WO2021224494A1

WO2021224494A1 - New treatments of viral infections

Info

Publication number: WO2021224494A1
Application number: PCT/EP2021/062223
Authority: WO
Inventors: Thomas Olin; Ali MOSHFEGH
Original assignee: Kancera AB
Current assignee: Kancera AB
Priority date: 2020-05-08
Filing date: 2021-05-07
Publication date: 2021-11-11
Anticipated expiration: 2022-11-08
Also published as: GB202006849D0

Abstract

There is provided a compound of formula (I), wherein R1, R2, Q1 and formula (II) are as defined herein, for use in the treatment or prevention of an exaggerated host immune response to a viral infection, and diseases and disorders caused by viral infections and/or the host immune response thereto, including coronavirus disease 2019.

Description

NEW TREATMENTS OF VIRAL INFECTIONS

Field of the Invention

This invention relates to new uses of known CX3CR1 antagonists. In particular, the invention relates to the use of such compounds in the treatment or prevention of an exaggerated host immune response to a viral infection and diseases and disorders caused by the viral infection and/or the host immune response thereto.

Background of Invention

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge

A virus is a submicroscopic infectious agent comprising genetic material (DNA or RNA) that is capable of infecting a biological organism. A virus invades and attaches itself to a living cell, after which it multiplies to produce more virus particles (virions), which attach to and enter susceptible cells.

A virus may either kill a cell or alter its functions, the by-products of which processes lead to the infection of other cells. This will then generally lead to what is termed as viral diseases (or a viral infection).

Following viral infection, an organism’s immune defence system is triggered. Lymphocytes and monocytes attempt to attack and destroy the invasive virus. This is referred to as the body’s innate or natural immunity. The innate immune response can often lead a patient feeling unwell or fatigued. If a patient’s immune system is compromised, or not effective enough to prevent the spread of a virus, this can lead to severe illness and, in some instances, morbidity and/or death.

This immune response in an important part of the organism’s natural response to infections. However, in some instances, particularly in subjects with a weakened immune system, an exaggerated host immune response occurs in which there is an overproduction of immune cells and inflammatory cytokines, leading to excessive inflammation, tissue damage in organs including the heart, lung, kidney and liver and an increased risk of mortality through multiple organ failure and/or secondary infections.

There is thus a clear need for treatments able to modulate or prevent this exaggerated immune response and thereby treat or prevent diseases or disorders caused by viral infections and/or the host immune response.

Antagonists of the fractal kine receptor (also known as CX3 chemokine receptor 1 (CX3CR1)) are disclosed in WO 2006/107258, Karlstrom et al., J. Med. Chem., 2013, 56, 3177-3190, WO 2019/219771 and WO 2020/008064.

Detailed Description of the Invention

It has now surprisingly been found that compounds of formula I, as described herein, appear to possess properties that render them useful in the treatment or prevention of exaggerated host immune responses to viral infections, such as coronavirus and more particularly severe acute respiratory syndrome coronavirus 2 infections. These properties may be due to the ability of the compounds to act as antagonists of the fractalkine receptor as the exaggerated host immune response may involve increased expression of fractalkine. These properties may also allow the compounds to treat diseases or disorders caused by viruses and/or the host immune response to the viral infection, or to prevent such diseases or disorders from occurring. Similarly, intervention with the compounds described herein may lead to the prevention or reduction in tissue damage occurring as a result of the host immune response, a reduced risk of secondary infections and a better outcome for the subject overall.

Consistent with this reasoning, elevated levels of serum fractalkine, and other serum endothelial cell adhesion molecules, have now been reported in coronavirus disease 2019 (COVID-2019) patients, with dramatically elevated levels observed in patients with severe disease (Tong et al. , The Journal of Infectious Diseases_^ 2020;222:894-8). Increased fractalkine expression has also been observed in the myocardium of a teenage patient recovering from severe acute respiratory syndrome coronavirus 2 infection, suggesting that cytokine storm induced by the infection was the main cause of myocardial injury Garau et al., ESC Heart Failure 2021; 8 766-773. It has also been suggested that convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation, including increased CX3CL1 (fractalkine) expression (Chioh et al, medRxiv preprint doi: https://doi.Org/10.1101/2020.11.16.20232835, 18 Nov 2020; eLife

2021 ;10:e64909 DOI: 10.7554/el_ife.64909).

It is also believed that severe acute respiratory syndrome coronavirus 2 (the causative virus of COVID-19) may block or reduce the function of the ACE2 receptor in endothelial cells after endocytosis of the viral particles, leading to increased expression of CX3CL1 , which in turn promotes thrombosis in COVID-19 patients (Rivas-Fuentes et al. , Medical Hypotheses, 151 (2021) 110570).

Further, the hyperinflammation of vital organs associated with the exaggerated immune response to viral infections, as seen in COVID-19 patients, is known to be associated with reduced blood flow to the tissue and hypoxia. These effects reduce the ability of antibody- based therapies, which largely rely on functional vasculature, to reach the target tissue. Therefore, small molecule fractalkine antagonists, such as compounds of formula I, which are more readily able to diffuse into hypoxic tissue, are likely to provide more effective treatments.

In a first aspect of the invention, there is provided a compound of formula I,

wherein

R¹ represents aryl or pyridyl, both of which are optionally substituted by one or more groups selected from halo, -CN, -C(O)NR³R⁴, -S(O)₂R⁵, C_{1 -6} alkyl, C_2-6 alkenyl or C_2-6 alkynyl, wherein the latter three groups are optionally substituted by one or more F;

R² represents H or C_{1 -6} alkyl optionally substituted by one or more F;

R³ and R⁴ each independently represent H or C_{1 -6} alkyl optionally substituted by one of more F; R⁵ represents C_{1 -6} alkyl optionally substituted by one or more F;

wherein indicates a point of attachment to the rest of the molecule;

Q¹ and Q² each independently represent H or -PO(OR⁶)(OR⁷);

Q³ represents H or -CH₂OPO(OR⁶)(OR⁷); and

Q⁴ represents -CH₂OPO(OR⁶)(OR⁷); wherein R⁶ and R⁷ each independently represent H, C_1-4 alkyl or C_2-4 alkenyl, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an exaggerated host immune response to a viral infection.

In an alternative first aspect of the invention, there is provided a method of treatment or prevention of an exaggerated host immune response to a viral infection in a subject, which method comprises administering a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

In a further alternative first aspect of the invention, there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prevention of an exaggerated host immune response to a viral infection.

Compounds of formula I, and pharmaceutically acceptable salts thereof may be referred to herein as “compounds of the invention”.

Compounds of the invention include (2R)-2-[(2-amino-5-{[(1S)-1- phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol

and 5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one

which are described in WO 2006/107528 and Karlstrom et a!., J. Med. Chem. , 2013, 56, 3177-3190 and analogues and phosphate/phosphonate derivatives thereof described in WO 2019/219771 and WO 2020/008064 (including in particular, the compounds of the examples). For the avoidance of doubt, the skilled person will understand that references herein to compounds of particular aspects of the invention (such as the first aspect of the invention, i.e. referring to compounds of formula I as defined in the first aspect of the invention) will include references to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.

Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared using techniques known to those skilled in the art, such as by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include those formed by reaction with corresponding acids, thus protonating the compound of the invention, to form carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxy- benzoate, salicylate, ni cotin ate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulphonate salts (e.g. benzenesulphonate, methyl-, bromo- or chloro-benzenesulphonate, xylenesulphonate, methanesulphonate, ethanesulphonate, propanesulphonate, hydroxy- ethanesulphonate, 1 or 2- naphthalene-sulphonate or 1 ,5-naphthalene-disulphonate salts) or sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.

Particular base addition salts that may be mentioned include salts formed by reaction with corresponding bases, thus removing a proton from compounds of the invention, to form salts with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine and tromethamine) and inorganic bases (such as ammonia).

More particular salts that may be mentioned include Li, Na, K and ammonium salts (including monosalts and disalts). In particular, for compounds of the invention wherein R⁶ and R⁷ each represent H particular salts that may be mentioned include diammonium salts, disodium salts, dilithium salts and dipotassium salts. For the avoidance of doubt, compounds of the invention may exist as solids, and thus the scope of the invention includes all amorphous, crystalline and part crystalline forms thereof, and may also exist as oils. Where compounds of the invention exist in crystalline and part crystalline forms, such forms may include solvates, which are included in the scope of the invention.

For the avoidance of doubt, compounds of the invention may also exist in solution (i.e. in solution in a suitable solvent). For example, compounds of the invention may exist in aqueous solution, in which case compounds of the invention may exist in the form of hydrates thereof.

Compounds of the invention may contain double bonds and, unless otherwise indicated, may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention (particularly those of sufficient stability to allow for isolation thereof).

Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism (i.e. existing in enantiomeric or diastereomeric forms). Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers (i.e. enantiomers) may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC techniques. Alternatively the desired enantiomer or diastereoisomer may be obtained from appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution; for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography), or by reaction with an appropriate chiral reagent or chiral catalyst, all of which methods and processes may be performed under conditions known to the skilled person. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of the invention. Unless otherwise specified, C_1-Z alkyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_3-Z cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic (so forming a C_4-z partial cycloalkyl group). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl and cyclohexyl. Similarly, part cyclic alkyl groups (which may also be referred to as “part cycloalkyl” groups) that may be mentioned include cyclopropylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) and/or spirocyclic. For the avoidance of doubt, particular alkyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkyl groups.

Unless otherwise specified, C_2-Z alkenyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_4-Z cycloalkenyl group). When there is a sufficient number (i.e. a minimum of five) of carbon atoms, such groups may also be part cyclic. For example, part cyclic alkenyl groups (which may also be referred to as “part cycloalkenyl” groups) that may be mentioned include cyclopentenylmethyl and cyclohexenylmethyl. When there is a sufficient number of carbon atoms, such groups may also be multicyclic (e.g. bicyclic or tricyclic) or spirocyclic. For the avoidance of doubt, particular alkenyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkenyl groups.

