Azithromycin derivatives for use in the treatment of infections

Abstract

The present invention concerns the use of azithromycin derivatives in methods of improving immune system defences, specifically host defence mechanisms, particularly in response to bacteria, viral and fungal infections, such as respiratory infections, More particularly, but not exclusively, this invention concerns the use of (2S,3R,4S,6R)-2-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-Ethyl-3,4,10,13- tetrahydroxy-3,5,8,10,12,14-hexamethyl-6-methyl-15-oxo-1-oxa-6-aza-11- cyclopentadecyloxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate for use in such methods.

Description

[0001] P039862WO - 22 August 2025

[0002] - 1 -

[0003] Medical Use

[0004] Field of the Invention

[0005] The present invention concerns the use of azithromycin derivatives in methods of improving immune system defences, specifically host defence mechanisms, particularly in response to bacteria, viral and fungal infections, such as respiratory infections. More particularly, but not exclusively, this invention concerns the use of (2S,3R,4S,6R)-2-[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2-Ethyl-3,4,10,13- tetrahy droxy-3 ,5,8,10,12,14-hexamethyl-6-m ethyl- 15 -oxo- 1 -oxa-6-aza- 11- cyclopentadecyloxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate for use in such methods.

[0006] Background of the Invention

[0007] The immune response is a complex network of organs, cells and proteins that defends the body against infection, whilst protecting the body's own cells. The system distinguishes self from non-self, defending the body against bacteria, viruses, and substances that appear foreign and harmful. It is made up of the innate (general) immune system and the adaptive (specialized) immune system. These two systems work closely together to protect the body.

[0008] The innate immune system is the body's first line of defence against intruders. It responds in the same way to all pathogens and foreign substances, which is why it is sometimes referred to as the "non-specific" immune system. It acts very quickly - for instance, it makes sure that bacteria that have entered the skin through a small wound are detected and destroyed on the spot within a few hours. But the innate immune system can’t always stop pathogens from spreading.

[0009] The innate immune system includes:

[0010] • protection offered by the skin and mucous membranes

[0011] • protection offered by immune system cells and proteins.

[0012] If the innate (general) immune system fails to destroy the pathogens, the adaptive (specialized) immune system takes over. The adaptive immune system specifically targets the type of pathogen that is causing the infection. However, to do that, it first needs to recognize the pathogen as such. This means that it is slower to respond than the innate immune system, but it is more specific when it does respond. P039862WO - 22 August 2025

[0013] - 2 -

[0014] It also has the advantage of being able to "remember" pathogens. Thus, the next time the adaptive immune system encounters a pathogen, it has done so previously, it can start fighting the pathogen faster. This memory means that some illnesses are only contracted once in your life, because afterwards the body becomes “immune” to them. It may take a few days for the adaptive immune system to respond the first time it comes into contact with the pathogen, but the next time the body can react immediately. The second infection then usually goes unnoticed or is at least milder.

[0015] The adaptive immune system is made up of:

[0016] • T cells in the tissue between the body's cells

[0017] • B cells also in the tissue between the body's cells

[0018] • Antibodies in the blood and other bodily fluids

[0019] Infections of the respiratory tract are common afflictions. They range from mild and moderate conditions, like the common cold and influenza, to severe infections that cause exacerbations and decline in lung function in those with underlying lung disease e.g. COPD and serious diseases like tuberculosis. The development of antimicrobial compounds that are effective at treating these diseases has been instrumental in reducing the burden incurred by these diseases, but many of these compounds produce unwanted side-effects when taken and increasingly are becoming less reliable due to the evolution of resistance to these compounds.

[0020] Another way of reducing the disease burden produced by these diseases, without the need for using antimicrobial compounds, is to prevent their contraction in the first place. One such method for preventing disease focuses on increasing the effectiveness of the natural immune system that is designed to defend against infections.

[0021] It has been surprisingly found that azithromycin derivatives, for example, compounds of formula (I) enhance host defence mechanisms in response to infections, such as bacterial, viral and fungal infections, thus reducing the likelihood of suffering from infections, particularly from respiratory infections. P039862WO - 22 August 2025

[0022] - 3 -

[0023] Summary of the Invention

[0024] In a first aspect of the invention provides a compound according to formula (I)

[0025] (I) for use in a method of raising, enhancing or maintaining one or more host defence mechanisms in a subject, for example, against viral, bacterial and / or fungal infections, wherein:

[0026] R1is selected from the group consisting of OH, carbamoyloxy, N-Ci-6-alkylcarbamoyloxy, N-(C6-i4-aryl-Ci-6-alkyl)carbamoyloxy, N,N-di-Ci-6-alkylcarbamoyloxy, N,N-di-alkylcarbamoyloxy with the two alkyl substituents together forming a 5- to 8-membered heterocycle together with the nitrogen atom of the carbamate moiety, Ci-6-alkylcarboxy and a moiety according to formula ( wherein

[0027] R6is selected from the group consisting of H, OH and Ci-6-alkyl, P039862WO - 22 August 2025

[0028] - 4 - whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to

[0029] 6 halogen and / or CN; and

[0030] R2is according to formula (III) wherein

[0031] R7is selected from the group consisting of Ci-6-alkyl, C6-i4-aryl-Ci-6-alkyl,

[0032] Cs-ealkylcarbonyl, Ce- 14-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl,

[0033] Ce-w-arylsulfonyl, Ci-6-alkyl-C6-i4-arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl,

[0034] C6-i4-aryl-O-Ci-6-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-Ci-6-alkyl-carbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.1)

[0035] (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and

[0036] Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN; and P039862WO - 22 August 2025

[0037] - 5 -

[0038] R8is selected from the group consisting of H; Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups; C3-6-alkylcarbonyl; HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.l) as depicted hereinbefore with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6; and heteroaryl carbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4-alkoxy, C2-4-alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen and / or CN;

[0039] R3is H; and

[0040] R4and R5are independently selected from H and Ci-6-alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and / or CN, or

[0041] R4and R5together form a single carbonyl group which forms a cyclic carbonate with both oxygen atoms it is bonded to; and with the proviso that the compound of formula (I) is not 2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-l l-[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13- [(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy- 3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one (Azithromycin); or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0042] In a further embodiment, the invention provides a compound according to formula (I), as defined herein, for use in a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against viral, bacterial and fungal infections in a subject, provided that if R6is H or methyl, then R8is not H, and provided that if R1is OH and R7is methyl, then R8is not H; and P039862WO - 22 August 2025

[0043] - 6 - provided that if R8is C4 alkylcarbonyl, then R1is not a moiety according to formula (II); or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0044] The invention further provides a compound of formula (I), as defined herein, for use in the manufacture of a medicament for use in a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against viral, bacterial and fungal infections in a subject.

[0045] The invention further provides a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against viral, bacterial and fungal infections in a subject comprising the administration of a compound of formula (I), as defined herein.

[0046] The invention further provides a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against viral, bacterial and fungal infections in a subject comprising the administration of an effective amount of a compound of formula (I), as defined herein.

[0047] According to a first aspect, the present invention provides Compound A [(2S,3R,4S,6R)-2-[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-Ethyl-3,4, 10,13- tetrahy droxy-3 ,5,8,10,12,14-hexamethyl-6-m ethyl- 15 -oxo- 1 -oxa-6-aza- I ley cl opentadecyloxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate], or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt, for use in a method of raising, enhancing or maintaining host defence mechanisms, for example, against bacterial, viral and / or fungal infections in a subject.

[0048] According to a further aspect, the present invention provides Compound A, or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt for use in the manufacture of a medicament for use in a P039862WO - 22 August 2025

[0049] - 7 - method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against bacterial, viral and / or fungal infections in a subject.

[0050] The invention further provides a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against bacterial, viral and fungal infections in a subject comprising the administration of Compound A, or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0051] The invention further provides a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against bacterial, viral and / or fungal infections in a subject comprising the administration of an effective amount of Compound A, or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0052] In one embodiment, the infection is selected from a bacterial infection, a viral infection and / or a fungal infection. In one embodiment the infection comprises a viral infection. In a further embodiment the infection comprises a bacterial infection. In a further embodiment, the infection comprises a fungal infection. In a further embodiment, the infection is a respiratory infection, for example, a respiratory infection caused or exacerbated by a viral, bacterial or fungal infection.

[0053] In an embodiment, the respiratory infection comprises a viral infection. In an embodiment, the viral infection is selected from adenovirus, paramyxoviruses, such as parainfluenza viruses and respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human rhinovirus (HRV), human parainfluenza virus (HPIV), and SARS- Cov-2. In other embodiments of the invention, the viral infection is selected from adenovirus, MERS-Cov and SARS-Cov-2. In another embodiment the viral infection is a rhinovirus.

[0054] In an embodiment, the respiratory infection comprises a bacterial infection. In an embodiment, the bacterial infection is selected from Mycoplasma pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, or Mycobacterium tuberculosis. In other embodiments, the bacterial infection is selected from Chlamydia, Coxiella burnetiid, Legionella pneumophila, Moraxella catarrhalis, Pseudomonas aeruginosa, P039862WO - 22 August 2025

[0055] - 8 -

[0056] Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, Corynebacterium diphtheriae, Mycoplasma pneumoniae, Bacillus anthracis and Enter obacter ales.

