unsaturated or aromatic containing 1 to 4 heteroatoms selected from nitrogen (unsubstituted or substituted by H or Cl-4 alkyl), oxygen and sulphur, unsubstituted or substituted on 1-3 ring carbon atoms by groups independently selected from unsubstituted or substituted Ci_₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄ dialkylamino, C - cycloalkylamino; a compound of Formula (II) is

(ID wherein

R1 represents H or a a-L-cladinosyl group of Formula (a); R4 represents H or CH₃;

R5 represents Ll-A, L2-A or L3-A;

LI represents -(CH )_a-Xl-(CH )_b-(NH)_c-;

L2 represents -C(0)-(CH₂)b-( N H)_c-;

L3 represendts

XI represents -N(R⁶)-, -NHC(O)- or -C(0)NH-;

Y represents -N(R⁷)-;

R⁶ and R⁷ independently represent H or Ci- alkyl; A is a moiety of Formula (c) or (d):

(c) (d) attached to the rest of the molecule through any available carbon atom;

R⁸ represents H or halogen or -OCH₃ or -CF₃ and is attached to Formula (c) or (d) at any available carbon atom; a is an integer from 2 to 6; b is an integer from 0 to 6; c is 0 or 1; m is an integer from 1 to 4; n is an integer from 1 to 4; provided that when c is 1 then b is an integer from 1 to 6; a compound of Formula (III) is

wherein

R1 represents FI or a a-L-cladinosyl group of Formula (a);

R9 represents Ll-A; or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate.

In a further aspect, the present invention is directed to the compounds of Formula (I), Formula (II) or Formula (III) for use in the prophylaxis and / or treatment of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses. In additional aspect, the present invention is also directed to the use of the compounds of Formula (I), Formula (II) or Formula (III) in the manufacture of a medicament for preventing and / or treating diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses.

In particular aspect, the compounds of Formula (I), Formula (II) or Formula (III) are provided for use in the prophylaxis and / or treatment of diseases caused by coronaviruses including but not limited to HCoV-OC43, HKU1, HCoV-NL63, HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2, in particular to MERS-CoV, SARS-CoV or SARS-CoV-2. Furthermore, it has also been unexpectedly demonstrated that the compounds of Formula (I), Formula (II) or Formula (III) exhibit good potency and exposure in vivo. This may result in low dosages regimen, and suitability for use alone or in combination with other therapeutic agents that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.

In additional aspect, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a particular aspect, said pharmaceutical composition additionally comprises further active ingredients suitable for use in combination with the compounds of the invention including but not limited to agent producing a broad-spectrum activity against several RNA and DNA viruses, agent for treatment of bacterial infections, agent for treatment and prevention of malaria, and/or agent that enlist natural immune system functions.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent including but not limited to agent producing a broad-spectrum activity against several RNA and DNA viruses, agent for treatment of bacterial infections, agent for treatment and prevention of malaria, and/or agent that enlist natural immune system functions.

Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with diseases caused by viruses belonging to the family of Coronaviridae, in particular coronavirus, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in the prophylaxis and / or treatment diseases caused by viruses belonging to the family of Coronaviridae, in particular coronavirus. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and/or treatment of diseases caused by coronavirus, including but not limited to HCoV-OC43, HKU1, HCoV- NL63, HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2, in particular to MERS-CoV, SARS-CoV or SARS-CoV-2.

Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.

The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.

The terms "compound (I)", "compound according to formula (I)" or "compound of formula (I)" may be used interchangeably to refer to the compound having structural formula (I). Same applies to compound (II) and compound (III).

'Alkyl' means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2- CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1 ,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2- CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

The term "substituted alkyl" as used herein, refers to a "Ci-C4 alkyl" group as previously defined, substituted by independent replacement of one, two, or three of the hydrogen atoms thereon with substituents including, but not limited to: halogen (such as fluoro, chloro or bromo); OH; oxo;. C1-C4 alkylamino (such as N-methylamino or N-ethylamino); -NC(0)-Cl-C4-alkyl (such as NC(O)-methyl); Cl- C4-alkylamino (such as dimethylamino, diethylamino or di- isopropylamino); C1-C4 alkyloxy (such as methoxy or ethoxy); C3-C6 cycloalkyloxy (such as cyclopropoxy or cyclohexyloxy).

The term "alkyloxy" or "alkoxy", as used herein, refers to a straight or branched chain Cl- 4alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom containing the specified number of carbon atoms. For example, Cl-4alkoxy means a straight or branched alkoxy containing at least 1 and at most 4 carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-l-oxy and 2- methylprop-2-oxy.

'Alkenyl' refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, particularly, from 2 to 6 carbon atoms and more particularly from 2 to 4 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

'Alkylene' refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight- chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2- CH2-), or -CH(CH3)- and the like.

'Amino' refers to the radical -NH2.

The term "aryl", as used herein, refers to a mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members including, but not limited to, phenyl, azulenyl, naphthyl, fluorenyl, tetrahydronaphthyl, indanyl, idenyl, anthracenyl and the like.

The term "substituted aryl", as used herein, refers to an aryl group, as previously defined, substituted by independent replacement of one, two, three or four of the hydrogen atoms thereon with substituents including, but not limited to unsubstituted or substituted Cl-4 alkyl (such as methyl or ethyl), unsubstituted or substituted C3-6 cycloalkyl (such as cyclopropyl or cyclohexyl), halogen (such as fluoro, chloro or bromo), OH, N02, Cl-4 alkyloxy (such as methyloxy or ethyloxy), C3-6 cycloalkyloxy (such as cyclopropyloxy or cyclohexyloxy), Cl-4 alkylamino (such as methylamino or ethylamino), Cl-4 dialkylamino (such as dimethylamino or diethylamino), C3-6 cycloalkylamino (such as cyclopropylamino or cyclohexylamino).

'Cycloalkyl' refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

'Halo' or'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

As used herein, the term "3 to 14 membered heterocycle" means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14-membered monocyclic, bicyclic or tricyclic ring (recognizing that rings with certain numbers of members cannot be bicyclic or tricyclic, e.g., a 3-membered ring can only be a monocyclic ring), any of which is saturated, unsaturated, or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to a second ring (e. g., a benzene ring). When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom). The nitrogen atom may be substituted or unsubstituted. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. Fused rings are also included (e.g. quinolinyl, iso quinolinyl, tetrahydroquinolinyl, lH-purin-6-yl, phenothiazinyl, acridinyl or phenoxazinyl).