Unless otherwise specified, C_2-Z alkynyl groups (where z is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain. For the avoidance of doubt, particular alkynyl groups that may be mentioned include straight chain (i.e. not branched and/or cyclic) alkynyl groups.

For the avoidance of doubt, unless otherwise specified, groups referred to herein as “alkyl”, “alkenyl” and/or “alkynyl” will be taken as referring to the highest degree of unsaturation in a bond present in such groups. For example, such a group having a carbon-carbon double bond and, in the same group, a carbon-carbon triple bond will be referred to as “alkynyl”. Alternatively, it may be particularly specified that that such groups will comprise only the degree of unsaturation specified (i.e. in one or more bond therein, as appropriate; e.g. in in one bond therein). For the avoidance of doubt, alkyl, alkenyl and alkynyl groups as described herein may also act as linker groups (i.e. groups joining two or more parts of the compound as described), in which case such groups may be referred to as “alkylene”, “alkenylene” and/or “alkynylene” groups, respectively.

As may be used herein, the term aryl may refer to C_6-14 (e.g. Ce-io) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. Ce aryl groups that may be mentioned include phenyl, naphthyl, 1 ,2,3,4- tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl, and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any suitable carbon atom of the ring system.

For the avoidance of doubt, references to polycyclic (e.g. bicyclic or tricyclic) groups (for example when employed in the context of heterocyclyl or cycloalkyl groups (e.g. heterocyclyl)) will refer to ring systems wherein at least two scissions would be required to convert such rings into a non-cyclic (i.e. straight or branched) chain, with the minimum number of such scissions corresponding to the number of rings defined (e.g. the term bicyclic may indicate that a minimum of two scissions would be required to convert the rings into a straight chain). For the avoidance of doubt, the term bicyclic (e.g. when employed in the context of alkyl groups) may refer to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring, to groups in which two non-adjacent atoms are linked by an alkyl (which, when linking two moieties, may be referred to as alkylene) group (optionally containing one or more heteroatoms), which later groups may be referred to as bridged, or to groups in which the second ring is attached to a single atom, which latter groups may be referred to as spiro compounds.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. compounds of the invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

Further for the avoidance of doubt, when it is specified that a substituent is itself optionally substituted by one or more substituents (e.g. C_{1 -3} alkyl optionally substituted by one or more F), these substituents where possible may be positioned on the same or different atoms. Such optional substituents may be present in any suitable number thereof (e.g. the relevant group may be substituted with one or more such substituents, such as one such substituent).

For the avoidance of doubt, where groups are referred to herein as being optionally substituted it is specifically contemplated that such optional substituents may be not present (i.e. references to such optional substituents may be removed), in which case the optionally substituted group may be referred to as being unsubstituted.

Where used herein, a wavy bond (i.e. , or the like) may indicate a (or the) point of

attachment of the relevant substituent to the core molecule (i.e. the compound of the compound of formula I to which the substituent is attached).

For the avoidance of doubt, the skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are obtainable, i.e. those that may be prepared in a stable form. That is, compounds of the invention include those that are sufficiently robust to survive isolation, e.g. from a reaction mixture, to a useful degree of purity.

In particular embodiments, there are provided compounds of the invention in which

and Q¹, Q² and Q³ each represent H.

In further embodiments, there are provided compounds of the invention in which at least one of Q¹, and Q², Q³ or Q⁴ represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷).

In such compounds of the invention, at least one of Q¹ and Q², Q³ or Q⁴ (i.e. at least one of Q¹ and Q²; or Q¹ and Q³; or Q¹ and Q⁴, as appropriate) represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷). Thus, certain compounds of the invention may contain one or two phosphate or phosphoamidic acid groups or esters thereof (-OPO(OR⁶)(OR⁷) or -N H PO(OR⁶) (OR⁷)/-NR^xPO(OR⁶) (OR⁷) , wherein R^x represents a carbon- based group (e.g. alkyl)) groups (i.e. one or two of of Q¹ and Q², Q³ or Q⁴ may represent -PO(OR⁶)(OR⁷) or -CH₂OP(OR⁶)(OR⁷) (as appropriate)). If one of Q¹ and Q², Q³ or Q⁴ represents -PO(OR⁶)(OR⁷) or -CH₂OP(OR⁶)(OR⁷), the remaining group represents H.

In more particular embodiments, one of Q¹ and Q², Q³ or Q⁴ represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷), and the remainder of Q¹, and (if present) Q² or Q³ represent H (Q⁴ either represents -CH₂OPO(OR⁶)(OR⁷) or is absent).

Particular compounds of the invention that may be mentioned include those in which if

one of Q¹ and Q² or Q³ represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷) and the other of Q¹, and Q² or Q³ represents H ; and

Q¹ represents H and Q⁴ represents -CH₂OPO(OR⁶)(OR⁷).

In particular embodiments that may be mentioned, represents

In more particular embodiments,

In alternative particular embodiments,

In particular embodiments that may be mentioned, Q¹ represents -PO(OR⁶)(OR⁷). In particular embodiments that may be mentioned,

Q¹ represents -PO(OR⁶)(OR⁷).

In further particular embodiments in which or

Q¹ represents -PO(OR⁶)(OR⁷); and Q² or Q³ (as appropriate) each represent H.

In particular embodiments, Q¹ represents -PO(OR⁶)(OR⁷).

In particular embodiments, Q² represents -PO(OR⁶)(OR⁷).

In more particular embodiments in which

Q² represents -PO(OR⁶)(OR⁷); and

Q¹ represents H.

In particular embodiments, Q³ represents -CH₂PO(OR⁶)(OR⁷). In more particular embodiments in which

Q³ represents -CH2PO(OR⁶)(OR⁷);and

Q¹ represents H.

In particular embodiments in which

Q¹ represents H.

In particular embodiments, Q² represents H.

In particular embodiments Q³ represents H.

In further particular embodiments, Q², Q³ or Q⁴ (as appropriate) represents H.

In particular compounds of the invention that may be mentioned,

Q¹ represents H or -PO(OR⁶)(OR⁷); and Q² represents H.

In particular embodiments of the compounds of the invention that may be mentioned, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro, bromo, -CN , -C(O)NR³R⁴, -S(O)₂R⁵, C_1-4 alkyl (for example C_{1 -3} alkyl, e.g. C_{1 -2} alkyl), C_2-6 alkenyl (for example C_2-3 alkenyl, e.g. ethenyl) or C_2-4 alkynyl (for example C_2-3 alkenyl, e.g. ethynyl) wherein the latter three groups are optionally substituted by one or more F, wherein R³, R⁴ and R⁵ are as defined herein. In further particular embodiments, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more fluoro, chloro, bromo, -CN, -C(O)NR³R⁴ or -S(O)₂Me group, wherein R³ and R⁴ are as defined herein.

In further particular embodiments, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro, bromo or methyl group.

In further particular embodiments, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) fluoro, chloro or bromo group.

In further particular embodiments, R¹ is selected from

wherein indicates the point of attachment to the rest of the molecule.

In further particular embodiments, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more (e.g. one) chloro group.

In more particular embodiments, R¹ represents phenyl (i.e. unsubstituted) or 5- chloropyridin-2-yl (e.g. phenyl).

In particular embodiments of the compounds of the invention, R² represents C_{1 -6} alkyl optionally substituted by one or more F.

In further particular embodiments, R² represents C_{1 -6} alkyl (i.e. unsubstituted). In more particular embodiments R² represents C_1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted). In yet more particular embodiments, R² represents trifluoromethyl, difluoromethyl, fluoromethyl or, particularly, methyl.

In further particular embodiments, R² represents H or, particularly, methyl. In particular embodiments, R³ and R⁴ each independently represent H or C_{1 -6} alkyl (i.e. unsubstituted). In more particular embodiments, R³ and R⁴ each independently represent C_1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted). In yet more particular embodiments, R³ and R⁴ each independently represent H, trifluoromethyl, difluoromethyl, fluoromethyl or methyl. In further particular embodiments R³ and R⁴ both represent H.

In particular embodiments, R⁵ represents C_1-6 alkyl (i.e. unsubstituted). In more particular embodiments R⁵ represents C_1-3 alkyl optionally substituted by one or more F (e.g. unsubstituted). In yet more particular embodiments, R⁵ represents trifluoromethyl, difluoromethyl, fluoromethyl or, particularly, methyl.

In particular embodiments that may be mentioned, R⁶ and R⁷ each independently represent C_1-3 alkyl (e.g. C_1-2 alkyl) or H. In more particular embodiments, R⁶ and R⁷ each represent H.

In further embodiments, R⁶ and R⁷ each represent methyl or each represent ethyl.

In further particular embodiments, R⁶ represents iso-propyl and R⁷ represents H.

In particular embodiments, the compound of formula I is a compound of formula IA

wherein R¹, R², Q¹ and are as defined herein, or a pharmaceutically acceptable salt thereof.

In more particular embodiments, the compound of formula I is a compound of formula lAa

wherein R¹, R², Q¹ and

are as defined herein, or a pharmaceutically acceptable salt thereof.

In particular embodiments of a compound of formula lAa that may be mentioned,

Q¹ represents H or -PO(OR⁶)(OR⁷);

Q² represents H;

R¹ represents phenyl or pyridyl both of which are optionally substituted by one or more (e.g. one) groups selected from the group consisting of chloro, fluoro, -CN, -CONH2 and - SO₂Me (particularly phenyl (i.e. unsubstituted));

R² represents H or C_1-3 alkyl (e.g. methyl);

R⁶ and R⁷ each independently represent C_1-3 alkyl (e.g. Me) or H; more particularly R⁶ represents iso-propyl and R⁷ represents H or R⁶ and R⁷ each represent H (e.g. R⁶ and R⁷ each represent H).