[0057] In an embodiment, the respiratory infection comprises a fungal infection. In an embodiment, the fungal infection is selected from Aspergillus sp., Candida sp, Coccidiodes sp., Pneumocystis jirovecii, and Histoplasma capsulatum. In other embodiments of the invention, the fungal infection is selected from Cryptococcus sp., and Sporothrix schenckii.

[0058] In an embodiment, the one or more host defence mechanisms comprises an increase in the level of one or more cytokines in the lung, for example, interleukin-8 (IL-8), interleukin-33 (IL-33) and interleukin-lbeta (IL-lbeta).

[0059] In an embodiment, the cytokines are selected IL-8 and / or IL-33. The mean increase in cytokines is relative to the placebo response level. In an embodiment, the mean total increase is from about 1% to about 100% above the placebo response level, for example about 5% to about 85%, for example, about 5% to about 50%, for example about 20%.

[0060] In a further embodiment, the cytokines comprise IL-8. The mean increase in IL-8 is relative to the placebo response. In an embodiment, the mean increase in IL-8 is from about 1% to about 50% above the placebo response, for example about 5% to about 30%, for example, about 10% to about 25%, for example about 20%.

[0061] In a further embodiment, the cytokines comprise IL-33. The mean increase in IL-33 is relative to the placebo response. In an embodiment, the mean increase in IL-33 is from about 1% to about 100% above the placebo response, for example about 20% to about 100%, for example, about 30% to about 100%, for example, about 40% to about 80% for example about 60%, about 70%, about 80% or about 90%

[0062] In an embodiment, the one or more host defence mechanisms comprises an increase in neutrophil activity in the lung.

[0063] In an embodiment, the one or more host defence mechanisms comprises increases in the activity of neutrophil elastase in the lung.

[0064] In an embodiment, the one or more host defence mechanisms comprises an increase in the activity of myeloperoxidase in the lung.

[0065] In an embodiment, the one or more host defence mechanisms comprise a natural body barrier, for example, the lung epithelium. P039862WO - 22 August 2025

[0066] - 9 -

[0067] In an embodiment, the one or more host defence mechanisms comprises the lung epithelial barrier.

[0068] In an embodiment, the host defence mechanisms comprise increases in one or more surfactant proteins, for example, the surfactant protein (SP-D) for example, as measured by increase in blood levels that reflect increased SP-D activity in the lung and hence overspill into the blood.

[0069] In an embodiment, the host defence mechanisms comprise an increase in macrophage markers, for example, MRC1 (CD206) expression, for example, as measured by RNA sequencing of BAL cells and / or bronchial brushings, and immortalised airway epithelial cells.

[0070] In one embodiment, the host defence mechanisms comprise an enhancement of the activity of macrophages, for example, type 2 macrophages.

[0071] In an embodiment, the method also comprises an anti-inflammatory response.

[0072] In an embodiment, the anti-inflammatory response comprises a decrease in the level of one or more cytokines selected from IL-6, TNF-a, MIPla, MIPip and MCP-1 in the lung.

[0073] In an embodiment, the enhancement of host defence comprises an increase in the level of IL-8, IL-33, IL-ip, intracellular adhesion molecule 1 and or albumin in bronchoalveolar lavage fluid (BALF).

[0074] In an embodiment, the subject is human. In an embodiment, the subject is elderly. In an embodiment, the subject is aged 60 or above. In an embodiment, the subject is aged between 60 and 100 years old, for example between 60 and 95 years old, 60 and 90 years old, 60 and 85 years old, 60 and 80 years old, 60 and 75 years old, 60 and 70 years old, 60 and 65 years old, or between 65 and 100 years old, 70 and 100 years old, 75 and 100 years old, 80 and 100 years old, 85 and 100 years old, 90 and 100 years old and 95 and 100 years old.

[0075] In an embodiment, the subject is immunocompromised. Immunocompromised in this context means the subject’s immune system is weakened or debilitated in some way as to reduce or in some cases eliminate their ability to fight and clear an infection.

[0076] In an embodiment, the subject is immunocompromised as a result of being elderly and / or having a naturally weakened immune system. In an embodiment, the P039862WO - 22 August 2025

[0077] - 10 - subject is immunocompromised as a result of taking a medication. Taking medications such as chemotherapy, antirheumatic drugs, and glucocorticoids may result in a subject becoming immunocompromised. High doses of these medications may increase the risk of becoming immunocompromised or increase the severity of the immunocompromised condition.

[0078] In an embodiment, the subject has one or more comorbidity. In an embodiment, the one or more comorbidity is selected from anaemia, COPD, asthma, congestive heart failure, chronic kidney disease, diabetes, cancer, for example, a cancer selected from lymphoma and chronic leukaemia, and obesity.

[0079] In a further embodiment, the subject is one who works in an at-risk occupation. Example of at-risk occupations include sculptors, painters, engravers, art restorers, gardeners, groundskeepers, park-keepers, food, drink and tobacco processors, plastics processors, moulders, agricultural worker, fishing workers, miners, and warehouse stock handlers and stackers. Such subjects are at risk of contracting respiratory diseases, such as COPD.

[0080] In a further embodiment, the subject is one who works with and comes into daily contact with those who often contract infections or are ill. Example of at-risk occupations include healthcare workers, childcare workers, teachers.

[0081] According to a further aspect, the present invention also provides a compound of formula (I), for example, (2S,3R,4S,6R)-2-

[0082] [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-Ethyl-3 ,4, 10,13 -tetrahydroxy- 3,5,8,10,12,14-hexamethyl-6-methyl-15-oxo-l-oxa-6-aza-l l-cyclopentadecyloxy]-4- (dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate for use in a method for any of:

[0083] (a) reducing susceptibility to an infection, for example, a bacterial, viral or fungal infection in a subject, for example, in an elderly and / or immunocompromised subject;

[0084] (b) improving the ability of a subject to control a respiratory disease or condition, during a respiratory viral infection;

[0085] (c) preventing or reducing the severity of a rhinovirus infection;

[0086] (d) reducing rhinovirus-induced airway inflammation; and / or

[0087] (e) preventing or reducing a viral, for example, rhinoviral, exacerbation of a respiratory condition in a subject, for example a respiratory condition selected P039862WO - 22 August 2025

[0088] - 11 - from chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis or lung conditions associated with lung transplantation or chronic glucocorticosteroid use.

[0089] Detailed Description

[0090] As described above, the invention provides compounds of Formula (I), as defined herein for use in a method of raising, enhancing or maintaining one or more host defence mechanisms, for example, against viral, bacterial and fungal infections in a subject. Preferred compounds of Formula (I) are the compounds according to the invention wherein R1is selected from the group consisting of OH, Ci-3-alkylcarboxy, a moiety according to formula (II)

[0091] (II) wherein R6is OH, and a moiety according to formula (IV)

[0092] (IV) wherein R9and R10are independently selected from the group consisting of H, C1-3- alkyl and C6-io-aryl-Ci-3-alkyl or are together alkyl forming a 5- or 6-membered aliphatic heterocycle together with the nitrogen atom they are both bonded to, whereby said heterocycle optionally contains one or two, preferably one further heteroatom(s) selected from the group consisting of N, O and S, preferably from the group consisting of N and O, more preferably optionally contains one or two further O atoms, yet more preferably optionally contains one further O atom, or said heterocycle is selected from the group consisting of piperidine, piperazine and morpholine, P039862WO - 22 August 2025

[0093] - 12 - preferably is morpholine, whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to 6 halogen and / or CN.

[0094] Particularly preferred compounds according to the invention are those wherein R1is OH.

[0095] In Formula (I), R2is a group of formula (III)

[0096] In an embodiment, R7is selected from the group consisting of Ci-6-alkyl, Ce-i4- aryl-Ci-6-alkyl, Ce- 14-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl, Ce-w-arylsulfonyl, Ci-6-alkyl-C6-i4-arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl, Ce-i4-aryl-O-Ci-6- alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-Ci-6-alkyl-carbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.1)

[0097] (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, P039862WO - 22 August 2025

[0098] - 13 -

[0099] C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and

[0100] Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN

[0101] In an another embodiment, R7is selected from the group consisting of Ci-6-alkyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl -carbonyl, C6-ioaryl-Ci-3-alkylcarbonyl, C6-io-aryl-0-Ci-3-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O- CO-NH-Ci-6-alkyl-CO- and a moiety according to formula (V.1) or formula (V.2).

[0102] More preferred compounds of the invention are those wherein R7is selected from the group consisting of Ci-3-alkyl, C6-io-aryl-Ci-3-alkyl, linear or branched, preferably branched C3-4-alkylcarbonyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkylcarbonyl, C6-io-aryl-0-Ci-3-alkylcarbonyl, Ce-io-aryl-Ci-3-alkyl-O- Ci-3-alkyl-carbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, C6-io-aryl-Ci-3-alkyl-0-CO-NH-Ci-3-alkyl-CO-, Ce-io-arylsulfonyl, and Ci-3-alkyl-C6-io-arylsulfonyl.

