Compounds and uses therefor

Abstract

Disclosed are glycanic compounds and their use for treating or inhibiting the development of an inflammatory condition or a condition associated with an activity of a cytokine, such as asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and dermatitis.

Description

TITLE OF THE INVENTION"COMPOUNDS AND USES THEREFOR"RELATED APPLICATIONS

[0001] This application claims priority to Australian Provisional Patent Application No. 2023902115 entitled "Compounds and uses therefor" filed 30 June 2023, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] This invention relates generally to glycanic compounds and their use for treating or inhibiting the development of an inflammatory condition or a condition associated with an activity of a cytokine, such as asthma, chronic obstructive pulmonary disease (CORD), acute respiratory distress syndrome (ARDS) and dermatitis.BACKGROUND OF THE INVENTION

[0003] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.

[0004] Asthma is a chronic lung disease with increasing incidence worldwide. The World Health Organization estimates that asthma affected about 262 million people worldwide in 2019 and caused about 455,000 deaths. Asthma is characterized by inflammation and muscle tightening around the airways, mucus hypersecretion and subepithelial fibrosis. Common symptoms include wheezing, coughing, shortness of breath and chest tightness. While asthma is unable to be cured, many asthma sufferers are able to manage their symptoms using the currently available therapies, including bronchodilators and steroids. However, some asthma sufferers, particularly moderate to severe asthmatic patients, have persistent disease despite the use of such therapies.

[0005] Cytokines, including chemokines, interferons, interleukins, lymphokines and tumor necrosis factors, are important intracellular signaling molecules. While these molecules are essential for normal cellular processes including cellular growth and maturation and play an essential role in the immune response, they also play a role in the development and / or progression of a number of immune-mediated conditions or diseases and cancer cell proliferation. Cytokines are particularly known to be associated with inflammatory conditions, such as asthma. In this regard, antibodies targeting IL-5 and IL-13 have been shown to provide benefit for severe asthma patients. However, an effective non-corticosteroid therapy for general use is yet to be developed. It is evident that more effective therapies for asthma and other inflammatory conditions are required.

[0006] Glycosaminoglycans (GAGs) are linear polysaccharides of very diverse structures. They occur naturally as the glycan moiety of proteoglycans and play pivotal roles in many biological processes within the human body, including the binding and presentation of certain cytokines / growth factors to their cell surface receptors, thereby enhancing receptor signaling. Glycosaminoglycans within extracellular matrices also sequester certain cytokines, growth factors, chemokines and enzymes in specific locations within tissues. However, GAG interactions with particular cytokines, growth factors, chemokines and enzymes can contribute to physiologically adverse processes such as excessive inflammation, cancer growth and metastasis and various immunological reactions with counterproductive outcomes. Currently, some of the best known GAGs belong to the heparin / heparan sulfate family of sulfated polysaccharides. Heparin is best known for its anticoagulant activity, but more recent data indicates that heparin can also have anti-inflammatory activity. Mechanistically these activities are the result of some of the structures in heparin / heparan sulfates binding to three-dimensional motifs on proteins. Given their ability to bind to and modulate the activity of biological regulators, GAGs have been proposed as potential therapeutic agents.

[0007] However, natural GAGs are not ideal therapeutic agents due to their extreme structural heterogeneity, particularly in their complex sulfation patterns, and the difficulties in isolating specific GAG structural entities. This means, generally the natural GAG structural motifs that best bind particular cytokines, growth factors, chemokines or enzymes are unknown. The synthesis of GAG structures is also extremely complex and the synthesis of even small GAG structures requires many synthetic steps. As the complex sulfation patterns of GAGs contributes to their protein binding characteristics, the multiple synthetic steps cannot be avoided when synthesizing GAGs for therapeutic purposes. Accordingly, GAGs or analogues or mimetics thereof which have more suitable therapeutic properties are desired.SUMMARY OF THE INVENTION

[0008] The present invention is predicated in part on the discovery of particular compounds that interact with and inhibit an activity of a cytokine, including IL-4, IL-5, IL-8 (CXCL8), IL-13 and / or IL-33. Accordingly, the Inventors have conceived that such compounds will be useful for treating and inhibiting the development of an inflammatory condition and / or a condition associated with an activity of a cytokine, such as asthma.

[0009] In one aspect, there is provided a compound of Formula I, II, III, IV, V or VI:5(VI) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L1L3L4L6L7L8L9L10L11L12L13L15L16L17L18L19L20L21L22L23L24L25L26L28, L29, L30, L31and L32are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L2, L5, L14and L27are independently selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18are independently selected from CH and N ; andR1is selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12alkenyl and optionally substituted C2-C12alkynyl.

[0010] In some embodiments, X1-X18are CH.

[0011] In some embodiments, L1, L3, L4, L6, L7, L8, L9, L10, L11, L12, L13, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L28, L29, L30and L32are independently selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene. In particular embodiments, L1, L3, L4, L6, L7, L8, |_9L10 |_11 |_12 L13 |_15 |_16 |_17 L18 |_19 L20 |_21 L22 L23 |_24 |_25 L26 L28 L29 L30 and L32 are optionally substituted C1-C3alkylene; especially methylene.

[0012] In some embodiments, L2and L31are independently selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene. In particular embodiments, L2and L31are each independently optionally substituted C2-C5alkylene, such as propylene (e.g. n- propylene).

[0013] In further embodiments, L5is selected from optionally substituted C3-C6alkylene, optionally substituted C3-C6alkenylene and optionally substituted C6-C6alkynylene. In specific embodiments, L5is optionally substituted C3-C6alkylene, especially butylene (e.g. n-butylene).

[0014] In some embodiments, L14and L17are independently selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene. In particular embodiments, L14is optionally substituted C2-C4alkylene, especially ethylene. In particular embodiments, L27is optionally substituted C2-C4alkylene, especially ethylene.

[0015] In specific embodiments, R1is selected from optionally substituted C6- C10alkyl, optionally substituted C6-C10alkenyl and optionally substituted C6-C10alkynyl. In particular embodiments, R1is optionally substituted C6-C10alkyl, such as octyl. In alternative embodiments, R1is methyl.

[0016] In some embodiments, the compound is a compound of Formula VII:or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0017] In alternative embodiments, the compound is a compound of FormulaVIII:or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0018] In alternative embodiments, the compound is a compound of FormulaIX:(IX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0019] In other embodiments, the compound is a compound of Formula X:(X) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0020] In a still further embodiment, the compound is a compound of FormulaXI:(XI) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0021] In an alternative embodiment, the compound is a compound of FormulaXII:(XII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0022] In another embodiment, the compound is a compound of Formula XIII:(XIII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0023] In particular embodiments, the compound is in the form of a salt, especially wherein the salt is the sodium salt.

[0024] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable carrier or diluent.

[0025] Further provided is a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in therapy.

[0026] In another aspect, there is provided a method of treating or inhibiting the development of an inflammatory condition in a subject, comprising, consisting or consisting essentially of administering a compound of the invention to the subject.

[0027] In some embodiments, the inflammatory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), dermatitis, nasal polyposis, esophagitis, vasculitis, rhinosinusitis, pruritis, rhinitis, sinusitis, urticaria, inflammatory bowel disease, multiple sclerosis, fibrosis, hypersensitivity pneumonitis, arthritis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity, bronchial hypertrophy and psoriasis; especially asthma, COPD, ARDS, dermatitis, rhinitis or sinusitis. In particular embodiments, the inflammatory condition is asthma. In alternative embodiments, the inflammatory condition is COPD. In specific embodiments, the inflammatory condition is ARDS.

[0028] In exemplary embodiments, the inflammatory condition is a chronic inflammatory condition.

[0029] In a further aspect, there is provided a method of treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, comprising, consisting or consisting essentially of administering a compound of the invention to the subject.

[0030] In some embodiments, the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33.

[0031] While the use of any route of administration is contemplated, in some embodiments, the compound is administered by oral, inhalation, intranasal, topical or intravenous administration.

[0032] In another aspect, there is provided a method of antagonizing a cytokine, comprising, consisting or consisting essentially of contacting the cytokine with a compound of the invention.

[0033] In some embodiments, the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33.

[0034] In yet another aspect, there is provided a use of a compound of the invention in the manufacture of a medicament for treating or inhibiting the development of an inflammatory condition in a subject.

[0035] Also encompassed herein is the use of a compound of the invention in the manufacture of a medicament for treating or inhibiting the development of a condition associated with the activity of a cytokine in a subject.

[0036] The invention further provides, in another aspect, a compound of the invention for use in treating or inhibiting the development of an inflammatory condition in a subject.

[0037] In yet another aspect, there is provided a compound of the invention for use in treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is a series of graphs showing the effect of G16, G19, G20, G21, G22, G23 and G24 on IL-5 dependent cell proliferation. Figure 1A shows the effect of the compounds at a concentration of 10 pg / mL, and Figure IB shows a dose-response curve for the compounds.

[0039] Figure 2 is a series of graphs showing the effect of G16, G19, G20, G21, G22, G23 and G24 on IL-13 dependent cell proliferation. Figure 2A shows the effect of the compounds at a concentration of 10 pg / mL, and Figure 2B shows a dose-response curve for the compounds.