The term "substituted 3-14 membered heterocycle", as used herein, refers to a 3-14 membered heterocycle group, as previously defined, substituted on 1-3 ring carbon atoms by independent replacement of one, two or three of the hydrogen atoms thereon with substituents including, but not limited to, unsubstituted or substituted Cl-4 alkyl (such as methyl or ethyl), unsubstituted or substituted C3-6 cycloalkyl (such as cyclopropyl or cyclohexyl), halogen (such as fluoro, chloro or bromo), OH, N02, Cl-4 alkyloxy (such as methyloxy or ethyloxy), C3-6 cycloalkyloxy (such as cyclopropyloxy or cyclohexyloxy), Cl-4 alkylamino (such as methylamino or ethylamino), C^A dialkylamino (such as dimethylamino or diethylamino), C3-6 cycloalkylamino (such as cyclopropylamino or cyclohexylamino).

As used herein, the term "aromatic heterocycle" or "heteroaryl" is intended to mean a stable 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14-membered monocyclic or bicyclic aromatic ring (recognizing that rings with certain numbers of members cannot be a bicyclic aromatic, e. g., a 5-membered ring can only be a monocyclic aromatic ring), which consists of carbon atoms and one or more heteroatoms, e. g., 1 or 1- 2 or 1-3 or 1-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e. g., 2,3-dihydroindole), though both may be (e.g., quinoline). The second ring can be fused as defined above for heterocycles. The nitrogen atom may be substituted or unsubstituted.

Examples of heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, 2,3- dihydrobenzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzo[l ,3]dioxolyl, benzo[l ,3]dioxanyl benzoxazolinyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, benzo[l ,2,5]thiadiazolyl, benzimidazolinyl, 3,4-dihydro- 2H-benzo[b][l,4]dioxepinyl, 4,5,6,7-tetrahydro- benzo[b]thiophenyl, carbazolyl, 4aH- carbazolyl, cinnolinyl, decahydroquinolinyl, dihydrofuro[2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4- oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,6H-l ,2,5- thiadiazinyl, 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl.

Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl, in particular quinolinyl.

The term "lower alcohol", as used herein, refers to a Cl-4alcohol, such as for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.

The term "inert solvent", as used herein, refers to a solvent that cannot react with the dissolved compounds including non-polar solvent such as hexane, toluene, diethyl ether, diisopropylether, chloroform, ethyl acetate, THF, dichloromethane; polar aprotic solvents such as acetonitrile, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, and polar protic solvents such as lower alcohol, acetic acid, formic acid and water.

One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

The term "carrier" refers to a diluent, excipient, and/or vehicle with which an active compound is administered. The pharmaceutical compositions of the invention may contain combinations of more than one carrier. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington: The Science and Practice of Pharmacy" 22nd Edition.

'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. The term "salts" can include acid addition salts or addition salts of free bases. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.

'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvation reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

"Subject" refers to an animal, which is preferably a mammal and more preferably human or a domestic animal. Most preferably, the subject is a human. As used herein, the term 'patient' is used synonymously with 'subject'.

'Effective amount' means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop) in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease including treating subjects who are at risk of developing disease caused by viruses belonging to the family of Coronaviridae. Non-limiting examples of prophylactic measures may include treatment of subjects who have been exposed to the virus, the treatment of subjects who intend to travels to a country where infections caused by viruses belonging to the family of Coronaviridae could occur and the treatment of subjects who otherwise risk exposure to said viruses.

'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician. 'Compound(s) of the invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

When ranges are referred to herein, for example but without limitation, Cl-4 alkyl, the citation of a range should be considered a representation of each member of said range.

Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Cl-8 alkyl, C2-8 alkenyl, C6-10 optionally substituted aryl, and (C6-C10ary)-(Cl-4-alkyl) esters of the compounds of the invention.

The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the 'natural isotopic form') or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an 'unnatural variant isotopic form') ft is understood that an atom may naturally exists as a mixture of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an 'uncommon isotope') has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or > 99% by number of the atoms of that atomic number (the latter embodiment referred to as an 'isotopically enriched variant form'). The term 'unnatural variant isotopic form' also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (²H or D), carbon-11 (ⁿC), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-15 (¹⁵N), oxygen-15 (¹⁵0), oxygen-17 (¹⁷0), oxygen-18 (¹⁸0), phosphorus-32 (³²P), sulphur-35 (³⁵S), chlorine-36 (³⁶CI), chlorine-37 (³⁷CI), fluorine-18 (¹⁸F) iodine-123 (¹²³l), iodine-125 (¹²⁵l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopicforms which incorporate deuterium i.e. ²H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as ⁿC, ¹⁸F, ¹⁵0 and ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.

Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.

'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually h). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.

THE INVENTION

The present invention is based on the identification that 9a-substituted, 3'-N-substituted, 2'-0- substituted 9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9- dihydro-9a-homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9- dihydro-9a-homoerythromycin A azalides have antiviral activity. These compounds can therefore be used in the treatment and/or prevention of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronavirus.

Accordingly, in the first aspect the present invention is directed to an 9a-substituted 9a-aza-9-deoxo- 9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A azalides selected from compounds having the Formula (I), Formula (II) or Formula (III), wherein a compound of Formula (I) is wherein

R1 represents H or a a-L-cladinosyl group of formula (a);

R2 represents H or a b-D-desosaminyl group of formula (b);

provided that when R2 is H then R1 is also H;

L represents -(CH )_P-X-Q-;

X represents -NR³, -NHC(=0) or -C(=0)NH;

R³ represents H or linear or branched Ci- alkyl;

Q represents a) single bond, b) Ci- alkylene linear or branched which is unsubstituted or substituted, c) C - alkenylene; p is an integer from 2 to 4;

(ID wherein

R5 represents Ll-A, L2-A or L3-A;

LI represents -(CH )_a-Xl-(CH )_b-(NH)_c-;

L2 represents -C(0)-(CH₂)b-(NH)_c-;

L3 represents

XI represents -N(R⁶)-, -NHC(O)- or -C(0)NH-;

Y represents -N(R⁷)-;

R⁶ and R⁷ independently represent H or Ci- alkyl;

A is a moiety of Formula (c) or (d):

(c) (d) attached to the rest of the molecule through any available carbon atom;

wherein

R1 represents FI or a a-L-cladinosyl group of Formula (a);

R9 represents Ll-A; or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate for use in the treatment and/or prophylaxis of diseases caused by viruses belonging to the family of Coronaviridae. In a further aspect, the present invention is directed to the compounds of Formula (I), Formula (II) or Formula (III) for use in the prophylaxis and / or treatment of diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses.

