Novel molecules

Abstract

To provide TLR2 agonist compounds and their compositions, and the use of such compounds and compositions in the prevention and / or treatment of respiratory infections, or diseases or conditions associated with viral or bacterial infections.SOLUTION: For example, a pharmaceutically acceptable salt, solvate, or prodrug of a compound represented by the following formula is presented.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] This application claims priority from Australian Provisional Patent Application No. 2019902231 (filed on 26 June 2019) and Australian Provisional Patent Application No. 2019904862 (filed on 20 December 2019). The entire contents of AU2019902231 and AU2019904862 are incorporated herein by reference.

[0002] [Field of the Invention] The present invention relates to compounds and their compositions, and to the use of such compounds and compositions in the prevention and / or treatment of respiratory infections, or respiratory diseases or conditions associated with viral or bacterial infections.

[0003] [Background of the Invention] Respiratory infections are one of the most common causes of human disease worldwide and are generally caused by viruses. According to the World Health Organisation (WHO), seasonal epidemics of influenza alone are estimated to result in approximately 3 to 5 million cases of severe illness and approximately 250,000 to 500,000 deaths annually worldwide.

[0004] Vaccines are available for some seasonal strains, such as influenza, but these have not always been shown to be sufficient due to several factors, such as infection during the induction period between vaccination and the formation of antibodies and immune cells. Seasonal vaccination also often requires modifications, including reformulation and administration, and may not provide protection over the desired full time period. In the case of other occurrences of influenza, such as the emergence of an unexpected global pandemic, vaccines are not always known, developed or available.

[0005] Viral respiratory infections can also exacerbate the severity of respiratory conditions, which can lead to exacerbations (flare-ups). Exacerbations can occur in conditions such as asthma and chronic obstructive pulmonary disease (COPD). Asthma and COPD exacerbations are the most clinically and economically significant forms of these diseases.

[0006] Despite the use of the best available up-to-date therapies, a large portion of exacerbations, particularly in asthma, continue to occur. When exacerbations occur, treatment options are limited and have made little progress in recent years. Treatment involves increasing the doses of inhaled bronchodilators and systemic or oral corticosteroids - the same drugs that were unable to prevent the exacerbations from occurring in the first place.

[0007] Therefore, there is a need for new or improved compounds and methods for the treatment and / or prevention of respiratory infections, or respiratory diseases associated with viral or bacterial infections.

[0008] Any reference to prior art herein does not admit or suggest that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art is reasonably foreseeable to be related to and / or combined with other parts of the prior art by a person skilled in the art.

[0009] [Summary of the Invention] The present invention provides Toll-like receptor 2 protein (TLR2) agonist compounds and compositions thereof. TLR2 agonists have previously been shown to have potential in the treatment of respiratory diseases and conditions associated with infectious agents such as viruses and bacteria. Advantageously, the compounds and compositions of the present application are active and can be used in therapeutic areas such as the treatment and / or prevention of respiratory diseases or conditions associated with viral or bacterial infections. Furthermore, the compounds and compositions of the present application can demonstrate increased stability that can be converted to a longer clearance rate after administration. The compounds of the present invention demonstrate improved solution stability compared to other related compounds.

[0010] In one aspect, the present invention has the structure: A-Y-B (wherein A is

Chemical formula

Chemical formula

[0011] wherein A in the compound has the structure: wherein A in the compound has the structure:

Chemical formula

[0012] In one aspect, the present invention provides the following formula:

Chemical formula

[0013] In one aspect, the present invention provides a compound of formula (VI):

Chemical formula

Chemical formula

[0014] In one embodiment, the present invention relates to formula (VII): A-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (VII) (wherein, A has the structure:

Chemical formula

Chemical formula

Chemical formula

[0015] In one embodiment, the compound is of formula (X):

Chemical formula

Chemical formula

[0016] The present invention also provides a composition comprising, consisting essentially of, or consisting of the compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0017] In one aspect, the present invention provides a method for treating and / or preventing a disease, the method comprising enhancing the innate immune response in a subject in need thereof by administering to the subject an effective amount of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0018] In another aspect, the present invention provides a method for treating and / or preventing a disease associated with or caused by an infectious agent, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0019] In another aspect, the present invention provides a method for treating and / or preventing a respiratory disease or condition associated with a viral or bacterial infection, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0020] In another aspect, the present invention provides a method for treating and / or preventing a respiratory infection, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0021] In another aspect, the present invention provides a method for reducing airway inflammation, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0022] The present invention also provides a method for improving a subject's ability to control a respiratory disease or condition during a respiratory virus infection, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0023] The present invention also provides a method for treating and / or preventing a disease or condition associated with the TLR2 receptor, the method comprising administering to a subject in need thereof a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0024] The present invention also provides a method for activating TLR2 activity within a cell, the method comprising contacting the cell with a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0025] In another aspect, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for enhancing the innate immune response in a subject.

[0026] In another aspect, the present invention provides the use of a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a disease caused by an infectious agent.

[0027] In another aspect, the present invention further provides the use of a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a respiratory disease or condition associated with viral or bacterial infection in a subject.

[0028] In another aspect, the present invention further provides the use of a compound of the present invention as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a respiratory infection in a subject.

[0029] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for reducing airway inflammation.

[0030] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for improving the ability of a subject to control a respiratory disease or condition during a respiratory virus infection.

[0031] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a disease or condition associated with the TLR2 receptor.

[0032] In one aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for enhancing the innate immune response in a subject.

[0033] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for preventing a disease caused by an infectious agent in a subject.

[0034] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating and / or preventing a respiratory disease or condition associated with a viral or bacterial infection in a subject.

[0035] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for reducing airway inflammation in a subject.

[0036] In another aspect, the present invention provides the use of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for controlling a respiratory disease or condition during a respiratory virus infection in a subject.

[0037] In another aspect, the present invention provides the use of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating and / or preventing a disease or condition associated with the TLR2 receptor.

[0038] In yet another aspect, the present invention further provides the use of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for activating intracellular TLR2.

[0039] The present invention also provides a kit for use in or when used in the method of the invention, - a compound of the invention as described herein; and optionally, - a written instruction explaining the use of the compound in the method of the invention comprising, consisting essentially of or consisting of these.

[0040] In yet a further aspect, the present invention provides a method for preparing a compound of the invention. In certain embodiments, the method comprises the steps outlined in the syntheses shown in the Examples.

[0041] Further aspects of the invention and further embodiments of the aspects described in the previous paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0042]

Figure 1

Figure 2

Figure 3

Figure 4

[0043] [Detailed Description of Embodiments] It will be understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features described or apparent from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0044] Specific embodiments of the invention are now referred to in more detail. The invention is described in connection with the embodiments, but it will be understood that the invention is not limited to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention as defined by the claims.

[0045] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the invention. The invention is in no way limited to the methods and materials described. It will be understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features described or apparent from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0046] All patents and publications referred to in this specification are hereby incorporated by reference in their entirety.

[0047] As used in this specification, unless the context requires otherwise, the term "comprise" and variations thereof, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0048] For the purposes of interpreting this specification, terms used in the singular also include the plural and vice versa.

[0049] General chemical terms used in the formulas herein have their ordinary meanings.

[0050] The term "aliphatic" is intended to include saturated and unsaturated, non-aromatic, straight-chain, branched-chain, acyclic, and cyclic hydrocarbons. Those skilled in the art will understand that aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl and (cycloalkyl)alkenyl groups. In various embodiments, the aliphatic group contains 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments, the aliphatic group contains 5 to 21, 9 to 21, or 11 to 21 carbon atoms, such as 11, 13, 15, 17, or 19 carbon atoms. In certain embodiments, the aliphatic group is saturated.

[0051] The term "heteroaliphatic" is intended to include aliphatic groups in which one or more chain and / or ring carbon atoms are independently replaced by heteroatoms, preferably heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, the heteroaliphatic is saturated. Examples of heteroaliphatic groups include straight-chain or branched-chain, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.

[0052] The term "alkyl" is intended to include saturated straight-chain and branched-chain hydrocarbon groups. In certain embodiments, the alkyl group has from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. In certain embodiments, the alkyl group has from 5 to 21, 9 to 21, or 11 to 21 carbon atoms, for example, 11, 13, 15, 17, or 19 carbon atoms. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

[0053] The term "alkenyl" is intended to include straight-chain and branched-chain alkyl groups having at least one double bond between two carbon atoms. In certain embodiments, the alkenyl group has from 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In certain embodiments, the alkenyl group has from 5 to 21, 9 to 21, or 11 to 21 carbon atoms, for example, 11, 13, 15, 17, or 19 carbon atoms. In certain embodiments, the alkenyl group has 1, 2, or 3 carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, and -C(CH3)=CH(CH3).

[0054] The term "alkynyl" is intended to include straight-chain and branched-chain alkyl groups having at least one triple bond between two carbon atoms. In certain embodiments, the alkynyl group has from 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In certain embodiments, the alkynyl group has 1, 2, or 3 carbon-carbon triple bonds. Examples include, but are not limited to, -C≡CH, -C≡CH3, -CH2C≡CH3, and -C≡CH2CH(CH2CH3)2.

[0055] The term "heteroalkyl" is intended to include an alkyl group in which one or more chain carbon atoms are substituted with a heteroatom selected from the group consisting of heteroatoms, preferably oxygen, nitrogen, and sulfur. In certain embodiments, the heteroalkyl is saturated. Examples of heteroalkyl groups include, for example, polyethylene glycol groups and polyethylene glycol ether groups.

[0056] The term "cycloalkyl" is intended to include monocyclic, bicyclic or tricyclic alkyl groups. In certain embodiments, the cycloalkyl group has 3 to 12, 3 to 10, 3 to 8, 3 to 6, 3 to 5 carbon atoms in the ring. In certain embodiments, the cycloalkyl group has 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, the cycloalkyl group has 3 to 8, 3 to 7, 3 to 6, 4 to 6, 3 to 5, or 4 to 5 ring carbon atoms. Bicyclic and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bicyclic and tricyclic cycloalkyl ring systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.

[0057] The term "cycloalkenyl" is intended to include a non-aromatic cycloalkyl group having at least one double bond between two carbon atoms. In certain embodiments, the cycloalkenyl group has 1, 2 or 3 double bonds. In certain embodiments, the cycloalkenyl group has 4 to 14, 5 to 14, 5 to 10, 5 to 8, or 5 to 6 carbon atoms in the ring. In certain embodiments, the cycloalkenyl group has 5, 6, 7, or 8 ring carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0058] The term "aryl" is intended to include cyclic aromatic hydrocarbon groups that contain no ring heteroatoms. Aryl groups include monocyclic, bicyclic, and tricyclic ring systems. Examples of aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl. In certain embodiments, the aryl group has 6 to 14, 6 to 12, or 6 to 10 carbon atoms in the ring. In certain embodiments, the aryl group is phenyl or naphthyl. Aryl groups include aromatic-aliphatic fused ring systems. Examples include, but are not limited to, indanyl and tetrahydronaphthyl.

[0059] The term "heterocyclyl" is intended to include non-aromatic ring systems that contain three or more ring atoms, one or more of which is a heteroatom. In certain embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In certain embodiments, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms. In certain embodiments, the heterocyclyl group includes monocyclic, bicyclic, and tricyclic rings having 3 to 16, 3 to 14, 3 to 12, 3 to 10, 3 to 8, or 3 to 6 ring atoms. Heterocyclyl groups include partially saturated and saturated ring systems, such as imidazolinyl and imidazolidinyl. Heterocyclyl groups include fused and bridged ring systems that contain heteroatoms, such as quinuclidyl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolidinyl, and trithianyl.

[0060] The term "heteroaryl" is intended to include aromatic ring systems containing five or more ring atoms, one or more of which are heteroatoms. In certain embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In certain embodiments, the heteroaryl group includes monocyclic, bicyclic, and tricyclic ring systems having 5 to 16, 5 to 14, 5 to 12, 5 to 10, 5 to 8, or 5 to 6 ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridinyl xanthinyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. The heteroaryl group includes fused ring systems in which all of the rings are aromatic, such as indolyl, and fused ring systems in which only one of the rings is aromatic, such as 2,3-dihydroindolyl.

[0061] The term "halo" or "halogen" is intended to include F, Cl, Br, and I.

[0062] The term "heteroatom" is intended to include oxygen, nitrogen, sulfur, or phosphorus. In certain embodiments, the heteroatom is selected from the group consisting of oxygen, nitrogen, and sulfur.