[0040] Figure 3 is a series of graphs showing the effect of G16, G19, G20, G21, G22, G23 and G24 on IL-4 dependent cell proliferation. Figure 3A shows the effect of the compounds at a concentration of 10 pg / mL, and Figure 3B shows a dose-response curve for the compounds.

[0041] Figure 4 is a series of graphs showing the effect of G16, G19, G20, G21, G22, G23 and G24 on IL-33 dependent cell proliferation. Figure 4A shows the effect of the compounds at a concentration of 10 pg / mL, and Figure 4B shows a dose-response curve for the compounds.

[0042] Figure 5 is a graph showing the effect of G16, G19, G20, G21, G22, G23 and G24 (50 pg / mL) on IL-8 dependent chemotaxis.

[0043] Figure 6 is a graph showing the effect of G16, G19, G20, G21, G22, G23 and G24 (10 pg / mL) on IL-2 dependent cell proliferation.

[0044] Figure 7 is a graph showing the effect of G16, G19, G20, G21, G22, G23 and G24 (10 pg / mL) on granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent cell proliferation.

[0045] Figure 8 is a graph showing the percentage weight change over time during the sensitization period following the first sensitization (1stsens) in the guinea pig ovalbumin model of allergic asthma (OVA sens) compared to a naive guinea pig.

[0046] Figure 9 is a series of graphs showing the airway inflammation in a mouse model of experimental allergic asthma in the presence of G24 (HDM / HDM / Gly- 121) compared to low molecular weight heparin (HDM / HDM / LMWH), the baseline control (SAL / SAL) and positive control (HDM / HDM / PBS). Figure 9A presents the leukocyte infiltration into bronchoalveolar lavage fluid (BAL), Figure 9B presents the macrophage infiltration into BAL, Figure 9C presents the eosinophil infiltration into BAL, Figure 9D presents the neutrophil infiltration into BAL and Figure 9E presents the lymphocyte infiltration into BAL.

[0047] Figure 10 is a series of graphs showing the airway hyperresponsiveness in a mouse model of experimental allergic asthma in the presence of G24 (HDM / HDM / Gly-121) compared to low molecular weight heparin (HDM / HDM / LMWH), the baseline control (SAL / SAL) and positive control (HDM / HDM / PBS). Figure 10A presents the change in airway resistance (Rn) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL), and Figure 10B presents the change in airway resistance following challenge with 10 mg / mL methacholine (Meh).

[0048] Figure 11 is a series of graphs showing the change in lung function parameters in a mouse model of experimental allergic asthma in the presence of G24 (HDM / HDM / Gly-121), compared to low molecular weight heparin (HDM / HDM / LMWH), the baseline control (SAL / SAL) and positive control (HDM / HDM / PBS). Figure 11A presents the percentage change in tissue damping (G) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL), Figure 11B presents the percentage change in tissue elastance (H) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL), Figure 11C presents the percentage change in respiratory system compliance (Crs) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL), Figure 11D presents the elastance of the respiratory system (Ers) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL) and Figure HE presents the respiratory system resistance (Rrs) following challenge with increasing amounts of methacholine (1.25 mg / mL to 10 mg / mL).

[0049] Figure 12 is a graph (Figure 12A) and series of histology images (Figure 12B) showing the collagen deposition and fibrosis in the small airways in a mouse model of experimental allergic asthma in the presence of G24 (HDM / HDM / Gly-121), compared to low molecular weight heparin (HDM / HDM / LMWH), the baseline control (SAL / SAL) and positive control (HDM / HDM / PBS). These sections were stained with Sirius Red andcounterstained with Fast Green. The Sirius Red stains collagen pink-red and the other proteins are stained green by the Fast Green reagent. Small airway epithelial cells are shown surrounding a central lumen. The basement membrane under the epithelial cells is indicated by collagen staining, but there is also clear evidence of collagen deposition in the surrounding tissues in the positive control (HDM / HDM / PBS), as well as some staining in the parenchyma of HDM / HDM / LMWH control. G24 (HDM / HDM / Gly-121) resembles the baseline control.

[0050] Figure 13 is a graph (Figure 13A) and series of histology images (Figure 13B) showing the number of mucus secreting cells (MSCs) in the small airways in a mouse model of experimental allergic asthma in the presence of G24 (HDM / HDM / Gly- 121), compared to low molecular weight heparin (HDM / HDM / LMWH), the baseline control (SAL / SAL) and positive control (HDM / HDM / PBS). The goblet cells within the airway epithelia are stained dark purple with PAS (Periodic Acid Schiff) stain to reveal the presence of mucopolysaccharides and glycoproteins within these cells.DETAILED DESCRIPTION OF THE INVENTION1. Definitions

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0052] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0053] By "about" is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0054] As used herein, the term "acute respiratory distress syndrome" or "ARDS" refers to a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the blood. ARDS is also referred to as noncardiogenic pulmonary edema, increased-permeability pulmonary edema, stiff lung, shock lung, or acute lung injury. ARDS can be caused by any major injury to the lung. Some common causes include, without limitation: breathing vomit into the lungs (aspiration), inhalingchemicals, lung transplant, pneumonia, septic shock (infection throughout the body) and trauma.

[0055] The terms "administration concurrently" or "administering concurrently" or "co-administering" and the like refer to the administration of a single composition containing two or more agents, or the administration of each agent as separate compositions and / or delivered by separate routes either contemporaneously or simultaneously or sequentially within a short enough period of time that the effective result is equivalent to that obtained when all such agents are administered as a single composition. By "simultaneously" is meant that the agents are administered at substantially the same time, and desirably together in the same composition. By "contemporaneously" it is meant that the agents are administered closely in time, e.g., one agent is administered within from about one minute to within about one day before or after another. Any contemporaneous time is useful. However, it will often be the case that when not administered simultaneously, the agents will be administered within about one minute to within about eight hours and suitably within less than about one to about four hours. When administered contemporaneously, the agents are suitably administered at the same site on the subject. The term "same site" includes the exact location, but can be within about 0.5 to about 15 centimeters, preferably from within about 0.5 to about 5 centimeters. The term "separately" as used herein means that the agents are administered at an interval, for example at an interval of about a day to several weeks or months. The agents may be administered in either order. The term "sequentially" as used herein means that the agents are administered in sequence, for example at an interval or intervals of minutes, hours, days or weeks. If appropriate the agents may be administered in a regular repeating cycle.

[0056] The term "agent" includes a compound that induces a desired pharmacological and / or physiological effect. The term also encompasses pharmaceutically acceptable and pharmacologically active ingredients of those compounds specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the above term is used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs, etc. The term "agent" is not to be construed narrowly but extends to small molecules, proteinaceous molecules such as peptides, polypeptides and proteins as well as compositions comprising them and genetic molecules such as RNA, DNA and mimetics and chemical analogs thereof as well as cellular agents.

[0057] The term "alkyl" refers to a straight or branched aliphatic hydrocarbon group, including a C1-C12alkyl, C2-C12alkyl, C6-C10alkyl, C7-C9alkyl and C8alkyl (octyl)unless otherwise noted. In particular embodiments, the alkyl is a straight aliphatic hydrocarbon group, such as methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, and the like.

[0058] As used herein, the term "alkylene" refers to divalent alkyl groups having from 1 to 8 carbon atoms, including from 2 to 8 carbon atoms, from 3 to 6 carbon atoms, from 1 to 5 carbon atoms, from 1 to 3 carbon atoms, from 2 to 5 carbon atoms, and from 2 to 4 carbon atoms. Examples of such alkylene groups include methylene (- CH2-), ethylene (-CH2CH2-), propylene, including n-propylene (-CH2CH2CH2-), butylene, including n-butylene (-CH2CH2CH2CH2-), and the like.

[0059] The term "alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched (preferably straight), including a C2-C12alkenyl, C6-C10alkenyl, C7-C9alkenyl and C8alkenyl unless otherwise noted. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.

[0060] As used herein, the term "alkenylene" refers to divalent alkenyl groups having from 2 to 8 carbon atoms, including from 3 to 6 carbon atoms, from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, and from 2 to 3 carbon atoms.

[0061] "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond (e.g. one carbon-carbon triple bond) and which may be straight or branched, preferably straight, including C2-C12alkynyl, C6-C10alkynyl, C7-C9alkynyl and C8alkynyl unless otherwise noted.

[0062] The term "alkynylene" refers to divalent alkynyl groups having from 2 to 8 carbon atoms, including from 3 to 6 carbon atoms, from 2 to 5 carbon atoms, from 2 to 4 carbon atoms, and from 2 to 3 carbon atoms.

[0063] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0064] The term "antagonist" and grammatical equivalents thereof (e.g. antagonize) as used herein refer to a molecule that partially or completely inhibits, by any mechanism, an effect of another molecule such as a receptor or intracellular mediator. In the context of the present invention, the term "antagonist" refers to a compound that partially or completely inhibits an activity of a cytokine, such as IL-4, IL- 5, IL-8, IL-13 and / or IL-33. In specific embodiments, the antagonist is a directantagonist that binds to or otherwise interacts with a cytokine (e.g. IL-4, IL-5, IL-8, IL- 13 or IL-33).