In additional aspect, the present invention is also directed to the use of the compounds of Formula (I), Formula (II) or Formula (III) in the manufacture of a medicament for preventing and / or treating diseases caused by viruses belonging to the family of Coronaviridae, in particular coronaviruses.

In additional aspect, the present invention is also directed to methods of treating and/or preventing diseases caused by viruses belonging to the family of Coronaviridae comprising the administration to the subject the therapeutically effective amount of compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate.

In one embodiment, the compound of the invention is according to Formula (I).

In one embodiment, the compound of the invention is according to Formula (II).

In one embodiment, the compound of the invention is according to Formula (III).

In one embodiment, the compound of the invention is according to Formula (I) or (III).

In one embodiment, the compound of the invention is according to Formula (I), (II) or (III), wherein R1 represents a-L-cladinosyl group of Formula (a). In further embodiment, the compound of the invention is according to Formula (I), (II) or (III), wherein R1 represents H.

In one embodiment, the compound of the invention is according to Formula (I), wherein R1 represents a-L-cladinosyl group of Formula (a) and R2 represents b-D-desosaminyl group of formula (b).

In one embodiment, the compound of the invention is according to Formula (I), wherein X is NR3, and R3 is H.

In one embodiment Q is single bond.

In one embodiment p is 2.

In one embodiment R4 is CF . In a further embodiment R4 is H.

In one embodiment R5 or R9 independently represent Ll-A, wherein LI is -(CFH )_a-Xl-(CH )_b-( N FH )_c-, XI is -N(R⁶)-, R⁶ is H, a is 2, and b=c= zero.

In one embodiment A and A1 independently represent moiety of Formula (c), wherein R⁶ is chloro.

In one embodiment, the compound of the invention is selected from: In one embodiment, the compounds of the invention are provided in a natural isotopic form.

In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. ²H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound. While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). The present invention also encompasses prodrugs of the Formula (I), (II) or (III) compounds, i.e., compounds which release an active parent drug according to Formula (I), (II) or (III) in vivo when administered to a mammalian subject. Prodrugs of a compound of Formula (I), (II) or (III) are prepared by modifying functional groups present in the compound of Formula (I), (II) or (III) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I), (II) or (III) wherein a hydroxy, amino, or carboxy group of a Formula (I), (II) or (III) compound is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino or carboxy group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives) of compounds of Formula (I) or any other derivative which upon being brought to the physiological pFH or through enzyme action is converted to the active parent drug.

The invention provides, inter alia, the subject matter of the following clauses: 1. A method for the therapeutic and/or prophylactic treatment of diseases caused by viruses belonging to the family of Coronaviridae in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9- deoxo-9-dihydro-9a-homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9- deoxo-9-dihydro-9a-homoerythromycin A azalide selected from compounds having the: Formula (I), Formula (II) or Formula (III), wherein a compound of Formula (I) is

wherein R1 represents H or a a-L-cladinosyl group of formula (a)

R2 represents H or a b-D-desosaminyl group of formula (b)

provided that when R2 is H then R1 is also H;

L represents -(CF J_p-X-Q-;

X represents NR³, -NHC(=0) or -C(=0)NH;

R³ represents FI or linear or branched Ci_₄alkyl;

Q represents a) single bond; b) Ci-₄alkylene linear or branched which is unsubstituted or substituted; c) C - alkenylene; p is an integer from 2 to 4;

A1 represents a) aryl is mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic ring which is unsubstituted or substituted by 1-4 groups selected from unsubstituted or substituted Ci-₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄dialkylamino, C - cycloalkylamino; b) 3-14 membered heterocycle, which is monocyclic, bicyclic or tricyclic ring any of which is saturated, unsaturated or aromatic containing 1 to 4 heteroatoms selected from nitrogen (unsubstituted or substituted by H or Cl-4 alkyl), oxygen and sulphur, unsubstituted or substituted on 1-3 ring carbon atoms by groups independently selected from unsubstituted or substituted Ci-₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO , Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄ dialkylamino, C - cycloalkylamino; compound of Formula (II) is

wherein

R5 represents Ll-A, L2-A or L3-A;

LI represents -(CH )_a-Xl-(CH )_b-(NH)_c-,

L2 represents -C(0)-(CH₂)b-(NH)_c-;

L3 represents XI represents -N(R⁶)-, -NHC(O)- or -C(0)NH-;

Y represents -N ( R⁷)-;

R⁶ and R⁷ independently represent H or Ci- alkyl;

A is a moiety of Formula (c) or (d):

(c) (d) attached to the rest of the molecule through any available carbon atom;

R⁸ represents H or halogen or -OCH or -CF and is attached to Formula (c) or (d) at any available carbon atom; a is an integer from 2 to 6; b is an integer from 0 to 6; c is 0 or 1; m is an integer from 1 to 4; n is an integer from 1 to 4; provided that when c is 1 then b is an integer from 1 to 6; compound of Formula (III) is

wherein

R1 represents FI or a a-L-cladinosyl group of Formula (a);

2. The method of clause 1, wherein the 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a-aza-9- deoxo-9-dihydro-9a-homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A azalide is selected from:

or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate.

3. The method of clause 1, wherein the therapeutic and/or prophylactic treatment of diseases caused by viruses belonging to the family of Coronaviridae in the subject in need of such treatment comprising administering to the subject the therapeutically effective amount of compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate.

4. The method of clause 1, wherein virus belonging to the family of Coronaviridae is coronavirus, including but not limited to HCoV-OC43, HKU1, HCoV-NL63, HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2.

5. The method of clause 4, wherein coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2.

6. A pharmaceutical composition comprising an effective amount of a pharmacologically active compound, or a pharmaceutically acceptable salt thereof, solvate, or pharmaceutically acceptable salt of the solvate in association with a pharmaceutically acceptable excipient, diluent and/or carrier, wherein said pharmacologically active compound is a compound of Formula (I), Formula (II) or Formula (III) according to any of clauses 1 - 2.