[0063] As used herein, the term "substituted" is intended to mean that one or more hydrogen atoms in the indicated group are substituted with one or more independently selected suitable substituents, provided that the substituents do not exceed the normal valency of each atom to which they are attached and that stable compounds are obtained by the substitution. In certain embodiments, suitable substituents for any of the compounds described herein include, but are not limited to, halo, CN, NO2, OH, NH2, NHR 100 , NR 100 R 200 , C 1~6 haloalkyl, C 1~6 haloalkoxy, C(O)NH2, C(O)NHR 100 , C(O)NR 100 R 200 , SO2R 100 , OR 100 , SR 100 , S(O)R 100 , C(O)R 100 , and C 1~6 aliphatic are included; where R 100 and R 200 are each independently C 1~6 aliphatic, such as C 1~6 alkyl.

[0064] As used herein, the term "carboxyl protecting group" is intended to mean a group that can be readily removed to provide the OH group of the carboxyl group and that protects the carboxyl group from unwanted reactions during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis, edited by T.W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (together with Albert Isidro-Llobet and Mercedes Alvarez), Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, alkyl and silyl groups such as methyl, ethyl, tert-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl.

[0065] As used herein, the term "amine protecting group" is intended to mean a group that can be readily removed to provide the NH2 group of an amine group and that protects the amine group from unwanted reactions during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis, edited by T.W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (together with Albert Isidro-Llobet and Mercedes Alvarez), Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, acyl and acyloxy groups such as acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyl, aminocaproyl, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxy-carbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichloro-benzyloxycarbonyl, and the like. Further examples include Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl), and Dde (1-(4,4-dimethyl-2,6-dioxohexylidene)ethyl).

[0066] As used herein, the term "carboxamide protecting group" is intended to mean a group that can be readily removed to provide the NH2 group of the carboxamide group and that protects the carboxamide group from unwanted reactions during the synthetic procedure. Such protecting groups are described in Protective Groups in Organic Synthesis, edited by T.W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (together with Albert Isidro-Llobet and Mercedes Alvarez), Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, 9-xanthenyl (Xan), trityl (Trt), methyltrityl (Mtt), cyclopropyldimethylcarbinyl (Cpd), and dimethylcyclopropylmethyl (Dmcp).

[0067] As used herein, the term "and / or" means "and", "or", or both.

[0068] The term "(s)" following a noun contemplates the singular and plural forms, or both.

[0069] The term "ester" refers to a carboxylic acid group in which the hydrogen of the hydroxyl group is substituted with a saturated, straight-chain (i.e., linear) or branched hydrocarbon group. Specific examples of alkyl groups are methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and 2,2-dimethylbutyl. The alkyl group can be a C1-C6 alkyl group. When used herein, terms that define the limit values of a range of lengths, such as "1 to 5" for example, mean any integer from 1 to 5, i.e., 1, 2, 3, 4 and 5. In other words, any range defined by two explicitly recited integers includes any integer that defines the limit values and any integer included in the range, and is meant to disclose that. The alkyl group can be a branched alkyl group.

[0070] References to numerical ranges disclosed herein (e.g., 1 to 10) incorporate references to all rational numbers within that range (e.g., 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, and 10), and further incorporate references to any range of rational numbers within that range (e.g., 2 to 8, 1.5 to 5.5, and 3.1 to 4.7), and thus all sub-ranges of all ranges explicitly disclosed herein are intended to be explicitly disclosed herein. These are merely examples of what is specifically intended, and all possible combinations of numbers between the recited minimum and maximum values are considered to be equally explicitly recited in this application.

[0071] As described above, the inventors have developed and optimized compounds for the treatment and / or prevention of respiratory diseases or conditions, particularly those associated with infectious agents such as bacteria or viruses. In particular, the compounds can provide significant protection from viral replication in the lungs when the compounds are administered to the upper respiratory tract. These compounds can have higher efficacy than other known TLR2 agonists. TLR2 agonist efficacy can also occur without significantly impairing TLR specificity and / or causing significant weight loss in the animal models described herein. Further, the compounds can be relatively resistant to hydrolysis and / or enzyme-mediated process degradation, and thus, for example, can demonstrate favorable stability within a formulation and / or biological matrix environment. The compounds of the invention demonstrate improved solution stability compared to other related compounds.

[0072] In one aspect, the invention provides a compound of formula (I): A-Y-B (I) (wherein A is

Chemical formula

Chemical formula

[0073] In certain embodiments, v is an integer selected from 2, 3, 4 or 5. In certain embodiments, v is 2.

[0074] In certain embodiments, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is H.

[0075] In certain embodiments, Z1 and Z2 are the same and are selected from the group consisting of -O-, -NR-, -S-, S(=O), S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, OC(=O)O-, NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-.

[0076] In certain embodiments, Z1 and Z2 are independently selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-.

[0077] In certain embodiments, w is an integer selected from 1 to 7. In certain embodiments, w is 1.

[0078] In certain embodiments, b is 0.

[0079] In certain embodiments, R 19 is H, C1-C6 alkyl, -C(=O)C1-C6 alkyl or -C(=O)C 11 -C 19It is selected from the group consisting of alkyl.

[0080] In certain embodiments, L1 and L2 are independently C5-C 21 aliphatic or C4-C 20 heteroaliphatic. In certain embodiments, L1 and L2 are independently C 10 -C 18 aliphatic or C 10 -C 18 heteroaliphatic. In certain embodiments, L1 and L2 are independently C 14 -alkyl and C 15 -alkyl. In certain embodiments, L1 and L2 are branched C 5~21 aliphatic. The branched C 5~21 aliphatic group may be branched at the carbon atom bonded to Z1 or Z2.

[0081] In certain embodiments, the present invention provides a compound of formula (I), wherein: v is an integer selected from 2 to 5; b is 0; R x R y R 13 R 14 R 15 R 16 and R 17 are H; Z1 and Z2 are independently selected from the group consisting of -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; w is an integer selected from 1 to 7; R 19 is H, C1-C6 alkyl, -C(=O)C1-C6 alkyl 又は -C(=O)C 11 -C 19 alkyl; L1 and L2 are independently C 10 -C 18Aliphatic or C 10 ~C 18 selected from heteroaliphatic.

[0082] In certain embodiments, X is S.

[0083] In certain embodiments, X is S(=O).

[0084] In certain embodiments, X is S(=O)2.

[0085] In certain embodiments, B represents a substituted PEG.

[0086] In certain embodiments, B is of the following formula B-I:

Chemical formula

Chemical formula

[0087] In certain embodiments, B is of the following formula B-II:

Chemical formula

Chemical formula

[0088] In certain embodiments of the substituted PEG of Formula B - I or B - II, q is 1.

[0089] In certain embodiments of the substituted PEG of Formula B - I or B - II, n can be from 10 to 14, such as 11, or from 24 to 30, such as 27.

[0090] In certain embodiments of the substituted PEG of Formula B - I or B - II, m is from 1 to 3, such as 2.

[0091] In certain embodiments of the substituted PEG of Formula B - I or B - II, when q is 1, R3 is -NH2.

[0092] In certain embodiments of the substituted PEG of Formula B - I or B - II, L is a natural α - amino acid residue.

[0093] In another aspect, the present invention provides a moiety (G) represented by the following formula: [Chemical formula] (wherein R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH and -CH2CH2C(=O)OR8, wherein any of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1-C6 alkyl; Z1, L1, Z2, L 2、 X, b, w, v, z, R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are as defined in the compound of formula (I) above) A compound comprising; A compound covalently attached to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided.

[0094] In certain embodiments, moiety G and PEG are [Chemical formula] directly linked via a covalent bond represented by. Typically, PEG is a substituted PEG, [Chemical formula] covalently linked at one end via an amide linker containing a carbonyl group linked to the covalent bond represented by.

[0095] In certain embodiments, the PEG is a substituted PEG. In certain embodiments, the substituted PEG has the formula:

Chemical formula

Chemical formula

[0096] In certain embodiments, when q is 1, R3 is -NH2.

[0097] In certain embodiments, L is a natural α-amino acid residue.

[0098] In one aspect, the present invention provides a compound of formula (VI):

Chemical formula

Chemical formula

[0099] In certain embodiments of the compound of formula (VI), v is 2, 3, 4 or 5, preferably 2 or 3, most preferably 2.

[0100] In certain embodiments of the compound of formula (VI), b is 0.

[0101] In certain embodiments of the compound of formula (VI), z is 1.

[0102] In certain embodiments, the compound of formula (VI) is of formula (VI’):

Chemical formula

[0103] In certain embodiments, the compound is of formula (VII): A-Y-NH-(CH2) p -O-(CH2-CH2-O) n -[(CH2) m -CO-L-] q R3 (VII) (wherein A and Y are as defined for the compound of formula (I), n is 3-100; m is 1, 2, 3 or 4; p is 2, 3 or 4; q is zero or 1; when q is 1, R3 is -NH2 or -OH; when q is zero, R3 is H; L is zero or consists of 1 to 10 units, where each unit is a natural α - amino acid residue or is derived from a natural α - amino acid and has the formula: [Chemical formula] represented by wherein R4 is H; R5 is an amino acid side chain or a second hydrogen) compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0104] In certain embodiments, the compound has the formula (X): [Chemical formula] (wherein n is from 3 to 100; k is from 3 to 100; m is 1, 2, 3 or 4; p is 2, 3 or 4; t is 2, 3 or 4; h is 1, 2, 3 or 4; q is zero or 1; wherein R1 and R2 are independently selected from the group consisting of H, -CH2OH, -CH2CH2OH, -CH(CH3)OH, -CH2OPO(OH)2, -CH2C(=O)NH2, -CH2CH2C(=O)OH and -CH2CH2C(=O)OR8, wherein any one of the alkyl hydrogens may be substituted with a halogen; R8 is selected from the group consisting of H and linear or branched C1 - C6 alkyl; when q = 1, R3 is -NH2 or -OH; when q = 0, R3 is H; L is zero or consists of 1 to 10 units, where each unit is a natural α - amino acid or is derived from a natural α - amino acid and has the formula: [Chemical formula] is represented by wherein R4 is H; R5 is an amino acid side chain or a second hydrogen; b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O)2-; Z1 and Z2 are each independently selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O)2-, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each case of b, v, w, and z 11 R 12 R x R y R 14 R 15 R 16 and R 17 are each independently H or C1-C6 aliphatic; R, R 13 and R 18 are each independently H or C1-C6 aliphatic; R 19 is H, C1-C6 aliphatic, an amino protecting group, L3-C(=O)-, or A2; L1 and L2 are each independently C5-C 21 aliphatic or C4-C 20 heteroaliphatic; L3 is C1-C 21 aliphatic or C2-C 20 heteroaliphatic; A2 is an amino acid or a peptide; wherein R, R 11 R 12 R13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , any aliphatic or heteroaliphatic present in any of L1, L2, and L3 is optionally substituted) compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0105] The present invention also provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Any of the compounds described herein or variations thereof may be included in the composition of the present invention.

[0106] As described above, the present invention provides Toll-like receptor 2 protein (TLR2) agonist compounds and compositions thereof. In humans, TLR2 plays a fundamental role in pathogen recognition and activation of the innate immune response. It is encoded by the TLR2 gene and is expressed on the surface of certain cells.

[0107] Without wishing to be bound by any theory or mechanism of action, the compounds of the present invention described herein are believed to be agonists of TLR2, exhibit activity upon binding to TLR2, and stimulate the innate immune system. The innate immune system forms an immediate defense against pathogens such as those that infect cells lining the respiratory tract and replicate intracellularly. Studies have shown that agents that stimulate the innate immune system can be useful in suppressing respiratory infections, which can provide protection from infection during isolation and during the period between inoculation and the formation of antibodies and immune cells. Such agents are considered useful for the treatment and / or prevention of respiratory infections, or respiratory diseases caused by or associated with infectious agents such as viruses (e.g., influenza A) or bacteria (e.g., pneumonia) in a non-antigen-specific manner.

[0108] In this regard, the compounds of the invention described herein can have activities of both activating human TLR2 and inhibiting viral progression, i.e., are at least equivalent to other TLR2 agonists such as Pam2Cys-Ser-K4, Pam2Cys-Ser-Ser-PEG, and Pam3Cys-Ser-PEG.