In particular embodiments, the compound of formula I is selected from the group consisting of:

(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1 ,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentan-1-ol

5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one

(2R)-2-[(2-Amino-5-{[(1 S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]- 4-methylpentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(2-chlorophenyi)ethyi]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methyl pentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methyl pentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methyipentyl dihydrogen phosphate

(2 ?)-2-[(2-Amino-5-{[1-(3-carbamoylphenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methyl pentyl dihydrogen phosphate

(2R)-2-{[2-Amino-5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)[1,3]thiazolo[4,5-d] pyrimidin-7-yl]amino}-4-methylpentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[4-(methylsulfonyl)benzyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-({2-Amino-5-[(1-pyridin-2-ylethyl)sulfanyl][1 ,3]thiazolo[4,5-d]pyrimidin-7-yl}amino)- 4-methylpentyl dihydrogen phosphate

(2R)-2-[(2-Amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]- 4-methylpentyl dimethyl phosphate

(2R)-2-[(2-Amino-5-{[(1 S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]- 4-methylpentyl diethyl phosphate

(2R)-2-[(2-Amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]- 4-methylpentyl bis(l-methylethyl) phosphate

(2R)-2-[(2-Amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-

4-methylpentyl 1-methylethyl hydrogen phosphate

(2R)-2-[(2-Amino-5-{[1-(2-fluorophenyl)ethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl diethyl phosphate

(2R)-2-[(2-Amino-5-{[1-(2-chlorophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methyl pentyl diethyl phosphate

(2R)-2-[(2-Amino-5-{[1-(5-chloropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl diethyl phosphate

(2R)-2-[(2-Amino-5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl diethyl phosphate

(2R)-2-[(2-Amino-5-{[1-(3-cyanophenyl)ethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7- yl)amino]-4-methylpentyl diethyl phosphate

[7-{[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-{[(1S)-1- phenylethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

[5-{[1-(2-Fluorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2- imino[1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

[5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-7-{[(1 )-1-(hydroxymethyl)-3-methylbutyl]amino}-2- imino[1,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

[5-{[1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}-2-imino[1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

[7-{[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino}-2-imino-5-[(1-pyridin-2- ylethyl)sulfanyl][1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yi]methyl dihydrogen phosphate

[5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}-2-imino[1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yi]methyi dihydrogen phosphate

[5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-2- imino[1 ,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

[5-{[(1S)-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}-2-oxo[1,3]thiazolo[4,5-d]pyrimidin-3(2H)-yl]methyl dihydrogen phosphate

(2R)-2-[(5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-d ]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-4-Methyl-2-({2-oxo-5-[(1-pyridin-2-ylethyl)sulfanyl]-2,3-dihydro[1,3]thiazolo[4,5- d] pyrimidin-7-yl}amino)pentyl dihydrogen phosphate

(2R)-4-Methyl-2-{[5-({1-[4-(methylsulfonyl)phenyl]ethyl}sulfanyl)-2-oxo-2,3- dihydro[1 ,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}pentyl dihydrogen phosphate

(2R)-2-[(5-{[1-(3-Carbamoylphenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-[(5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1 ,3]thiazolo[4,5- d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-[(5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-2-oxo-2,3-dihydro[1,3]thiazolo[4,5- d]pyhmidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate

(2R)-2-[(5-{[(1S)-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3- dihydro[1 ,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentyl dimethyl phosphate

(2R)-2-[(5-{[(1S)-1-(5-Chloropyridin-2-yl)ethyl]sulfanyl}-2-oxo-2,3- dihydro[1 ,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpeniyl diethyl phosphate

(7-{[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino}-5-{[(1S)-1- phenylethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-2-yl)phosphoramidic acid

(5-{[1-(2-Chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2-yl)phosphoramidic acid

(7-{[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2- ylethyl)sulfanyl][1,3]thiazolo[4,5-d]pyrimidin-2-yl)phosphoramidic acid

(5-{[1-(3-Cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]ihiazolo[4,5-d]pyrimidin-2-yl)phosphoramidic acid

(5-{[1-(3-Fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2-yl)phosphoramidic acid

Diethyl (7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1S)-1- phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

Dimethyl (7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-{[(1 S)-1- phenylethyl]sulfanyl}[1 ,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

Diethyl (5-{[1-(2-chlorophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1 ,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

Diethyl (7-{[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino}-5-[(1-pyridin-2- ylethyl)sulfanyl][1,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

Diethyl (5-{[1-(3-cyanophenyl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

Diethyl (5-{[1-(3-fluoropyridin-2-yl)ethyl]sulfanyl}-7-{[(1R)-1-(hydroxymethyl)-3- methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2-yl)amidophosphate

or a pharmaceutically acceptable salt thereof.

In more particular embodiments, the compound of formula I is selected from the group consisting of

(2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentan-1-ol

(Compound 1), and

(2R)-2-[(2-Amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]- 4-methylpentyl dihydrogen phosphate

or a pharmaceutically acceptable salt thereof.

In particular embodiments, the compound of formula I is (2R)-2-[(2-amino-5-{[(1S)-1- phenylethyl]thio}[1 ,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol

(Compound 1)

In particular embodiments, the compound of formula I is (2R)-2-[(2-Amino-5-{[(1 S)-1- phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate (Compound 2)

Medical uses

The compounds of the invention are useful in the treatment or prevention of an exaggerated host immune response to a viral infection induced by the innate immune system.

The host immune response is the process by which the body’s immune system interacts with and responds to viruses that it encounters. In particular, the host immune response involves an immune response in which virus replication-induced production of cytokines epithelium recruits innate immune cells to the site of infection. These leukocytes, including, neutrophils, monocytes, macrophages, dendritic cells, eosinophils, natural killer cells, innate lymphoid cells such as gd T cells, become activated in response to the virus, to stop the virus and protect tissues of the host while triggering the adaptive arm of the immune system.

An exaggerated host immune response occurs when there is an overactivation of immune cells leading to an extensive tissue infiltration and to over production of inflammatory cytokines. Together, the factors cause a stepwise progression to excessive inflammation and a cytokine storm, leading to damage and fibrosis in tissues including e.g. the heart, vasculature, lung, kidney, liver intestine and nerves. An exaggerated host immune response may also induce coagulation disorder, endotheliitis and vasculitis. If it is not controlled or does not abate naturally, this immune response can result in death.

An exaggerated host immune response may also be described as an excessive (host) immune response. The excessive inflammation resulting from the exaggerated host immune response may also be termed hyperinflammation.

Thus, in particular embodiments of the uses and methods described herein, there is provided, the compounds of the invention (including pharmaceutically acceptable salts thereof) for use in the treatment or prevention (e.g. prevention) of viral infection-induced hyperinflammation.

Similarly, there is provided a method of treatment or prevention (e.g. prevention) of viral infection- induced hyperinflammation in a subject, which method comprises administering a therapeutically effective amount the compounds of the invention (including pharmaceutically acceptable salts thereof), to a subject in need thereof.

In a further alternative first aspect of the invention, there is provided the use of the compounds of the invention (including pharmaceutically acceptable salts thereof), for the manufacture of a medicament for the treatment or prevention (e.g. prevention) of viral infection-induced hyperinflammation.

In certain diseases or disorders caused by viral infections, including coronavirus disease 2019, the exaggerated host response principally occurs due to a second wave of innate immunity which plays a considerable role in disease progression.

This second wave of innate immunity is thought to be caused by ineffective or inadequate clearance of the virus during the early stage of the infection as a result of the normal immune response. This generally occurs when the subject’s adaptive immune system is not effective in clearing the virus and/or in subjects that are immunosuppressed, as, for example, reflected by lymphopenia.

An analogous situation occurs in subjects with dengue fever (caused by the Dengue virus). In certain cases, the dengue fever develops into severe dengue ( also known dengue hemorrhagic fever) and/or dengue shock syndrome. Severe dengue occurs most frequently when subjects are infected for a second time with a different strain of dengue virus to the initial infection. It is believed that the compounds of the invention may be effective in the treatment or prevention of disorders involving a second wave of innate immunity.

It is believed that the compounds of the invention exert their effects through acting as antagonists of the CX3CR1 receptor (fractalkine receptor). Thus, in particular embodiments of the methods and uses described herein, the compounds of the invention act as antagonists of the CX3CR1 (fractalkine) receptor.

For the avoidance of doubt, compounds of the invention are therefore useful because they possess pharmacological activity, and/or are metabolised in the body following administration (e.g. oral or parenteral administration) to form compounds that possess pharmacological activity.

The skilled person will understand that references to the treatment of a particular condition (or, similarly, to treating that condition) will take their normal meanings in the field of medicine. In particular, the terms may refer to achieving a reduction in the severity and/or frequency of occurrence of one or more clinical symptom associated with the condition, as adjudged by a physician attending a patient having or being susceptible to such symptoms. For example, for the treatment of treatment of an exaggerated host immune response to a viral infection, the term may refer to achieving a reduction in the degree of inflammation or tissue damage in an organ (e.g. the lungs) and/or the reduction in the severity and/or frequency of a symptom associated with inflammation or tissue damage in an organ (e.g. the lungs), (e.g. cough, oxygenation, dyspnea, respiratory distress and/or respiratory failure).

As used herein, the term prevention (and, similarly, preventing) will include references to the prophylaxis of the disease or disorder (and vice-versa). As such, references to prevention may also be references to prophylaxis, and vice versa. In particular, such terms term may refer to achieving a reduction (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) in the likelihood of the patient (or healthy subject) developing the condition (which may be understood as meaning that the condition of the patient changes such that patient is diagnosed by a physician as having, e.g. requiring treatment for, the relevant disease or disorder).

In particular, the compounds of the invention may attenuate the host immune response and thereby achieve a reduction in the likelihood of a subject (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction) developing of an exaggerated host immune response to a viral infection. Similarly, the compounds of the invention may cause a reduction in the severity of the host immune response (e.g. as measured by the degree of inflammation and/or tissue damage and function). Accordingly, the compounds of the invention may prevent the development of disorders and/or complications caused by excessive inflammation and/or tissue damage occurring during the host immune response to a viral infection.

Thus, in particular embodiments, the compounds of the invention (including pharmaceutically acceptable salts thereof) are for use in the prevention of an exaggerated host immune response to a viral infection (and similarly there is provided a method of prevention of an exaggerated host immune response to a viral infection comprising administering the compounds of the invention as described herein and the use of the compounds of the invention in the manufacture of medicament for the prevention of an exaggerated host immune response to a viral infection). This prevention of an exaggerated host immune response to a viral infection may include the prevention of tissue and/or the prevention of diseases and disorders caused by the virus and/or the host response, as described herein.