[0065] The term "associated with" when used in relation to conditions associated with an activity of a cytokine means that the activity of a cytokine contributes, either directly or indirectly, to the pathogenesis or progression of the condition, including of one or more symptoms of the condition. The cytokine activity may, for example, directly lead to the pathogenesis (i.e. development) of the condition or the development of one or more symptoms of the condition. Alternatively or in addition, the cytokine activity may result in the progression (i.e. worsening) of the condition or one or more symptoms of the condition.

[0066] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Thus, the use of the term "comprising" and the like indicates that the listed integers are required or mandatory, but that other integers are optional and may or may not be present. By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0067] As used herein, the term "dosage unit form" refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.

[0068] By "effective amount", in the context of treating or preventing a condition is meant the administration of an amount of an agent or composition to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and / or treating existing symptoms, of that condition. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.Non-limiting symptoms of inflammatory conditions include, but are not limited to, pain, redness, swelling and / or loss of tissue function.

[0069] As used herein, the phrase "inhibit the development of" refers to a prophylactic treatment which increases the resistance of a subject to developing the disease or condition or, in other words, decreases the likelihood that the subject will develop the disease or condition as well as a treatment after the disease or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse. This phrase also includes within its scope preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it.

[0070] The term "inhibitor" as used herein refers to an agent that decreases or inhibits at least one function or biological activity of a target molecule, such as a cytokine (e.g. IL-4, IL-5, IL-8, IL-13 and / or IL-33). A function or activity of a cytokine may include, for example, immune cell proliferation, differentiation, recruitment, activation and / or maturation (e.g. B cells, T cells, basophils, eosinophils, neutrophils, macrophages, leukocytes and the like), interaction with a receptor (e.g. binding to a receptor), activation of a receptor or triggering secretion or production of a further cytokine (e.g. IL-5, IL-9, IL-13 and / or GM-CSF).

[0071] The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted with one or more non- hydrogen substituent groups. In certain embodiments, the substituent groups are one or more groups independently selected from the group consisting of halogen, C1-C6alkyl (e.g. methyl or ethyl), C2-C6alkenyl and C2-C6alkynyl, especially halogen and C1-C6alkyl. In some embodiments, the optional substituent groups are one or more groups independently selected from the group consisting of methyl, ethyl and halogen, especially methyl. In exemplary embodiments, each optionally substituted group (e.g. alkylene, alkenylene, alkynylene, alkyl, alkenyl or alkynyl) may be substituted with 1-3 substituents, including 1, 2 or 3 substituents, such as 1, 2 or 3 methyl groups.

[0072] The terms "patient", "subject", "host" or "individual" used interchangeably herein, refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy or prophylaxis is desired. Suitable vertebrate animals that fall within the scope of the present disclosure include, but are not restricted to, any member of the subphylum Chordata including primates (e.g. humans, monkeys and apes, and includes species of monkeys such as from the genus Macaca (e.g. cynomolgus monkeys such as Macaca fascicularis, and / or rhesus monkeys (Macaca mulatta)) and baboon (Papio ursinus), as well as marmosets (species from the genus Callithrix), squirrel monkeys (species from the genus Saimiri) andtamarins (species from the genus Saguinus), as well as species of apes such as chimpanzees (Pan troglodytes'), rodents (e.g. mice rats, guinea pigs), lagomorphs (e.g. rabbits, hares), bovines (e.g. cattle), ovines (e.g. sheep), caprines (e.g. goats), porcines (e.g. pigs), equines (e.g. horses), canines (e.g. dogs), felines (e.g. cats), avians (e.g. chickens, turkeys, ducks, geese, companion birds such as canaries, budgerigars etc.), marine mammals (e.g. dolphins, whales), reptiles (e.g. snakes, frogs, lizards etc.), and fish. In specific embodiments, the subject is a primate such as a human in need of treating or inhibiting the development of a viral infection. However, it will be understood that the terms "patient," "subject," "host" or "individual" do not imply that symptoms are present.

[0073] By "pharmaceutically acceptable carrier" is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, fillers, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives and the like.

[0074] Similarly, a "pharmaceutically acceptable" salt, solvate, ester or prodrug of a compound as provided herein is a salt, solvate, ester or prodrug that is not biologically or otherwise undesirable.

[0075] The terms "reduce", "inhibit", "decrease", "prevent", and grammatical equivalents when used in reference to the level of a substance and / or phenomenon in a first sample relative to a second sample, mean that the quantity of substance and / or phenomenon in the first sample is lower than in the second sample by any amount that is statistically significant using any art-accepted statistical method of analysis. When these terms are used to refer to the action of a compound or agent, the first sample may be a sample in the presence of the compound or agent and the second sample may be a comparative sample without the compound or agent. In one embodiment, the reduction may be determined subjectively, for example when a patient refers to their subjective perception of disease symptoms, such as coughing, wheezing, chest tightness, shortness of breath, pain, headache, fatigue, motor symptoms, etc. In another embodiment, the reduction may be determined objectively, for example when the lung function of a patient is greater than the function at an earlier time point in the patent or the sputum eosinophil count (or another biomarker) in a sample from a patient is lower than in an earlier sample from the patient. In another embodiment, the quantity of substance and / or phenomenon in the first sample is at least 10% lower than the quantity of the same substance and / or phenomenon in a second sample. In another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 25% lowerthan the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 50% lower than the quantity of the same substance and / or phenomenon in a second sample. In a further embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 75% lower than the quantity of the same substance and / or phenomenon in a second sample. In yet another embodiment, the quantity of the substance and / or phenomenon in the first sample is at least 90% lower than the quantity of the same substance and / or phenomenon in a second sample.

[0076] As used herein, the terms "salts" and "prodrugs" include any pharmaceutically acceptable salt, ester, hydrate or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof. The term "pharmaceutically acceptable salts" refers without limitation to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g. by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate and valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent,or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In particular embodiments, the salt is the sodium salt. Lists of suitable salts are found in, for example, Remington: The Science and Practice of Pharmacy, Loyd V. Allen, Jr (Ed), The Pharmaceutical Press, London, 22ndEdition, September 2012; Stahl and Wermuth (2002) Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; and Berge et al. (1977) Journal of Pharmaceutical Science, 66: 1-19, each of which is incorporated herein by reference in its entirety.

[0077] As used herein, the terms "treatment", "treating", and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be therapeutic in terms of a partial or complete cure for a disease or condition (e.g. a viral infection) and / or adverse effect attributable to the disease or condition. These terms also cover any treatment of a condition or disease in a subject, particularly in a human, and include: (a) inhibiting the disease or condition, i.e. arresting its development; or (b) relieving the disease or condition, i.e. causing regression of the disease or condition.

[0078] Each embodiment described herein is to be applied mutatis mutandis to each and every embodiment unless specifically stated otherwise.2. Compounds

[0079] The present invention is predicated in part on the discovery of particular compounds that interact with and inhibit an activity of a cytokine, including IL-4, IL-5, IL-8, IL-13 and / or IL-33. Accordingly, the Inventors have conceived that such compounds will be useful for treating and inhibiting the development of an inflammatory condition and / or a condition associated with an activity of a cytokine, such as asthma.

[0080] Accordingly, one aspect of the invention provides a compound of Formula I, II, III, IV, V or VI:or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L1L3L4L6L7L8L9L10L11L12L13L15L16L17L18L19L20L21L22L23L24L25L26L28, L29, L30, L31and L32are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L2, L5, L14and L27are independently selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18are independently selected from CH and N ; andR1is selected from optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl and optionally substituted C2-C12alkynyl.

[0081] Suitable optional substituents include, but are not limited to, methyl, ethyl and halogen. In particular embodiments, each optionally substituted alkylene, alkenylene, alkynylene, alkyl, alkenyl or alkynyl group may be substituted with 1-3 substituents, especially 1-3 methyl groups. In some embodiments, the alkylene, alkenylene, alkynylene, alkyl, alkenyl and alkynyl groups are unsubstituted.

[0082] In particular embodiments, X1-X18are CH. For the avoidance of any doubt, when X1-X18are CH, the carbon atom is a member of the ring (i.e. the ring is a triazole).

[0083] In some embodiments, L1is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0084] In some embodiments, L2is selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene; especially optionally substituted C2-C5alkylene; more especially C2-C5alkylene; most especially propylene (e.g. n-propylene).

[0085] In some embodiments, L3is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0086] In particular embodiments, L4is selected from optionally substituted C1- C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0087] In some embodiments, L5is selected from optionally substituted C3-C6alkylene, optionally substituted C3-C6alkenylene and optionally substituted C6-C6alkynylene; especially optionally substituted C3-C6alkylene; more especially C3-C6alkylene; most especially butylene (e.g. n-butylene).

[0088] In particular embodiments, L6is selected from optionally substituted C1- C3 alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0089] In specific embodiments, L7is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0090] In some embodiments, L8is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0091] In some embodiments, L9is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0092] In particular embodiments, L10is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0093] In some embodiments, L11is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0094] In some embodiments, L12is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0095] In some embodiments, L13is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0096] In some embodiments, L14is selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene; especially optionally substituted C2-C4alkylene; more especially C2-C4alkylene; most especially ethylene.