[0109] As used herein, "Ser" refers to the amino acid serine, and "Cys" refers to the amino acid cysteine.

[0110] As used herein, "PEG" refers to the polymeric compound polyethylene glycol. Unless otherwise defined, references to "PEG" include polymers of any length of ethylene oxide. References to PEG also include substituted PEGs. In certain embodiments, the substituted PEG can be defined by Formula B-I or B-II described herein.

[0111] Accordingly, in one aspect, the invention provides a method of treating and / or preventing a disease, comprising enhancing the innate immune response in a subject by administering to the subject in need thereof an effective amount of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0112] In another aspect, the invention provides a method of treating and / or preventing a disease caused by an infectious agent, comprising administering to a subject in need thereof an effective amount of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0113] In another aspect, the invention provides a method of treating and / or preventing a respiratory disease or condition associated with viral or bacterial infection, comprising administering to a subject in need thereof a compound of the invention described herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0114] In another aspect, the present invention provides a method for treating and / or preventing a respiratory infection, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof. Preferably, the method further comprises the step of identifying a subject suffering from a respiratory infection.

[0115] In another aspect, the present invention provides a method for reducing airway inflammation, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0116] The present invention also provides a method for improving the ability of a subject to control a respiratory disease or condition during a respiratory virus infection, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof. Preferably, the infection is not a rhinovirus infection.

[0117] The present invention also provides a method for treating and / or preventing a disease or condition associated with the TLR2 receptor, the method comprising administering to a subject in need thereof a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0118] The present invention also provides a method for activating intracellular TLR2 activity, the method comprising contacting a cell with a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the cell is contacted with the compound by administration of the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a composition comprising the compound, pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof. In certain embodiments, the cell is provided in the form of a cell culture.

[0119] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for enhancing the innate immune response in a subject.

[0120] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a disease caused by an infectious agent.

[0121] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a respiratory disease or condition associated with viral or bacterial infection in a subject.

[0122] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a respiratory infection in a subject.

[0123] In yet another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a respiratory infection.

[0124] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for reducing airway inflammation.

[0125] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for improving the ability to control a respiratory disease or condition during a respiratory virus infection. Preferably, the infection is not a rhinovirus infection.

[0126] In another aspect, the present invention further provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for treating and / or preventing a disease or condition associated with the TLR2 receptor.

[0127] In one aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for enhancing the innate immune response in a subject.

[0128] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for preventing a disease caused by an infectious agent in a subject.

[0129] In another aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof for treating and / or preventing a respiratory disease or condition associated with a viral or bacterial infection in a subject.

[0130] In a further aspect, the present invention provides the use of a compound of the present invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof (a) for treating and / or preventing a respiratory infection in a subject; (b) for reducing airway inflammation in a subject; (c) for controlling a respiratory disease or condition during a respiratory virus infection in a subject; (d) for treating and / or preventing a disease or condition associated with the TLR2 receptor.

[0131] In any of these aspects, the compound can be administered in a composition. Typically, the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient. The composition can be formulated for administration to the upper and / or lower respiratory tract, for example by inhalation or intranasally.

[0132] In any aspect of the invention, a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof can be conjugated to another compound. The other compound can be any of those described herein.

[0133] In any aspect of the invention, a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once a day or once a week.

[0134] In any aspect of the invention, when prevention or prophylaxis is intended or required, the compound is administered to the subject before any clinically or biochemically detectable symptom of viral infection.

[0135] In any aspect of the invention, administration of a compound of the invention described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject reduces the viral load in the subject. Preferably, the viral load is reduced in the respiratory tract, for example in the upper and / or lower respiratory tract. Preferably, the viral load is reduced in the lungs.

[0136] In any aspect herein, the infectious agent can be a virus. Preferably, the virus is associated with infection of the respiratory tract. Even more preferably, the virus is influenza. In any aspect, the virus is not a rhinovirus.

[0137] Influenza (commonly referred to as "the flu") is an infectious disease caused by RNA viruses (influenza viruses) of the family Orthomyxoviridae that infect birds and mammals. The most common symptoms of this disease are chills, fever, sore throat, muscle aches, severe headache, cough, weakness / fatigue, and general malaise.

[0138] Influenza viruses constitute three of the five genera of the family Orthomyxoviridae. Influenza A and B viruses co-circulate during seasonal epidemics and can cause severe influenza infections. Influenza C virus infections are less common but can be severe and cause local epidemics.

[0139] Influenza A viruses can be classified into different serotypes or subtypes based on the antibody response to these viruses. Influenza A viruses are classified into subtypes based on two proteins on the surface of the virus: hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1 - H18 and N1 - N11, respectively). The subtypes identified in humans are H1N1, H1N2, H2N2, H3N2, H5N1, H7N2, H7N3, H7N7, H9N2, and H10N7.

[0140] Influenza has a major impact on public health, along with profound economic effects, in addition to devastating health problems including morbidity and even mortality. Therefore, there is a need for therapeutic agents that can prevent infection or reduce the severity of infection in individuals.

[0141] In any aspect or embodiment of the present invention, the influenza infection that requires treatment or prevention is an infection caused by a virus selected from the group consisting of influenza A, B, or C.

[0142] The term "respiratory disease" or "respiratory condition" refers to any one of several diseases that involve inflammation and affect the components of the respiratory system, including the upper respiratory tract (including the nasal cavity, pharynx, and larynx) and the lower respiratory tract (including the trachea, bronchi, and lungs). Inflammation in the upper and lower respiratory tracts can be associated with or caused by viral infections or allergens. The anti-inflammatory activity of the compounds, either alone or when co-administered with glucocorticoids, is expected to make them particularly suitable for the treatment of these diseases or conditions.

[0143] Symptoms of respiratory diseases can include coughing, excessive phlegm production, shortness of breath with audible wheezing, or a feeling of chest compression. Exercise capacity can be significantly limited. In asthma, FEV1.0 (forced expiratory volume in 1 second), as a percentage predicted nomographically based on body weight, height, and age, can be decreased in relation to peak expiratory flow rate during forced exhalation. In COPD, FEV1.0 as a ratio of FVC is typically decreased to less than 0.7. The impact of each of these conditions can also be measured by the number of lost work / school days, sleep disturbances, the need for bronchodilators, the need for glucocorticoids, including oral glucocorticoids.

[0144] The presence, improvement, treatment, or prevention of a respiratory disease can be determined by any clinically or biochemically relevant method of the subject or a biopsy derived therefrom. For example, the parameters measured can be the presence or extent of lung function, signs and symptoms of obstruction; exercise tolerance; nocturnal awakening; number of lost school or work days; bronchodilator use; inhaled corticosteroid (ICS) dosage; oral glucocorticoid (GC) use; the need for other drug therapies; the need for medical procedures; hospitalization.

[0145] As used herein, the term "respiratory infection" means an infection by a virus or bacterium at any location in the respiratory tract. Examples of respiratory infections include, but are not limited to, colds, sinusitis, pharyngeal infections, tonsillitis, laryngitis, bronchitis, pneumonia, or bronchiolitis. Preferably, in any embodiment of the present invention, the respiratory infection is a cold.

[0146] An individual can be identified as having a respiratory infection by a viral test and may exhibit symptoms such as itchy watery eyes, runny nose, nasal congestion, sneezing, pharyngitis, cough, headache, fever, malaise, fatigue, and weakness. In one aspect, a subject having a respiratory infection may not have any other respiratory conditions. Detection of the presence or amount of the virus can be performed by PCR / sequencing of RNA isolated from a clinical sample (nasal wash, sputum, BAL) or serum.

[0147] The term "pharmaceutically acceptable" can be used to represent any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound that, when administered to a subject, can provide (directly or indirectly) the compounds of the invention described herein, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or active metabolites or residues thereof.

[0148] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0149] Examples of base salts include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium salts such as those formed from triethylamine, alkoxyammonium salts such as those formed with ethanolamine, and salts formed from amino acids such as ethylenediamine, choline, or arginine, lysine, or histidine. General information on the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts" P.H. Stahl, C.G. Wermuth, 1st edition, 2002, Wiley-VCH.

[0150] In the case of compounds that are solids, it is understood by those skilled in the art that the compounds, agents, solvates, and salts of the present invention may exist in different crystalline forms or polymorphs, and all of these are intended to be included within the scope of the present invention and the defined formula.

[0151] The term "polymorph" includes any crystalline form of the compounds of the present invention described herein, such as anhydrous forms, hydrated forms, solvate forms, and mixed solvate forms.

[0152] It will be understood that the compounds of the present invention may have chiral centers and thus may exist in the R or S configuration. The compounds may be provided in racemic form or in enantiomer- or diastereomer-enriched form. Enantiomer- and diastereomer-enriched forms of the compounds can be obtained by any of asymmetric synthesis, incorporation of chiral pool materials, or stereoselective resolution. Thus, the compounds may be provided as purified enantiomers or diastereomers, or mixtures of any ratio thereof. The isomers can usually be separated by chromatography methods or using resolving agents. Alternatively, the individual isomers can be prepared by asymmetric synthesis using chiral intermediates. If the compound has a carbon-carbon double bond, it may exist in the Z or E form, and all isomers of the compound are included in the present invention.

[0153] When applicable, the compounds of the present invention are intended to include solvated and unsolvated forms of the compounds. As used herein, the term "solvate" refers to a variable stoichiometric amount of a complex formed by the binding of a solvent to a compound of the present invention. Thus, a solvate may contain less than a stoichiometric amount of solvent, an equimolar amount of solvent, or more than a stoichiometric amount of solvent compared to the compound of the present invention. Such solvents for the present invention should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. Most preferably, the solvent used is water. A solvate where the solvent is water may be referred to as a hydrate.

[0154] Basic nitrogen-containing groups can be quaternized with substances such as lower alkyl halides like methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; and dialkyl sulfates like dimethyl and diethyl sulfates.

[0155] The compounds described herein also include isotopic forms such as the substitution of hydrogen with deuterium.

[0156] The compounds of the present invention can exist in optically active and racemic forms and can be isolated in such forms. As will be understood by those skilled in the art, the present invention is intended to encompass any racemate, optically active or stereoisomer, or mixtures thereof of the compounds of the present invention having the useful properties described herein. Methods for preparing such forms (e.g., resolution of racemic mixtures by recrystallization, synthesis from optically active starting materials, chiral synthesis, or separation by chiral chromatography) are well known in the art. In a preferred embodiment, the following *With respect to the carbon shown by, the compounds of the present invention are provided as a racemic mixture. In another preferred embodiment, the compounds of the present invention are provided in an enantiomerically enriched form at the following chiral centers in part A of the carbon atom (

Chemical formula

[0157] In any aspect or embodiment of the present invention, the compounds of the present invention are chiral centers at the following carbon atoms of part A ( * shown by):

Chemical formula

Chemical formula

[0158] In any aspect or embodiment of the present invention, the compounds of the present invention are chiral centers at the following carbon atoms of part A ( * shown by):

Chemical formula

Chemical formula

[0159] In any aspect or embodiment of the invention, the compounds of the invention can be provided in an enriched chiral form at the chiral center at the following carbon atom of moiety A( ** shown as):

Chemical formula

Chemical formula

[0160] In any aspect or embodiment of the invention, the compounds of the invention may be provided in an enantiomerically enriched form at the chiral centers at the following carbon atoms of moiety A ( ** shown as):

Chemical formula

Chemical formula

[0161] In any aspect or embodiment of the invention, the compounds of the invention may be provided in an enantiomerically enriched form at the chiral centers at the following carbon atoms of moiety A ( * and ** shown as):

Chemical formula

Chemical formula

[0162] In any aspect or embodiment of the present invention, the compounds of the present invention are provided in an enriched chiral form at the chiral centers ([[]] * and ** represented by) at the following carbon atoms of part A:

Chemical formula

Chemical formula

[0163] In any aspect or embodiment of the present invention, the compounds of the present invention have chiral centers at the following carbon atoms of moiety A ( * and ** shown as):

Chemical formula

Chemical formula

[0164] In any aspect or embodiment of the present invention, the compounds of the present invention have chiral centers at the following carbon atoms of moiety A ( * and ** as shown):

Chemical formula

Chemical formula

[0165] In any aspect or embodiment of the present invention, the compounds of the present invention have chiral centers in the Y moiety of the compound ( *** as shown):

Chemical formula

[0166] In any aspect or embodiment of the present invention, the compounds of the present invention have a chiral center in the Y moiety of the compound ( *** as shown by):

Chemical formula

[0167] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the R diastereomers around the chiral center shown by * in moiety A of the compounds described herein.