As used herein, the terms subject and patient may be used interchangeably. References to a subject (or patient), or to subjects (or patients), will refer to a living subject being treated, including mammalian (e.g. human) subjects (or patients). In particular, references to a subject (or patient) will refer to a human subject (or patient).

For the avoidance of doubt, the skilled person will understand that such treatment or prevention will be performed in a patient (or subject) in need thereof. The need of a patient (or subject) for such treatment or prevention may be assessed by those skilled the art using routine techniques.

As used herein, the terms disease and disorder (and, similarly, the terms condition, illness, medical problem, and the like) may be used interchangeably.

As used herein, the term effective amount will refer to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be observed in a manner that is objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and/or feels an effect). In particular, the effect may be observed (e.g. measured) in a manner that is objective, using appropriate tests as known to those skilled in the art.

In certain embodiments, the exaggerated host immune response is caused by a virus selected from the group consisting of a coronavirus, Cytomegalovirus, Dengue virus, an influenza virus, a parainfluenza virus and a respiratory syncytial virus.

In particular embodiments, the exaggerated host immune response is caused by a virus selected from the group consisting of a coronavirus, Dengue virus, an influenza virus, and a parainfluenza virus.

In more particular embodiments the exaggerated host immune response is caused by a coronavirus, Cytomegalovirus, Dengue virus or a respiratory syncytial virus. In yet more particular embodiments, the exaggerated host immune response is caused by a coronavirus, such as severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome coronavirus 2.

In certain embodiments, the exaggerated host immune response is caused by a combination of viruses selected from the group consisting of a coronavirus, Cytomegalovirus, Dengue virus, an influenza virus, a parainfluenza virus and a respiratory syncytial virus. In particular, the exaggerated host immune response is caused by a combination of coronavirus and Cytomegalovirus, for example, a combination of severe acute respiratory syndrome coronavirus and Cytomegalovirus or a combination of severe acute respiratory syndrome coronavirus 2 and Cytomegalovirus. More particularly, the exaggerated host immune response occurs as a result of a patient being infected by Cyromegalovirus, then subsequently infected with a second virus (particularly a coronavirus and more particularly, severe acute respiratory syndrome coronavirus 2), which infections may be concurrent or sequential.

In particular embodiments, the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection includes the treatment or prevention (e.g. prevention) of tissue damage caused by the viral infection and/or the exaggerated host immune response. In particular, the tissue damage is damage to heart tissue, lung tissue, kidney tissue or liver tissue. More particularly, the tissue damage is damage to lung tissue.

In particular embodiments, the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection includes the treatment or prevention (e.g. prevention) of a disease or disorder caused by the viral infection and/or the exaggerated host immune response.

The skilled person will understand that references to a disease or disorder (or tissue damage) being caused by the viral infection and/or the exaggerated host immune response to a viral infection indicates the disease or disorder (or tissue damage) occurring as a result of the host immune response.

The disease or disorder (or tissue damage) may occur, and thus be treated, concurrently with the exaggerated host immune response or may persist once the exaggerated host immune response is no longer present, and thus be treatment may continue once the host immune response is no longer present. In the case of prevention of a disease or disorder (or tissue damage) the administration of the compounds of the invention may prevent the disease or disorder (or tissue damage) from occurring as a result of the exaggerated host immune response or may cause the disease or disorder to manifest less severely, thereby causing the patient to experience milder and/or less frequent symptoms and/or to experience a reduced risk of mortality.

Accordingly, in certain embodiments, there is provided a compound of formula I, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a viral infection-induced disease or disorder, (e.g. a viral infection-induced inflammatory disease or disorder).

In alternative embodiments, there is provided a method of treatment or prevention of a viral infection-induced disease or disorder (e.g. a viral infection-induced inflammatory disease or disorder) in a subject, which method comprises administering a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

In further alternative embodiments, there is provided the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection-induced disease or disorder (e.g. a viral infection-induced inflammatory disease or disorder).

In particular embodiments, the disease or disorder caused by the viral infection and/or the exaggerated host immune response (the infection-induced disease or disorder) is selected from the list consisting of a heart disorder (e.g. myocarditis, endocarditis, heart failure, ventricular hypertrophy, cardiac fibrosis, arrythmia), a lung disorder (e.g. acute respiratory distress syndrome, severe acute respiratory syndrome, pulmonary embolism, pulmonary hypertension, lung fibrosis), a kidney disorder (e.g. acute kidney injury, glomerulonephritis, renal fibrosis), a liver disorder (e.g. hepatitis, acute liver failure, liver fibrosis/cirrhosis), gastrointestinal inflammatory disease, a vascular disorder (e.g. coagulation disorder, vasculitis, endotheliitis, hypertension), a neurological disorder (e.g. stroke and seizures, neuritis, pain), sepsis, cytokine release syndrome and/or systemic inflammatory response syndrome.

In particular embodiments, the disease or disoder is dengue fever. In particular embodiments, the treatment or prevention of dengue fever comprisies the treatment or prevention of severe dengue and/or dengue shock syndrome. Such treatment may include the treatment or prevention (e.g. prevention) of tissue damage caused by the viral infection and/or the exaggerated host immune response

In more particular embodiments, the disease or disorder is selected from the list consisting of pneumonia, severe acute respiratory syndrome, acute respiratory distress syndrome, vasculitis, sepsis, cytokine release syndrome and/or systemic inflammatory response syndrome.

In more particular embodiments, the disease or disorder is selected from sepsis, severe acute respiratory syndrome (e.g. coronavirus disease 2019 (COVID-19)) and acute respiratory distress syndrome.

In more particular embodiments, the disease or disorder is severe acute respiratory syndrome. In yet more particular embodiments, the disease is coronavirus disease 2019 (COVID-19).

COVID-19 appears to process through different stages of increasing disease severity. (COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal, https://doi.Org/10.1016/j.healun.2020.03.012).

Stage I of COVID-19 refers to the early stages of infection and initial immune response to the virus associated with mild symptoms. If the subject is unable to adequately clear the viral infection during stage I the disease progresses to stage II, which is characterised by an escalating systemic host immune response leading to a severe pulmonary inflammation. During stage II, patients develop viral pneumonia and may also begin to develop hypoxia. Markers of systemic inflammation also become elevated during stage II. During this stage inflammatory biomarkers are significantly elevated, typically including IL- 1, IL-6 , Interferon gamma, TNFa, C-reactive protein. A minority of subjects then transition into stage III of the disease, which involves systemic acute life threatening hyperinflammation. Treatment in intensive care is necessary during this stage and there is a risk of shock, repiratory failure, multiple organ failure and death.

The features of the stages of COVID-19 are summarised Table 1.

Table 1.

It is believed that treatment with the compounds of the invention (including pharmaceutically acceptable salts thereof) may reduce the likelihood of the disease progressing to stage II, and, parti cuarly, stage III, and therefore prevent severe disease from occuring. Thus, in particular embodiments of the treatment of coronavirus disease 2019, the compound of the invention or pharmaceutically acceptable salt thereof, is administered during stage I (viral response) and/or stage II (host immune response) of the disease. More particularly, the compound is administered during stage I (viral response) and stage II (host immune response). More particularly, the compound is administered during first administered during late stage I (viral response) or during stage II (host immune response) of the disease but prior to intensive care (stage III).

In particular embodiments of the treatment of COVID-19, the treatment comprises the treatment or prevention (e.g. prevention) of acute respiratory distress syndrome, systemic inflammatory response syndrome and/or cardiac failure.

In further particular embodiments, the treatment of COVID-19 is in a hypoxic subject. In particular, a subject may be considered to be hypoxic if they have an arterial oxygen saturation level of below 94% (e.g. below 90%).

In further particular embodiments, the treatment of COVI D-19 is in a subject with a clinically significant viral titre after 5 or more days from the initial infection (for example after 7 or more days, e.g. after 7 to 10 days).

The skilled person will understand the phrase clinically significant viral titre to refer to a level of the virus indicating inadequate clearance of the infection, placing the patient at risk of the disease progressing to the more severe stages (Stage II and Stage III).

In further particular emobdiments, the treatment of COVID-19 is: in a subject that has an oxygen saturation level of below 94% (e.g. below 90%); and/or in a subject with a clinically-significant viral titre after 5 or more days from the initial infection (for example after 7 or more days, e.g. after 7 to 10 days); and/or in a subject with a C- reactive protein (CRP) level of 10 mg/L or more.

As discussed above, the treatment may continue once the host immune response is no longer present. For example, in the case of a subject who has had a COVID-19 infection said subject may subsequently require treatment for long COVID. Long COVID may otherwise be referred to as post-acute sequelae of SARS-CoV-2 infection, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), and long-haul COVID. The skilled person will understand that the term long COVID relates to a disorder characterized by long-term effects that persist after the typical convalescence period from COVID-19. Symptoms accociated with long COVID (i.e. symptoms that occur after a COVID-19 infection in a subject) include extreme tiredness (fatigue), shortness of breath, chest pain or tightness, problems with memory and concentration (i.e. "brain fog"), difficulty sleeping (e.g. insomnia), heart palpitations, dizziness, pins and needles, joint pain, depression and anxiety, tinnitus, earaches, nausia , diarrhoea, stomach aches, loss of appetite, high temperature, cough, headaches, sore throat, changes to sense of smell or taste, and rashes.

In particular embodiments, the subject recieving treatment for long COVID may have received (or be receiving) treatment for COVID-19, for example, any of the treatments defined herein. In alternative embodiments, the subject receiving treatment for long COVID may not have received (or be receiving) any treatment for COVID-19.

In particular embodiments, the treatment or prevention (e.g. prevention) of an exaggerated host immune response to a viral infection is in a subject with an increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections.

Subjects at increased risk of experiencing an exaggerated host immune response and/or other complications in response to a viral infection include those with weakened immune systems, for example as a result of advanced age and/or chronic or long-term illness.