[0097] In some embodiments, L15is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0098] In some embodiments, L16is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0099] In some embodiments, L17is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0100] In some embodiments, L18is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0101] In some embodiments, L19is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0102] In some embodiments, L20is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0103] In some embodiments, L21is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0104] In some embodiments, L22is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0105] In some embodiments, L23is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0106] In some embodiments, L24is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0107] In some embodiments, L25is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0108] In some embodiments, L26is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0109] In some embodiments, L27is selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene; especially optionally substituted C2-C4alkylene; more especially C2-C4alkylene; most especially ethylene.

[0110] In some embodiments, L28is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0111] In some embodiments, L29is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0112] In some embodiments, L30is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0113] In some embodiments, L31is selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene; especially optionally substituted C2-C5alkylene; more especially C2-C5alkylene; most especially propylene (e.g. n-propylene).

[0114] In some embodiments, L32is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; especially optionally substituted C1-C3alkylene; more especially C1-C3alkylene; most especially methylene.

[0115] In some embodiments, R1is selected from optionally substituted C6-C10alkyl, optionally substituted C6-C10alkenyl and optionally substituted C6-C10alkynyl; especially optionally substituted C6-C10alkyl; more especially C6-C10alkyl. In particular embodiments, R1is selected from optionally substituted C7-C9alkyl, optionally substituted C7-C9alkenyl and optionally substituted C7-C9alkynyl; especially optionally substituted C7-C9alkyl; more especially C7-C9alkyl; most especially octyl.

[0116] In some embodiments, R1is selected from optionally substituted C1-C10 alkyl, optionally substituted C2-C10alkenyl and optionally substituted C2-C10alkynyl; especially optionally substituted C1-C10alkyl; more especially C1-C8alkyl. In particular embodiments, R1is selected from C1-C8alkyl, C2-C8alkenyl and C2-C8alkynyl; especially optionally C1-C8alkyl; more especially methyl or octyl; most especially octyl.

[0117] In specific embodiments, the compound is a compound of Formula I:or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L1and L3are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L2is selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; andX1and X2are independently selected from CH and N.

[0118] Suitable embodiments of each of L1, L2, L3, X1and X2are discussed supra.

[0119] In particular embodiments:L1is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L2is selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L3is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; andX1and X2are independently selected from CH and N.

[0120] In further embodiments:L1is optionally substituted C1-C3alkylene;L2is optionally substituted C2-C5alkylene;L3is optionally substituted C1-C3alkylene; andX1and X2are independently selected from CH and N.

[0121] In particular embodiments:L1is methylene;L2is propylene (e.g. n-propylene);L3is methylene; andX1and X2are CH.

[0122] In specific embodiments, the compound of Formula I is a compound of Formula VII:(VII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0123] In specific embodiments the compound is a compound of Formula II:(II) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L4, L6, L7and L8are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L5is selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene;X3, X4and X5are independently selected from CH and N; andR1is selected from optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl and optionally substituted C2-C12alkynyl.

[0124] Suitable embodiments of each of L4, L5, L6, L7, L8, X3, X4, X5and R1are discussed supra.

[0125] In particular embodiments:L4is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L5is selected from optionally substituted C3-C6alkylene, optionally substituted C3-C6alkenylene and optionally substituted C6-C6alkynylene;L6is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L7is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L8is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;X3, X4and X5are independently selected from CH and N; andR1is selected from optionally substituted C1-C10 alkyl, optionally substituted C2-C10alkenyl and optionally substituted C2-C10alkynyl.

[0126] In particular embodiments:L4is optionally substituted C1-C3alkylene;L5is optionally substituted C3-C6alkylene;L6is optionally substituted C1-C3alkylene;L7is optionally substituted C1-C3alkylene;L8is optionally substituted C1-C3alkylene;X3, X4and X5are independently selected from CH and N; andR1is optionally substituted C1-C8alkyl.

[0127] In particular embodiments:L4is methylene;L5is butylene (e.g. n-butylene);L6is methylene;L7is methylene;L8is methylene;X3, X4and X5are CH; andR1is C1-C8alkyl, especially octyl or methyl.

[0128] In particular embodiments, the compound of Formula II is a compound of Formula VIII:(VIII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0129] In some embodiments, the compound is a compound of Formula IX:(IX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0130] In alternative embodiments, the compound is a compound of FormulaIII:(III) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L9, L10, L11, L12, L13, L15, L16, L17, L18and L19are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L14is selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; and X6, X7, X8, X9, X10and X11are independently selected from CH and N.

[0131] Suitable embodiments of each of L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, X6, X7, X8, X9, X10and X11are discussed supra.

[0132] In particular embodiments:L9is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L10is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L11is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L12is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L13is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L14is selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene;L15is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; L16is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L17is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L18is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L19is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; andX6, X7, Xs, X9, X10and X11are independently selected from CH and N.

[0133] In specific embodiments:L9is optionally substituted C1-C3alkylene;L10is optionally substituted C1-C3alkylene;L11is optionally substituted C1-C3alkylene;L12is optionally substituted C1-C3alkylene;L13is optionally substituted C1-C3alkylene;L14is optionally substituted C2-C4alkylene;L15is optionally substituted C1-C3alkylene; L16is optionally substituted C1-C3alkylene;L17is optionally substituted C1-C3alkylene;L18is optionally substituted C1-C3alkylene;L19is optionally substituted C1-C3alkylene; and X6, X7, X8, X9, X10and X11are independently selected from CH and N.

[0134] In some embodiments:L9is methylene;L10is methylene;L11is methylene;L12is methylene;L13is methylene;L14is ethylene;L15is methylene; L16is methylene;L17is methylene;L18is methylene;L19is methylene; and X6, X7, X8, X9, X10and X11are CH.

[0135] In some embodiments, the compound of Formula III is a compound ofFormula X:(X) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0136] In alternative embodiments, the compound is a compound of FormulaIV:(IV) wherein:L20, L21, L22and L23are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene; andX12and X13are independently selected from CH and N.

[0137] Suitable embodiments of each of L20, L21, L22, L23, X12and X13are discussed supra.

[0138] In particular embodiments:L20is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L21is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L22is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L23is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; andX12and X13are independently selected from CH and N.

[0139] In specific embodiments:L20is optionally substituted C1-C3alkylene;L21is optionally substituted C1-C3alkylene;L22is optionally substituted C1-C3alkylene;L23is optionally substituted C1-C3alkylene; andX12and X13are independently selected from CH and N.

[0140] In some embodiments:L20is methylene;L21is methylene;L22is methylene;L23is methylene; andX12and X13are CH.

[0141] In some embodiments, the compound is a compound of Formula XI:(XI) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0142] In alternative embodiments, the compound is a compound of Formula V:or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein:L24, L25, L26, L28, L29and L30are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L27is optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene or optionally substituted C2-C8alkynylene; andX14, X15, X16and X17are independently selected from CH and N .

[0143] Suitable embodiments of each of L24, L25, L26, L27, L28, L29, L30, X14, X15, X16and X17are discussed supra.

[0144] In particular embodiments:L24is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L25is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L26is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L27is selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene;L28is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L29is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene;L30is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; andX14, X15, X16and X17are independently selected from CH and N .

[0145] In specific embodiments:L24is optionally substituted C1-C3alkylene;L25is optionally substituted C1-C3alkylene;L26is optionally substituted C1-C3alkylene;L27is optionally substituted C2-C4alkylene;L28is optionally substituted C1-C3alkylene;L29is optionally substituted C1-C3alkylene;L30is optionally substituted C1-C3alkylene; andX14, X15, X16and X17are independently selected from CH and N .

[0146] In some embodiments:L24is methylene;L25is methylene;L26is methylene;L27is ethylene;L28is methylene;L29is methylene;L30is methylene; andX14, X15, X16and X17are CH.

[0147] In some embodiments, the compound is a compound of Formula XII:(XII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0148] In alternative embodiments, the compound is a compound of FormulaVI:(VI) or a or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L31and L32are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene; andX18is selected from CH and N.

[0149] Suitable embodiments of each of L31, L32and X18are discussed supra.

[0150] In particular embodiments:L31is selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L32is selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene; andX18is CH or N.

[0151] In specific embodiments:L31is optionally substituted C2-C5alkylene;L32is optionally substituted C1-C3alkylene; andX18is CH or N.

[0152] In some embodiments:L31is propylene (e.g. n-propylene);L32is methylene; andX18is CH.

[0153] In some embodiments, the compound is a compound of Formula XIII:(XIII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0154] In particular embodiments, the invention provides a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII, or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0155] Provided herein is a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the inventionprovides a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0156] Further provided herein is a compound of Formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0157] In another aspect, there is provided a compound of Formula III or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0158] As discussed above, the invention provides a compound of Formula IV or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula IV or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0159] Further provided herein is a compound of Formula V or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula V or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0160] In another aspect, there is provided a compound of Formula VI or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula VI or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0161] Further provided herein is a compound of Formula VII or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula VII or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0162] Also provided herein is a compound of Formula VIII or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula VIII or a pharmaceutically acceptable saltthereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0163] In another aspect, there is provided a compound of Formula IX or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula IX or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0164] Further provided herein, in another aspect is a compound of Formula X or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula X or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0165] Also provided herein is a compound of Formula XI or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula XI or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0166] Further provided herein, in another aspect, is a compound of Formula XII or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula XII or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0167] In a further aspect, there is provided a compound of Formula XIII or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the invention provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof. In some embodiments, the salt is the potassium, lithium or sodium salt, especially the sodium salt.