[0168] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the S diastereomers around the chiral center shown by * in moiety A of the compounds described herein.

[0169] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the R diastereomer around the chiral center represented by ** in part A of the compound described herein.

[0170] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the R diastereomer around the chiral center represented by ** in part A of the compound described herein.

[0171] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the R diastereomer around the chiral center represented by *** in the Y moiety.

[0172] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the S diastereomer around the chiral center represented by *** in the Y moiety.

[0173] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the R diastereomer around the chiral center represented by * in part A, the R diastereomer around the chiral center represented by ** in part A and the R diastereomer around the chiral center represented by *** in the Y moiety.

[0174] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the R diastereomer around the chiral center represented by * in part A, the S diastereomer around the chiral center represented by ** in part A and the R diastereomer around the chiral center represented by *** in part Y.

[0175] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the R diastereomer around the chiral center represented by * in part A, the R diastereomer around the chiral center represented by ** in part A and the S diastereomer around the chiral center represented by *** in part Y.

[0176] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the R diastereomer around the chiral center represented by * in part A, the S diastereomer around the chiral center represented by ** in part A and the S diastereomer around the chiral center represented by *** in part Y.

[0177] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the R diastereomer around the chiral center represented by *The S diastereomer around the chiral center shown by ** the R diastereomer around the chiral center shown by *** and the R diastereomer around the chiral center shown by

[0178] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the S diastereomer around the chiral center shown by * the S diastereomer around the chiral center shown by ** and the R diastereomer around the chiral center shown by *** in part A and in the Y part.

[0179] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the S diastereomer around the chiral center shown by * the S diastereomer around the chiral center shown by ** the R diastereomer around the chiral center shown by *** and the S diastereomer around the chiral center shown by

[0180] In any aspect of the present invention, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compounds present in the composition are the S diastereomer around the chiral center shown by * the S diastereomer around the chiral center shown by ** the S diastereomer around the chiral center shown by *** and the S diastereomer around the chiral center shown by

[0181] The compounds of the present invention demonstrate improved solution stability under accelerated degradation conditions compared to other related compounds. Solution stability can be evaluated by measuring the concentration of the compound in solution on day 0 and comparing the concentration of the compound after a period such as 14 days. Solution stability can be evaluated under ambient conditions, for example 25 °C and 65% relative humidity, or under accelerated conditions, for example 40 °C and 75% relative humidity. Typically, under accelerated conditions, the acceptable stability of the compound of interest for the practice of the present invention when stored in solution for 14 days will be the retention of at least 80% of the concentration of the compound in solution compared to the initial concentration of the compound in solution. Typically, the solution can be a physiological saline solution (e.g., 0.9% aqueous NaCl) or phosphate buffered saline (PBS; e.g., pH 7.4). In certain embodiments, the compounds of the present invention after 14 days of storage in PBS buffer at pH 7.4 are at least about 80%, 85%, 90%, 91%, 92% or more compared to the amount of compound detected in solution on day 0.

[0182] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but which, upon administration to a subject or patient, is modified in vivo to produce a compound of the invention described herein. For example, a prodrug can be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine or sulfhydryl group is bonded to an optional group which, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying the functional groups present in the compound, such that the modification is cleaved in vivo to produce the parent compound.

[0183] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently attached to the free amino and amide groups of the compounds of the present invention. The amino acid residues include the 20 natural amino acids commonly denoted by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently attached to the above substituents of the compounds of the present invention.

[0184] The compounds of the present invention or pharmaceutically acceptable salts, solvates, or prodrugs thereof described herein can be covalent irreversible or covalent reversible agonists of the active site of a protein.

[0185] When a protecting group (PG) is shown, one of ordinary skill in the art will readily understand which type of protecting group is suitable. Examples of suitable amine protecting groups for the purposes described herein include, but are not limited to, tert-butyloxycarbonyl (t-Boc) and 9H-fluoren-9-ylmethoxycarbonyl (Fmoc).

[0186] The pharmaceutical composition can be formulated from the compounds of the invention described herein for any suitable route of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, respiratory (e.g., nasal, inhalation, intralung), vaginal, rectal, or parenteral administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intra-articular synovial sac, and intraperitoneal injection, and any similar injection or infusion technique. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, one or more compounds can be combined preferably with a sterile aqueous solution that is isotonic with the recipient's blood. Such formulations can be prepared by dissolving the solid active ingredient in water containing a physiologically compatible substance such as sodium chloride or glycine, adjusting the buffered pH to that compatible with physiological conditions for producing an aqueous solution, and rendering the solution sterile. The formulations can be present in single or multiple dose containers, such as sealed ampoules or vials. Examples of components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington’s Pharmaceutical Sciences. Preferably, the composition is formulated for administration to the airways, for example, by intralung administration (e.g., inhalation) or intranasal administration. The composition can be administered to the upper and / or lower airways.

[0187] Preferably, the pharmaceutical composition is in a form suitable for administration via the respiratory route and can be in any form such as a powder, liquid, or suspension. Such a composition can target tissues including lung tissue (including alveoli, terminal bronchioles, bronchioles, and bronchi) or the nasal cavity (including paranasal sinuses, frontal sinus, ethmoid sinus, maxillary sinus, sphenoid sinus, superior turbinate, middle turbinate, and inferior turbinate).

[0188] For the purposes of this specification, the term "administering" and variations of that term including "administer" and "administration" include contacting, applying, delivering or providing the compounds or compositions of the invention to a living being or surface by any suitable means.

[0189] The dosage of the bioactive compounds according to the invention can vary within a wide range and can be adjusted according to individual requirements. The active compounds according to the invention are generally administered in a therapeutically effective amount.

[0190] The compositions according to the invention should be administered in an effective amount. The terms "therapeutically effective amount" or "effective amount" generally refer to an amount of a compound of the invention, a pharmaceutically acceptable salt, polymorph or prodrug thereof as described herein that (i) treats a particular disease, condition or disorder, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. Undesirable effects, such as side effects, may optionally occur together with the desired therapeutic effect; therefore, a physician takes into account the balance of potential benefits against potential risks in determining what is the appropriate "effective amount".

[0191] The exact amount required can vary from subject to subject depending on the species, age and general condition of the subject, the method of administration, etc. Therefore, it would be impossible to define an exact "effective amount". However, the appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using only routine experimentation. In one aspect, the dosage administered to a subject is any dosage that reduces the viral load. Preferably, the dosage does not significantly increase inflammation, for example, does not significantly increase the absolute neutrophil count in the lungs or the percentage of neutrophils in the total BAL cells. The term "therapeutically effective amount" or "effective amount" also refers to the amount of a compound of formula (I), formula (II), formula (III), formula (IV) and / or formula (V) or a pharmaceutically acceptable salt, solvate or prodrug thereof that results in improvement or treatment of symptoms of a respiratory infection, or a respiratory disease or condition associated with a viral or bacterial infection.

[0192] In certain embodiments, an effective amount for a human subject is in the range of about 250 nanomoles / kg body weight / dose to 0.005 nanomoles / kg body weight / dose. Preferably, the range is from about 250 nanomoles / kg body weight / dose to 0.05 nanomoles / kg body weight / dose. In certain embodiments, the weight / dose range is about 250 nanomoles / kg to 0.1 nanomoles / kg, about 50 nanomoles / kg to 0.1 nanomoles / kg, about 5 nanomoles / kg to 0.1 nmol / kg, about 2.5 nanomoles / kg to 0.25 nanomoles / kg, or about 0.5 nanomoles / kg to 0.1 nanomoles / kg body weight / dose. In certain embodiments, the amount is 250 nanomoles, 50 nanomoles, 5 nanomoles, 2.5 nanomoles, 0.5 nanomoles, 0.25 nanomoles, 0.1 nanomoles or 0.05 nanomoles / kg body weight / dose or a compound of approximately such an amount. The dosing schedule can be adjusted according to the needs of the situation and adjusted to provide an optimal therapeutic dose.

[0193] The compounds of the invention described herein can be formulated as a composition for inhalation, including a dry powder, spray, mist, or aerosol. This would be particularly preferred for the treatment of respiratory infections. In the case of an inhalation formulation, the composition or combination provided herein can be delivered by any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered-dose inhalers containing a propellant such as CFC or HFA, or a physiologically and environmentally acceptable propellant. Other suitable devices are breath-actuated inhalers, multi-dose dry powder inhalers, and aerosol nebulizers. An aerosol formulation for use in the present method typically contains a propellant, a surfactant, and a co-solvent, and can be filled into a conventional aerosol container sealed with a suitable metering valve.

[0194] An inhalant composition can include a liquid or powder composition containing an active ingredient suitable for spraying and intratracheal use, or an aerosol composition administered via an aerosol unit that dispenses a measured quantity. Suitable liquid compositions contain the active ingredient in an aqueous pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solution is administered by a pump or squeeze-actuated spray dispenser, or by any other conventional means that causes the required amount of the liquid composition to be inhaled into the patient's lungs or enables inhalation into the patient's lungs. For example, suitable formulations where the carrier is liquid, such as nasal sprays or nasal medications, include aqueous or oily solutions of the active ingredient. Alternatively, the composition can be a dry powder and can be administered to the airway as defined herein.

[0195] It will be understood that the specific dosage level for any particular patient can vary depending on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, eating habits, time of administration, route of administration, and rate of excretion, combination drugs (i.e., other drugs used to treat the patient), and the severity of the specific disorder being treated.

[0196] However, it will be understood that the specific dosage level for any particular subject can vary depending on a variety of factors including the activity of the specific compound used, age, body weight, general health, gender, eating habits, time of administration, route of administration, and rate of excretion, combination drugs (i.e., other drugs used to treat the subject), and the severity of the specific disorder being treated. The dosage can generally be lower when the compound is administered locally rather than systemically and for prophylactic rather than therapeutic purposes. Such treatment can be administered according to the required frequency and for a period of time determined by the treating physician as necessary. Those skilled in the art will understand that the dosing schedule or therapeutically effective amount of the compounds of the invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof, to be administered may need to be optimized for each individual. The pharmaceutical composition may contain an active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg, most preferably in the range of about 1 to 200 mg. A daily dosage of about 0.01 to 100 mg / kg body weight, preferably about 0.1 to about 50 mg / kg body weight, may be appropriate. The daily dosage may be administered as a single or multiple doses per day.

[0197] It will also be understood that different dosages may be required to treat different disorders.

[0198] As used herein, the term "treating" or "treatment" of a subject includes the application or administration of a compound or composition of the invention to the subject (or the application or administration of a compound of the invention to cells or tissues from the subject) for the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, reducing, changing, treating, suppressing exacerbation, soothing, improving, or acting on a disease or condition, a symptom of a disease or condition, or a risk (or susceptibility thereto) of a disease or condition. The term "treatment" refers to any indicator of success in the treatment or improvement of an injury, condition or disease, including: reduction; remission; decrease in the rate of exacerbation; reduction in the severity of the disease; stabilization, reduction or making the injury, condition or disease more tolerable to the subject; decrease in the rate of exacerbation or debilitation; reduction of debilitation at the end point of exacerbation; or any objective or subjective parameter such as improvement in the physical or mental health of the subject.

[0199] As used herein, "preventing" or "prevention" is intended to refer at least to a decrease in the likelihood of risk (or susceptibility thereto) of contracting a disease or disorder (i.e., such that at least one clinical symptom of the disease does not occur in a patient who is exposed to or is susceptible to the disease but who has not yet developed or manifested symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known to physicians.

[0200] "Subject" includes any human or non-human animal. Thus, in addition to being useful for human treatment, the compounds of the invention may also be useful for veterinary treatment of mammals including companion animals and livestock such as, but not limited to, dogs, cats, horses, cows, sheep, and pigs.

[0201] The compounds of the invention can be administered with a pharmaceutical carrier, diluent or excipient as described above.

[0202]

Table 1

[0203]

Table 2

[0204]

Table 3

[0205]

Table 4

[0206]

Table 5

[0207]

Table 6

[0208]

Table 7

[0209]

Table 8

[0210]

Table 9

[0211]

Table 10

[0212]

Table 11

[0213]

Table 12

[0214] It will be understood that the invention as disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features described or apparent from the text or drawings. All such different combinations constitute various alternative aspects of the invention.