[0103] Yet more preferably R7is selected from the group consisting of methyl, benzyl, benzoyl, naphthylsulfonyl, methylphenylsulfonyl, isopropyl carbonyl, succinyl, benzyl carbonyl, phenoxyethylcarbonyl, benzyloxymethylcarbonyl, benzyl-O-CO-NH- P039862WO - 22 August 2025

[0104] - 14 -

[0105] CH2-CO- and a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN.

[0106] In an embodiment, R8is selected from the group consisting of H, G,-i 4-ary 1 carbonyl (optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups), HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.l) as depicted hereinbefore with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, aryl and heteroarylcarbonyl having a 5- to 10-membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4-alkoxy, C2-4-alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl, and / or CN;

[0107] Preferably R8is selected from the group consisting of H, Ce-io-arylcarbonyl, Ce-io-arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci

[0108] 2-alkoxy groups), linear or branched, preferably branched C3-4-alkylcarbonyl, HOOC- (CH2)m-(CO)- (with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2), a moiety according to formula (V.2) as depicted hereinbefore (wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3), Ci-3-alkylsulfonyl-bi-C6-io-aryl-carbonyl, and heteroaryl carbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, most preferably 1 heteroatom, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, preferably from the group consisting of N and O, most preferably being N, the ring of the heteroaryl carbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of Ci-2-alkyl, Ci-2-alkoxy, C2-3-alkenyl, C2-3-alkenoxy, halogen, in particular F and Cl, and CN, preferably selected from the group consisting of P039862WO - 22 August 2025

[0109] - 15 - methyl, methoxy, F and Cl, most preferably selected from the group consisting of methyl and Cl.

[0110] Preferably R8is selected from the group consisting of H, Ce-io-arylcarbonyl, Ce-io-arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups), bi-Ce-io-aryl-carbonyl (optionally substituted by 1 to 6 halogen, Ci-salkylsulphonyl and / or CN) and HOOC-(CH2)m-(CO)- (with m being from 1 to 3, most preferably 1 or 2).

[0111] Yet more preferably R8is selected from the group consisting of isopropyl carbonyl, succinyl, benzoyl, iodobenzoyl, ethylphenylcarbonyl, methoxyphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthylcarbonyl, a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, pyrazolyl carbonyl, dimethylpyrazolylcarbonyl, thiophenyl, chlorothiophenyl, pyridylcarbonyl and quinolylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN.

[0112] For particularly preferred compounds of the invention R1is OH; and / or R7is selected from the group consisting of Ci-3-alkyl, in particular methyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-Ci-2-alkyl-O-CO-NH-Ci-2-alkyl-CO- and phenyl-O- Ci-3-alkylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R7is optionally substituted by 1 to 3 halogen and / or CN; and / or

[0113] R8is selected from the group consisting of H, HOOC-(CH2)m-(CO)- with m being from 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthyl carbonyl, whereby alkyl, aryl and / or the heterocycle in R8is optionally substituted by 1 to 3 halogen and / or CN.

[0114] For particularly preferred compounds of the invention R1is OH; R8is H and R7is selected from the group consisting of Ci-3-alkyl, in particular methyl, a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3, phenyl-Ci-2-alkyl-O-CO-NH-Ci-2-alkyl-CO- and phenyl-O- Ci-3-alkylcarbonyl, whereby alkyl, aryl and / or the heterocycle in R7is optionally substituted by 1 to 3 halogen and / or CN. Preferably, the R7group contains at least one aromatic ring. P039862WO - 22 August 2025

[0115] - 16 -

[0116] For particularly preferred compounds of the invention R1is OH; R7is Me and R8is selected from the group consisting of H, HOOC-(CH2)m-(CO)- with m being from 1 to 3, preferably 1 or 2, most preferably 2, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl and naphthyl carbonyl, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 3 halogen and / or CN. Preferably, the R8group contains at least one aromatic ring.

[0117] A particularly preferred group of compounds of the invention is the group in which R1is OH; R8is H and R7is selected from the group consisting of Ce-io-aryl- Ci-3-alkyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkylcarbonyl, Ce-io-aryl-O- Ci-3-alkylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl-carbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, Ce-io-aryl- Ci-3-alkyl-O-CO-NH-Ci-3-alkyl-CO-, Ce-io-arylsulfonyl, and Ci-3-alkyl-Ce-io- arylsulfonyl; whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6, preferably 1 to 3 halogen and / or CN groups.

[0118] A particularly preferred group of compounds of the invention is the group in which R1is OH; R8is H and R7is selected from the group consisting of benzyl, benzoyl, methylbenzoyl, ethylbenzoyl, methoxybenzoyl, ethoxybenzoyl, methylsulfonylphenylbenzoyl naphthyl carbonyl, naphthylsulfonyl, methylphenylsulfonyl, succinyl, and a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3. For R7benzyl, benzoyl, naphthylsulfonyl, methylphenylsulfonyl, succinyl, and a moiety according to formula (V.2) wherein Ar is phenyl, n and p each are the same and 1 or 2 and q is 2 or 3 are especially preferred.

[0119] An alternative particularly preferred compounds of the invention is the group in which R1is OH; R7is Me and R8is selected from the group consisting of Ce-io- arylcarbonyl, Ce-io-arylcarbonyl substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups, branched C3-4-alkylcarbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.2) as depicted hereinbefore wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 P039862WO - 22 August 2025

[0120] - 17 - or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3, Ci-3-alkylsulfonyl-bi-C6-io-aryl-carbonyl, and heteroarylcarbonyl having a 5-, 6- or 10-membered ring containing 1, 2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms, most preferably 1 heteroatom, with the heteroatom(s) in each case being selected from the group consisting of N, O and S, preferably from the group consisting of N and O, most preferably being N, the ring of the heteroarylcarbonyl optionally being substituted by 1 or 2 substituents selected from the group consisting of Ci-2-alkyl, Ci-2-alkoxy, C2-3-alkenyl, C2-3-alkenoxy, halogen, in particular F and Cl, and CN, preferably selected from the group consisting of methyl, methoxy, F and Cl, most preferably selected from the group consisting of methyl and Cl. Within the R8group, an alkyl, aryl and / or heterocyclic group may optionally be substituted by 1 to 6, preferably 1 to 3 halogen atoms and / or CN group(s).

[0121] A further particularly preferred compounds of the invention is the group in which R1is OH; R7is Me and R8is selected from the group consisting of isopropyl carbonyl, succinyl, benzoyl, halobenzoyl (for example iodobenzoyl), ethylphenylcarbonyl, methoxyphenylcarbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl, a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2, pyrazolyl carbonyl, dimethylpyrazolylcarbonyl, thiophenyl, chlorothiophenyl, pyridyl carbonyl and quinolylcarbonyl.

[0122] A particularly preferred group of compounds of the invention are compounds of Formula (I) herein

[0123] R1is OH;

[0124] R2is according to formula (III)

[0125] (III) wherein

[0126] R7is Ci-6-alkyl; and P039862WO - 22 August 2025

[0127] - 18 -

[0128] R8is selected from the group consisting of Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from Ci-3-alkyl sulfonyl groups and / or Ci-3-alkyl groups; HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.1)

[0129] (V.1) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6;

[0130] R3is H; and

[0131] R4and R5are both H; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0132] In such a compound, for example R7is Me. For example, R7is Me and R8is selected from the group consisting of Ce-io-arylcarbonyl, Ce-io-arylcarbonyl substituted with 1 to 3 Ci-2-alkyl sulfonyl groups or Ci-2-alkyl groups, HOOC-(CH2)m-(CO)- with m being from 0 to 3, preferably 1 to 3, most preferably 1 or 2, a moiety according to formula (V.l) as depicted hereinbefore wherein Ar is Ce-io-aryl and n, p and q each are independently from 0 to 3, preferably n and p each are independently 1 or 2 and q is 2 or 3, most preferably n and p each are the same and 1 or 2 and q is 2 or 3. Within the R8group, an alkyl, aryl and / or heterocyclic group may optionally be substituted by 1 to 6, for example 1 to 3 halogen atoms and / or CN group(s). For example, R7is Me and R8is selected from the group consisting of succinyl, benzoyl, halobenzoyl (for example iodobenzoyl), ethylphenyl carbonyl, methylsulfonylphenylbenzoyl, naphthyl carbonyl and a moiety according to formula (V.2) wherein Ar is phenyl, n=p=l and q=2. P039862WO - 22 August 2025

[0133] - 19 -

[0134] Further preferred compounds for the methods and uses of the invention are selected from the group consisting of:

[0135] (2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-l l-{[(2S,3R,4S,6R)-4- (dimethylamino)-3 -hydroxy-6-methyloxan-2-yl]oxy } -2-ethyl-3 ,4, 10,13 -tetrahydroxy -

[0136] 3.5.6.8.10.12.14-heptam ethyl- 1 -oxa-6-azacy clopentadecan- 15 -one;