[0168] In some embodiments, the compound of the invention is G16, G19, G20, G21, G22, G23 or G24.

[0169] The compounds of the invention may also be in the form of pharmaceutically acceptable salts, solvates or prodrugs. In some embodiments, the compounds may be in the form of hydrates.

[0170] While any suitable salt is contemplated, in some embodiments, compounds of the invention are in the form of a pharmaceutically acceptable salt. In particular embodiments, the salt is the potassium, lithium or sodium salt, especially thesodium salt. A skilled person will be well aware of methods for preparing suitable salts of the compounds of the invention.

[0171] In some embodiments, the prodrug is an ester, such as O-neopentyl ester (e.g. as described in Gordon et al. (2018) J Med Chem, 61: 10340-10344, the entire content of which is incorporated herein by reference).

[0172] The compounds may be prepared using techniques known in the art, such as the methods disclosed in WO 2018 / 068090 Al, the entire contents of which are incorporated herein by reference.3. Compositions

[0173] While it is possible that the compounds of the invention may be administered in an undiluted form, it is preferable to present such compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds may be in the form of a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of the invention and a pharmaceutically acceptable carrier or diluent.

[0174] The compound may be formulated into the pharmaceutical composition as a neutral or salt form, especially as a sodium salt.

[0175] As will be appreciated by those skilled in the art, the choice of pharmaceutically acceptable carrier or diluent will be dependent on the route of administration and on the nature of the condition and subject to be treated. The particular carrier or delivery system and route of administration may be readily determined by a person skilled in the art. The carrier or delivery system and route of administration should be carefully selected to ensure that the activity of the compound is not depleted during preparation of the formulation and the compound is able to reach the site of action intact. The pharmaceutical compositions of the invention may be administered through a variety of routes including, but not limited to, oral, rectal, topical, intranasal, inhalation, intraocular, transmucosal, intestinal, enteral, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intracerebral, intravaginal, intravesical, intravenous or intraperitoneal administration. In particular embodiments, the pharmaceutical composition is administered via oral, inhalation, intranasal, topical or intravenous administration; especially oral, inhalation or intranasal administration.

[0176] The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for the preparation of sterile injectable solutions. Such forms should be stable under the conditions of manufacture and storage and may be preserved against reduction, oxidation and microbial contamination.

[0177] A person skilled in the art will readily be able to determine appropriate formulations for the compounds using conventional approaches. Techniques for formulation and administration may be found in, for example, Remington: The Science and Practice of Pharmacy, Loyd V. Allen, Jr (Ed), The Pharmaceutical Press, London, 22ndEdition, September 2012.

[0178] Identification of preferred pH ranges and suitable excipients, such as antioxidants, is routine in the art, for example, as described in Katdare and Chaubel (2006) Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems (CRC Press). Buffer systems are routinely used to provide pH values of a desired range and may include, but are not limited to, carboxylic acid buffers, such as acetate, citrate, lactate, tartrate and succinate; glycine; histidine; phosphate; tris(hydroxymethyl)aminomethane (Tris); arginine; sodium hydroxide; glutamate; and carbonate buffers. Suitable antioxidants may include, but are not limited to, phenolic compounds such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole; vitamin E; ascorbic acid; reducing agents such as methionine or sulphite; metal chelators such as ethylene diamine tetraacetic acid (EDTA); cysteine hydrochloride; sodium bisulfite; sodium metabisulfite; sodium sulfite; ascorbyl palmitate; lecithin; propyl gallate; and alpha-tocopherol.

[0179] For injection, the compound may be formulated in an aqueous solution, suitably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, dextrose solution or physiological saline buffer, such as phosphate buffered saline (PBS). For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0180] The compositions of the present invention may be formulated for administration in the form of liquids, containing acceptable diluents (such as saline and sterile water), or may be in the form of lotions, creams or gels containing acceptable diluents or carriers to impart the desired texture, consistency, viscosity and appearance. Acceptable diluents and carriers are familiar to those skilled in the art and include, but are not restricted to, ethoxylated and nonethoxylated surfactants, fatty alcohols, fatty acids, hydrocarbon oils (such as palm oil, coconut oil, and mineral oil), cocoa butter waxes, silicon oils, pH balancers, cellulose derivatives, emulsifying agents such as non- ionic organic and inorganic bases, preserving agents, wax esters, steroid alcohols, triglyceride esters, phospholipids such as lecithin and cephalin, polyhydric alcohol esters, fatty alcohol esters, hydrophilic lanolin derivatives and hydrophilic beeswax derivatives.

[0181] Alternatively, the compound can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration, which is also contemplated for the practice of the invention. Such carriersenable the compounds of the invention to be formulated in dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. These carriers may be selected from sugars, chitosan, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water.

[0182] Pharmaceutical formulations for parenteral administration include aqueous solutions of the composition in water-soluble form. Additionally, suspensions of the compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0183] Sterile solutions may be prepared by combining the compound in the required amount in the appropriate solvent with other excipients as described above as required, followed by sterilization, such as filtration. Generally, dispersions are prepared by incorporating the various sterilized active compounds into a sterile vehicle which contains the basic dispersion medium and the required excipients as described above. Sterile dry powders may be prepared by vacuum- or freeze-drying a sterile solution comprising the active compounds and other required excipients as described above.

[0184] Pharmaceutical preparations for oral use can be obtained by combining the compounds with solid excipients and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatine, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0185] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of particle doses.

[0186] Pharmaceuticals which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0187] The compounds may be incorporated into modified-release preparations and formulations, for example, polymeric microsphere formulations, and oil- or gel-based formulations.

[0188] The compounds may be administered in a local rather than systemic manner, such as by injection directly into a tissue, which is preferably subcutaneous or omental tissue, often in a depot or sustained release formulation. In other embodiments, the compound is systemically administered.

[0189] Furthermore, the compound may be administered in a targeted drug delivery system, such as in a particle which is suitable targeted to and taken up selectively by a cell or tissue. In some embodiments, the compound is contained or otherwise associated with a vehicle selected from liposomes, micelles, dendrimers, biodegradable particles, artificial DNA nanostructure, lipid-based nanoparticles and carbon or old nanoparticles. In illustrative examples of this type, the vehicle is selected from poly(lactic acid) (PLA), poly(g lycol ic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), PLA-PEG copolymers and combinations thereof.

[0190] In cases of local administration or selective uptake, the effective local concentration of the agent may not be related to plasma concentration.

[0191] In some embodiments, the compositions are suitable for inhalation or intranasal delivery and are in the form of, for example, solutions, aerosols, dry powders, suspensions or emulsions. For example, the composition may be administered to the respiratory tract as a nasal or pulmonary inhalation aerosol or solution for a nebulizer, or as a microfine powder (e.g. with particles in the order of about 1 to about 10 μm in diameter or less) for insufflation, alone or in combination with an inert carrier, such aslactose, glucose or mannitol, or with other pharmaceutically acceptable excipients, such as beta-cyclodextrin, starch, sodium carboxymethylcellulose and the like. The composition may be administered by, for example, a dry powder inhaler, a soft mist inhaler, a nebulizer or a metered dose inhaler.

[0192] Aerosol formulations include those in which the compound is provided in a pressurised pack with a suitable propellant such as a metered dose inhaler. Whilst the propellant may be a chlorofluorocarbon (CFC) (such as dichlorodifluoromethane, trichlorofluoromethane or 1,2-dichlorotetrafluoroethane), the propellant is more preferably a non-chlorofluorocarbon propellant such as an inert gas (e.g. carbon dioxide, nitrogen or nitrogen dioxide), a hydrofluoroalkane [e.g. 1,1,1,2-tetrafluoroethane (HFA- 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227), 1,1-difluoroethane (HFC-152a) or 1,1,1,2,3,3,3-heptafluoroethane (HFA-227ea)], hydrochlorofluorocarbon, hydrofluoroolefin [e.g. 1,3,3,3-tetrafluoroprop-l-ene (HFO-1234ze) or 2, 3,3,3- tetrafluoroprop-l-ene (HFO-1234yf)] or compressed gas (e.g. compressed air). The aerosol may conveniently also contain a surfactant such as lecithin. The dose of the compound may be controlled by provision of a metered valve. It has been found that a particle size of approximately 1 to 5 μm is useful for delivery to the lung, as particles smaller than 1 μm are generally exhaled without delivery to the lung, and particles larger than 10 μm are mostly trapped by oropharyngeal deposition and do not reach the lung. Devices propelled by HFA-134a deliver smaller droplets which penetrate more readily into the bronchial airways. For drug delivery via the nasal passage, a suitable particle size is, for example, 20-80 μm, as smaller particles (less than 10 μm) get carried into the tracheobrachial region, whilst bigger particles (greater than 100 μm) get rapidly cleared from the nasal passageway.