[0215] [Example 1 - Synthesis of Compounds] [Example 1.1 - Synthesis A Using Fmoc Solid Phase Chemistry] The compounds of the invention, including those represented by formula (I), are compounds of formula A-I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0216] In certain embodiments, B’ comprises a substituted PEG of formula B-I. In these embodiments, the following series of solid-phase reactions can be used: a) Optionally, using Fmoc chemistry, coupling a compound derived from 1 to 10 α-amino acids or natural α-amino acids that constitute L to the solid-phase resin, b) Coupling PG-NH-(CH2) p -O-(CH2CH2O) n -(CH2) m -COOH to the solid-phase resin or, if L is present, to the substituted resin (where PG represents an amino protecting group compatible with Fmoc chemistry); c) Removing PG; d) Coupling PG-NH-CR 13 R 14 -COOH (where PG’ represents an amino protecting group compatible with Fmoc chemistry); e) Removing PG’; f) Coupling the acid of formula (A-I); g) Optionally, removing R 19 and optionally acylating and / or alkylating to introduce R 18 and / or R 19 ; and h) Removing the compound from the solid support.

[0217] In certain embodiments, B’ comprises a substituted PEG represented by formula (B-II), and the following series of solid-phase reactions can be used: a) Optionally, coupling a compound derived from 1 to 10 α-amino acids or natural α-amino acids that make up L to the solid-phase resin using Fmoc chemistry; b) Coupling PG-NH-(CH2) t -O-(CH2CH2O) k -(CH2) h -COOH to the solid-phase resin or, if L is present, to the substituted resin (where PG represents an amino protecting group compatible with Fmoc chemistry); c) Removing PG; d) Coupling PG’-NH-(CH2) p -O-(CH2CH2O) n -(CH2) m -COOH (where PG’ represents an amino protecting group compatible with Fmoc chemistry); e) Removing PG’; f) Coupling PG’’-NH-CR 13 R 14 -COOH (where PG’’ represents an amino protecting group compatible with Fmoc chemistry); g) Removing PG’’; h) Coupling the acid of formula (A-I); i) Optionally, removing R 19 and optionally acylating and / or alkylating to incorporate R 18 and / or R 19 ; and j) Removing the compound from the solid-phase resin.

[0218] It will be understood that the exact order of events can differ from that outlined, and additional steps, such as oxidation of cysteine sulfur to sulfoxide, can be added if necessary and convenient for the synthesis.

[0219] [Synthesis of Intermediates for Use in Solid-Phase Coupling A in Example 1.2] Formula A-II:

Chemical formula

[0220] Scheme 1 represents the synthesis of an embodiment of the compound of formula A-II, in which X is S, L1-Z1 is -OC(O)E-C g’ H (g’+2) where E is -O- or -NH-, and g' is 11, 12, 13, 14, 15, 16, 17, 18 or 19; L2-Z2 is -OC(O)E-C g’ H (g’+2) where E is -O- or -NH-, and g' is 11, 12, 13, 14, 15, 16, 17, 18 or 19; R 19 is PG3, which is an amino protecting group.

[0221] [Scheme 1]

Chemical formula

[0222] The epoxide of formula (VI') is reacted with a suitably protected cysteine analogue, such as tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(((R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)thio)-D-cysteinato (where PG2 is a tert-butyl ester and PG3 is Fmoc) under reducing conditions to obtain an alcohol of formula (VII'). It will be understood that the alcohol of formula (VII') can be composed of two or more stereoisomers, and if stereoisomers are present, they can be separated by chiral preparative chromatography if necessary.

[0223] The alcohol of formula (VII') is acylated using a suitable reagent to obtain a carbonyl-containing adduct of formula (VIII'). If an ester is required, an acid chloride can be reacted in the presence of a suitable base and solvent; if a carbamate is required, an isocyanate can be reacted in the presence of a suitable base and solvent, and if a carbonate is required, a chloroformate can be reacted in the presence of a suitable base and solvent. Next, the carbonyl-containing adduct of formula (VIII') can be deprotected using a suitable reagent to expose the carboxylic acid of formula (IX'), for example, when PG2 is tert-butyl, trifluoroacetic acid can be used to preferentially remove the tert-butyl group.

[0224] Next, the acid of formula (IX’) can be used as a reagent in solid-phase synthesis to add groups of formulas Y and B.

[0225] [Example 1.3 - Synthesis B Using Fmoc Solid-Phase Chemistry] The compounds of the present invention (wherein z is 1, w is 1, and b is 0) including those represented by formula (I) are resin-bound peptides of the following formula:

Chemical formula

Chemical formula

Chemical formula

[0226] After any sulfur deprotection, this resin-bound peptide is a 1,2-epoxy-alkanol of the following formula:

Chemical formula

[0227] The diol moiety of the resin-bound compound S-1 is further reacted, for example, by diol functionalization with a palmitic acid group or a lauryl carbamate group to obtain the compound of the present invention.

[0228] [Example 1.4 - Synthesis and Characterization of Compounds 3, 4, 15, and 16] [Synthesis of Compounds 3 and 4] The synthesis of compounds 3 and 4 is shown below in Scheme 2.

[0229] Fmoc-Gly was added to the solid support as the first amino acid, and then, in 2 ml of dimethylformamide (DMF) over 2 hours, in the presence of a 2-fold excess of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (HBTU), hydroxybenzotriazole (HOBT), and a 4-fold excess of diisopropylethylamine (DIPEA), a 2-fold molar excess of Fmoc-NHCH2CH2O-(PEG) 11 -CH2CH2COOH or Fmoc-NHCH2CH2O-(PEG) 27 -CH2CH2COOH was coupled. Next, Fmoc-Ser(tBu)-OH was coupled to obtain intermediate A2, and then Boc-Cys(StBu)A1 was coupled. The thiol-tert-butyl group on the cysteine residue was removed by incubating the peptide resin in 0.5 M dithiothreitol in DMF for 1 hour at room temperature. 250 mg of Boc-Cys-Ser(tBu)CH2CH2O-(PEG) saturated in DMF 11-CH2CH2C(O)Gly resin or Boc-Cys-Ser(tBu)CH2CH2O-(PEG) 27 To -CH2CH2C(O)Gly resin (0.25 mmol / g, 0.25 g = 0.0625 mmol), 250 μl of R-(+)-1,2-epoxy-butan-4-ol [(R)-2-(oxiran-2-yl)ethan-1-ol] (M W = 88.11, d = 1.1, 250 μl = 3.125 mmol corresponding to 50-fold excess of the free sulfhydryl groups present on the peptide resin) and 25 μl of diisopropylethylamine (DIPEA, M W = 129.2, d = 0.74, 25 μl = 0.14 mmol) were added. The reaction mixture was placed in a water bath at 50 °C for 2 h and then washed thoroughly with DMF to obtain intermediate A3.

[0230] Palmitic acid (320 mg, 1.25 mmol), DIPCDI (225 uL, 1.5 mmol) and 4-dimethylaminopyridine (DMAP; 15.25 mg, 0.125 mmol) were dissolved in 2 mL of dichloromethane (DCM) and then added to resin-bound BOC-Dhc-peptide resin A3 (0.0625 mmol, 0.25 g). The mixture was shaken at room temperature for 16 h. The supernatant was removed by filtration, and the solid support was washed thoroughly with DCM and dimethylformamide (DMF) to remove the urea residue and then subjected to the cleavage process described below.

[0231] The solid support with the assembled lipopeptide was exposed to reagent B (93% TFA, 5% water and 2% triisopropylsilane) for 2 h. To isolate the product, most of the TFA was removed, and then the residue was dissolved in 50% acetonitrile and purified immediately using the purification protocol described below or the material was lyophilized and stored for later purification.

[0232] [Scheme 2. Synthesis of Compound 3 (x = 11) and Compound 4 (x = 27)]

Chemical Structure

[0233] Next, after glycidolation, to 250 mg of peptide resin washed with toluene, 100 μl of ethyl methyl sulfide (M W = 76.16, d = 0.842, 100 μl = 1.10 mmol) was added, followed by 105 μl of tetradecyl isocyanate (MW = 239, d = 0.869, 105 μl = 0.38 mmol, i.e., 3-fold excess of each hydroxyl group present on the solid support) and finally 210 μl of dibutyltin dilaurate (M W = 631.6, d = 1.053, 210 μl = 0.35 mmol). The reaction mixture was sparged with nitrogen gas for about 5 minutes and mixed overnight at room temperature (Intelli-Mixer, RM-2, program F26 used). The reaction mixture was transferred to a 50 ml tube and chloroform was added until it reached 50 ml. After about 5 minutes of sonication, the white precipitate formed during the reaction was dissolved. The solid support was washed with DMF and acetonitrile, and the final product obtained after cleavage from the support (as described above) was purified by HPLC.

[0234] [Scheme 3. Synthesis of Compounds 15 (x = 11) and 16 (x = 27)] [Chemical formula] [Synthesis of Compound 20] Compound 20 was synthesized by standard Fmoc solid-phase peptide synthesis starting from Fmoc-RINK MBHA PS resin. Removal of the Fmoc group after each coupling was carried out using 20% piperidine in DMF. Fmoc-Gly-OH (2-fold excess), Fmoc-NH-PEG 28The coupling of -CH2CH2COOH (1.4-fold excess), Fmoc-Ser(tBu)-OH (2-fold excess), and N-(Boc)-S-((R)-2,3-dihydroxybutyl)-L-cysteine (1.5-fold excess) was carried out in DMF using an equimolar excess of ethyl cyano(hydroxyimino)acetate (Oxyma Pure) and diisopropylcarbodiimide (DIC) as coupling agents. Myristyl chloroformate coupling was carried out at room temperature for 18 hours using myristyl chloroformate (12 equivalents relative to the resin molar amount) and DIEA (24 equivalents relative to the resin molar amount) in dry DCM. This coupling was repeated three times ("recoupling"). The first recoupling was carried out at room temperature for 18 hours using myristyl chloroformate (12 equivalents relative to the resin molar amount) and NMM (24 equivalents relative to the resin molar amount) in dry DCM / THF (85 / 15). The second recoupling was carried out at room temperature for 41 hours using myristyl chloroformate (6 equivalents relative to the resin molar amount) and NMM (12 equivalents relative to the resin molar amount) in dry DCM / THF (85 / 15). Finally, the third recoupling was carried out at room temperature for 21.5 hours using myristyl chloroformate (6 equivalents relative to the resin molar amount) and NMM (12 equivalents relative to the resin molar amount) in dry DCM / THF / toluene (85 / 15 / 5).

[0235] Cleavage of the peptide from the resin, removal of the N-terminal Boc group, and deprotection of the serine side chain were carried out by exposure of the resin to a solution of 93% trifluoroacetic acid (TFA), 5% H2O, and 3% triisopropylsilane (TIPS) for 1.5 hours. After the cleavage reaction, the mixture was evaporated, and the resulting residue was redissolved in 30% acetonitrile / water and lyophilized.

[0236] [Synthesis of Compound 24] Compound 24 was synthesized by standard Fmoc solid-phase peptide synthesis starting from chlorotrityl chloride resin with an initial substitution of 1.6 meq / g. The first amino acid, Fmoc-Gly-OH, was first loaded onto the resin using a 0.5-fold molar excess of Fmoc-Gly-OH and DIEA (1.5-fold excess), followed by capping with DMF / MeOH / DIEA (80 / 10 / 10) and Fmoc deprotection, to obtain dry-loaded H-Gly-CT resin with a final substitution of 0.67 meq / g. Removal of the Fmoc group after each coupling was carried out using 20% piperidine in DMF. Fmoc-NH-PEG 28 -CH2CH2COOH (1.4 equivalents) was coupled using (7-azabenzotriazol-1-yloxy)tris-pyrrolidinophosphonium hexafluorophosphate (PyAOp; 1.4 equivalents) and diisopropylethylamine (DIEA; 3.2 equivalents) in DMF, while the coupling of Fmoc-Ser(tBu)-OH (2 equivalents) and N-(Boc)-S-((R)-2,4-dihydroxybutyl)-L-cysteine (1.5 equivalents) was carried out in DMF using an equimolar excess of Oxyma Pure and DIC as the coupling agent. Palmitic acid coupling was carried out at room temperature for 24 hours using palmitic acid (20 equivalents relative to resin moles), DIC (20 equivalents), and DMAP (2 equivalents) in DCM / THF (85 / 15) (v / v).