Thus, in particular embodiments, the treatment is in an immunosuppressed subject, for example characterized by lymphopenia.

As mentioned, particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications in response to a viral infection are those with weakened immune systems as a result of advanced age. Such subjects include the elderly, e.g. subjects who are 65 years old or over. Thus, in particular embodiments, the treatment is in a subject who is 65 years old or over.

Particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections include subjects who are:

(a) aged 70 years or older;

(b) suffering from an underlying health condition selected from chronic long-term respiratory diseases, chronic heart disease, chronic kidney disease, chronic liver disease, chronic neurological conditions, diabetes, disorders of the spleen, a weakened immune system and/or a body mass index of 40 or above; (c) pregnant; and/or

(d) in a group characterized by elevated levels of CX3CL1 and/or circulating CX3CR1 positive cells, particularly T-cells and/or monocytes.

Particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of viral infections include subjects who are in a group characterized by elevated levels of CX3CL1 and/or circulating CX3CR1 positive cells, particularly T-cells and/or monocytes.

(a) aged 70 years or older;

(b) suffering from an underlying health condition selected from chronic long-term respiratory diseases, chronic heart disease, chronic kidney disease, chronic liver disease, chronic neurological conditions, diabetes, disorders of the spleen, a weakened immune system and/or a body mass index of 40 or above; and/or

(c) pregnant.

Further particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of infectious illnesses include subjects who are:

(a) an organ transplant recipient on immunosuppression medication

(b) a cancer patient undergoing chemotherapy or radiotherapy;

(c) a patient with a cancer of the blood or bone marrow;

(d) a patient with severe chest condition, such as cystic fibrosis or severe asthma; and/or

(e) a patient with a severe disease of body systems, such as severe kidney disease requiring dialysis.

Other particular subjects at increased risk of experiencing an exaggerated host immune response and/or other complications as a result of infectious illnesses include subjects who are (or have been) infected with Cytomegalovirus. Infection with cytomegalovirus frequently does not provoke a serious or exaggerated host immune response, but affects the immune system such that the likelihood of a patient experiencing an exaggerated immune response is increased when the patient is subsequently (and/or concurrently) infected with a further virus, such as a coronavirus, e.g. severe acute respiratory syndrome coronavirus 2. Pharmaceutical compositions

The compounds for use in the methods of treatment disclosed herein (i.e. the compounds of the invention) may be administered alone or by way of known pharmaceutical compositions/formulations. Such pharmaceutical compositions/formulations would include a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient.

Accordingly, in a further embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, for use in the treatment and/or prevention of infection-induced inflammation.

In a further embodiment of the invention, there is provided a method of treatment and/or prevention of infection-induced inflammation in a subject, which method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, to a subject in need thereof.

In a further embodiment of the invention, there is provided the use of a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient, for the manufacture of a medicament for the treatment and/or prevention of infection- induced inflammation.

As used herein, the term pharmaceutically acceptable excipients includes vehicles, adjuvants, carriers, diluents, pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like. In particular, such excipients may include adjuvants, diluents or carriers.

In particular embodiments, the pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient.

The skilled person will understand that compounds of the invention act systemically and/or locally (i.e. at a particular site), and may therefore be administered accordingly using suitable techniques known to those skilled in the art. In particular, the compounds of the invention may act systemically.

The skilled person will understand that compounds and compositions as described herein will normally be administered orally, intravenously, intraocularly, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. In particular, the compounds may be administered orally (i.e. through per oral administration) or intravenously.

Pharmaceutical compositions as described herein will include compositions in the form of tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral (e.g. intravenous) or intramuscular administration, and the like.

Thus, in particular embodiments, the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms to be taken orally or by injection, suppositories, creams, gels, foams, inhalants (e.g. to be applied intranasally), or forms suitable for topical administration (e.g. eye drops). For the avoidance of doubt, in such embodiments, compounds of the invention may be present as a solid (e.g. a solid dispersion), liquid (e.g. in solution) or in other forms, such as in the form of micelles.

For example, in the preparation of pharmaceutical formulations for oral administration, the compound may be mixed with solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or compressed into tablets.

Soft gelatin capsules may be prepared with capsules containing one or more active compounds (e.g. compounds of the first and, therefore, second and third aspects of the invention, and optionally additional therapeutic agents), together with, for example, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Similarly, hard gelatine capsules may contain such compound(s) in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the compound(s) mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil, or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the compound(s) and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of the compound(s) in a pharmaceutically acceptable solvent (e.g. water). These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in an amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

Dosages

The skilled person will understand that compounds of the invention may be administered (for example, as compositions/formulations as described hereinabove) at varying doses, with suitable doses being determined by one of skill in the art. Oral, pulmonary and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably about 0.1 to about 5.0 mg/kg/day, and more preferably about 0.5 to about 3.0 mg/kg/day. For example, when administered orally, treatment with such compounds may comprise administration of a formulations typically containing between about 0.01 mg to about 5000 mg, for example between about 0.1 mg to about 500 mg, or between 1 mg to about 400 mg (e.g. about 20 mg to about 200 mg), of the active ingredient(s). When administered intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.

In particular, the compounds of the invention may be administered orally at a dose of 100 to 600 mg per day (e.g. 50 to 300 mg twice daily) and/or intravenously at a dose sufficient to achieve a steady state plasma concentration of 300 nM to 2 mM for a period of at least 6 hours.

Advantageously, the compound of formula I, or pharmaceutically acceptable salt thereof, is administered:

(i) orally at a dose of between about 100 mg to about 700 mg per day (such as between about 410 mg and 700 mg, for example between about 450 mg to about 600 mg (e.g. about 500 mg); and/or

(ii) intravenously at a dose sufficient to achieve a steady state plasma concentration of the active compound of above about 1 mM (such as above about 1.2 pM for example above about 1.4 pM (e.g. above about 1.5 pM) for a period of at least 6 hours ( such as for at least 10 hours, for example at least 12 hours (e.g. about 12 to about 24 hours).

References to the active compound may be understood to refer to the compound that binds to and exerts the effect at the relevant receptor (the CX3CR1 receptor). In compounds of formula I in which at least one of Q¹, and Q², Q³ or Q⁴ represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷), these groups may be removed in vivo, in which case, the active compound refers to the corresponding compound in which the relevant group(s) of Q¹, and Q², Q³ and Q⁴ represents H.

For example, it has been shown that Compound 2 metabolises in vivo to form Compound 1.

References to the active ingredient in a composition/formulation may refer to the compound that exerts the effect at the relevant receptor (i.e. the active compound) or the relevant salt form or derivative thereof present in the composition/formulation. When dosages are expressed in milligrams, this may refer to the weight of the relevant salt form or derivative, or, alternatively, may refer to the weight of the active compound within the salt form/derivative. In particular, references to the active ingredient refer to the compound that exerts the effect at the relevant receptor.

In certain embodiments, for oral administration, the daily dose may be administered in divided doses of two, three or four times daily. More particularly, the compound may be administered at a twice daily dose of between 205 and 300 mg (e.g. 250 mg).

In particular embodiments, the compound is administered orally at a twice daily dose of 125 mg of the active ingredient.

The compound of formula I, or pharmaceutically acceptable salt thereof may be administered for a period of between 5 to 30 days (for example 5 to 25 days, e.g. 10 to 21 days). In particular embodiments, the treatment is continued for 7 days.

In particular embodiments that may be mentioned the compound of formula I, or pharmaceutically acceptable salt thereof, is administered for a period of 10 to 21 days:

(i) orally at a dose 250 mg twice daily; and/or

(ii) intravenously at a dose sufficient to achieve a steady state plasma concentration of the active compound of above about 1.4 mM (e.g. above 1.5 mM) for a period of 12 to 24 hours.

When used herein in relation to a specific value (such as an amount), the term “about” (or similar terms, such as “approximately”) will be understood as indicating that such values may vary by up to 10% (particularly, up to 5%, such as up to 1%) of the value defined. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.

Combinations and kits-of-parts

The skilled person will understand that treatment with compounds of the invention may further comprise (i.e. be combined with) further treatment(s) or preventative methods for the same condition, or related conditions. In particular, treatment with compounds of the invention may be combined with other means for the treatment of patients with viral infections, such as treatment with one or more other therapeutic agent that is useful in the in the treatment of patients with viral infections, as known to those skilled in the art.

As described herein, compounds of the invention may also be combined with one or more other (i.e. different) therapeutic agents (i.e. agents that are not compounds of the invention) that are useful in the treatment of patients with viral infections. Such combination products that provide for the administration of a compound of the invention in conjunction with one or more other therapeutic agent may be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the one or more other therapeutic agent).

Therapeutic agents that may be used in conjunction with the compounds of the invention include one or more of the variously-applied standard treatments for viral infections, including antiviral medicines (e.g. oseltamivir, remdesivir, favilavir, simeprevir, daclatasvir, sofosbuvir, ribavirin, umifenovir, lopinavir, ritonavir, teicoplanin, the TMPRSS2 inhibitor, camostat, Actembra (Roche), TZLS-501 , AT-100 (rhSP-D), OYA1 (OyaGen9), BPI-002 (BeyondSpring), NP-120 (Ifenprodil; Algernon Pharmaceuticals), Galidesivir (Biocryst Pharma), REGN3048-3051 and Kevzara (SNG001 ; Synairgen Research), antiinflammatory agents (e.g. NSAIDs, such as ibuprofen, ketorolac, naproxen and the like, chloroquine, hydroxychloroquine, interferons, tocilizumab, lenalidomide, pomalidomide and thalidomide), analgesics (e.g. paracetamol or opioids), antitussive agents (e.g. dextromethorphan).

Thus, according to a further aspect of the invention, there is provided a combination product comprising:

(I) a compound of the invention, as hereinbefore defined (including all embodiments and particular features thereof); and

(II) one or more other therapeutic agent that is useful in the treatment of patients with viral infections. wherein each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically acceptable excipient.