[0193] The compound may also be provided in a pharmaceutical formulation which forms a gel in the nasal cavity. The compound may also be formulated in a powder composition which may be presented in unit dose form for example in capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0194] It is advantageous to formulate the compositions in dosage unit form for ease of administration and uniformity of dosage. The determination of the novel dosage unit forms of the present invention is dictated by and directly dependent on the unique characteristics of the active material, the particular therapeutic effect to be achieved and the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

[0195] While the compound of the invention may be the sole active agent administered to the subject, the administration of other active agents concurrently with said compound is within the scope of the invention. For example, in some embodiments, the compound may be administered concurrently with one or more anti-inflammatory agents, anti-asthmatics, bronchodilators or cytokine inhibitors. The compound may be therapeutically used after the other active agent or may be therapeutically used together with the other active agent. The compound may be administered separately, simultaneously or sequentially with the other active agent.

[0196] Accordingly, in another aspect of the invention, there is provided a composition comprising a compound of the invention (such as a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII) and an anti-inflammatory agent, anti- asthmatic agent, bronchodilator or a cytokine inhibitor.

[0197] In some embodiments, the ancillary active agent is an anti-inflammatory agent, representative examples of which include steroidal anti-inflammatory agents such as but not limited to compounds containing a 17-carbon 4-ring system, including sterols, various hormones (as anabolic steroids), and glycosides. Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, fluticasone (e.g. fluticasone propionate or fluticasone furoate), budesonide, ciclesonide, mometasone, and mixtures thereof.

[0198] Alternatively, the anti-inflammatory agent may be a nonsteroidal anti- inflammatory agent, non-limiting examples of which include agents that are aspirin-like in their action, including, but not limited to, ibuprofen (ADVIL), naproxen sodium (ALEVE), and acetaminophen (TYLENOL). Additional examples of non-steroidal anti-inflammatory agents include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisa I, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Mixtures of these non- steroidal anti-inflammatory agents also may be employed, as well as the dermatologically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application.

[0199] In other embodiments, the anti-inflammatory agent includes, without limitation, transforming growth factor-beta 3 (TGF-β3), an anti-tumor necrosis factor- alpha (TNF-α) agent, an inhibitor or antagonist of IL-6 or IL-6 receptor, IL-1 receptor, IL- iβ, TNF, GM-CSF, IFN-y, JAK-STAT signaling, CCR2, CCR5, complement component C5, IRAK4 and M-CSF receptor, or a combination thereof.

[0200] In some embodiments, the ancillary active agent is an anti-asthmatic agent, representative examples of which include montelukast, zafirlukast, zileuton, a combination therapy such as a beta agonist and a corticosteroid (e.g. fluticasone- salmeterol, budesonide-formoterol, formoterol-mometasone or fluticasone furoate- vilanterol), theophylline, a beta agonist (e.g. albuterol or levalbuterol), an anticholinergic agent (e.g. ipratropium or tiotropium), omalizumab, mepolizumab, dupilumab, reslizumab or benralizumab.

[0201] In some embodiments, the ancillary active agent is a bronchodilator, representative examples of which include albuterol, ipratropium, levalbuterol, aclidinium, arformoterol, formoterol, indacaterol, tiotropium, ipratropium, salmeterol, umeclidinium, a combination therapy (e.g. fluticasone and vilanterol, fluticasone, umeclidinium and vilanterol, formoterol and budesonide, salmeterol and fluticasone, aclidium and formoterol, albuterol and ipratropium, formoterol and glycopyrrolate, glycopyrrolate and indacaterol, olodaterol and tiotropium or umeclidinium and vilanterol) or a phosphodiesterase-4 inhibitor such as roflumilast.

[0202] The ancillary agent may, in some embodiments, be a cytokine inhibitor.For example, the agent may be an IL-5 inhibitor such as mepolizumab, reslizumab or benralizumab; an IL-13 inhibitor such as lebrikizumab, tralokinumab or eblasakimab; an IL-4 inhibitor such as dupilumab, manfidokimab, pascolizumab or pitrakinra; an IL-33inhibitor; or an IL-8 inhibitor such as BMS-986253 or reparixin. The cytokine inhibitor may also include a JAK inhibitor. Representative JAK inhibitors include those disclosed in U.S. Pat. No. 10,022,378, such as Jakafi, Tofacitinib, and Baricitinib, as well as LY3009104 / INCB28050, Pacritinib / SB1518, VX-509, GLPG0634, INC424, R-348, CYT387, TG 10138, AEG 3482, and pharmaceutically acceptable salts and prodrugs thereof. Still further examples include CEP-701 (Lestaurtinib), AZD1480, INC424, R-348, CYT387, TG 10138, AEG 3482, 7-iodo-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4- aminophenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl) acrylamide, 7-(3- aminophenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl) acrylamide, N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, methyl 2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxylate, N-(4-morpholinophenyl)- 5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(4-amino-3-methoxyphenyl)-N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N,N-dimethyl- 3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 1- ethyl-3-(2-methoxy-4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin- -7- yl)phenyl)urea, N-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)methanesulfonamide, 2-methoxy-4-(2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)phenol, 2-cyano-N-(3-(2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)phenyl)acetamide, N-(cyanomethyl)-2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidine-7-carboxamide, N-(3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 1- ethyl-3-(4-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)-2- (trifluoromethoxy)phenyl)urea, N-(3-nitrophenyl)-7-phenylthieno[3,2-d]pyrimidin-2- amine, 7-iodo-N-(3-nitrophenyl)thieno[3,2-d]pyrimidin-2-amine, Nl-(7-(2- ethylphenyl)thieno[3,2-d]pyrimidin-2-yl)benzene-l,3-diamine, N-tert-butyl-3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, Nl-(7- iodothieno[3,2-d]pyrimidin-2-yl)benzene-l,3-diamine, 7-(4-amino-3- (trifluoromethoxy)phenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2- ethylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N- (cyanomethyl)-N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)methanesulfonamide, N-(cyanomethyl)-N-(4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, N-(3- (5-methyl-2-(4-morpholinophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-7- yl)phenyl)methanesulfonamide, 4-(5-methyl-2-(4-morpholinophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4-(5-methyl-2-(4- morpholinophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide, 7-iodo-N-(4-morpholinophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, 7-(2- isopropylphenyl)-N-(4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-bromo-N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N7-(2-isopropylphenyl)-N2-(4- morpholinophenyl)thieno[3,2-d]pyrimidine-2,7-diamine, N7-(4-isopropylphenyl)-N2-(4- morpholinophenyl)thieno[3,2-d]pyrimidine-2,7-diamine, 7-(5-amino-2-methylphenyl)-N- (4-morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, N-(cyanomethyl)-4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, 7-iodo-N-(3- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4-amino-3-nitrophenyl)-N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-methoxypyridin-3-yl)-N-(4- morpholinophenyl)thieno[3,2-d]pyrimidin-2-amine, (3-(7-iodothieno[3,2-d]pyrimidin-2- ylamino)phenyl)methanol, N-tert-butyl-3-(2-(3-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)benzenesulfonamide, N-tert-butyl-3-(2-(3- (hydroxymethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4- morpholinophenyl)-7-(4-nitrophenylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-amine, N-tert- butyl-3-(2-(3,4,5-trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7- yl)benzenesulfonamide, 7-(4-amino-3-nitrophenyl)-N-(3,4-dimethoxyphenyl)thieno[3,2- d ]pyri mid in-2-a mine, N-(3,4-dimethoxyphenyl)-7-(2-methoxypyridin-3-yl)thieno[3,2- d ]pyri mid in-2-a mine, N-tert-butyl-3-(2-(3,4-dimethoxyphenylamino)thieno[3,2- d]pyrimidin-7-yl)benzenesulfonamide, 7-(2-aminopyrimidin-5-yl)-N-(3,4- dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7-(2,6- d imethoxypyrid in-3-yl)thieno[3, 2-d]-pyri mid in-2-a mine, N-(3,4-dimethoxyphenyl)-7- (2,4-dimethoxypyrimidin-5-yl)thieno[3,2-d]pyrimidin-2-amine, 7-iodo-N-(4- (morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-tert-butyl-3-(2-(4- (morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 2- cyano-N-(4-methyl-3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyri mid in-7- yl)phenyl)acetamide, ethyl 3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-7- yl)benzoate, 7-bromo-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)thieno[3,2-d]pyri mid in-2- amine, N-(3-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)acetamide, N-(cyanomethyl)-3-(2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2-(4-morpholinophenylamino)thieno[3,2- d]pyrimidin-7-yl)benzamide, N-tert-butyl-3-(2-(4-(l-ethylpiperidin-4- yloxy)phenylamino)thieno-[3,2-d]pyrimidin-7-yl)benzenesulfonamide, tert-butyl-4-(2-(4- (morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-lH-pyrazole-l- carboxylate, 7-bromo-N-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)thieno[3,2- d ]pyri mid in-2-a mine, N-tert-butyl-3-(2-(4-((4-ethylpiperazin-l-yl)methyl)phenylamino)- -thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, N-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)-7-(lH-pyrazol-4-yl)thieno[3,2-d]pyrimidin-2-amine, N-(cyanomethyl)- 3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide, N-tert- butyl-3-(2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2-d]-pyrimidin-7- yl)benzenesulfonamide, tert-butyl pyrrolidin-l-yl)ethoxy)phenylamino)thieno[3,2- d ]pyri mid in-7-yl)benzylcarba mate, 3-(2-(4-(2-(pyrrolidin-l- yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzenesulfonamide, 7-(3-chloro-4- fluorophenyl)-N-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)thieno-[3,2-d]pyrimidin-2-amine, tert-butyl 4-(2-(4-(l-ethylpiperidin-4-yloxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)- lH-pyrazole-l-carboxylate, 7(benzo[d][l,3]dioxol-5-yl)-N-(4- (morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, tert-butyl 5-(2-(4- (morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)-lH-indole-l-carboxylate, 7-(2-aminopyrimidin-5-yl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2- amine, tert-butyl 4-(2-(-4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)- 5,6-di-hydropyridine-l(2H)-carboxylate, tert-butyl morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, N-(3-(2- (4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N-(4- (2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, N- (3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7- yl)phenyl)methanesulfonamide, 7-(4-(4-methylpiperazin-l-yl)phenyl)-N-(4- (morpholinomethyl)phenyl)thieno-[3,2-d]pyrimidin-2-amine, N-(2-methoxy-4-(2-(4- (morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)acetamide, 7- bromo-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, (3-(2-(3,4,5- trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, (4-(2-(3,4,5- trimethoxyphenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, (3-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, (4-(2-(4- morpholinophenylamino)thieno[3,2-d]pyrimidin-7-yl)phenyl)methanol, N-(pyrrolidin-l- yl)ethoxy)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzyl) methanesulfonamide, tert- butyl morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-7-yl)benzylcarbamate, N- (4-(morpholinomethyl)phenyl)-7-(3-(piperazin-l-yl)phenyl)thieno[3,2-d]pyrimidin-2- amine, 7-(6-(2-morpholinoethylamino)pyridin-3-yl)-N-(3,4,5- trimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(2-ethylphenyl)-N-(4-(2- (pyrrolidin-l-yl)ethoxy)phenyl)thieno[3,2-d]pyrimidin-2-amine, 7-(4- (aminomethyl)phenyl)-N-(4-(morpholinomethyl)phenyl)thieno[3,2-d]pyrimidin-2-amine, N-(4-(l-ethylpiperidin-4-yloxy)phenyl)-7-(lH-pyrazol-4-yl)thieno[3,2-d]pyrimidin-2- amine, N-(2,4-dimethoxyphenyl)-7-phenylthieno[3,2-d]pyrimidin-2-amine, 7-bromo-N- (3,4-dimethoxyphenyl)thieno[3,2-d]pyrimidin-2-amine, N-(3,4-dimethoxyphenyl)-7- phenylthieno[3,2-d]pyrimidin-2-amine, and pharmaceutically acceptable salts and prodrugs thereof.