[0137] (2S,3R,4S,6R)-4-(dimethylamino)-2-

[0138] { [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0139] 3.5.6.8.10.12.14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy}-6- methyloxan-3-yl benzoate;

[0140] (3aR,4R,7R,8S,9S,10R,l lS,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-3- (benzoyloxy)-4-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-ethyl-l 1 -hydroxy- 3a,7,9,l l,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[l,3]dioxolo[4,5-c]l- oxa-6-azacyclopentadecan-8-yl morpholine-4-carboxylate;

[0141] (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,l lS,13R,16R,16aR)-8- [(benzylcarbamoyl)oxy]-4-ethyl-l l-hydroxy-3a,7,9,l l,13,15,16-heptamethyl-2,6- dioxo-tetradecahydro-2H-[l,3]dioxolo[4,5-c]l-oxa-6-azacyclopentadecan-10-yl]oxy}- 4-(dimethylamino)-6-methyloxan-3-yl benzoate;

[0142] (2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-1 l-{[(2S,3R,4S,6R)-4- [benzyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10- trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-

[0143] 3.5.6.8.10.12.14-heptam ethyl- 1 -oxa-6-azacy clopentadecan- 15 -one;

[0144] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0145] 3.4.10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2- yl]oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l- yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzamide;

[0146] N-[(2S,3R.4S,6R)-2-{ [{2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzamide;

[0147] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl-

[0148] 3.4.10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl] oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}- 3-hydroxy-6-methyloxan-4-yl]-N-methylnaphthalene-2-sulfonamide; P039862WO - 22 August 2025

[0149] - 20 -

[0150] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N- methylnaphthalene-2-sulfonamide;

[0151] N-[(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10-trihydroxy-13-{[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2- yl]oxy}-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l - yl]oxy}-3-hydroxy-6-methyloxan-4-yl]-N,4-dimethylbenzene-l -sulfonamide;

[0152] (2S,3R,4S,6R)-2-{ [(2R,3R,4R,5R,8R, 10R, 11R,12S,13S,14R)-4,13- bis(acetyloxy)-2-ethyl-3,10-dihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadecan-11 -yl]oxy }-4-(dimethylamino)-6-methyloxan-3-yl benzoate;

[0153] (2S,3R,4S,6R)-4-(dimethylamino)-2-

[0154] { [(2R,3 S,4R, 5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0155] 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-6- methyloxan-3-yl 4-(4-methanesulfonylphenyl)benzoate;

[0156] (2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 10R, 1 lR,12S,13S,14R)-2-ethyl-3,4,10,13- tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l- yl]oxy}-6-methyl-4-(N-methylnaphthalene-2-sulfonamido)oxan-3-yl benzoate;

[0157] {2S,3R,4S,6R)-4-(dimethylamino)-2-

[0158] { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0159] 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-6- methyloxan-3-yl 4-iodobenzoate;

[0160] 1 -benzyl (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l 1R, 12S, 13S,14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-3, 5, 6, 8, 10, 12, 14-heptam ethyl- 15-oxo-l- oxa-6-azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl (2R)-2-

[0161] {[(benzyloxy)carbonyl]amino}pentanedioate; benzyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)- 2 { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0162] 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-3- hydroxy-6-methyloxan-4-yl](methyl)carbamoyl } butanoate;

[0163] 4-{[(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0164] { [(2R,3 S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-3, 4, 10, 13 -tetrahydroxy- P039862WO - 22 August 2025

[0165] - 21 -

[0166] 3.5.6.8.10.12.14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-l l-yl]oxy}-6- m ethyl oxan-3 -y 1 ] oxy } -4 -oxobutanoi c aci d;

[0167] 3-{ [(2S,3R,4S,6R)-2-{ [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-

[0168] 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptam ethyl- 15 -oxo- 1 -oxa-6- azacyclopentadecan-l l-yl]oxy}-3-hydroxy-6-methyloxan-4- yl](methyl)carbamoyl}propanoic acid; and

[0169] (2S,3R,4S,6R)-4-(dimethylamino)-2-

[0170] { [(2R,3 S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0171] 3.5.6.8.10.12.14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy}-6- m ethyl oxan-3 -yl pyri dine-3 -carb oxy 1 ate;

[0172] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0173] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0174] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadec-1 l-yl]oxy]-6- methyl-tetrahydropyran-3-yl] 2,5-dimethylpyrazole-3-carboxylate;

[0175] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0176] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0177] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadec-1 l-yl]oxy]-6- m ethyl -tetrahy dropy ran-3 -y 1 ] 5 -chi orothi ophene-2 -carb oxy 1 ate;

[0178] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0179] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0180] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadec-1 l-yl]oxy]-6- methyl-tetrahydropyran-3 -yl] 4-ethylbenzoate;

[0181] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0182] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0183] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadec-1 l-yl]oxy]-6- methyl-tetrahydropyran-3 -yl] 4-m ethoxybenzoate;

[0184] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0185] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0186] 3,5, 6, 8, 10, 12,14-heptam ethyl- 15 -oxo- 1 -oxa-6-azacy clopentadec- 11 -yl] oxy ] -6-methyl- tetrahydropyran-3-yl] naphthal ene-2-carboxylate;

[0187] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0188] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0189] 3,5, 6, 8, 10, 12,14-heptam ethyl- 15 -oxo- 1 -oxa-6-azacy clopentadec- 11 -yl] oxy ] -6-methyl- P039862WO - 22 August 2025

[0190] - 22 - tetrahydropyran-3-yl] quinoline-3 -carboxylate;

[0191] 2-benzyloxy-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)- 2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl- acetamide; benzyl N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2- ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl- amino]-2-oxo-ethyl]carbamate;

[0192] N-[(2S,3R,4S,6R)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptamethyl- 15 -oxo- 1 -oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3- phenoxy-propanamide;

[0193] N-[(2S,3R,4S,6R)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptamethyl- 15 -oxo- 1 -oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-2- phenyl-acetamide;

[0194] (2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy- 11 - [(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydropyran-2-yl]oxy-

[0195] 3.5.6.8.10.12.14-heptamethyl- 1 -oxa-6-azacy clopentadecan- 15 -one;

[0196] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0197] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0198] 3,5, 6, 8, 10, 12,14-heptamethyl- 15 -oxo- 1 -oxa-6-azacy clopentadec- 11 -yl] oxy ] -6-methyl- tetrahydropyran-3-yl] 2-methylpropanoate; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0199] Most preferably compounds of formula (I) for the methods and uses of the invention are selected from the group consisting of:

[0200] (2S,3R,4S,6R)-4-(dimethylamino)-2-

[0201] { [(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0202] 3.5.6.8.10.12.14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy}-6- methyloxan-3-yl benzoate; P039862WO - 22 August 2025

[0203] - 23 -

[0204] (2S,3R,4S,6R)-4-(dimethylamino)-2-

[0205] { [(2R,3 S,4R, 5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0206] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy} -6- methyloxan-3-yl 4-(4-methanesulfonylphenyl)benzoate;

[0207] 1 -benzyl (2S,3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,l 1R, 12S, 13S,14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-3, 5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l- oxa-6-azacyclopentadecan-l l-yl]oxy}-6-methyloxan-3-yl (2R)-2-

[0208] {[(benzyloxy)carbonyl]amino}pentanedioate; benzyl (2R)-2-{[(benzyloxy)carbonyl]amino}-4-{[(2S,3R,4S,6R)-

[0209] 2 { [(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3 ,4, 10,13 -tetrahydroxy-

[0210] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy}-3- hydroxy-6-methyloxan-4-yl](methyl)carbamoyl } butanoate;

[0211] 4-{[(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0212] { [(2R,3 S,4R,5R,8R, 10R, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0213] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadecan-1 l-yl]oxy}-6- m ethyl oxan-3 -y 1 ] oxy } -4 -oxobutanoi c aci d;

[0214] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0215] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0216] 3,5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo-l-oxa-6-azacy cl opentadec-1 l-yl]oxy]-6- methyl-tetrahydropyran-3 -yl] 4-ethylbenzoate;

[0217] [(2S,3R,4S,6R)-4-(dimethylamino)-2-

[0218] [[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-2-ethyl-3,4, 10, 13 -tetrahydroxy-

[0219] 3,5, 6, 8, 10, 12,14-heptam ethyl- 15 -oxo- 1 -oxa-6-azacy clopentadec- 11 -yl] oxy ] -6-methyl- tetrahydropyran-3-yl] naphthal ene-2-carboxylate; benzyl N-[2-[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,l lR,12S,13S,14R)-2- ethyl-3, 4, 10,13-tetrahy droxy-3, 5, 6, 8, 10, 12, 14-heptamethyl-l 5-oxo- l-oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-methyl- amino]-2-oxo-ethyl]carbamate; and

[0220] N-[(2S,3R,4S,6R)-2-[[(2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S,14R)-2-ethyl- 3,4,10,13 -tetrahydroxy-3 ,5,6,8,10,12,14-heptamethyl- 15-oxo- 1 -oxa-6- azacyclopentadec-ll-yl]oxy]-3-hydroxy-6-methyl-tetrahydropyran-4-yl]-N-methyl-3- phenoxy-propanamide, P039862WO - 22 August 2025

[0221] - 24 - or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

[0222] The invention also provides compounds defined herein in a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable excipient, whereby this also includes compounds for which R8can be H if R1is OH and R7, for use in uses of the invention, such as in a method of raising, enhancing or maintaining one or more host defence mechanisms against an infection in a subject.