In a further aspect of the invention, there is provided a kit-of-parts comprising:

(a) a pharmaceutical formulation as hereinbefore defined; and (b) one or more other therapeutic agent that is useful in the treatment of patients with viral infections, optionally in admixture with one or more pharmaceutically acceptable excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction (i.e. concomitantly or sequentially) with the other.

With respect to the kits-of-parts as described herein, by “administration in conjunction with” (and similarly “administered in conjunction with”) we include that respective formulations are administered, sequentially, separately or simultaneously, as part of a medical intervention directed towards treatment of the relevant condition.

Thus, in relation to the present invention, the term “administration in conjunction with” (and similarly “administered in conjunction with”) includes that the two active ingredients (i.e. a compound of the invention and a further agent for the treatment and/or prevention of fractalkine-related diseases, or compositions comprising the same) are administered (optionally repeatedly) either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment and/or prevention of the relevant condition, than if either agent is administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment and/or prevention. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of, treatment and/or prevention of a particular condition will depend upon the condition to be treated and/or prevented, but may be achieved routinely by the skilled person.

Further, in the context of the present invention, the term “in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration of the other component. When used in this context, the terms “administered simultaneously” and “administered at the same time as” includes instances where the individual doses of the compound of the invention and the additional compound for the treatment patients with viral infections, or pharmaceutically acceptable salts thereof, are administered within 48 hours (e.g. within 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.

As used herein, references to other therapeutic agents that are “useful” in a certain manner (e.g. in the treatment of a certain disease or disorder) will refer to agents that are known to be suitable for use in that manner (e.g. agents commonly used for that purpose). Such references may therefore be replaced with references to agents “suitable for” the relevant purpose.

Preparation of compounds/compositions

Pharmaceutical compositions/formulations, combination products and kits as described herein may be prepared in accordance with standard and/or accepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a process for the preparation of a pharmaceutical composition/formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with one or more pharmaceutically acceptable excipient.

In further aspects of the invention, there is provided a process for the preparation of a combination product or kit-of- parts as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, with the other therapeutic agent that is useful in the treatment of the relevant disease or disorder, and at least one pharmaceutically-acceptable excipient.

As used herein, references to bringing into association will mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit-of-parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit-of-parts may be:

(i)provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii)packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.

Compounds of the invention as described herein may be prepared in accordance with techniques that are well known to those skilled in the art. In particular, methods for the preparation of the compounds of the invention are disclosed in WO 2006/107258, Karl strom et al., J. Med. Chem., 2013, 56, 3177-3190 (including the attached supporting information), WO 2019/219771 and WO 2020/008064. The uses and method described herein may have the advantage that they block disease driving innate immune cells, which dominate the early inflammatory process of the host immune response thereby reducing inflammation and/or tissue damage compared to existing treatments for viral infections and diseases or disorders caused thereby. In the case of certain viruses, such as SARS CoV-2, these effects may also be relevant during the second wave of the immune response associated with exaggerated inflammation, leading to reduced tissue damage ocurring during this stage of the infection. The uses and methods described herein may also have the advantage that they attenuate the host immune response without affecting the antibody response to the virus antigen, such that the desired virus-directed host response is retained.

The uses and methods described herein may also have the advantage that, in the treatment or prevention of an exaggerated host response to a viral infection , they may be more convenient for the subject than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it/they may have other useful pharmacological properties over, similar methods (treatments) known in the prior art, whether for use in the treatment of an exaggerated host immune response to a viral infection, diseases or disorders caused by such a host immune response, viral infections generally, or otherwise.

Figures

The following drawings are provided to illustrate various aspects of the present inventive concept and are not intended to limit the scope of the present invention unless specified herein.

Figure 1 shows mean plasma concentration-time profiles of Compound 2 and Compound 1 after 30 min IV infusion of Compound 2 at 25 mg/kg or a PO dose of Compound 2 at 35 mg/kg in male Beagle dogs.

Examples

Abbreviations

AUC_inf: Area under the plasma concentration-time curve extrapolated to infinity

AUC_last: Area under the plasma concentration-time curve from time zero to last quantifiable concentration bid: twice daily

BQL: Below quantification limit

C_max: Peak plasma concentration

CV: Coefficient of variation

DPBS: Dulbecco's phosphate-buffered saline

EDTA-K2: Ethylenediaminetetraacetic acid dipotassium salt dihydrate

FACS: Fluorescence-activated cell sorting

FEU: Fibrinogen equivalent units hr: Hours

IP: Investigational product

MAD: Multiple ascending dose

LLOQ: Lower limit of quantification

PCR: Polymerase chain reaction

SAD: Single ascending dose

SD: Standard deviation

SEM: Standard error of the mean

Example 1 Clinical Trial Evaluating Efficacy of (2R)-2-((2-amino-5-{[ 1S)-1- phenylethyl1thio}[1.3]thiazolof4.5-d]pyrimidin-7-yl)aminol-4-methylpentan-1-ol

(Compound 1) in subjects admitted to hospital for care of COVID-19

Primary objective

The primary objective is to determine and compare the effects of oral administration of Compound 1 versus placebo, on oxygen exchange and respiration in subjects admitted to the hospital for care of COVID-19 infection.

Secondary objectives

Rates of adverse events (AEs) and serious adverse events (SAEs).

Clinical outcome measures reflecting the severity and progression of disease.

The effect on different types of leukocytes and cytokines.

Pharmacokinetics (PK) of Compound 1.

Blood gas.

Inclusion criteria:

1. Written Informed Consent obtained and documented according to ICH/GCP and national/local regulations prior to any study specific procedure. 2. Males and females aged >18-85 years at the time of signing the informed consent form. Female subjects must be post-menopausal or use contraceptive methods with a failure rate of < 1% to prevent pregnancy*. Male subject must be willing to use condoms with spermicide, and if he has a fertile partner, she must use contraceptive methods with a failure rate of < 1% to prevent pregnancy*. Male subjects must also refrain from donating sperm from the first dose until three months after dosing with investigational product (IP).

3. Patients with symptoms and signs of SARS-CoV-2 infection according to WHO case definition. Symptoms must include shortness of breath, with an onset which occurred ≤ 10 days before admission, and the COVID-19 diagnosis must be confirmed by laboratory testing (PCR-positive). In addition, moderately impaired oxygenation as demonstrated by oxygen saturation < 93% but > 87% on room air, or requiring 1-5 L/min of oxygen to obtain an oxygen saturation of ≥ 92%, and at least one of the following laboratory values:

A. Ferritin: > 300 ng/mL for men and > 150 ng/mL for women

B. C-reactive protein (CRP): ³ 10 mg/L

C. D-dimer elevated above the age-adjusted lower limit: ≤ 50 years; < 0.5 mg/L FEU

> 50 years; age-related, calculated as follows: 0.5 mg/L FEU + 0.01 mg/L FEU for every year over 50 (i.e. one who is 70 years old has thus a reference limit of < 0.7 mg/L FEU; on who is 90 years old has a reference limit of < 0.9 mg/L FEU)

Willingness and ability to comply with study procedures, visit schedules, study restrictions and requirements.

Study design and methodology

The study is a phase II, randomized, 2-arm parallel-group, double-blind study to explore the efficacy, safety, tolerability and pharmacokinetics of Compound 1 versus placebo in COVID-19 subjects in need of oxygen treatment.

If at screening all criteria for study participation are fulfilled and informed consent is signed, the subject is then enrolled and randomized into one of two arms. After randomization, the subjects will receive Compound 1 or placebo. The Compound 1 or placebo treatment will continue for one week. After the treatment period the subjects will return to ordinary clinical follow-up, but a study follow-up visit will be planned for Day 21 and 90.

Investigational product, dosage and mode of administration.

Compound 1 is provided as 125 mg capsules (2 capsules BID) or a placebo.

Example 2 - Pharmacokinetic studies in dogs

Objective

The purpose of this study was to characterize the pharmacokinetics parameters of Compound 2 ((2R)-2-[(2-Amino-5-{[(1 S)-1-phenylethyl]sulfanyl}[1 ,3]thiazolo[4,5- d]pyrimidin-7-yl)amino]-4-methylpentyl dihydrogen phosphate) and Compound 1 ((2R)-2- [(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4- methylpentan-1-ol) following intravenous (IV) infusion and oral (PO) administration of Compound 2 in male beagle dogs.

This was a non-GLP study but was be conducted in accordance with Chempartner Standard Operating Procedures (SOPs).

Dosing, Sampling, Sample Processing and Sample Storage

The IV infusion dose was conducted via cephalic vein for 30 min. The oral (PO) administration was conducted via oral gavage.

The animals were restrained manually, and approximately 0.5 mL blood/time point was collected from non-dosed cephalic vein into pre-chilled EDTA-K2 tubes at designated time points. Blood samples were put on wet ice and centrifuged at 4 °C to obtain plasma within 15 minutes of sample collection.

Plasma samples were snap frozen in dry ice for temporary storage and transferred into - 80 °C freezer until analysis. The backup samples were discarded one month after in-life completion.

Results

The concentration-time data and pharmacokinetic parameters of Compound 2 and Compound 1 in dog plasma after PO and IV infusion administrations are tabulated in Table 2 to Table 5 below and shown graphically in Figure 1. The results show that the exposure of Compound 1 in plasma is high compared to the exposure of Compound 2 following both PO and IV administration of Compound 2. Following PO administration, nearly all Compound 2 is transformed to Compound 1 over the course of the study (24 hr) as seen from an AUC ratio Compound 1/Compound 2 of >4000. Thus, a high level exposure of Compound 1 can be achieved with PO and IV administration of Compound 2.

Recalculation of the Compound 1 AUC data to average plasma concentration ( C_ave) values gave C_ave of ca 12 mM for both PO and IV administration routes. These C_ave values can be compared with a C_ave of 1.9 mM for Compound 1 in human healthy volunteers when dosed 300 mg BID over 7 days, which resulted in a decrease of CX3CR1 frequency and surface density on subsets of immune cells (see Example 3 below).

parameters of Compound 2 after a PO dose of 35 mg/kg in male Beagle dogs.

parameters of Compound 1 after a PO dose of Compound 2 at 35 mg/kg in male Beagle dogs.

parameters of Compound 2 after 30 min IV infusion dose of 25 mg/kg in male Beagle dogs.

parameters of Compound 1 after 30 min IV infusion dose of Compound 2 at 25 mg/kg in male Beagle dogs. Example 3 - Pharmacodynamic studies in human

Overall Study Design and Plan Description

The objective was to determine (amongst other things) the pharmacodynamics of

Compound 1 in healthy female and male volunteers (elderly included). The study design included both single ascending dose (SAD) and multiple ascending dose (MAD) where each cohort included a total of 8 subjects. The study was run as a double-blind, placebo- controlled and randomised study.