[0203] Alternatively, or in addition, HMGB1 antibodies and / or COX-2 inhibitors can be used. Examples of such compounds include Actemra (Roche). Celebrex (celecoxib), a COX-2 inhibitor, can be used.

[0204] The compound of the invention may also be administered concurrently with a cancer therapy, such as a radiotherapy, surgery, chemotherapy, hormone ablation therapy, pro-apoptosis therapy or immunotherapy. Suitable therapies are known in the art.

[0205] As previously described, the compound may be compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. Suitable unit dosages and maximum daily dosages of the compound of the invention may be determined in accordance with the unit doses and maximum daily doses used conventionally. In some embodiments, a unit dosage form may comprise the compound in an amount in the range of from about 0.25 pg to about 2000 mg. The compound may be present in an amount of from about 0.25 pg to about 2000 mg / mL of carrier. In embodiments where the pharmaceutical composition comprises one or more additional active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.4. Methods of Use

[0206] The compounds of the invention have been found to interact with and inhibit an activity of a cytokine, including IL-4, IL-5, IL-8, IL-13 and / or IL-33. Accordingly, the Inventors have conceived that such compounds will be useful for treating and inhibiting the development of an inflammatory condition and / or a condition associated with an activity of a cytokine, such as asthma. Therefore, a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in therapy is contemplated.

[0207] In one aspect, there is provided a method of treating or inhibiting the development of an inflammatory condition in a subject, comprising, consisting or consisting essentially of administering a compound of the invention to the subject. The invention further provides a use of a compound of the invention for treating or inhibiting the development of an inflammatory condition in a subject, a use of a compound of the invention in the manufacture of a medicament for treating or inhibiting the development of an inflammatory condition in a subject, and a compound of the invention for use in treating or inhibiting the development of an inflammatory condition in a subject.

[0208] An inflammatory condition includes any condition characterised by or associated with inflammation, or the complex biological response to a noxious stimulus, such as damage, auto-immunity and / or an infection by a microbial pathogen (e.g. a virusor bacteria). The response is typically mediated in part by the activity of cytokines, chemokines and / or inflammatory cells, such as neutrophils, monocytes, lymphocytes, eosinophils and / or macrophages. An inflammatory condition may be characterised by, for example, pain, redness, swelling and / or loss of tissue function.

[0209] The inflammatory condition may be an acute inflammatory condition (e.g. an inflammatory condition lasting for less than six months) or a chronic inflammatory condition (e.g. an inflammatory condition lasting for at least six months), preferably a chronic inflammatory condition.

[0210] Suitable inflammatory conditions include, but are not limited to, asthma (e.g. allergic asthma, non-allergic asthma, severe refractory asthma, asthma exacerbations, steroid resistant asthma, steroid sensitive asthma, eosinophilic asthma or non-eosinophilic asthma), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), dermatitis (e.g. contact dermatitis or atopic dermatitis), nasal polyposis, esophagitis (e.g. eosinophilic esophagitis), vasculitis (e.g. eosinophilic granulomatosis with polyangiitis), rhinosinusitis, pruritis, rhinitis, sinusitis, urticaria, inflammatory bowel disease (e.g. colitis or Crohn's disease), multiple sclerosis, fibrosis, hypersensitivity pneumonitis, arthritis (e.g. rheumatoid arthritis, osteoarthritis or psoriatic arthritis), autoimmune hepatitis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity, bronchial hypertrophy and psoriasis.

[0211] In some embodiments, the inflammatory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease (CORD), acute respiratory distress syndrome (ARDS), dermatitis, nasal polyposis, esophagitis, vasculitis, rhinosinusitis, pruritis, rhinitis, sinusitis, urticaria, inflammatory bowel disease, multiple sclerosis, fibrosis, hypersensitivity pneumonitis, arthritis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity, bronchial hypertrophy and psoriasis; especially asthma, CORD, ARDS, dermatitis, rhinitis or sinusitis.

[0212] In particular embodiments, the condition is a respiratory condition, such as asthma, COPD, ARDS, esophagitis, rhinosinusitis, rhinitis, sinusitis, hypersensitivity pneumonitis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, IPF, allergic bronchopulmonary aspergillosis in a cystic fibrosispatient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity or bronchial hypertrophy.

[0213] In particular embodiments, the inflammatory condition is asthma. The asthma may be, for example, allergic asthma, non-allergic asthma, severe refractory asthma, asthma exacerbations, steroid resistant asthma, steroid sensitive asthma, eosinophilic asthma or non-eosinophilic asthma; especially allergic asthma or eosinophilic asthma.

[0214] In alternative embodiments, the inflammatory condition is COPD. The COPD may be associated with, for example, emphysema, chronic bronchitis or asthma; especially chronic bronchitis or asthma; more especially asthma. Symptoms of COPD may include shortness of breath, wheezing, chest tightness, a chronic cough, respiratory infections, swelling, weight loss and fatigue.

[0215] Alternatively, the inflammatory condition is ARDS. The ARDS may be a result of lung injury due to, for example, an infection (e.g. sepsis), trauma, severe pneumonia, pancreatitis, blood transfusions, inhalation of harmful substances and the like. In exemplary embodiments, the subject may have one or more symptoms selected from mild, moderate or severe hypoxemia as determined by Partial Pressure of arterial oxygen / Fraction of inspired oxygen (PaC2 / FiO2) or positive end-expiratory pressure (PEEP), bilateral opacities, respiratory failure, shortness of breath, labored breathing, cough, fever, increased heart rate, low blood pressure, confusion, extreme fatigue, rapid breathing, organ failure, chest pain, bluish coloring of nails or lips, an change in the level of one or more inflammatory markers, or need for mechanical ventilation.

[0216] In some embodiments, the inflammatory condition is an allergic inflammatory condition (i.e. the condition involves allergic inflammation). Suitable conditions include, for example, allergic asthma, atopic dermatitis, allergic respiratory disease, allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic esophagitis, eosinophilic granulomatosis with polyangiitis, allergic rhinosinusitis, allergic rhinitis, allergic sinusitis, allergic pruritis, allergic urticaria, hypersensitivity pneumonitis and eosinophilic bronchitis.

[0217] In some embodiments, the inflammatory condition is associated with or characterised by eosinophilic inflammation.