[0223] Depending upon the substituents present in compounds of the formula (I), the compounds may form esters, amides, carbamates and / or salts. Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein a counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of formula (I) and their pharmaceutically acceptable esters, amides or carbamates salts, or solvates thereof.

[0224] Suitable salts for use in methods according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cj-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in P039862WO - 22 August 2025

[0225] - 25 - obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.

[0226] Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore, be formed.

[0227] Compounds of formula (I) for use in methods of the invention may have an appropriate group converted to an ester, an amide or a carbamate. Thus typical ester and amide groups formed from an acid group in the compound of formula (I) include -COORB, -CONRB2, -SCh.OR6, or -SO2.NRB2, while typical ester and amide and carbamate groups formed from an -OH or -NHRBgroup in the compound of formula (I) include -O.CO.RB, -NRB.CO.RB, -NRB.CO2RB-O.SO2RB, and -NRB.SO2RB, wherein each RBis independently selected from the group consisting of hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs-scycloalkyl, Cs-scycloalkylCi-ealkyl, Ce-ioaryl and Ce-io arylCi-ealkyl, each optionally substituted by from 1 to 3 halogen atoms. Preferably, each RBis independently selected from the group consisting of hydrogen and Ci-4alkyl. For example, in compounds of formula (I), one or more of the OH groups that are present when one or more of R3, R4and R5are H can be converted to an ester of formula -O.CO.RB; that is to say that the compound would have one or more of R3, R4and R5represented by CO.RB, RBbeing as given immediately above.

[0228] A compound which, upon administration to the recipient, is capable of being converted into a compound of formula (I) as described above, or an active metabolite or residue thereof, is known as a “prodrug”. A prodrug may, for example, be converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Certain esters, amides and carbamates described above can be prodrugs. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward P039862WO - 22 August 2025

[0229] - 26 -

[0230] B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, which are incorporated herein by reference.

[0231] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

[0232] The compounds of the invention contain several chiral (asymmetric) centres and the molecules as a whole are chiral. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.

[0233] The compounds for use in methods of the invention can be prepared by methods well known in the art. Azithromycin (Azm) is widely available from commercial sources, including Sigma-Aldrich. The key intermediate Descladinose Azm (Example 1) can be prepared by selective acidic hydrolysis of Azm using methanol HCl(aq), following a published protocol as shown in Scheme 1. The key intermediates demethylated Azm (Intermediate A), and demethylated Descladinose Azm (Intermediate B) can be prepared by N-demethylation using iodine and NaOAc in MeOH or iPrOH, which method is set out in US3,725,385 and also described in European Journal of Medicinal Chemistry 49 (2012) 365-378, entry 5.1.3. That is also shown in Scheme 1 :

[0234] P039862WO - 22 August 2025

[0235] Intermediate A Intermediate B

[0236] Scheme 1

[0237] The advanced intermediates shown in Scheme 1 can be derivatised to compounds of the invention using standard coupling techniques.

[0238] The amount of active ingredient’ which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0239] Certain compounds for use in methods of the invention have better oral bioavailability than others. A compound with particularly good bioavailability (particularly oral bioavailability) is especially useful in the treatment of conditions that are suited to treatment by systemic drug delivery. A compound with poorer bioavailability, on the other hand, lends itself to topical delivery (and systemic side effects will be minimized by the low bioavailability) and thus to the treatment of P039862WO - 22 August 2025

[0240] - 28 - conditions that are suited to treatment by topical drug delivery (for example by inhalation or by dermal, buccal, sublingual or intraocular application.

[0241] Oral dosages of the compositions for use in methods of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably 0.01 mg per kg of body weight per day (mg / kg / day) to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day, for adult humans. The typical daily dose is thus from about 1 mg to about 500 mg of the active ingredient, preferably from about 20 mg to about 500 mg of active ingredient, for example 50 mg to 500 mg, for example 100 mg to 400 mg, for example 200 mg to 300 mg, for example 250 mg of the active ingredient. For oral administration, the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, 250, 300, 350, 375, 400, 450 or 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.

[0242] Advantageously, compounds for use in methods of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0243] While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition. Accordingly, the invention provides a pharmaceutical formulation comprising a compound for uses in methods according to the invention, and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as “carrier” materials). Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below.

[0244] The pharmaceutical formulations for use in methods according to the invention include those suitable for oral, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators), and topical (including dermal, buccal, sublingual, and P039862WO - 22 August 2025

[0245] - 29 - intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

[0246] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0247] Formulations for use in methods of the present invention suitable for oral administration for use in methods of the invention may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0248] A tablet for use in methods of the invention may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally.

[0249] Exemplary compositions for use in methods of the invention for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, P039862WO - 22 August 2025

[0250] - 30 - methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Moulded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (Avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavours, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

[0251] Formulations for use in methods of the invention for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water- P039862WO - 22 August 2025

[0252] - 31 - for-inj ection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0253] Exemplary compositions for use in methods of the invention for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0254] Formulations for use in methods of the invention for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatine and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0255] Preferred unit dosage formulations for use in methods of the invention are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

[0256] It should be understood that in addition to the ingredients particularly mentioned above, the formulations for use in methods of the invention of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

[0257] Whilst a compound for use in methods of the invention of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further active agents. Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for example a further compound useful in the P039862WO - 22 August 2025

[0258] - 32 - treatment of a respiratory condition or disease, for example a compound useful in the treatment of an eosinophil-associated pathology, Type-2 inflammation or COPD.

[0259] Further active agents for use in methods of the invention include inhaled corticosteroids (for example fluticasone (Flonase®, Flovent HF A), budesonide (Pulmicort Flexhaler, Rhinocort), flunisolide (Aerospan HF A), ciclesonide (Alvesco, Omnaris, Zetonna), beclomethasone (Qnasl, Qvar), mometasone (Asmanex) or fluticasone furoate (Amuity Ellipta)), Leukotriene modifiers(for example montelukast (Singulair), zafirlukast (Accolate) or zileuton (Zyflo); Long-acting beta agonists (for example salmeterol (Serevent) or formoterol (Foradil, Perforomist); Combination inhalers (for example fluticasone-salmeterol (Advair Diskus / Seretide), budesonide- formoterol (Symbicort) or formoterol-mometasone (Dulera) containing a long-acting beta agonist along with a corticosteroid); Theophylline (for example Theo-24 or Elixophyllin), Short-acting beta agonists (for example albuterol (ProAir HF A, Ventolin HF A, others) and levalbuterol (Xopenex)), Ipratropium (Atrovent) or oral or intravenous corticosteroids (for example prednisone or methylprednisolone).

[0260] Further active agents for use in methods of the invention further include shortacting bronchodilators (for example albuterol (ProAir HF A, Ventolin HF A, others), levalbuterol (Xopenex), and ipratropium (Atrovent)), long-acting bronchodilators (including tiotropium (Spiriva), salmeterol (Serevent), formoterol (Foradil, Perforomist), arformoterol (Brovana), indacaterol (Arcapta) and aclidinium (Tudorza)), Inhaled steroids (including Fluticasone (Flovent) and budesonide (Pulmicort), Combination inhalers (for example combining bronchodilators and inhaled steroids, for example Salmeterol and fluticasone (Advair) and formoterol and budesonide (Symbicort)), Oral steroids, Phosphodiesterase-4 inhibitors (for example roflumilast (Daliresp)), Theophylline and Antibiotics.

[0261] The above other therapeutic agents, when employed in combination with the compounds for use in methods of the invention of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0262] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances. P039862WO - 22 August 2025

[0263] - 33 -

[0264] The term ‘about’ refers to a tolerance of ±20% of the relevant value, for example ±15% of the relevant value, such as ±10% of the relevant value or ±5% of the relevant value.

[0265] As used herein, the term "alkyl" means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, n-propyl, isopropyl, n-butyl groups. Among branched alkyl groups, there may be mentioned t-butyl, i-butyl, 1 -ethylpropyl and 1 -ethylbutyl groups.

[0266] As used herein, the term “alkoxy” means the group O-alkyl, where “alkyl” is used as described above. Examples of alkoxy groups include methoxy and ethoxy groups. Other examples include propoxy and butoxy.

[0267] As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Preferred alkenyl groups include ethenyl, 1- propenyl and 2- propenyl.

[0268] As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Preferred alkynyl groups include ethynyl 1- propynyl and 2- propynyl.

[0269] As used herein, the term "cycloalkyl" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may, for example, be fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycloheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicyclo [2. 2.1]hept-2-yl. Preferably, the cycloalkyl group is monocyclic.