Subjects were screened for eligibility within 21 days prior to start of study treatment and according to the following study-specific eligibility criteria.

Both the SAD and MAD parts were performed in a randomized and double-blind manner except the first two subjects in the initial dose part.

Inclusion Criteria

For inclusion in the study, subjects had to fulfil the following criteria:

1. Provision of written informed consent prior to any study specific procedures.

2. Body weight ≥ 50 kg.

3. Body Mass Index (BMI) ≥ 19 and ≤ 30 kg/m² at screening. 4. Healthy male and female subjects aged ≥ 18 and ≤ 65 years at screening, or healthy elderly male and female subjects aged > 65 at screening (for one elderly MAD cohort).

5. Male subject must use condom with spermicide and if he has a fertile partner, she must use contraceptive methods with a failure rate of < 1% to prevent pregnancy* and drug exposure of a partner and refrain from donating sperm from the first dose until three months after dosing with investigational product (IP).

* Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occulasion, vasectomy, sexual abstinence.

6. Female subject must be of non-childbearing potential (defined as pre-menopausal females with a documented tubal ligation or hysterectomy or bilateral oophorectomy; or as post-menopausal females defined as 12 months’ amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulation hormone 25-140 IE/L and estradiol < 200 pmol/L is confirmatory]).

7. Willingness and ability to comply with study procedures, visit schedules, study restrictions and requirements.

Women of non-childbearing potential were recruited and included in Part 2 (SAD), from cohort 2:2 and onwards. The aim was to have at least two female subjects in each cohort from cohort 2:2, throughout Part 2 (SAD) and in Part 3 (MAD).

Exclusion Criteria

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

1. History of clinically significant cardio- or cerebrovascular, pulmonary, renal, hepatic, neurological, mental, metabolic, endocrine, haematological or gastrointestinal disorder or any other major disorder that may interfere with the objectives of the study, as judged by the investigator.

2. Any clinically significant abnormalities in physical examination, vital signs, ECG, clinical chemistry, haematology or urinalysis results at the time for screening or prior to randomisation, as judged by the investigator 3. Clinically significant illness within the 5 days prior to the administration of the investigational product

4. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody or human immunodeficiency virus (HIV)

5. Known or suspected drug or alcohol abuse or positive screen for drugs of abuse test at screening visit or any time prior to randomisation

6. Current smoker or stopped with smoking < 3 months before first dosing with the IP in this trial

7. History of severe allergy/ hypersensitivity or ongoing allergy/ hypersensitivity

8. Subject who has received any investigational drug within the last 3 months before administration of investigational product

9. Plasma donation within one month of screening visit, or any blood donation/ blood loss > 450 mL during the 3 months prior to screening visit

10. Use of the herbal remedy St. John’s Wort within three weeks prior to the first dose of the investigational product (induces cytochrome P450-3A4)

11. Use of prescribed medication during the three weeks prior to the administration of the investigational product (or longer if the prescribed medication has a half-life long enough to potentially expose the subject to any significant systemic exposure, as judged by the investigator)

12. Use of OTC drugs (including herbals, vitamins and minerals) during one week prior to the administration of the investigational product or need for concomitant medication during the study. However, occasional paracetamol for pain relief is allowed (maximum 4 g per 24 hours)

13. Female subjects: Positive pregnancy test at screening visit or at any time prior to randomisation

14. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements

15. Subject has an eGFR < 90 mL/min/1.73m2 at screening for 18-65 years and an eGFR <80 for subjects older than 65 years.

SAD Study The SAD study included five cohorts (per cohort: 6 with dosed with Compound 1; 2 dosed with placebo), with the option to extend with up to two additional dose levels if needed. No additional cohorts were added.

SAD study subjects were admitted to the study clinic from the day before dosing (Day -1) and until at least 24 hours post-dosing (Day 2) or longer at the discretion of the Investigator. Subjects returned to the clinic for a follow-up visit during day 6-10.

Blood sampling was performed on Day -1 or Day 1 pre-dose; and at estimated Cmax (1 h).

MAD Study

The MAD study included four cohorts (per cohort: 6 with dosed with Compound 1 ; 2 dosed with placebo, administrated during 7 consecutive days). The forth cohort was a panel in elderly (> 65 years old) volunteers. The MAD study had the possibility to be extended with two optional cohorts depending on the results from the previous cohorts. No additional cohorts were dosed.

The selection of starting dose and dosing regimen was based on safety and tolerability and PK simulations on the data from the first four SAD cohorts. Subjects were enrolled to the subsequent cohorts and dose escalation was based on the safety and pharmacokinetics from previous cohorts.

In the MAD study, subjects were admitted to the study clinic from the day before dosing (Day -1) until at least 24 hours after the last dose (Day 8) or longer at the discretion of the Investigator. Subjects returned to the clinic for a follow-up visit 6-10 days after the last dose.

Blood sampling was performed on Day -1 or Day 1 pre-dose; Day 1 at estimated Cmax; Day 2 at estimated Cmax; and Day 7 at estimated Cmax.

Treatments Administrated

Compound 1 (2 mg/mL, 5 mg/mL and 10 mg/mL) or placebo was administrated as oral suspension in single dose or as multiple dose for 7 days. For cohorts 3:3 and 3:4 in the MAD study, Compound 1 or placebo was administrated as drug in capsule 100 mg.

In the morning of each treatment day, the site personnel administrated the IP as a single dose in fasted condition. The total volume of water (250 mL) administered with the IP was adjusted so that all subjects received the same total volume. The maximum time for administration of suspension was 2 minutes from start of administration. The IP was administered in the morning between 08:00 and 11:00. In the MAD part of the study, where the IP was administered twice per day, the second dose was administered within a 12- hour interval from the morning dose.

Investigational Product (IP)

Compound 1 was provided from Kancera AB to QPS, Netherlands. The IP was provided as Compound 1 2 mg/mL, 5 mg/mL and 10 mg/mL, or placebo, oral suspensions. For cohorts 3:3 and 3:4 Compound 1 or placebo was provided as drug in capsule 100 mg.

Preparation, handling and release of IP (active and placebo) was carried out by QPS Netherlands in accordance with current Good Manufacturing Practice (GMP).

FACS Method

The collected human whole blood was stimulated ex vivo in PBS with 110 nM CX3CL1 (fractalkine/FKN) or H20/0.1%BSA (non-stimulated control) for 1 minute. Actin polymerization was assessed in lymphocytes and monocytes by staining of filamentous actin with phalloidin-A488, immunostaining of lymphocyte and monocyte with anti-CD3-PE CY7, anti-CD45 APC-Cy7, anti-CD19 BV421 , anti-HLA-DR PE, anti-CD14 BV510, and anti-CD16 APC and cells were examined using flow cytometry. The expression of CX3CR1 on lymphocytes and monocytes was assessed in non-stimulated samples (H20/0.1 % BSA) by surface immunostaining with anti-CX3CR1 PerCp-Cy5.5, immunostaining of lymphocyte and monocyte with anti-CD3-PE CY7, anti-CD45 APC-Cy7, anti-CD19 BV421, anti-CD14-BV510 and anti-CD16 APC and cells were examined using flow cytometry.

Data sets analysed

The objective was to determine subsets of lymphocytes and monocytes expressing fractal kine receptor CX3CR1 (CX3CR1+ cells) and the level (density) of this receptor on the cell surface of these cells in whole blood of healthy subjects treated with Compound 1.

Samples taken at estimated Cmax from each subject were analysed by FACS in duplicates. Means from each duplicate were used in the analysis of CX3CR1 cells (frequency) and CX3CR1 surface density (median fluorescence intensity - MFI) for each subject. Due to individual variations in CX3CR1+ cell frequency and surface density of CX3CR1 among subjects, all duplicate means were also normalized to the corresponding baseline value (pre-dose) before statistical analysis.

Prior to analysis of study samples, the FACS method was validated by use of internal controls. Whole blood from external subjects was treated with 7 mM of Compound 1 ex vivo for one hour prior to execution of analysis.

The difference between placebo and Compound 1 treated subjects in baseline normalized frequency of CX3CR1+ cells and surface density of CX3CR1, respectively, is shown in Table 7, Table 8 and Table 9.

Cohorts SAD 2:3, 2:4 and MAD 3:1 are incomplete.

Statistical analysis

One-way Anova was used to study sampled data relationship for frequency of CX3CR1 + cells (%) and surface density (MFI) of the CX3CR1 raw data. A two-tailed parallel t-test analysis was performed on frequency of CX3CR1+ cells (%) and surface density (MFI) of CX3CR1 raw data. A two-tailed unpaired t-test analysis was performed on frequency of CX3CR1+ cells (%) and surface density (MFI) of CX3CR1 normalised data.

Frequency and surface density of CX3CR1 in whole blood cells in SAD and MAD SAD Cohort 2:5, 2500 mg Difference in mean baseline normalized frequency of CX3CR1+ cells and -surface density of CX3CR1 on lymphocytes (NK-cells, T-cells and B-cells) and monocyte subtypes (classical, intermediate and non-classical monocytes) after a single 2500 mg dose between placebo and Compound 1 is shown in Table 7. The results show that there was no significant difference in the frequency of CX3CR1 + cells between placebo and Compound 1 treatment in the SAD 2:5 (2500 mg) cohort. A statistically significant decrease in CX3CR1 surface density was observed for all cell types except for B-cells in Compound 1 treated versus placebo treated subjects.

density of CX3CR1 between placebo and Compound 1 after 2500 mg single-dose to healthy volunteers. Placebo n=2, Compound 1 n=4.