[0237] Cleavage of the peptide from the resin, removal of the N-terminal Boc group, and serine side-chain deprotection were carried out by exposing the resin to a solution of 93% TFA, 5% H2O, and 3% TIPS for 1.5 hours. After the cleavage reaction, the mixture was evaporated, and the resulting residue was redissolved in 30% acetonitrile / water and lyophilized.

[0238] [Synthesis of Compound 36] Compound 36 was synthesized by standard Fmoc solid-phase peptide synthesis starting from Fmoc-RINK MBHA PS resin. Removal of the Fmoc group after each coupling was carried out using 20% piperidine in DMF. Couplings of Fmoc-Gly-OH (2-fold excess), Fmoc-NH-PEG 28 -CH2CH2COOH (1.4-fold excess), Fmoc-Ser(tBu)-OH (2-fold excess), and N-(Boc)-S-((R)-2,3-dihydroxybutyl)-L-cysteine (1.5-fold excess) were performed in DMF using an equimolar excess of Oxyma Pure and DIC as the coupling agents. 2-Methyl-palmitic acid coupling was carried out at room temperature for approximately 20 hours using 2-methyl-palmitic acid (20 equivalents relative to the resin molar amount), DIC (20 equivalents), and DMAP (2 equivalents) in DCM / THF (85 / 15) (v / v).

[0239] Cleavage of the peptide from the resin, removal of the N-terminal Boc group, and deprotection of the serine side chain were carried out by exposing the resin to a solution of 93% TFA, 5% H2O, and 3% TIPS over 1.5 hours. After the cleavage reaction, the mixture was evaporated, and the resulting residue was redissolved in 30% acetonitrile / water and lyophilized.

[0240] [Purification and Characterization] [Purification and Characterization] After cleavage from the solid-phase support, each of the analogs was purified by reverse-phase HPLC according to either Protocol A or B described below.

[0241] Protocol A: Reverse-phase HPLC was performed using an Agilent Zorbax 300SB-C3, 5um column (9.4mm x 250mm; Agilent Technology, Australia) attached to an Agilent HPLC 1260 Infinity system (Agilent Technologies, Santa Clara, California, USA) with a chromatogram developed using buffer A (0.1% trifluoroacetic acid in water) and buffer B (0.1% trifluoroacetic acid in acetonitrile).

[0242] Protocol B: Reverse-phase chromatography was performed using a gradient of acetonitrile in [0.1% TFA / water] with a Novasep Axial Compression Column (5 cm diameter) packed with cyanopropyl stationary phase (Daisogel SP-120-CN-P). After lyophilization of the intermediate, ion exchange was performed on Dowex ion exchange resin to obtain the peptide as the acetate salt.

[0243] Compounds 3, 4, 15 and 16 prepared as described above were purified by Protocol A and compounds 20, 24 and 36 prepared as described above were purified by Protocol B.

[0244] Identification and purity determination of the target material were performed using an in-line HPLC-MS system under the following conditions: Condition A: The following gradient conditions: 0 - 5 minutes, 20% of B; 5 - 32 minutes, 20% of B to 100% of B; 32 - 40 minutes, 100% of B to 20% of B were used with an HPLC column: Agilent Zorbax 300 - SB C3 (150×0.5 mm; 5 μm). The flow rate was 20 μl / min. LC - MS: Agilent 1100 series LC / MSD ion trap mass spectrometer and an in - line Agilent 1100 series capillary LC system. The mass spectrometer was operated using electrospray ionization configured in the positive ion mode. A series of charged ions were deconvoluted for the identification of peptide materials using data analysis software manufactured by Agilent Technologies, and then the materials were characterized by LC - MS.

[0245] Condition B: Analytical reverse - phase HPLC using a cyanopropyl column (Daiso Fine Chem, SP - 120 - 3 - CN - P, 150×4.6 mm, 3 μm, 120 Å). Peptides were also analyzed by ESI LC - MS in the positive ion mode using a Finnigan LCQ Deca XPMax.

[0246] Compounds 3, 4, 15, and 16, prepared and purified as described above, were found to be over 95% pure according to Condition A.

[0247] Compounds 20, 24, and 36, prepared and purified as described above, were found to be over 95% pure according to Condition B.

[0248] The experimental mass (m / z) was consistent with the molecular weight calculated for each compound.

[0249] [Peptide Quantification] The quantification of Compounds 3, 4, 15, and 16 was performed by hydrolysis of the samples under reduced pressure at 110 °C in sealed glass vials in the presence of 6 N HCl containing 0.1% phenol. Next, derivatization of the amino acids was performed using Waters AccQTag reagent according to the manufacturer's instructions, followed by analysis on a Waters Acquity UPLC System (Waters Millipore) using an AccQTag ultra column (2.1 mm × 100 mm; Waters Millipore). Quantification of the other compounds can be performed by a similar protocol.

[0250] [1.5 - Synthesis of Sulfone and Sulfoxide Analogs of Compounds 15 and 16] Sulfone and sulfoxide derivatives of Compounds 15 and 16 can be obtained by the same synthetic route described above, with omission of the ethylmethyl sulfide scavenger from the carbamate formation step and optional omission of the nitrogen sparge. This reaction can result in a mixture of thiol, sulfone, and sulfoxide derivatives, which can be separated and purified by HPLC.

[0251] Alternatively, sulfone or sulfoxide derivatives can be prepared by oxidation of the corresponding sulfide with an oxidizing agent such as meta-chloroperbenzoic acid (MCPBA) or tert-butyl hydroperoxide (t-BuOOH) under appropriate conditions.

[0252] [Example 2 - Activation of Human TLR2] The potency of the compounds as activators of human and mouse TLR-2s was tested in an in vitro assay. The assay evaluates NF-κB activation in the HEKBlue-mTLR-2 cell line. These cells are stably transfected with mouse TLR-2 and endogenously express TLR-1 and TLR-6 at levels sufficient to permit full functional TLR-1 / 2 and TLR-2 / 6 activation.

[0253] Toll-like receptor 2 (TLR2) stimulation is tested by evaluating NF-κB activation in the HEKBlue-hTLR2 cell line. These cells are stably transfected with human TLR2 and endogenously express TLR1 and TLR6 at levels sufficient to enable full functional TLR1 / 2 and TLR2 / 6 activation. The activity of the test substance is tested for human TLR2 as a promising agonist. The test substance is evaluated at seven concentrations and compared to a control ligand. These steps are performed in triplicate.

[0254] [NF-κB reporter gene assay protocol] This assay was performed as previously described (Jackson et al. 2004; Lau et al. 2006; Sandor et al. 2003; Zeng et al 2010). HEK293T cells were cultured in 96-well plates at 4 × 10 4 cells / well and transfected 24 hours later with 5 ng of TLR2 expression plasmid with or without 100 ng of NF-κB luciferase reporter gene [50 ng of TK-renilla (Renilla) - luciferase expression plasmid (Promega corporation, Madison, USA)] in the presence of 0.8 μl of Fugene 6 (Roche Diagnostic). Compounds were added to the wells 24 hours later at the concentrations shown in the histogram. Cell lysates were prepared 5 hours after stimulation using reporter lysis buffer (Promega Corporation, Madison, USA). Luciferase activity in the cell lysates was determined using a reagent kit (Promega Corporation, Madison, USA) and a FLUOstar microplate reader (BMG Labtech, Ortenberg, Germany). NF-κB-dependent firefly luciferase activity was normalized using NF-κB-dependent renilla luciferase activity. Relative stimulation was calculated as the ratio of the stimulated sample to the unstimulated sample.

[0255] The results of this assay for Compounds 3, 4, 15 and 16 are shown in Figure 1. These data indicate that these compounds exhibit significant activity at TLR2.

[0256] [Example 3 - URT Virus Inoculation] In these examples, an upper respiratory tract (URT) influenza virus inoculation model is utilized in mice with a dose of infectious virus that replicates in the URT and then progresses to the lungs. The URT model is used to determine which compounds can prevent the replication and seeding of influenza virus from the URT to the lungs.

[0257] The cytokine and chemokine profiles in the turbinates, trachea, lungs and sera of animals after URT treatment with three - dose or single - dose compounds are also measured.

[0258] The cytokine profile of mice inoculated with Udorn virus is also measured after pretreatment with three doses of the compounds of the present invention.

[0259] [Experimental Animals] Groups of male or female C57BL / 6 mice of similar weekly age (e.g., about 6 - 8 weeks old) are used in all tests. After saline, compound administration or virus inoculation, the mice are monitored daily for weight changes, and behavioral or physical changes.

[0260] [URT Administration of Compounds] The mice are anesthetized by isoflurane inhalation and various doses of compounds diluted in saline or saline are administered intranasally using a pipettor. In multi - agent treatment experiments, the mice are administered three doses of the compounds of the present invention every other day for 5 days.

[0261] [Preparation of Influenza Virus] A / Udorn / 307 / 72 (H3N2) influenza virus (i.e., Udorn virus) is propagated in the chorioallantoic cavity of 10 - day - old embryonated chicken eggs. The eggs are inoculated with approximately 10 in 0.1 ml of saline 3Inoculate with the pfu virus. After incubation at 35 °C for 2 days, cool the eggs at 4 °C, collect the allantoic fluid, and clarify it by centrifugation. Determine the viral infectivity titer (pfu / mL) by the plaque assay described below, and store a certain volume of the allantoic fluid at -80 °C until use.

[0262] [URT virus inoculation] Anesthetize the mice with isoflurane and inoculate intranasally with 500 pfu of Udorn virus in 10 μl of physiological saline using a pipettor. On the 5th day after inoculation, collect the turbinates, trachea, and lungs to evaluate the viral load.

[0263] [Extraction and preparation of turbinates, trachea, and lung homogenates] Kill the mice by CO2 asphyxiation 24 hours after treatment or 5 days after influenza inoculation. Collect the turbinates, trachea, and lungs from each mouse into 1.5 mL of RPMI-1640 medium containing antibiotics (100 μg / mL penicillin, 180 μg / mL streptomycin, and 24 μg / mL gentamicin), and maintain on ice until processing. Homogenize the tissues using a tissue homogenizer, and then centrifuge the resulting organ homogenates at 2,000 rpm for 5 minutes to remove cell debris. Collect the supernatant and store at -80 °C until subsequent measurement.

[0264] [Evaluation of virus titer] Determine the titer of infectious Udorn virus by plaque assay on a confluent monolayer of Madin-Darby canine kidney (MDCK) cells. In a 6-well tissue culture plate, in 3 ml of RP10 (RPMI-1640 medium supplemented with 10% (v / v) heat-inactivated FCS, 260 μg / mL glutamine, 200 μg / mL sodium pyruvate, and antibiotics), 1.2×10 6Individual MDCK cells were seeded. After incubation overnight at 37°C in 5% CO2, the confluent monolayer was washed with RPMI. Serial dilutions of the test supernatant in RPMI containing antibiotics were added to duplicate wells of the monolayer. After incubation at 37°C in 5% CO2 for 45 minutes, the monolayer was overlaid with 3 mL of agarose overlay medium containing 0.9% agarose and treated with 2 μg / mL trypsin-TPCK in Leibovitz L15 medium pH 6.8 containing glutamine and antibiotics. The plates were incubated at 37°C in 5% CO2 for 3 days, and then virus-mediated cytolysis was counted as plaques on the cell layer. The total organ virus titer (plaque-forming units, PFU) for each individual animal was calculated.

[0265] [Determination of cytokine levels in turbinates, trachea, lung and serum] IFN-γ, IL-2, IL-4, TNF, IL-10, IL-6, KC, MCP-1, RANTES, IL-12 / IL-23p40 and IL-17A present in turbinate, trachea, and lung homogenates and serum samples were measured using the BD Cytometric Bead Array (CBA) Flex Kit according to the manufacturer's instructions, except that a total of 0.15 μl of each capture bead suspension and 0.15 μl of each PE detection reagent were used in 50 μl of the sample. Samples were analyzed using a Bection Dickinson FACSCanto II flow cytometer and the data were analyzed using FCAP Array multiplex software.

[0266] [Statistical analysis] One-way analysis of variance (ANOVA) with Tukey's comparison for all column tests can be used. Two-way ANOVA with Bonferroni test can be used to compare the same treatment groups in single and 3-times repeated dosing regimens. A p-value ≤ 0.0322 was considered statistically significant. Statistical analysis was performed using a suitable software such as GraphPad Prism, version 7.0.