7. The pharmaceutical composition according to clause 6 for use in the treatment and/or prophylaxis of diseases caused by viruses belonging to the family of Coronaviridae.

8. A compound of Formula (I), Formula (II) or Formula (III) or pharmaceutically acceptable salt thereof for use in the treatment and/or prophylaxis of diseases caused by viruses belonging to the family of Coronaviridae.

9. The compound of clause 8, wherein viruses belonging to the family of Coronaviridae are coronaviruses, including but not limited to FICoV-OC43, FIKU1, FICoV-NL63, FICoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2.

10. The compound of clause 9, wherein coronavirus is MERS-CoV, SARS-CoV, or SARS-CoV-2. CHEMICAL SYNTHETIC PROCEDURES

Azalide compounds described by Formula (I), Formula (II), and Formula (III) may be prepared by methods described in international patent applications WO 2007/125414, WO 2009/016142 and WO 2010/086351, which are incorporated by reference herein in their entireties. Particularly, the compounds may be prepared in accordance with the process described, for example, in WO 2007/125414 on pages 51-53.

It will be appreciated by those skilled in the art that it may be desirable to use protected derivatives of intermediates used in the preparation of the compounds of Formula (I), (II) or (III). Protection and deprotection of functional groups may be performed by methods known in the art. Hydroxyl or amino groups may be protected with any hydroxyl or amino protecting group (for example, as described in Green and Wuts. Protective Groups in Organic Synthesis. John Wiley and Sons, New York, 1999). The protecting groups may be removed by conventional techniques. For example, acyl groups (such as alkanoyl, alkoxycarbonyl and aryloyl groups) may be removed by solvolysis (e.g., by hydrolysis under acidic or basic conditions). Arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl) may be cleaved by hydrogenolysis in the presence of a catalyst such as palladium-on-carbon.

The synthesis of the target compound is completed by removing any protecting groups, which are present in the penultimate intermediate using standard techniques, which are well-known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel and the like, or by recrystallization.

PHARMACEUTICAL COMPOSITIONS

While it is possible that, for use in the methods of the invention, a compound of Formula (I), (II) or (III) may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical composition, e.g., wherein the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula (I), (II) or (III), generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

The compounds of the invention may be formulated for administration in any convenient way for use in human or veterinary medicine and the invention therefore includes within its scope pharmaceutical compositions comprising a compound of the invention adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in "Remington: The Science and Practice of Pharmacy" 22nd Edition. The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).

It will be appreciated that pharmaceutical compositions for use in accordance with the present invention may be in the form of oral, parenternal, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.

There may be different composition/formulation requirements depending on the different delivery systems. It is to be understood that not all of the compounds need to be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes. By way of example, the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by multiple routes.

The present invention further relates to pharmaceutical formulations containing a therapeutically effective quantity of a compound of Formula I, II and III or one of its salts mixed with a pharmaceutically acceptable vehicle. The pharmaceutical formulations of the present invention can be liquids that are suitable for oral and/or parenteral administration, for example, drops, syrups, solutions, injectable solutions that are ready for use or are prepared by the dilution of a freeze-dried product but are preferably solid or semisolid as tablets, capsules, granules, powders, pellets, pessaries, suppositories, creams, salves, gels, ointments; or solutions, suspensions, emulsions, or other forms suitable for administration by the transdermal route or by inhalation.

The compounds of the invention can be administered for immediate-, delayed-, modified-, sustained- , pulsed-or controlled-release applications.

The most preferred oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules. This release profile can be achieved without limitation by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the Gl tract wherein a lesion or inflammation site has been identified. Or a delayed release can be achieved by a coating that is simply slow to disintegrate. Or the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.

Suitable compositions for delayed or positioned release and/or enteric coated oral formulations include tablet formulations film coated with materials that are water resistant, pH sensitive, digested or emulsified by intestinal juices or sloughed off at a slow but regular rate when moistened. Suitable coating materials include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of metacrylic acid and its esters, and combinations thereof. Plasticizers such as, but not limited to polyethylene glycol, dibutylphthalate, triacetin and castor oil may be used. A pigment may also be used to color the film. Suppositories are be prepared by using carriers like cocoa butter, suppository bases such as Suppocire C, and Suppocire NA50 (supplied by Gattefosse Deutschland GmbH, D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C8-C18 triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides, and whitepsol (hydrogenated plant oils derivatives with additives). Enemas are formulated by using the appropriate active compound according to the present invention and solvents or excipients for suspensions. Suspensions are produced by using micronized compounds, and appropriate vehicle containing suspension stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrolidone, N-vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrated caster oil, polyoxyethylene alkyl ethers, and pluronic and appropriate buffer system in pH range of 6.5 to 8. The use of preservatives, masking agents is suitable. The average diameter of micronized particles can be between 430 1 and 20 micrometers, or can be less than 1 micrometer. Compounds can also be incorporated in the formulation by using their water-soluble salt forms.

Alternatively, materials may be incorporated into the matrix of the tablet e.g. hydroxypropyl methylcellulose, ethyl cellulose or polymers of acrylic and metacrylic acid esters. These latter materials may also be applied to tablets by compression coating.

Pharmaceutical compositions can be prepared by mixing a therapeutically effective amount of the active substance with a pharmaceutically acceptable carrier that can have different forms, depending on the way of administration. Pharmaceutical compositions can be prepared by using conventional pharmaceutical excipients and methods of preparation. The forms for oral administration can be capsules, powders or tablets where usual solid vehicles including lactose, starch, glucose, methylcellulose, magnesium stearate, di-calcium phosphate, mannitol may be added, as well as usual liquid oral excipients including, but not limited to, ethanol, glycerol, and water. All excipients may be mixed with disintegrating agents, solvents, granulating agents, moisturizers and binders. When a solid carrier is used for preparation of oral compositions (e.g., starch, sugar, kaolin, binders disintegrating agents) preparation can be in the form of powder, capsules containing granules or coated particles, tablets, hard gelatin capsules, or granules without limitation, and the amount of the solid carrier can vary (between 1 mg to Ig). Tablets and capsules are the preferred oral composition forms.

Pharmaceutical compositions containing compounds of the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.

Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the present invention include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone.

Examples of pharmaceutically acceptable binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.

Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulfate.

Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.

Examples of suitable pharmaceutically acceptable odorants for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions. Examples of suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.

Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.

Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.

Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).

Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetriacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.