[0270] As used herein, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. A naphthyl group may be attached through the 1 or the 2 position. In a bicyclic aromatic group, one of the rings may, for example, be partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl. Specifically, the term C5-10 aryl is used herein P039862WO - 22 August 2025

[0271] - 34 - to mean a group comprising from 5 to 10 carbon atoms in a monocyclic or bicyclic aromatic group. A particularly preferred C5-10 aryl group is phenyl.

[0272] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.

[0273] As used herein, the term "heterocyclyl" means an aromatic or a non-aromatic cyclic group of carbon atoms wherein from one to three of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. A heterocyclyl group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or only in one of the rings. A heteroatom is preferably O or N. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.

[0274] Examples of monocyclic non-aromatic heterocyclyl groups (also referred to as monocyclic heterocycloalkyl rings) include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.

[0275] Examples of bicyclic heterocyclyl groups in which one of the rings is non- aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzoazepanyl.

[0276] Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl and pyrimidinyl.

[0277] Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl and benzodr oxazole.

[0278] Examples of preferred heterocyclyl groups include piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrimidinyl and indolyl. Preferred heterocyclyl groups also include thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, isoxazolyl and imidazolyl. P039862WO - 22 August 2025

[0279] - 35 -

[0280] As used herein the term “cycloalkylalkyl” means a group cycloalkyl-alkyl- attached through the alkyl group, “cycloalkyl” and “alkyl” being understood to have the meanings outlined above.

[0281] As used herein the term ‘host defence’ refers to the innate immune system. The innate immune system includes:

[0282] (i) Physical Barriers: Physical barriers like skin and mucous membranes.

[0283] (ii) Chemical Barriers: Antimicrobial substances in bodily secretions, such as lysozyme in tears, and the acidic environment of the stomach.

[0284] (iii) Cellular Components: Phagocytic cells like macrophages and neutrophils.

[0285] (iv) Inflammation: A localized response to infection that brings immune cells and molecules to the site of injury or invasion.

[0286] As used herein the term ‘enhancing’ when used in the context of ‘enhancing one or more host defence mechanisms’ refers to increasing the number or activity / intensity of mechanisms / processes involved in host defence.

[0287] As used herein the term ‘raising’ when used in the context of ‘raising one or more host defence mechanisms’ refers to the process of a biological organism, such as a mammal, such as a human, recognising a non-self antigen and commencing the host defence processes by which the organism protects itself from the agent or organism displaying said antigen.

[0288] As used herein the term ‘maintaining’ when used in the context of ‘maintaining one or more host defence mechanisms’ refers to continuing the number or activity / intensity of mechanisms / processes involved in host defence.

[0289] Equivalents

[0290] The invention has been described broadly and generically herein. Those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no P039862WO - 22 August 2025

[0291] - 36 - more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present invention. Further, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0292] Incorporation by Reference

[0293] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[0294] The following examples illustrate the invention, with the accompanying figure:

[0295] Figure 1. Log2 fold change in BALF biomarkers at 6 h after LPS administration on Day 21. Comparison of the changes betweenplacebo and Compound A.

[0296] Figure 2. Compound A (Cpd A), or azithromycin, have cytotoxic effects on RV infected cells. Figure shows supernatant lactose dehydrogenase (LDH) activity in control and treated primary bronchial epithelia cell cultures derived from human asthma patients.

[0297] Figure 3. IFN-|3 gene expression in BECs from human asthma patients. Cells were pretreated for 24 hours with Compound A (Cpd A) before infection with P039862WO - 22 August 2025

[0298] - 37 -

[0299] 0.05 MOI RV. Expression data shows mRNA level 24 hours after RV infection.

[0300] Figure 4. Compound A (Cpd A) reduces viral load as shown by the reduction in RV1B gene expression. Cells were pretreated for 24 hours with Compound A before infection with 0.05 MOI RV. Expression data shows mRNA level 24 hours after RV infection.

[0301] Figure 5. Compound A (Cpd A) augments MDA5 gene expression in BECs from asthma patients infected with RV. Cells were pretreated for 24 hours with Compound A before infection with 0.05 MOI RV. Expression data shows mRNA level 24 hours after RV infection.

[0302] Examples

[0303] General methods

[0304] Methods for the preparation of compounds of formula (I) can, for example, be found in International Patent application publication number: WO 2017 / 085329. Reversed phase chromatography was performed on X-bridge, prep Cl 8 (5 pm), 50 mM ammonium bicarbonate / acetonitrile gradient.

[0305] Example 1: Descladinose Azithromycin:

[0306] (2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-ll-[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13-tetrahydroxy-

[0307] 3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one)

[0308] To a solution of Azithromycin ((2R,3S,4R,5R,8R,1OR,11R,12S,13S,14R)-11- [(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2- ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl- tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan- 15 -one) (10 g, 13.35 mmol) in methanol (100 mL) HC1 (I M) was added until pH was P039862WO - 22 August 2025

[0309] - 38 - stabilized at 1.25 and the resulting solution was stirred for 24 h at room temperature. The mixture was again pH adjusted but using NaOH (1 M) to pH 10.75. The mixture was stirred for 1 h and portioned between NaHCO3 (5%) and DCM. The aqueous phase was washed with a second portion of DCM and the combined organic fractions were dried over magnesium sulphate and the solvent removed under reduced pressure giving the product as a white foam. A sample was purified by straight phase silica chromatography (DCM to 5% methanol in DCM, 0.1% triethylamine added to the mobile phase)

[0310] Example 2: (2S,3R,4S,6R)-4-(dimethylamino)-2- [[(2R,3S,4R,5R,8R,1OR,11R,12S,13S, 14R)-2-ethyl-3,4,10,13-tetrahydroxy-

[0311] 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll-yl]oxy]-6- methyl-tetrahydropyran-3-yl] benzoate)

[0312] To a mixture of (2R,3 S,4R,5R,8R, 10R, 1 lR,12S,13S,14R)-ll-[(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10,13- tetrahy droxy-3 ,5,6,8,10,12,14-heptam ethyl- 1 -oxa-6-azacy clopentadecan- 15 -one (Example 1) (0.5 g, 0.8500 mmol) and Triethylamine (428.2 mg, 4.23 mmol) in DCM (5 ml), cooled on ice, was added benzoyl chloride (356.9 mg, 2.54 mmol). The reaction mixture was allowed to reach room temperature. After 3 days good conversion to the desired benzoylated product was obtained and the mixture was portioned between DCM and saturated sodium hydrogen carbonate solution. The organic phase was dried over magnesium sulphate and concentrated to a white foam. The product was purified using reversed phase chromatography. P039862WO - 22 August 2025

[0313] - 39 -

[0314] Example 3

[0315] A double blind, placebo-controlled, parallel group clinical study to assess the pharmacodynamics of (2S,3R,4S,6R)-4-(dimethylamino)-2- [[(2R,3S,4R,5R,8R,1OR,11R,12S,13S, 14R)-2-ethyl-3,4,10,13-tetrahydroxy- 3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-ll-yl]oxy]-6- methyl-tetrahydropyran-3-yl] benzoate)[Compound A] in response to lipopolysaccharide (LPS) challenge in healthy, non-smoking volunteers.

[0316] Study Design and Methods

[0317] A randomised, double-blind, placebo-controlled proof-of-pharmacology study to assess the effect of Compound A on lung and blood biomarkers after inhaled LPS was conducted. After providing informed consent, eligible participants were randomised in a 1 : 1 ratio to take either Compound A (375 mg) or placebo as oral capsules once daily for 21 days starting on Day 1 with visits at Days 7, 14, and 21 for assessments of safety and tolerability and systemic exposure to Compound A. On Day 21, 2 hours after the last investigational product (IP) intake, participants underwent an inhaled LPS challenge1to induce airway inflammation, which was followed by bronchoscopy and bronchoalveolar lavage fluid (BALF) collection 6 hours later.

[0318] For the assessment of biomarkers in blood, samples were taken before, and 6 hours after the LPS inhalation on Day 21 and 24 hours after the LPS inhalation (on Day 22).

[0319] The schedule of assessments performed in the study is in the Table 1 below.

[0320] Table 1

[0321] 1LPS (List Biological Laboratories, Inc., USA,) solution for inhalation (20000 endotoxin units per inhalation), inhaled (using a breath-actuated nebulizer). P039862WO - 22 August 2025

[0322] -40 - P039862WO - 22 August 2025

[0323] - 41 -

[0324] Table legendaHeight at Screening only.bHaematology, biochemistry, and coagulation. SARS-CoV-2 testing was done as per the study centre’s standards.cPredose.d4 hours postdose.eTriplicate measurement at Day 1 (predose). Single measurements at other visits. Triplicate if single measurement >60 msec increase in QTcF from Baseline or >500 msec absolute QTc.fPulse, blood pressure, temperature.

[0325] 8Full physical examination.

[0326] IIAbbreviated examination.