[0267] [Evaluation of the Effect of Pretreatment with Various Doses of the Compounds of the Invention on the Results of URT Inoculation with Udorn Virus] This experiment is conducted to determine the antiviral effect of URT pretreatment with various doses of the compounds of the invention.

[0268] On day 0, mice (5 animals / group) were anesthetized with isoflurane and then administered intranasally in 10 μl either physiological saline, 5 nanomoles, 0.1 nanomole or 0.005 nanomole of any of the compounds of the invention. One day after administration of the compounds of the invention, the mice were anesthetized with isoflurane and then inoculated intranasally with 500 pfu of Udorn virus in a volume of 10 μl. The mice were sacrificed on day 5, and the turbinates, trachea and lungs were removed, homogenized and frozen for subsequent analysis.

[0269] The experimental design is summarized in the following schematic diagram.

Chemical formula

[0270] [Example 5 - TLR2 Activation by Various Compounds] A comparison of the ability of various compounds to stimulate luciferase activity in an NF-κB cell-based reporter system is determined. HEK293T cells transiently co-transfected with a human TLR2 plasmid and a luciferase-NF-κB plasmid reporter system are exposed to various dilutions of each compound. Successful receptor binding and subsequent signaling events are determined by measuring the luminescence due to luciferase activity.

[0271] [Example 6 - TLR Binding and Specificity] The compounds of the invention are evaluated for their ability to activate various other TLR pattern recognition receptors. These evaluations are performed using both human and mouse TLR panels. These assays detect a secreted placental alkaline phosphatase (SEAP) reporter under the control of a promoter that can be induced by NF-κB activation in HEK293 cells.

[0272] The secreted placental alkaline phosphatase (SEAP) reporter is under the control of a promoter that is inducible by the transcription factor NF-κB. This reporter gene enables the monitoring of TLR-mediated signaling based on the activation of NF-κB. In a 96-well plate (total volume of 200 μL) containing appropriate cells (50,000 - 75,000 cells / well), 20 μL of the test substance or positive control ligand is added to the well. The medium added to the well is designed for the detection of NF-κB-inducible SEAP expression. After incubation for 16 - 24 hours, the optical density (OD) is read at 650 nm using a Molecular Devices SpectraMax 340PC absorbance detector.

[0273] [Control Ligand] hTLR2: 1×108 cells / mL of HKLM (heat-killed Listeria monocytogenes) hTLR3: 1 μg / mL of poly(I:C) HMW hTLR4: 100 ng / mL of Escherichia coli (E.coli) K12 LPS hTLR5: 100 ng / mL of flagellin from Salmonella typhimurium hTLR7: 1 μg / mL of CL307 hTLR8: 1 μg / mL of CL075 hTLR9: 1 μg / mL of CpG ODN2006.

[0274] [Example 7 - Stability I] The stability was evaluated by tracking the changes in the absolute peak area and % peak area of the compounds of the present invention subjected to the following conditions, relative to the peak area and % peak area obtained from freshly prepared solutions of the related compounds. The compounds were formulated in each of the following formulations: 1. Phosphate Buffered Saline (PBS), pH 7.4. For example, the PBS buffer may contain 8 g of NaCl, 0.2 g of KCl, 1.15 g of disodium hydrogen phosphate and 0.2 g of potassium dihydrogen phosphate in 1 liter of MilliQ water. 2. 0.9% w / w saline (pH 5.8). For example, the saline solution may be prepared by dissolving sodium chloride (1.855 g) in 200 mL of Milli-Q water.

[0275] The stability of each formulation was evaluated under the following conditions: 1. 25 °C / 60% relative humidity (ICH ambient) 2. 40 °C / 75% relative humidity (ICH accelerated)

[0276] [Sample Preparation] Solutions of each compound (2 mL) at approximately 1 mg / mL were accurately prepared in PBS and saline diluent systems. The actual concentrations are shown in Table 1.

[0277] [Table 13]

[0278] All compounds were heated to approximately 60 °C with hot tap water flowing for approximately 30 seconds and then vortex mixed for an additional 30 seconds.

[0279] Each vial in Table 1 was further aliquoted into three separate HPLC vials and then stored at 4 - 8 °C (refrigerator), 25 °C / 65% RH and 40 °C / 75% RH for 2 weeks. The vials were wrapped with aluminum foil to block light over the storage period.

[0280] [Equipment and Operating Parameters] The Shimadzu Nexera UHPLC equipped with a diode array detector was used to monitor the change in peak area at t = 0 and t = 2 weeks.

[0281] Using the Shimadzu LCMS-8030 system, the selectivity of the HPLC method was verified by identifying impurity and degradation product peaks and examining possible co-eluting components across the main HPLC peaks.

[0282] [UHPLC Parameters] Column - Phenomenex Kinetex biphenyl, 50 × 2.1 mm, 2.6 μm, part no.00B - 4622 - AN Vial - 2 mL Agilent clear glass with multiple injection septa, part no.226 - 50512 - 00 Mobile Phase A - 5 mM ammonium formate in Milli - Q water Mobile Phase B - Acetonitrile, Merck LC - MS grade Needle Rinse Solution - 1:1 water:methanol Injection Volume: 1 μL Column Temperature: 40 °C Autosampler Temperature: 20 °C Total Flow Rate: 0.5 mL / min Total Run Time: 10 minutes UV - vis Wavelength: 205 nm

[0283] [Table 14]

[0284] [Table 15]

[0285] [LCMS Parameters] LC Injection Volume: 0.1 μL Interface: ESI Interface Temperature: 350 °C Desolvation Temperature: 250 °C Nebulizer Flow Rate: 3 L / min Heating Block: 400 °C Dry Gas Flow Rate: 15 L / min Q3 Scan Mode: Positive Start Time: 1 minute End time: 8 minutes Start m / z: 400 End m / z: 2000 (INNA - 011) Scanning speed: 15000 μ / sec

[0286] [Stability results] Samples of Compounds 3, 4, 15, and 16 were analyzed using either gradient 1 (for Compounds 3 and 4) or 2 (for Compounds 15 and 16). The results are shown in Tables 4 and 5 below, and Figures 2 and 3. The results for storage at 40 °C are shown in Table 4, and the results for storage at 25 °C are shown in Table 5.

[0287] Stability results are compared as the percentage of the peak area of the main HPLC peak at time zero, where the peak area from the sample after being subjected to the relevant conditions was normalized to 100% to exclude the contribution of impurities to the total peak area. Figure 2 shows the two - week data calculated by this method. Figure 3 shows a second dataset generated using the area of the main peak expressed as a percentage of the area at time zero.

[0288]

Table 16

[0289]

Table 17

[0290] Each of Compounds 3, 4, 15, and 16 showed considerable stability over a two - week test period, suggesting that they may be suitably stable during storage and after administration.

[0291] [Example 8 - Stability II] The relative stabilities of Compounds 4, 16, 20, 24, and 36 and the relative stability of Compound (8) of WO 2019 / 119067 were evaluated under accelerated conditions (40 °C / 75% RH) over 9 days. Each compound was prepared at a concentration of 1 mg / mL in an aqueous formulation of 0.1% w / v EDTA / 0.9% w / v saline buffered to pH 5.

[0292] The structure of Compound (8) of WO 2019 / 119067 is as follows:

Chemical formula

[0293] Stability was measured using reverse-phase HPLC with a UV detector analysis wavelength of 205 nm. The peak area of each compound at day 9 was compared to the area at time zero. The compound stability at day 9 was calculated as a percentage of the time-zero peak area data.

[0294] Compound stability was further evaluated by comparison to a control sample of the same compound. The control sample was prepared at a concentration of 1 mg / mL in an aqueous formulation of 0.1% w / v EDTA / 0.9% w / v saline buffered to pH 5 and frozen during the course of the study. The thawed sample was sonicated and measured by HPLC.

[0295] Data for each compound are summarized in Table 6.

[0296]

Table 18

[0297] Each of Compounds 4, 16, 20, 24, and 36 was shown to have significant stability over the 9-day test period. Each of these compounds also had superior stability under accelerated conditions compared to the comparative example compound.

[0298] The stability of the compound over a longer period is evaluated by long-term exposure to accelerated conditions, for example, over 28 days.

[0299] [Example 9 - Activation of Human TLR2 II] The efficacy of the compound as an activator of human TLR-2s is tested in an in vitro assay in HEK-BLUE-hTLR2 cells.

[0300] [Culture of HEK-BLUE-hTLR2 Cells] HEK-BLUE-hTLR2 cells are designed to examine the stimulation of human TLR2 (hTLR2) by monitoring the activation of NF-kB. HEK-BLUE-hTLR2 cells are obtained by co-transfection of hTLR2 and the SEAP (secreted embryonic alkaline phosphatase) reporter gene into HEK293 cells. Stimulation by a TLR2 ligand activates NF-kB, which induces the production of SEAP.

[0301] HEK-BLUE-hTLR2 cells were purchased from InvivoGen (San Diego, CA, USA). The cells were grown in DMEM supplemented with 10% FCS, 100 U / ml penicillin, 100 μg / ml streptomycin, 2 mM L-glutamine, 100 μg / mL Normocin in the presence of the selection antibiotics purchased from InvivoGen, and subcultured when reaching 70% confluence according to the manufacturer's recommendation. The cells were removed and resuspended in the test medium as suggested by the manufacturer for testing.

[0302] [Testing of Compounds] i) Serial dilutions of each compound are prepared in physiological saline, and 20 μl of each dilution per well in a flat-bottom 96-well plate are added in triplicate and placed in the incubator while waiting for the cells. ii) Remove the HEK-BLUE-hTLR2 cells from the T-75 flask in the incubator and discard the growth medium. iii) Gently rinse the cells with 10 ml of pre-warmed PBS. iv) Add 5 ml of pre-warmed PBS, bring the cells to 37 °C for 2 minutes, and then remove the cells by gently pipetting the PBS on and off the surface to which the cells are attached. v) Prepare a cell suspension at a density of 280,000 cells / ml in HEK-Blue™ Detection medium (purchased from InvivoGen and prepared according to the manufacturer's instructions), vi) Immediately add 180 μl of the cell suspension per well of the plate containing the solution of the compound. Then return the plate to the incubator at 37 °C for 16 hours and read at 620 nm using an ELISA reader.

[0303] The results of this assay for compounds 4, 20, 24, and 36 are shown in Figure 4. These data indicate that these compounds exhibit significant activity at TLR2.

Claims

1. Structure: A - Y - B (wherein A is represented by 【Chemical 1】 and in the formula wherein b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O) ２ -; Z １ and Z ２ each independently represents —O—, —NR—, —S—, S(═O), S(═O) ２ —, —C(═O)O—, —OC(═O)—, —C(═O)NR—, —NRC(═O)—, —C(═O)S—, —SC(═O)—, OC(═O)O—, NRC(═O)O—, —OC(═O)NR—, and —NRC(═O)NR—, and is selected from the group consisting of; R １１ , R １２ , R ｘ , R ｙ , R １４ , R １５ , R １６ , and R １７ are each, independently, H or C １ ~C ６ and are aliphatic; R, R １３ and R １８ each independently is H or C １ ~C ６ is aliphatic; R １９ is H, C １ ~C ６ aliphatic, an amino protecting group, L ３ -C(=O)-, or A ２ and; L １ and L ２ are each, independently, C ５ to C ２１ aliphatic or C ４ to C ２０ heteroaliphatic; L ３ is C １ to C ２１ aliphatic or C ２ to C ２０ heteroaliphatic; A ２ is an amino acid or a peptide; Here, any of R, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ｘ , R ｙ , L １ , L ２ , and any of L ３ is optionally substituted with any aliphatic or heteroaliphatic present in any of them; Y is [Chemical 2] and wherein, R １ and R ２ are independently selected from the group consisting of H, -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, -CH ２ OPO(OH) ２ , -CH ２ C(=O)NH ２ , -CH ２ CH ２ C(=O)OH and -CH ２ CH ２ C(=O)OR ８ ; provided that any one of said alkyl hydrogens may be substituted with a halogen; R ８ is selected from the group consisting of H and linear or branched C １ to C ６ alkyl; B represents polyethylene glycol (PEG)), a compound comprising or a pharmaceutically acceptable salt, solvate or prodrug thereof.