The compounds of the invention may also, for example, be formulated as suppositories e.g., containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g., containing conventional pessary bases.

The compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g., eye ear or nose drops) or pour-ons.

For application topically to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol, and water. Such compositions may also contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and odorants.

Examples of pharmaceutically acceptable polymers suitable for such topical compositions include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.

As indicated, the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134AT"") or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

For topical administration by inhalation the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.

The pharmaceutical compositions of the invention may contain from 0.01 to 99% weight per volume of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active material.

A therapeutically effective amount of the compound of the present invention can be determined by methods known in the art. The therapeutically effective quantities will depend on the age and on the general physiological condition of the patient, the route of administration and the pharmaceutical formulation used. It will also be determined by the strain of coronavirus that has infected the subject. The therapeutic doses will generally be between about 10 and 2000 mg/day and preferably between about 30 and 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 100-200 mg/day. The amount of the compound required for prophylactic treatment, referred to as a prophylactically-effective dosage, is generally the same as described for therapeutic treatment.

Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead of every day. The dose and the administration frequency will depend on the clinical signs and symptoms that the coronavirus strain causes, which confirm maintenance of the remission phase, with the reduction or absence of at least one or more preferably more than one of clinical signs of the acute phase known to the person skilled in the art.

EXAMPLES

The features and advantages of the invention are more fully shown by the following non-limiting examples.

The therapeutic effect of compounds of the present invention was determined in experiments provided in the examples.

Example 1: Structures of example compounds used for determining therapeutic effects are presented in Table 1.

Table 1.

Example 2: In vitro screening protocol for SARS antiviral activity

The in vitro screens for determining antiviral activity were performed in Vero E6 cell line. Cells were maintained in minimal essential medium (MEM) supplemented with 10% FBS, 1% penicillin- streptomycin and 1% L-glutamine. SARS-CoV-2297/20 Zagreb p4/3d, was amplified in Vero E6 cells for 2 days, when the cytopathic effect was visible. SARS-CoV-2-containing supernatants were collected and clarified by centrifugation. Titers of SARS-CoV-2 on Vero E6 cells were determined by plaque assay. All procedures using live SARS-CoV-2 were performed under biosafety level 3 conditions.

Compounds were dissolved in DMSO, diluted in the testing cell culture media and tested at double dilutions startingfrom 50uM concentration. Chloroquine and remdesivir were used as positive controls due to their known in vitro inhibitory effects against SARS-CoV-2.

Neutral red assay

Testing antiviral activity of the selected compounds was performed first by using neutral red assay. Vero E6 cells were seeded into 96-well plates at 3 x 10⁴ cells per well and cultured overnight at 37°C. Cells were infected with SARS-CoV-2 297/20 Zagreb p4/3d, with multiplicity of infection, MOI=0,5, at 37°C for 1 hour and then the medium was removed and replaced with the medium containing drug dilutions. Plates were cultured at 37°C for 72 h. Cell survival was assessed after removing the media, washing with PBS and treating cells with neutral red medium containing 40 pg/ml of neutral red in MEM media supplemented with 2 % of FBS, for 1 hour at 37°C. Cells were washed with PBS and de- stained with ethanol (50%) and glacial acetic acid (1%), A540 read using spectraflourometer (SpectraMax i3x).

Drug toxicity was assayed using an identical drug compound plate where SARS-CoV-2 was not added to cells. The same neutral red procedure as above was applied for determining cell survival.

Outlier data points were defined as values that were greater than the median plus 3 standard errors (o) and were excluded from calculations. The calculation used to measure the antiviral activity of the compounds was the Percent Normal. The Percent Normal monitors the reduction in cytolysis of cells due to the presence of compound treatment and is determined as follows: Percent Normal = (T — V)/(N - V), where T represents the signal of cells infected with SARS-CoV and treated with compound, V represents the signal of cells infected with SARS-CoV but vehicle treated, and N represents the signal of the normal control cells that are neither infected nor treated with compound. After normalization, average activity values were calculated between replicate measurements at the same treatment doses along with oi, the accompanying standard error estimates. Drug response curves were represented by a logistic sigmoidal function with a maximal effect level

the concentration at half-maximal activity of the compound (EC ), and a Hill coefficient representing the sigmoidal transition. The fitted curve parameters were used to calculate the concentration at which the drug response reached an absolute inhibition of 50% (EC ), limited to the maximum tested concentration for inactive compounds. Compounds were considered active if the antiviral activity observed was >50% Percent Normal with no or low corresponding cytotoxicity. All data were analyzed with Microsoft Excel and GraphPad Prism (version 8.4.3. for Windows) software. PIN data was calculated in excel and GraphPad Prism was used for statistical analysis and calculation of EC50 values.

The concentrations of drugs that gave half-maximal response (EC ) are presented in Table 2. Table 2.

Example 3: In vitro screening protocols for antiviral activity against other coronaviruses

Human corona virus 229E (VR-740, ATCC), Betacoronavirus 1 (VR-1558 (OC43), ATCC) and Human Coronavirus strain NL63 (FR-304, IRR) were used as representative human corona viruses. Viruses were propagated and anti-viral assays developed in MRC5, human lung fibroblast cells (CCL-171, ATCC), and Vero, monkey lung epithelial cells (CRL-1586, ATCC). Cell lines were maintained in EMEM media (ATCC) with 10% FBS (Biowest) with 1% penicillin-streptomycin (Gibco). Compounds were dissolved in DMSO and testing concentrations were prepared in DMSO, 1000 time concentrated. MRC5 cells were plated in 96well white plates (Greiner) at 10000 cells/well density and Vero cells at 20000 cells/well density. The following day, media was replaced with 50 pL/well EMEM media with 2% FBS, 100 nLof the compounds were added and viruses were added in 50 pL/well. HCoV 229E and HCoV OC43 viruses were added to MRC5 cells and HCoV NL63 virus was added to Vero cells. All plates were incubated for 4 days upon which to MRC5 cells 50 pL/well of Viral ToxGlo Assay (Promega) solution was added for ATP determination and to Vero cells 50 pL/well of Cyto Tox-Fluor Assay (Promega) solution was added for extracellular protease determination. ATP was measured using luminescence while protease content was measured using fluorescence (480/520 nm). The same procedure was used for measuring compounds effects on cell viability except for virus addition. All tested conditions were done in three replicas. Chloroquine, remdesivir and azithromycin were used as positive controls due to their known in vitro inhibitory effects against SARS-CoV-2.