Mean ± SEM, two-tailed unpaired t-test. CM: Classical monocytes, IM: Intermediate monocytes, NCM: Non-classical monocytes. The significance levels are presented by P values. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. NS stands for not statistically significant.

MAD Cohort 3:3, 300 mg bid

Mean baseline normalized -frequency of CX3CR1+ cells and -surface density of CX3CR1 on lymphocytes (NK-cells, T-cells and B-cells) and monocyte subtypes (classical, intermediate and non-classical monocytes) after 300 mg bid between placebo and Compound 1 treatments are shown in Table 8. A significant drecrese in frequency of CX3CR1+ NK and T-cells was observed on day 2 in Compound 1 treated subjects vs placebo (-38% and -47%, respectively). The differences were less pronounced on day 7.

A statistically significant decrease in CX3CR1 surface density was observed in Compound 1 treated subjects vs placebo for NK and T-cells. The largest difference was observed on day 7 (-62% and -48%, respectively). The largest effect on CX3CR1 surface density for classical, intermediate and non-classical monocytes was observed on day 1 (-62%, -68% and -44% respectively).

density of CX3CR1 between placebo and Compound 1 on day 1 , 2 and 7 after 300 mg bid administration to healthy volunteers for seven days. Placebo n=2, Compound 1 n=6.

Mean ± SEM, two-tailed unpaired t-test. CM: Classical monocytes, IM: Intermediate monocytes, NCM: Non-classical monocytes. The significance levels are presented by P values. *P<0.05, **P<0.01 , ***P<0.001 , ****P<0.0001. NS stands for not statistically significant.

MAD Cohort 3:4, 300 mg bid elderly (65 years old and over) subjects Mean baseline normalized -frequency of CX3CR1+ cells and -surface density of CX3CR1 on lymphocytes (NK-cells, T-cells and B-cells) and monocyte subtypes (classical, intermediate and non-classical monocytes) after 300 mg bid in the elderly subject cohort between placebo and Compound 1 treatments are shown in Table 9. A significant decrease in frequency of CX3CR1+ NK and T-cells was observed on days 2 and 7 in Compound 1 treated elderly subjects vs placebo with maximal decrease on day 2 (-99%) for T-cells and day 7 (-30%) for NK cells.

A significant decrease between treatment groups in CX3CR1 surface density of NK and T-cells was seen and was most pronounced on day 2 (-71% and -36%) and for intermediate and non-classical monocytes on day 1 (-23% and -51%).

density of CX3CR1 between placebo and Compound 1 on day 1 , 2 and 7 after 300 mg bid administration to healthy elderly volunteers. Placebo n=2, Compound 1 n=6.

Mean ± SEM, two-tailed unpaired t-test. CM: Classical monocytes, IM: Intermediate monocytes, NCM: Non-classical monocytes. The significance levels are presented by P values. *P<0.05, **P<0.01 , ***P<0.001 , ****P<0.0001. NS stands for not statistically significant. Conclusion

Single dose of 2500 mg and multiple doses of 300 mg bid (young and elderly subjects) qualified for analysis.

After single dose administration a significant decrease in CX3CR1 surface density on NK cells, T-cells and monocytes was observed in Compound 1 treated vs placebo. There was no significant change in the frequency of CX3CR1+ cells.

After 300 mg multiple dose administration over 7 days in young and elderly subjects there was a significant decrease in frequency of CX3CR1+ cells at various time points, while the decrease in receptor surface density was present at most time points. In summary, at 300 mg bid a significant decrease in surface density of CX3CR1 on NK, T- cells and monocytes was seen.

The ability of the compounds of the invention to decreasing the surface density of CX3CR1 on NK, T-cells and monocytes suggests that they may be useful in modulating the immune response and thereforeare believed to be likely to be useful in the treatment or prevention of an exaggerated host immune response to a viral infection, as defined hereinabove. The fact that the compounds have also been shown to have this effect in the elderly patient group is also significant as it suggests likely utility in this higher risk patient group.

Further, neither Compound 1 or Compound 2 affected B-cells, which are important for antibody-response to viral infections. This suggests that treatment with the compounds of the invention may have benefits over treatment with corticosteroids, which are known to affect B cell function.

Claims

1. A compound of formula I,

wherein

R¹ represents aryl or pyridyl, both of which are optionally substituted by one or more groups selected from halo, -CN, -C(O)NR³R⁴, -S(O)₂R⁵, C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl, wherein the latter three groups are optionally substituted by one or more F;

R² represents H or C_1-6 alkyl optionally substituted by one or more F;

R³ and R⁴ each independently represent H or C_{1 -6} alkyl optionally substituted by one of more F;

R⁵ represents C_1-6 alkyl optionally substituted by one or more F;

wherein indicates a point of attachment to the rest of the molecule;

Q¹ and Q² each independently represent H or -PO(OR⁶)(OR⁷);

Q³ represents H or -CH₂OPO(OR⁶)(OR⁷); and

2. A method of treatment or prevention of an exaggerated host immune response to a viral infection in a subject, which method comprises administering a therapeutically effective amount of a compound as defined in Claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

3. The use of a compound as defined in Claim 1 , or a pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prevention of an exaggerated host immune response to a viral infection.

4. A compound for use, method or use as claimed in any one of Claims 1 to 3, wherein, in the compound of formula I,

and Q¹, Q² and Q³ each represent H.

5. A compound for use, method or use as claimed in any one of Claims 1 to 3, wherein, in the compound of formula I, at least one of Q¹, and Q², Q³ or Q⁴ represents -PO(OR⁶)(OR⁷) or -CH₂OPO(OR⁶)(OR⁷).

6. A compound for use, method or use as claimed in any one of Claims 1 to 3, wherein, in the compound of formula I,

Q¹ represents H or -PO(OR⁶)(OR⁷); and Q² represents H.

7. A compound for use, method or use as claimed in any one of Claims 1 to 6, wherein, in the compound of formula I, R¹ represents phenyl or pyridyl, both of which are optionally substituted by one or more fluoro, chloro or bromo group.

8. A compound for use, method or use as claimed in Claim 7, wherein, in the compound of formula I, R¹ represents phenyl or 5-chloropyridin-2-yl.

9. A compound for use, method or use as claimed in any one of Claims 1 to 8, wherein, in the compound of formula I, R² represents methyl.

10. A compound for use, method or use as claimed in any one of Claims 1 to 9, wherein the compound of formula I is a compound of formula IA,

wherein R¹, R², Q¹ and

are as defined in any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

11. A compound for use, method or use as claimed in any one of Claims 1 to 3 or 6 to 10, wherein the compound of formula I is selected from

or a pharmaceutically acceptable salt thereof.

12. A compound for use, method or use as claimed in any one of the preceding claims, wherein the exaggerated host immune response is caused by a virus selected from the group consisting of a coronavirus, Cytomegalovirus, Dengue virus, an influenza virus, a parainfluenza virus and a respiratory syncytial virus.

13. A compound for use, method or use as claimed in Claim 12, wherein the exaggerated host immune response is caused by a coronavirus.

14. A compound for use, method or use as claimed in Claim 13, wherein the coronavirus is severe acute respiratory syndrome coronavirus or severe acute respiratory syndrome coronavirus 2.

15. A compound for use, method or use as claimed in any one of the preceding claims, wherein the treatment and or prevention of an exaggerated host immune response to a viral infection includes the treatment or prevention of tissue damage caused by the viral infection and/or the exaggerated host immune response.

16. A compound for use, method or use as claimed in Claim 15, wherein the tissue damage is damage to lung tissue.

17. A compound for use, method or use as claimed in any one of the preceding claims, wherein the treatment or prevention of an exaggerated host immune response to a viral infection includes the treatment or prevention of a disease or disorder caused by the viral infection and/or the exaggerated host immune response.

18. A compound for use, method or use as claimed in Claim 17, wherein the disease or disorder is selected from the list consisting of heart disorder, a lung disorder, a kidney disorder, a coagulation disorder, a liver disorder, gastrointestinal inflammatory disease, a vascular disorder, a neurological disorder, sepsis, cytokine release syndrome and/or systemic inflammatory response syndrome.

19. A compound for use, method or use as claimed in Claim 17 or Claim 18, wherein the disease is selected from the list consisting of sepsis, severe acute respiratory syndrome and acute respiratory distress syndrome.

20. A compound for use, method or use as claimed in any one of Claims 17 to 19, wherein the disease is severe acute respiratory syndrome.

21. A compound for use, method or use as claimed in any one of Claims 17 to Claim 20, wherein the disease is coronavirus disease 2019.

22. A compound for use, method or use as claimed in Claim 21 , wherein the compound of formula I, or pharmaceutically acceptable salt thereof, is administered during stage I and/or stage II of the disease.

23. A compound for use, method or use as claimed in any one of the preceding claims, wherein the compound of formula I, or pharmaceutically acceptable salt thereof, is administered:

(i) orally at a dose of between about 100 mg to about 700 mg per day; and/or

(ii) intravenously at a dose sufficient to achieve a steady state plasma concentration of the active compound of above about 0,3 mM for a period of at least 6 hours.

24. A compound for use, method or use a claimed in any one of the preceding claims, wherein the compound of formula I is administered for a period of 5 to 30 days.

25. A compound for use, method or use as claimed in any one of the preceding claims, wherein the subject receiving treatment is:

(a) aged 70 years or older;

(b) suffering from an underlying health condition selected from chronic long-term respiratory diseases, chronic heart disease, chronic kidney disease, chronic liver disease, chronic neurological conditions, diabetes, disorders of the spleen, a weakened immune system and/or a body mass index of 40 or above;

(c) pregnant; and/or

(d) characterized by elevated levels of CX3CL1 and/or circulating CX3CR1 positive cells, particularly T-cells and/or monocytes.

26. A compound for use, method or use as claimed in any one of the preceding claims, wherein the subject receiving treatment is:

(a) an organ transplant recipient on immunosuppression medication

(b) a cancer patient undergoing chemotherapy or radiotherapy;

(c) a patient with a cancer of the blood or bone marrow;