2. A compound comprising A and PEG, wherein said A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue, where A in said compound has the structure: 【Chemical Formula 3】 having in the formula b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, for example 2 to 5, provided that: the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O) -; ２ selected from - -; Z １ and Z ２ each independently is selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, S(=O) ２ -, -C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each case of b, v, w, and z １１ , R １２ , R ｘ , R ｙ , R １４ , R １５ , R １６ , and R １７ is each independently H or C １ ~C ６ is aliphatic; R, R １３ and R １８ are each, independently, H or C １ ~C ６ is aliphatic; R １９ is H, C １ ~C ６ aliphatic, an amino protecting group, L ３ -C(=O)-, or A ２ and; L １ and L ２ are each, independently, C ５ -C ２１ aliphatic or C ４ -C ２０ heteroaliphatic; L ３ is C １ to C ２１ aliphatic or C ２ to C ２０ heteroaliphatic; A ２ is an amino acid or a peptide; Here, any aliphatic or heteroaliphatic present in any of R, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ｘ , R ｙ , L １ , L ２ , and L ３ is optionally substituted; a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The following formula: 【Chemical Formula 4】 (wherein R １ and R ２ are independently H, -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, -CH ２ OPO(OH) ２ , -CH ２ C(=O)NH ２ , -CH ２ CH ２ C(=O)OH and -CH ２ CH ２ C(=O)OR ８ is selected from the group consisting of, wherein any one of said alkyl hydrogens may be substituted with a halogen; R ８ is selected from the group consisting of H and linear or branched C １ -C ６ alkyl; b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O) -; ２ selected from; Z １ and Z ２ each independently is selected from the group consisting of -O-, -NR-, -S-, -S(=O)-, -S(=O) ２ -,-C(=O)O-, -OC(=O)-, -C(=O)NR-, -NRC(=O)-, -C(=O)S-, -SC(=O)-, -OC(=O)O-, -NRC(=O)O-, -OC(=O)NR-, and -NRC(=O)NR-; R in each case of b, v, w, and z １１ , R １２ , R ｘ , R ｙ , R １４ , R １５ , R １６ , and R １７ is each independently H or C １ ~C ６ is aliphatic; R, R １３ and R １８ each independently is H or C １ ~C ６ is aliphatic; R １９ is H, C １ ~C ６ aliphatic, an amino protecting group, L ３ -C(=O)-, or A ２ and; L １ and L ２ are each, independently, C ５ to C ２１ aliphatic or C ４ to C ２０ heteroaliphatic; L ３ is C １ to C ２１ aliphatic or C ２ to C ２０ heteroaliphatic; A ２ is an amino acid or a peptide; Here, any of R, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ｘ , R ｙ , L １ , L ２ , and any aliphatic or heteroaliphatic present in any of L ３ is optionally substituted) a compound comprising a compound covalently bonded to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.

4. Said PEG is a substituted PEG represented by the following formula: 【Chemical Formula 5】 wherein n is from 3 to 100; m is 1, 2, 3 or 4; p is 2, 3 or 4; q is zero or 1; L is zero or consists of 1 to 10 units, where each unit is a natural α - amino acid or is derived from a natural α - amino acid and is represented by the formula: R ３ is H, -NH ２ or -OH, and when q is zero, R ３ is H, and when q is 1, R ３ is -NH ２ or -OH; represented by 【Chemical Formula 6】

5. In the formula, R ４ is H; R ５ The compound according to any one of claims 1 to 3, wherein R is a side chain of the amino acid or a second hydrogen. Formula (VI): (wherein [Chemical Formula 7] n is from 3 to 100; m is 1, 2, 3 or 4; p is 2, 3 or 4; q is zero or 1; L is zero or consists of 1 to 10 units, where each unit is a natural α - amino acid or is derived from a natural α - amino acid and is represented by the formula: R １ and R ２ are each independently H, -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, -CH ２ OPO(OH) ２ , -CH ２ C(=O)NH ２ , -CH ２ CH ２ C(=O)OH and CH ２ CH ２ C(=O)OR ８ selected from the group consisting of, wherein any one of said alkyl hydrogens may be substituted with a halogen; R ８ is selected from the group consisting of H and linear or branched C １ ~C ６ alkyl; When q = 1, R ３ is -NH ２ or -OH; When q = 0, R ３ is H; represented by 【Chemical 8】 b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, provided that: wherein, R ４ is H; R ５ is the side chain or second hydrogen of the amino acid; the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; a compound of X is selected from -S-, -S(=O)-, and -S(=O) ２ -; Z １ and Z ２ each independently represents —O—, —NR—, —S—, —S(═O)—, —S(═O) ２ —, —C(═O)O—, —OC(═O)—, —C(═O)NR—, —NRC(═O)—, —C(═O)S—, —SC(═O)—, —OC(═O)O—, —NRC(═O)O—, —OC(═O)NR—, and —NRC(═O)NR—, and is selected from the group consisting of; R in each case of b, v, w, and z １１ , R １２ , R ｘ , R ｙ , R １４ , R １５ , R １６ , and R １７ is each independently H or C １ ~C ６ is aliphatic; R, R １３ and R １８ each independently is H or C １ ~C ６ is aliphatic; R １９ is H, C １ ~C ６ aliphatic, an amino protecting group, L ３ -C(=O)-, or A ２ and; L １ and L ２ are each, independently, C ５ to C ２１ aliphatic or C ４ to C ２０ heteroaliphatic; L ３ is C １ to C ２１ aliphatic or C ２ to C ２０ heteroaliphatic; A ２ is an amino acid or a peptide; Here, any of R, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ｘ , R ｙ , L １ , L ２ , and any aliphatic or heteroaliphatic present in any of L ３ is optionally substituted) ​ or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 6** Formula (VII): A-Y-NH-(CH ２ ) ｐ -O-(CH ２ -CH ２ -O) ｎ -[(CH ２ ) ｍ -CO-L-] ｑ R ３ (VII) (wherein, A has the structure: 【Chemical Formula 9】 ; Y is 【Chemical 10】 ; In the formula, R １ and R ２ are independently H, -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )OH, -CH ２ OPO(OH) ２ , -CH ２ C(=O)NH ２ , -CH ２ CH ２ C(=O)OH and -CH ２ CH ２ C(=O)OR ８ is selected from the group consisting of, wherein any one of the alkyl hydrogens may be substituted with a halogen; R ８ is selected from the group consisting of H and linear or branched C １ ~C ６ alkyl; n is from 3 to 100; m is 1, 2, 3 or 4; p is 2, 3 or 4; q is zero or 1; When q is 1, R ３ is —NH ２ or —OH; When q is zero, R ３ is H; L is zero or consists of 1 to 10 units, where each unit is a natural α-amino acid or derived from a natural α-amino acid and is represented by the formula: 【Chemical 11】 ; wherein, R ４ is H; R ５ is the side chain or second hydrogen of the amino acid; b and w are each independently an integer from 0 to 7, v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; the sum of b and w is from 0 to 7; z is 1 or 2; X is selected from -S-, -S(=O)-, and -S(=O) ２ -; Z １ and Z ２ each independently represents —O—, —NR—, —S—, —S(═O)—, —S(═O) ２ —, —C(═O)O—, —OC(═O)—, —C(═O)NR—, —NRC(═O)—, —C(═O)S—, —SC(═O)—, —OC(═O)O—, —NRC(═O)O—, —OC(═O)NR—, and —NRC(═O)NR—; R in each case of b, v, w, and z １１ , R １２ , R ｘ , R ｙ , R １４ , R １５ , R １６ , and R １７ is each independently H or C １ ~C ６ is aliphatic; R, R １３ and R １８ each independently is H or C １ ~C ６ is aliphatic; R １９ is H, C １ ~C ６ aliphatic, an amino protecting group, L ３ -C(=O)-, or A ２ and; L １ and L ２ are each, independently, C ５ ~C ２１ aliphatic or C ４ ~C ２０ heteroaliphatic; L ３ is C １ to C ２１ aliphatic or C ２ to C ２０ heteroaliphatic; A ２ is an amino acid or a peptide; Here, any of R, R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ｘ , R ｙ , L １ , L ２ , and any aliphatic or heteroaliphatic present in any of L ３ is optionally substituted) a compound; or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 7** The compound according to any one of claims 4 to 6, wherein q is 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 8** The compound according to any one of claims 4 to 7, wherein n is from 10 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 9** The compound according to claim 8, wherein n is 11, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 10** The compound according to any one of claims 4 to 7, wherein n is from 24 to 30, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 11** The compound according to claim 10, wherein n is 27, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 12** The compound according to any one of claims 4 to 11, wherein m is from 1 to 3, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 13** The compound according to claim 12, wherein m is 2, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 14** The compound according to any one of claims 1 to 13, wherein v is from 2 to 5, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 15** R ｘ 、R ｙ 、R １１ 、R １２ 、R １３ 、R １４ 、R １５ 、R １６ 、and R １７ is H, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 16** Z １ and Z ２ are the same and are selected from the group consisting of —O—, —NR—, —S—, S(═O), S(═O) ２ —, —C(═O)O—, —OC(═O)—, —C(═O)NR—, —NRC(═O)—, —C(═O)S—, —SC(═O)—, OC(═O)O—, NRC(═O)O—, —OC(═O)NR—, and —NRC(═O)NR—, a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 17** The compound according to any one of claims 1 to 16, wherein w is an integer from 1 to 7, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 18** The compound according to any one of claims 1 to 17, wherein b is 0, or a pharmaceutically acceptable salt, solvate or prodrug thereof. **Claim 19** the compound is ＊ a chiral center represented by: 【Chemical Formula 12】 The R stereoisomer of the compound around, the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

20. The following formula: 【Chemical 13】 by ＊＊ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the chiral center represented by ＊＊ has the L-configuration.

21. The following formula: 【Chemical Formula 14】 by ＊＊＊ The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the chiral center represented by ＊＊＊ has the L-configuration.

22. The compound according to any one of claims 1 to 21, wherein X is S.

23. The following Compounds 1 to 36 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from any one of

24. A composition comprising the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

25. A method for treating and / or preventing a disease, comprising enhancing the innate immune response in a subject by administering an effective amount of the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the composition according to claim 24, to the subject in need thereof.

26. A method for treating and / or preventing a disease caused by an infectious agent, comprising administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the composition according to claim 24.

27. A method for treating and / or preventing a respiratory disease or condition associated with viral or bacterial infection, comprising administering to a subject in need thereof the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the composition according to claim 24.

28. A method for treating and / or preventing a respiratory infection, comprising administering to a subject in need thereof the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the composition according to claim 24.

29. A method for reducing airway inflammation, comprising administering to a subject in need thereof the compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the composition according to claim 24.

30. The method according to claim 29, further comprising the step of identifying a subject having a respiratory disease or condition.

31. A method of improving the ability of a subject to control a respiratory disease or condition during a respiratory virus infection, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a composition according to claim 24.

32. The method according to claim 30, wherein the infection is not a rhinovirus infection.

33. A method of treating and / or preventing a disease or condition associated with the TLR2 receptor, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a composition according to claim 24.

34. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for enhancing the innate immune response in a subject.

35. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating and / or preventing a disease caused by an infectious agent.

36. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating and / or preventing a respiratory disease or condition associated with a viral or bacterial infection in a subject.

37. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating and / or preventing a respiratory infection in a subject.

38. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for reducing airway inflammation.

39. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for improving the ability of a subject to control a respiratory disease or condition during a respiratory virus infection.

40. Use according to claim 39, wherein the infection is not a rhinovirus infection.

41. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating and / or preventing a disease or condition associated with the TLR2 receptor.

42. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for enhancing the innate immune response in a subject.

43. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for preventing a disease caused by an infectious agent in a subject.

44. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for treating and / or preventing a respiratory disease or condition associated with a viral or bacterial infection in a subject.

45. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for treating and / or preventing a respiratory infection in a subject.

46. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for reducing airway inflammation in a subject.

47. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for controlling a respiratory disease or condition during a respiratory virus infection in a subject.

48. The compound according to claim 47, wherein the infection is not a rhinovirus infection.

49. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for treating and / or preventing a disease or condition associated with the TLR2 receptor.

50. A kit for use in or when used in the method according to any one of claims 25 to 33, comprising: - a compound according to any one of claims 1 to 23; and optionally, - written instructions explaining the use of the compound in the method and including, consisting essentially of, or consisting of the foregoing.

51. A method of activating TLR2 activity in a cell, the method comprising contacting the cell with a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1 to 23.

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