All data were analyzed with Microsoft Excel and GraphPad Prism (version 8.4.3. for Windows) software. PIN data was calculated in excel and GraphPad Prism was used for statistical analysis and calculation of EC_5O values.

The concentrations of drugs that gave half-maximal response (EC₅o) are presented in Table 3. Table 3.

Example 4: In vitro screening protocols for determining cytotoxicity against FlepG2 cells

FlepG2 cells were maintained in complete RPMI 1640 medium supplemented with 10% Foetal Bovine Serum at 37-C in a 5% C02 atmosphere. Each culture in the 96-well plates contained 50000 cells which were exposed to serial dilutions (1:2) of tested compounds (initially dissolved in DMSO and subsequently diluted in supplemented RPMI 1640 medium). Plates were incubated for 24 h at 37°C in 5% C02. The cytotoxicity assay was performed using the MTS CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, USA). After the addition of MTS reagent and 2 h of incubation at 37°C in 5% C02, the absorbance at 490 nm was recorded and Tox₅o determined based on the obtained response curves.

The concentrations of drugs where cells growth was inhibited by 50% (Tox₅o) are presented in Table 4. Table 4.

Example 5: In vitro screening protocols for MERS antiviral activity

Vero E6 cell line was maintained in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS). The Jordan strain of MERS-CoV was amplified in Vero E6 cells at a MOI of 0.01. On day 4 after infection, when the cytopathic effect (CPE) was visible, virus-containing supernatants were collected and clarified by centrifugation. The MERS-CoV titers on Vero E6 cells were determined by plaque assay. All procedures using live MERS-CoV were performed under biosafety level 3 conditions.

Compounds were dissolved in DMSO and diluted in the testing cell culture media. Compounds were plated at 2 times the final concentrations such that the addition of 50 pi resulted in the appropriate final concentration (100-mI final assay volume).

For cell-based enzyme-linked immunosorbent assay (ELISA) screen, Vero E6 cells were seeded at 40,000 cells in 100 mI DMEM plus 10% FBS per well in black-, opaque-, or clear-bottom 96 well-plates. After 24 h, test compounds were added to 3 cell plates in 50 mI. The DMSO concentration was kept at 0.05% or lower.

Duplicate Vero E6 seeded plates were used for detecting inhibition of MERS-CoV, and one plate was used for determining the cytotoxicity of compounds. For infection, duplicate plates were pretreated with compounds for 1 h before the plates were transferred into the containment laboratory to add MERS-CoV strain at an MOI of 0.1 in 50 pi of DMEM plus 10% FBS. After 48 h, plates were fixed with 10% neutral buffered formalin and removed from biocontainment. MERS-CoV infection was detected with a rabbit polyclonal antibody to the Spike protein followed by staining with Alexa Fluor 594 goat anti-rabbit IgG (H+L) antibody (Life Technologies). Fluorescence was quantified on a plate reader with an excitation wavelength of 590 nm and emission wavelength of 617 nm.

To detect cellular toxicity of drugs in the MERS-CoV screen, one of the three plates that received the test drugs was used to evaluate the cytotoxicity of drugs and was not infected with virus. At 48 h after drug addition, cell plates were analyzed using the CellTiter Glo luminescent cell viability assay kit according to the manufacturer's directions (Promega), and luminescence was read on the luminometer plate reader.

A minimum of four replicates were performed on two separate days. Outlier data points were defined as values that were greater than the median plus 3 standard errors (o) and were excluded from calculations. Raw phenotype measurements (T) from each treated well were converted to normalized fractional inhibition, I, by the formula 1 = 1 - (T/V), relative to the median, V, of vehicle-treated wells arranged around the plate. Compounds were considered active if the antiviral activity observed was >50% I with no or low corresponding cytotoxicity (<30% I).

Example 6

Antiviral activity can be similarly determined using a variety of conditions, viral strains and tools different from the assays described herein. The assays described in Examples 2 - 5 can be repeated using compounds according to Formula (I) (II) and (III) as well as cell types and viral strains from different sources and with different characteristics to determine the antiviral activity of the compounds.

Example 7: Metabolite identification in vitro

Metabolite identification in vitro was performed using cryopreserved rat and human hepatocytes (XenoTech), (Peric et al., 2021). Test compounds (10 mM) were incubated for 4 and 24h at 37 °C in supplemented DMEM containing 0.5 x 106 cells/mL. The reaction was stopped by addition of 80:20 acetonitrile:methanol: 1% formic acid. Samples were analyzed by LC-MS/MS and examined by ACD (Advanced Chemistry Development) IntelliXtract software for potential metabolites. The results for compound 2 are presented in Table 5. Table 5.

Example 8: Pharmacokinetic evaluation in mice

For pharmacokinetic (PK) studies in mice, animals were dosed either by intravenous (IV) or oral (PO) route. For IV administration, the dosing volume was 10 mL/kg for a total dose of 12.5 mg/kg, and for PO administration, the dosing volume was 20 mL/kg for a total dose of 12.5 mg/kg (Peric et al., 2021). Dosing solutions were prepared in 100% saline (2.5 mg/mL) both for IV and PO administration. Following IV dosing, blood samples were collected at 5 and 15 minutes, 1, 3, 6, 8, 24 and 48 hours post dose. Following oral dosing, blood samples were collected at 15 and 30 minutes, 1, 2, 4, 6, 8, 24 and 48 hours post-dose. For studies performed in Swiss albino CD-I mice, in order to obtain simultaneous blood and plasma profiles and blood-to-plasma (B/P) ratio, PK was performed using terminal sampling of n=3 animals per time point and data evaluated using composite analysis. For whole blood samples analysis, 25 pi of fresh blood were mixed with 25 mI of saponine solution (0.1% in water) and immediately frozen on dry ice. Plasma was obtained by centrifugation of fresh blood at 2500xg for 10 min. Both blood and plasma samples were stored frozen at -80 -C until analysis.

Diluted blood and plasma samples were processed under standard liquid-liquid extraction procedures using acetonitrile containing internal standard (clarithromycin, 100 ng/mL) and analyzed by LC-MS/MS in positive ion mode with electrospray. Samples were assayed for parent compound using a Sciex API 4000 and Sciex API-2000 Triple Quadrupole Mass Spectrometer (Sciex, Division of MDS Inc.), against a series of matrix matched calibration curve standards, using multiple reaction monitoring (MRM) at the specific transitions for each compound. Noncompartmental analysis was performed using WinNonlin, version 4.1. (Pharsight) and the main pharmacokinetic parameters were estimated.