[0327] 1Additional vital signs / spirometry / safety assessments as per the study centre’s standard operational procedures for safety of LPS and bronchoscopy procedures. Participants had to have fasted for 12 hours and received additional medication before the procedure.j6 hours after LPS inhalation (ie, 8 hours post-dose).kBefore and 6 hours after LPS inhalation.

[0328] I24 hours after LPS inhalation.

[0329] III2 hours post dose.

[0330] IIBlood test at Screening, then in urine. P039862WO - 22 August 2025

[0331] - 42 -

[0332] ° 4 hours after LPS inhalation.

[0333] BAL = bronchoalveolar lavage, BMI = body mass index, ECG = electrocardiogram, ET = early termination, FU = follow-up, IP = investigational product, LPS = lipopolysaccharide, QTcF = corrected QT interval by Fredericia, WOCBP = women of childbearing potential.

[0334] Biomarkers assessed included:

[0335] . BALF: albumin, protein, TNF-a, IL-6, IL-8, IL-ip, MIP-la, MIP-ip, MCP 1 , IC AM- 1 , Surfactant Protein -D (SP-D), IL33 ,

[0336] . Blood: SP-D

[0337] Assays used for BALF are shown in Table 2 below

[0338] Table 2 P039862WO - 22 August 2025

[0339] -43 - P039862WO - 22 August 2025

[0340] - 44 -

[0341] Table 3

[0342] Results 49 subjects were randomised (23 to Compound A and 26 to placebo). 40 subjects (20 Compound A and 20 placebo) completed the study defined as completing the study, having LPS challenge, BALF collection and blood sample collection for biomarkers. An additional 2 subjects completed dosing, had the LPS challenge and blood sample collection for biomarkers. P039862WO - 22 August 2025

[0343] Pharmacodynamic results

[0344] BALF

[0345] In BALF there was no difference in neutrophil numbers between the Compound A and Placebo groups. Neutrophil elastase (NE) (difference p=0.108), and myeloperoxidase (MPO) (difference p=0.301) were numerically higher with Compound A than Placebo.

[0346] Table 4

[0347] IL-8, IL-33 and IL-lbeta were numerically higher with Compound A treatment than Placebo.

[0348] BALF IL-6, TNF-a, MIP-la, MIP-ip and MCP-1 were numerically lower in the Compound A group than Placebo group. Protein and albumin were comparable in the Compound A and Placebo group.

[0349] BALF biomarkers are summarised in Figure 1.

[0350] Blood

[0351] Serum concentrations of SP-D increased significantly in the Compound A group in response to LPS at both 6 hours and 24 hours compared with pre-LPS but not in the Placebo group. The difference in the Compound A group before and 24 hours after LPS challenge was -0.33 (95 % CI -0.52, -0.14; p=0.0007), whilst the difference in the Placebo group was -0.09 (95 % CI -0.28, 0.10; p=0.3351). The difference in the Compound A group before and 6 hours after LPS challenge was -0.20 (95 % CI -0.39, -0.01; p=0.0386), whilst the difference in the Placebo group was 0.06 (95 % CI -0.13, 0.25; p= 0.5156).

[0352] Mean and median SP-D levels following Placebo and Compound A are shown in Table 5 below. P039862WO - 22 August 2025

[0353] - 46 -

[0354] Table 5

[0355] Conclusion

[0356] In healthy, non-smoking, volunteers Compound A treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst inhibiting inflammatory site pro-inflammatory mediators

[0357] Example 4

[0358] Studies of effects of Compound A on bronchial epithelial cells derived from asthma patients, infected with Rhinovirus (RV)

[0359] Primary bronchial epithelial cells (BECs) from asthma patients (n=6-9) were pretreated with Compound A (3, 10 pM) or azithromycin (3 or 10 pM) for 24 hours before infection with rhinovirus (RV1B) for 6, 24 or 48 hours. Gene expression of IFN-P, MDA5, CCL20 and TNF-a as well as viral RNA was measured using RT- qPCR. Lactate dehydrogenase (LDH) activity was measured in cell supernatants as a marker of cell toxicity.

[0360] Results:

[0361] Compound A treatment (3, 10 pM) of RV1B infected BECs did not alter the LDH activity in cell supernatants after 24 hours, indicating a lack of cytotoxicity (Figure 2).

[0362] Compound A (10 pM) significantly increased RV-induced mRNA expression of IFN- P (6.6-fold compared to RV alone, p=0.01) (Figure 3) and, concomitantly, significantly reduced viral load (mRNA) (0.7-fold compared to RV alone, p=0.003), in BECs at 24 hours post infection (Figure 4). Compound A also induces the pattern recognition receptor, MDA5, expression (3-fold compared to RV alone, p=0.1), correlating with the Compound A-induced IFN-P response (Figure 5). P039862WO - 22 August 2025

[0363] - 47 -

[0364] Compound A treatment did not alter RV-induced mRNA expression of TNF-a nor CCL20. Compared to azithromycin, the effects of Compound A on the BEC anti-viral and pro-inflammatory response were similar, as shown in Table 6.

[0365] Table 6. Anti-viral and innate immune responses were similar between Compound A and azithromycin.

[0366] Cpd A: compound A; AZM: azithromycin. * = significantly different; nc = no change Compared to RV alone. Treatments 10 pM. Arrows alone indicate trend; blank cells indicate gene expression was not measured.

[0367] Conclusion: Compound A improves anti-viral activity in BECs from asthma patients directly, and via increasing the IFN-|3 response. This suggests Compound A could, by modulating epithelial antiviral immunity, be a beneficial treatment for reducing viral- induced exacerbations in asthma without the risk of contributing to antimicrobial resistance.

[0368] Methods

[0369] Culturing of bronchial epithelial cells

[0370] Primary cultures of human bronchial epithelial cells (BECs) from asthmatic donors were obtained by bronchoscopy using a fibre-optic bronchoscope (Olympus, IT160, Tokyo, Japan). For sampling of epithelial cells from bronchi standard sterile- sheared nylon cytology brushes were used. The procedure was performed in accordance with standard published ethical guidelines and was processed as described previously [Ghanizada et al (2025) Frontiers in Allergy .1605109], The patients showed no clinical signs of an infection. Written informed consent was obtained from all participants, and the study was approved by the regional ethical review board at Lund University. BECs were cultured in bronchial epithelial growth medium. BECs were seeded into 12-well plates (Nunc, Life Technologies, Carlsbad, CA, USA) and P039862WO - 22 August 2025

[0371] - 48 - experiments were initiated when the cell monolayer was 80-90% confluent. In all experiments cells were used at passage 2-3.

[0372] Azithromycin and Compound A

[0373] Azithromycin (Sigma-Aldrich, Stockholm, Sweden) and Compound A were dissolved in dimethyl sulfoxide (DMSO) and BECs were exposed to azithromycin and Compound A 24 hours prior to infection with rhinovirus and continuous throughout the experiment.

[0374] Rhinovirus infection

[0375] Rhinovirus RV1B (Human rhinovirus IB strain B632, catalogue number VR-1645, ATCC) was grown in Ohio HeLa cells (European Collection of Cell Cultures) and obtained from clarified cell lysates and the infectious titre was determined using a 50% tissue culture infectious dose (TCID). BECs were then pretreated with Compound A or azithromycin for 24 hours, then infected with 0.05 MOI RV1B. RV1B was added to the cells for 1 hour at room temperature with shaking. The virus was removed, and the cells were washed with phosphate-buffered saline (PBS). Six-, 24- or 48-hours post infection, cells harvested for RNA, and cell supernatants were collected for protein release analyses.

[0376] Measurement of IFN-fi, MDA5, TNF-a and CCL20 mRNA

[0377] Total RNA was extracted using a RNA isolation kit (Nucleospin® RNA II, Macherey -Nagel, Duren, Germany) and 1 pg RNA was reverse transcribed to cDNA (Precision Nanoscript Reverse Transcription Kit, PrimerDesign, Southampton, UK). Quantitative real-time PCR was performed for real-time detection of PCR products on a Mx3005P qPCR system (Stratagene, La Jolla, CA, USA) using standard cycling parameters. Primers were obtained from Qiagen (Sollentuna, Sweden) or PrimerDesign (Southampton, UK). Target genes were normalized to UBC / GAPDH expression and related to unstimulated control using the AACt method.

[0378] Measurement of Protein Release

[0379] Concentrations of proteins IL-33, SP-D, TSLP, TNF-a, and IL-28b (IFN-A.3) in BEC supernatants were measured using a customised multiplex immunofluorescence as per the manufacturer’s instructions.