PK parameters estimated in blood after intravenous and oral gavage (12.5 mg/kg) administration to CD-I mice (N=3) for compounds 1, 2 and 3 compared to azithromycin are presented in Table 6. Table 6.

^a DNAUC calculated as AUCO-t divided by the dose administered; ^b B/P values were calculated as the ratio of AUCO-t measured in parallel in whole blood and plasma after oral administration; ^c % extrapolated AUC > 20%.

Example 9: Pharmacokinetic evaluation in rats

For the in vivo pharmacokinetic study male Sprague-Dawley rats (Charles River), weighing approx, 350 g were used. Compound were dosed IV at 2-5 mg/kg (5 mL/kg dosing volume) and PO at a dose of 10- 25 mg/kg (10 mL/kg) (Peric et al., 2021). Rats were fasted for 6-12 hours (overnight fasting) prior oral administration. For serial blood sampling, rats (n=3) dosed with an IV bolus of compound had blood collected at the following time-points after dosing: 5, 10, 2040, 60, 120, 240, 480, 1440 and 1800 min. Rats (n=3) dosed orally had blood collected at the following time-points after dosing: 15, 30, 60, 120, 240, 360, 480, 1440 and 1800 min.

Dosing solutions were prepared in 100% saline both for IV and PO. After both routes of administration, blood samples were collected from the tail vein up to 30 h, haemolysed and frozen until analysis. Samples were prepared for analysis by protein precipitation with six volumes of ACN:MeOFI 2:1 (v/v) containing internal standard and analyzed by LC-MS/MS in positive ion mode with electrospray. Subsequently, samples were assayed as described in mice PK section.

PK parameters (mean (SD), N=3) for compounds 1, 2 and 3 estimated in blood after intravenous (2 mg/kg) and oral gavage (10 mg/kg) administration to SD rat (N=3) are presented in Table 7.

Table 7.

^a compound 1 was administered at IV dose 5 mg/kg and PO dose of 25 mg/kg Example 10: Pharmacokinetic studies in dogs and monkeys

Non-naive male cynomolgus monkeys or male beagle dogs were used for single dose PK studies and were fasted overnight prior to administration of test compound (Peric et al., 2021). Food was returned four hours post dose, and water was provided freely throughout the studies. Dosing solutions were prepared in 0.9% saline supplemented to a final concentration of 1% acetic acid. An IV dose of 2 mg/kg (dose volume of 1 ml/kg), and a PO dose of 10 mg/kg were administered (dose volume of 5 ml/kg) to monkeys and dogs (3 animals per dose group). After IV dosing, blood samples were collected at 5, 10, 15, and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96, 144, and 168 h post dose. After oral dosing, blood samples were collected 15, and 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96, 144, and 168 h post dose. Blood samples were stored at -80 °C until analysis and were assayed as described in mice PK section.

PK parameters (mean (SD), N=3) of compound 2 estimated in blood after intravenous (2 mg/kg) and oral gavage (10 mg/kg) administration to Beagle dogs and Cynomolgus monkeys are presented in Table 8.

Table 8.

Example 11: Accumulation and retention in human cells

Accumulation and retention in human primary cells was determined as described in detail previously (Stepanic et al., 2011). Briefly, normal human bronchial epithelial cells (NHBE, CC-2541, Lonza), normal human lung fibroblasts (NHLF, CC-2512, Lonza), and bronchial smooth muscle cells (BSMC, CC-2576, Lonza) were cultivated according to the protocols of the suppliers. Fluman polymorphonuclear cells (PMN) and monocytes from healthy volunteers were isolated from buffy coats. Monocytes were isolated by negative selection on magnetic separator. Monocyte derived macrophages (MDM) were obtained by cultivating monocytes with 5 ng/mL rhGMCSF for 10 days. To determine compound accumulation cells were incubated with 3-10 mM compound in their corresponding culture medium for 3 h at 37 °C 5% C02, washed and lysed. To measure cellular retention of the compound, after being washed, drug-loaded cells were incubated in fresh medium for 3 h, washed and lysed. Compound concentrations were determined by HPLC-MS/MS analysis (Peric et al., 2021).

Accumulation and retention of compound 1 in polymorphonuclear leukocytes (PMN), normal human bronchial epithelium (NHBE), normal human lung fibroblasts (NHLF), bronchial smooth muscle cells (BSMC) and monocyte derived macrophages (MDM) expressed as % of azithromycin measurements is presented in Table 9. Mean values of minimum three experiments ±SD are given.

Table 9.

Example 12: In vivo efficacy assay 1

BALB/c mice (16-19 g) were inoculated with 50 pL containing 10⁴°-10⁴·⁴ CCID₅o of mouse-adapted v2163 virus by the i.n. route. Groups of mice were administered 100 pL of the testing compounds by the intraperitoneal (i.p.) route once daily before virus exposure and physiological saline solution was used as a placebo. Mice for toxicity controls were treated with PSS using the treatment regimes described above but without virus exposure. Mice were observed daily, and group weights were taken periodically throughout the test period. The average weight loss was calculated on 3 days post virus inoculation and significance between treatments evaluated by one-way analysis of variance followed by Newman-Keuls multiple comparison test. Compound toxicity in uninfected mice was evaluated in terms of weight change and adverse events. On days 3 and 6 post infection, three to five surviving mice from each treatment group were sacrificed. The remaining mice were held and observed for death up to day 14 post virus exposure. Animals that lost greater than 30% of their initial body weight in this experiment were humanely euthanized and the day of euthanasia was designated as the day of death. Lungs from sacrificed mice were observed for gross pathology and discoloration and assigned a score ranging from 0 (normal appearing lung) to 4 (maximal plum coloration in 100% of lung). Mouse lung samples from each test group were pooled and homogenized in MEM solution and assayed in duplicate for infectious virus using the method described below for virus yield assays using triplicate wells of Vero 76 cells. Titers were compared to controls by analysis of variance on log-transformed values assuming equal variance and normal distribution (Day et al., 2009).

Example 13: In vivo efficacy assay 2

25-28 week old male and female mice genetically deleted for carboxylesterase 1C ( Ceslc -/-) were anaesthetized with ketamine/xylazine and infected with 10⁴pfu/50pl (prophylactic studies) or 10³pfu/50pl (therapeutic studies) SARS-CoV. Animals were weighed daily to monitor virus-associated weight loss and to determine the appropriate dose volume of testing compounds or vehicle. Compound or vehicle was administered i.v. once daily. On 2 and 5 days post infection (prophylactic) or 2 and 4 or 6 days post infection (therapeutic), animals were sacrificed by isofluorane overdose and the large left lobe was frozen at -80°C for viral titration via plaque assay. Aberrations in lung function were determined by whole body plethysmography (WBP, Data Sciences International) (Sheahan et al., 2017).

Example 14

In vivo efficacy can be similarly determined using a variety of conditions, viral strains, animal models and tools different from the assays described herein. The assays described in Examples 12-13 can be repeated using compounds according to Formula (I), Formula (II), Formula (III) as well as viral strains and animal models with different characteristics and parameters to determine the in vivo efficacy of the compounds.

Reference List

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Claims

1. An 9a-substituted, 3'-N-substituted, 2'-0-substituted 9a-aza-9-deoxo-9-dihydro-9a- homoerythromycin A, 5-0-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 5-0-decladinosyl-3-0-dedesosaminyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A azalide selected from compounds having the: Formula (I), Formula (II) or Formula (III), wherein a compound of Formula (I) is

wherein R1 represents H or a a-L-cladinosyl group of formula (a)

R2 represents H or a b-D-desosaminyl group of formula (b)

provided that when R2 is H then R1 is also H;

L represents -(CF J_p-X-Q-;

X represents NR³, -NHC(=0) or -C(=0)NH;

R³ represents H or linear or branched Ci- alkyl;

A1 represents a) aryl is mono-, bicyclic or tricyclic carbocyclic ring system having at least one aromatic ring which is unsubstituted or substituted by 1-4 groups selected from unsubstituted or substituted C alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO2, C alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄dialkylamino, C - cycloalkylamino; b) 3-14 membered heterocycle, which is monocyclic, bicyclic or tricyclic ring any of which is saturated, unsaturated or aromatic containing 1 to 4 heteroatoms selected from nitrogen (unsubstituted or substituted by H or Cl-4 alkyl), oxygen and sulphur, unsubstituted or substituted on 1-3 ring carbon atoms by groups independently selected from unsubstituted or substituted Ci_₄ alkyl, unsubstituted or substituted C cycloalkyl, halogen, OH, NO2, Ci-₄ alkyloxy, C cycloalkyloxy, Ci-₄ alkylamino, Ci-₄ dialkylamino, C - cycloalkylamino; a compound of Formula (II) is

(ID wherein

R1 represents H or a a-L-cladinosyl group of Formula (a); R4 represents H or CH3;

R5 represents Ll-A, L2-A or L3-A;

LI represents -(CH2)a-Xl-(CH2)b-(NH)_c-,

L2 represents -C(0)-(CH2)b-( N H)_c-;

L3 represents

XI represents -N(R⁶)-, -NHC(O)- or -C(0)NH-; Y represents -N(R⁷)-;

R⁶ and R⁷ independently represent FI or Ci-₃alkyl;

A is a moiety of Formula (c) or (d):

(c) (d) attached to the rest of the molecule through any available carbon atom;

R⁸ represents H or halogen or -OCH3 or -CF3 and is attached to Formula (c) or (d) at any available carbon atom; a is an integer from 2 to 6; b is an integer from 0 to 6; c is 0 or 1; m is an integer from 1 to 4; n is an integer from 1 to 4; provided that when c is 1 then b is an integer from 1 to 6; a compound of Formula (III) is

wherein

R1 represents FI or a a-L-cladinosyl group of Formula (a);

2. The azalide compound for use according to claim 1, wherein azalide is compound of Formula (I).

3. The azalide compound for use according to claim 1, wherein azalide is compound of Formula (II).

4. The azalide compound for use according to claim 1, wherein azalide is compound of Formula (III).

5. The azalide compound for use according to claims 1 -4, selected from:

6. A pharmaceutical composition comprising pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any of claims 1 - 5.

7. The pharmaceutical composition according to claim 6, wherein it comprises a further therapeutic agent.

8. The pharmaceutical composition according to claim 7, wherein further therapeutic agent is selected from agent producing a broad-spectrum activity against several RNA and DNA viruses, agent for treatment of bacterial infections, agent for treatment and prevention of malaria, and/or agent that enlist natural immune system functions.

9. The pharmaceutical composition according to claim 8, wherein further therapeutic agent is agent producing a broad-spectrum activity against several RNA and DNA viruses, including but not limited to anti-viral agents selected from lopinavir, ritonavir, remdesivir, galidesivi, umefinovir, darunavir, cobicistat, arbidol hydrochloride, oseltamivir and ribavirin.

10. The pharmaceutical composition according to claim 8, wherein further therapeutic agent is agent for treatment of bacterial infections including but not limited to teicoplanin, azithromycin, cefuroxime, metronidazole and levofloxacin.

11. The pharmaceutical composition according to claim 8, wherein further therapeutic agent is agent for treatment and prevention of malaria including but not limited to chloroquine and hydroxychloroquine.

12. The pharmaceutical composition according to clause 8, wherein further therapeutic agent is agent that enlist natural immune system functions including but not limited to monoclonal antibodies and interferon-alpha 2b.

13. A compound or pharmaceutically acceptable salt thereof according to any of claims 1 - 5, or a pharmaceutical composition according to any of claims 6-12, for use in the prophylaxis and /or treatment of diseases caused by viruses belonging to the family of Coronaviridae.

14. A compound or pharmaceutically acceptable salt thereof according to any of claims 1 - 5, or a pharmaceutical composition according to any of claims 6 -13, wherein viruses belonging to the family of Coronaviridae is coronavirus, including but not limited to HCoV-OC43, HKU1, HCoV-NL63, HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2.

15. The compound or pharmaceutical composition according to claims 1-14, wherein coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2.

16. The compound or pharmaceutical composition according to claims 1-14, wherein coronavirus is MERS-CoV.

17. The compound or pharmaceutical composition according to claims 1-14, wherein coronavirus is SARS-CoV.

18. The compound or pharmaceutical composition according to claims 1-14, wherein coronavirus is SARS-CoV-2.