Claims

P039862WO - 22 August 2025Claims1. A compound according to formula (I):for use in a method of raising, enhancing or maintaining one or more host defence mechanisms against an infection in a subject; whereinR1is selected from the group consisting of OH, carbamoyloxy, N-Ci-6-alkylcarbamoyloxy, N-(C6-i4-aryl-Ci-6-alkyl)carbamoyloxy,N,N-di-Ci-6-alkylcarbamoyloxy, N,N-di-alkylcarbamoyloxy with the two alkyl substituents together forming a 5- to 8-membered heterocycle together with the nitrogen atom of the carbamate moiety, Ci-6-alkylcarboxy and a moiety according to formula (II)(II),P039862WO - 22 August 2025- 2 - whereinR6is selected from the group consisting of H, OH and Ci-6-alkyl, whereby alkyl, aryl and / or the heterocycle in R1is optionally substituted by 1 to 6 halogen and / or CN; andR2is according to formula (III)wherein R7is selected from the group consisting of Ci-6-alkyl, C6-i4-aryl-Ci-6-alkyl,C3-6-alkylcarbonyl, Ce- 14-ary 1 carbonyl, Ci-6-alkyl-C6-i4-arylcarbonyl, Ce-w-arylsulfonyl, Ci-6-alkyl-C6-i4-arylsulfonyl, C6-i4-aryl-Ci-6-alkylcarbonyl, C6-i4-aryl-O-Ci-6-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-Ci-6-alkyl-carbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 6,P039862WO - 22 August 2025- 3 - with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO-, and Ce-w-arylsulfonyl, and Ci-6-alkyl-C6-i4-arylsulfonyl, whereby alkyl and / or aryl in R7is optionally substituted by 1 to 6 halogen and / or CN; andR8is selected from the group consisting of H, Ce-i 4-ary 1 carbonyl (optionally substituted with 1 to 5 groups selected from halogen atoms, Ci-3-alkyl sulfonyl groups, Ci-3-alkyl groups and / or Ci-3-alkoxy groups), C3-6-alkylcarbonyl, HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.1) as depicted hereinbefore with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6, aryl, and heteroaryl carbonyl having a 5- to 10- membered ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, the ring of the heteroaryl carbonyl optionally being substituted by 1 to 3 substituents selected from the group consisting of Ci-4-alkyl, Ci-4-alkoxy, C2-4- alkenyl, C2-4-alkenoxy, halogen and CN, whereby alkyl and / or aryl in R8is optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl and / or CN;R3is H; andR4and R5are independently selected from H and Ci-6-alkylcarbonyl, whereby alkyl is optionally substituted by 1 to 6 halogen and / or CN, orR4and R5together form a single carbonyl group which forms a cyclic carbonate with both oxygen atoms it is bonded to; and with the proviso that the compound of formula (I) is not 2R,3 S,4R,5R,8R, 1 OR, 11R, 12S, 13 S, 14R)-11 -[(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2-ethyl-3,4,10- trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-P039862WO - 22 August 2025- 4 - tetrahydropyran-2-yl]oxy-3,5,6,8, 10, 12, 14-heptamethyl-l-oxa-6- azacyclopentadecan-15-one ; or a pharmaceutically acceptable ester, amide, carbamate, solvate or salt thereof, including a salt of such an ester, amide or carbamate, and a solvate of such an ester, amide, carbamate or salt.

2. The compound for use, as claimed in claim 1 wherein the infection comprises a bacterial, viral and / or fungal infection.

3. The compound for use, as claimed in claim 1 or claim 2 wherein the infection comprises a respiratory infection.

4. The compound for use as claimed in any one of the preceding claims wherein the infection comprises a viral infection and the viral infection is selected from parainfluenza viruses, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human rhinovirus (HRV), human parainfluenza virus (HPIV), rhinovirus and SARS-Cov-2.

5. The compound for use as claimed in any one of claims 1 to 3 wherein the infection comprises a bacterial infection and the bacterial infection is selected from Mycoplasma pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, Mycobacterium tuberculosis, Chlamydia, Coxiella burnetiid, Legionella pneumophila, Moraxella catarrhalis, Pseudomonas aeruginosa, Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae, Corynebacterium diphtheriae, Mycoplasma pneumoniae, and Bacillus anthracis.

6. The compound for use as claimed in any claims 1 to 3 wherein the infection comprises a fungal infection and the fungal infection is selected from Aspergillus sp., Candida sp, Coccidiodes sp., Pneumocystis jirovecii and Histoplasma capsulatum.

7. The compound for use as claimed in any one of the preceding claims, wherein the one or more host defence mechanisms comprises an increase in the level of one of more cytokines.P039862WO - 22 August 2025- 5 -8. The compound for use as claimed in claim 7, wherein the one or more cytokines comprise a cytokine selected from IL-8 and / or IL-33.

9. The compound for use as claimed in one of claims 1 to 6, wherein the one or more host defence mechanisms comprises an increase in neutrophil activity.

10. The compound for use as claimed in any one of claims 1 to 6, wherein the one or more host defence mechanisms comprises an increase in the activity of neutrophil elastase.

11. The compound for use as claimed in any one of claims 1 to 6, wherein the one or more host defence mechanisms comprises an increase in the activity of myeloperoxidase.

12. The compound for use, as claimed in any one of claims 1 to 6 where the one of more host defence mechanisms comprises an increase in macrophage activity, for example, type 2 macrophage activity.

13. The compound for use, as claimed in any one of claims 1 to 6 where the one of more host defence mechanisms comprises an increase in one or more macrophage markers, for example, MRC1 (CD206) gene expression.

14. The compound for use as claimed in any one of claims 1 to 6, wherein the one or more host defence mechanisms is a natural body barrier, for example, the lung epithelium.

15. The compound for use as claimed in any one of claims 1 to 6, wherein the one or more host defence mechanisms comprises increases in the level of one of more surfactant proteins, for example, surfactant protein, SP-D.

16. A compound of formula (I), as defined in claim 1, for use in a method for any of:(a), reducing susceptibility to an infection, for example, a bacterial, viral or fungal infection in a subject, for example, in an elderly and / or immunocompromised subject;(b). improving the ability of a subject to control a respiratory disease or, condition during a respiratory viral infection;(c). preventing or reducing the severity of a rhinovirus infection;P039862WO - 22 August 2025- 6 -(d). reducing rhinovirus-induced airway inflammation; and / or(e). preventing or reducing a viral, for example, rhinoviral, exacerbation of a respiratory condition in a subject, for example a respiratory condition selected from chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis or lung conditions associated with lung transplantation or chronic glucocorticosteroid use.

17. The compound for use as claimed in any one of the preceding claims, wherein the method also comprises an anti-inflammatory response.

18. The compound for use as claimed in claim 17, wherein the anti-inflammatory response comprises a decrease in the level of one of more cytokines selected from IL-6, TNF-a, MIPla, MIPip and MCP-1 in the lung.

19. The compound for use as claimed in any one of the preceding claims wherein the subject is human, for example, wherein the subject is elderly, for example, wherein the subject is aged 60 or above.

20. The compound for use as claimed in any one of claims 1 to 19, wherein the subject is immunocompromised.

21. The compound for use as claimed in any one of claims 1 to 20, wherein the subject has one or more comorbidities, for example, one or more comorbidities selected from anaemia, COPD, asthma, congestive heart failure, chronic kidney disease, diabetes, cancer, for example, a cancer selected from lymphoma and chronic leukaemia, and obesity.

22. The compound for use according to any one of the preceding claims, whereinR1is OH;R2is according to formula (III)P039862WO - 22 August 2025- 7 -(III) whereinR7is Ci-6-alkyl; andR8is selected from the group consisting of Ce-i 4-ary 1 carbonyl optionally substituted with 1 to 5 groups selected from Ci-3-alkyl sulfonyl groups and / or Ci-3-alkyl groups; HOOC-(CH2)m-(CO)- with m being from 0 to 6, a substituent of formula (V.l)(V. l) with Ar being Ce-i 4-ary 1 and n, p and q being independently from 0 to 6;R3is H; andR4and R5are both H.

23. The compound for use as claimed in any one of claims 1 to 21 wherein R8is selected from the group consisting of H, Ce-io-arylcarbonyl, Ce-io-arylcarbonyl (substituted with 1 to 3 halogen atoms, Ci-2-alkyl groups and / or Ci-2-alkoxy groups), bi-Ce-io-aryl-carbonyl (optionally substituted by 1 to 6 halogen, Ci-3alkylsulphonyl and / or CN) and HOOC-(CH2)m-(CO)- (with m being from 1 to 3, most preferably 1 or 2).

24. The compound for use as claimed in any one of claims 1 to 21 wherein R7is selected from the group consisting of Ci-6-alkyl, Ce-io-arylcarbonyl, C6-io-aryl-Ci-3-alkyl-0-Ci-3-alkyl-carbonyl, C6-io-aryl-Ci-3-alkylcarbonyl, C6-io-aryl-0-Ci-3-alkylcarbonyl, C6-i4-aryl-Ci-6-alkyl-O-CO-NH-Ci-6-alkyl-CO- and a moiety according to formula (V.1) or formula (V.2).P039862WO - 22 August 2025- 8 -25. The compound for use as claimed in any one of claims 1 to 21 wherein the compound of formula (I) is (2S,3R,4S,6R)-2-[(2R,3 S,4R, 5R, 8R, 1 OR, 11R, 12S, 13 S, 14R)-2-Ethyl-3 ,4, 10,13 -tetrahydroxy- 3,5,8,10,12,14-hexamethyl-6-m ethyl- 15 -oxo- 1 -oxa-6-aza- 11- cyclopentadecyloxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate.

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