[0218] The inflammatory condition may suitably be associated with the activity of one or more cytokines, such as IL-4, IL-5, IL-8, IL-13 and / or IL-33. In some embodiments, the condition is associated with the activity of a Th2-type cytokine, such as IL-4, IL-5 and / or IL-13. The inflammatory condition may be associated with IL-33, which is a member of the IL-1 superfamily of cytokines. IL-33 induces production ofTh2-type cytokines by helper T cells, type II innate lymphoid cells, mast cells, eosinophils and / or basophils. Alternatively, the cytokine may be a chemokine such as IL-8 (CXCL8).

[0219] While the use of any route of administration is contemplated, in some embodiments, the compound is administered by oral, inhalation, intranasal, topical or intravenous administration.

[0220] In another aspect, there is provided a method of treating or inhibiting the development of a respiratory condition in a subject, comprising, consisting or consisting essentially of administering a compound of the invention to the subject. The invention also provides a use of a compound of the invention for treating or inhibiting the development of a respiratory condition in a subject, a use of a compound of the invention in the manufacture of a medicament for treating or inhibiting the development of a respiratory condition in a subject, and a compound of the invention for use in treating or inhibiting the development of a respiratory condition in a subject.

[0221] In particular embodiments, the condition is asthma, COPD, ARDS, esophagitis, rhinosinusitis, rhinitis, sinusitis, hypersensitivity pneumonitis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, IPF, allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity or bronchial hypertrophy; especially asthma COPD, ARDS, rhinitis or sinusitis; more especially asthma.

[0222] In particular embodiments, the respiratory condition is characterised by inflammation, and / or is associated with elevated activity or levels of one or more cytokines relative to the activity or levels of the corresponding cytokine in a subject without the condition. Suitable cytokines include, for example, IL-4, IL-5, IL-8, IL-13 and / or IL-33. In some embodiments, the cytokine is a Th2-type cytokine, such as IL-4, IL-5 and / or IL-13. In some embodiments, the cytokine is IL-33. Alternatively, the cytokine may be a chemokine such as IL-8 (CXCL8).

[0223] In a further aspect, there is provided a method of treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, comprising, consisting or consisting essentially of administering a compound of the invention to the subject. Also provided is a use of a compound of the invention for treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, a use of a compound of the invention in the manufacture of a medicament for treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, and a compound of the invention for use in treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject.

[0224] The cytokine may be, for example, IL-4, IL-5, IL-8, IL-13 and / or IL-33.In some embodiments, the cytokine is a Th2-type cytokine, such as IL-4, IL-5 and / or IL- 13. In some embodiments, the cytokine is IL-33. Alternatively, the cytokine may be a chemokine such as IL-8 (CXCL8).

[0225] Suitable conditions include conditions which are characterised by or associated with activity (e.g. elevated activity) of one or more cytokines, such as one or more of the cytokines listed supra. The activity of the one or more cytokines may be elevated in an immune cell (e.g. an eosinophil, leukocyte, T cell such as a Th2 cell, basophil, dendritic cell, macrophage or mast cell) relative to a corresponding immune cell from a subject without the condition, or a corresponding non-activated / resting immune cell. The condition may involve increased or elevated expression of the one or more cytokines in an immune cell relative to expression in a corresponding immune cell from a subject without the condition.

[0226] Representative conditions include, but are not limited to, asthma (e.g. eosinophilic asthma), COPD, ARDS, dermatitis (e.g. atopic dermatitis), nasal polyposis, sinusitis, rhinosinusitis, esophagitis (e.g. eosinophilic esophagitis), vasculitis (e.g. eosinophilic granulomatosis with polyangiitis), hypereosinophilic syndrome, drug reaction with eosinophilia and systemic symptoms, pruritis, rhinitis (such as allergic rhinitis), esophagitis (e.g. eosinophilic esophagitis), urticaria, asthma and CORD overlap syndrome (ACOS), an allergic response, chronic bronchitis, emphysema, chronic rhinosinusitis with or without nasal polyps, inflammatory bowel disease (e.g. colitis or Crohn's disease), hypersensitivity pneumonitis, multiple sclerosis, arthritis (e.g. osteoarthritis, rheumatoid arthritis and psoriatic arthritis), fibrosis, IPF, psoriasis, autoimmune hepatitis, ischemia reperfusion injury, systemic lupus erythematosus, primary Sjogren's syndrome, systemic sclerosis, gout, ankylosing spondylitis, a cancer (e.g. breast, prostate, lung or renal cancer or metastatic cancer) or an inflammatory condition as discussed herein.

[0227] While the use of any route of administration is contemplated, in some embodiments, the compound is administered by oral, inhalation, intranasal, topical or intravenous administration.

[0228] In another aspect, there is provided a method of antagonizing or inhibiting an activity of a cytokine, comprising, consisting or consisting essentially of contacting the cytokine with a compound of the invention. Also provided herein is a use of a compound of the invention for antagonizing or inhibiting an activity of a cytokine, a use of a compound of the invention in the manufacture of a medicament for antagonizing or inhibiting an activity of a cytokine, and a compound of the invention for use in antagonizing or inhibiting an activity of a cytokine. In particular embodiments, the compound inhibits at least one activity of a cytokine.

[0229] In some embodiments, the method or use is an in vitro method or use. Alternatively, the method or use may be conducted in vivo. The methods and uses may involve contacting a preparation comprising the cytokine with the compound of the invention (for in vitro methods and uses), or contacting a cell expressing the cytokine with the compound of the invention (for in vitro and in vivo methods and uses). Suitable cells include, but are not limited to, immune cells such as an eosinophil, leukocyte, T cell (e.g. Th2 cell), basophil, dendritic cell, macrophage or mast cell; or fibroblast, endothelial cell or epithelial cell of the skin, gastrointestinal tract or respiratory tract.

[0230] In some embodiments, the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33. In some embodiments, the cytokine is a Th2-type cytokine, such as IL-4, IL-5 and / or IL-13. In some embodiments, the cytokine is IL-33. Alternatively, the cytokine may be a chemokine such as IL-8 (CXCL8).

[0231] An activity of a cytokine, such as IL-4, IL-5, IL-8, IL-13 and / or IL-33, may include, for example, immune cell proliferation, differentiation, recruitment, activation and / or maturation (e.g. B cells, T cells, basophils, eosinophils, neutrophils, macrophages, leukocytes and the like), interaction with a receptor (e.g. binding to a receptor, such as ST2, IL-4 receptor, IL-5 receptor, IL-8 receptor, IL-13 receptor, or multimers or combinations thereof), activation of a receptor (e.g. ST2, IL-4 receptor, IL- 5 receptor, IL-8 receptor, IL-13 receptor, or multimers or combinations thereof) or triggering secretion or production of a further cytokine (e.g. IL-5, IL-9, IL-13, IL-4 and / or GM-CSF).

[0232] When conducted in vivo, the method may involve administering the compound of the invention to a subject in need thereof, such as a subject having an inflammatory condition or elevated activity or expression of one or more cytokines in an immune cell (e.g. an eosinophil, leukocyte, T cell such as a Th2 cell, basophil, dendritic cell, macrophage or mast cell) relative to the activity or expression of said cytokine in a corresponding non-activated / resting immune cell. Suitable inflammatory conditions are described supra.

[0233] While administration of a single compound is contemplated, the invention further contemplates administering a second compound of the invention, such as a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII, or a pharmaceutically acceptable salt, solvate or prodrug thereof to the subject in any one of the above aspects. The second compound may be administered concurrently with the first compound, for example, in a single composition.

[0234] Any one of the aspects described above may involve administration of an effective amount of the compound of the invention as described in Section 3 supra. The compound may be administered in the form of, for example, a pharmaceuticalcomposition as described herein. The compound of the invention may be administered to the subject by any route of administration suitable to effect treatment or inhibition of the development of the inflammatory condition, condition associated with an activity of a cytokine, or antagonism of the cytokine. A skilled person will be well aware of suitable routes of administration, such as one or more of the routes of administration discussed in Section 3 supra. For example, in some embodiments, the compound is administered by oral, inhalation, intranasal, topical or intravenous administration; especially inhalation or intranasal administration.

[0235] The dosage and frequency of administration will depend on the subject, the disorder to be treated and the route of administration. A skilled person will readily be able to determine suitable dosages and frequency of such dosages. For example, the compound may be administered in an amount in the range of from about 0.25 pg to about 2000 mg, and may be administered at a frequency of, for example, once daily, or twice or three times daily. The treatment may be continued for multiple days, weeks, months or years. In embodiments where the pharmaceutical composition comprises one or more additional active agents, the dosages and frequency of administration are determined by reference to the usual dose and manner of administration of the said agents.

[0236] Any one of the methods described above may, in some embodiments, involve the administration of one or more further active agents as described in Section 3 supra, such as an anti-inflammatory agent, anti-asthmatic agent, bronchodilator or a cytokine inhibitor.

[0237] A skilled person would be well aware of suitable assays used to evaluate the antagonism or inhibition of an activity of a cytokine. The method may, for example, include contacting a cytokine with a compound and assessing the binding affinity or the inhibition of the interaction with a receptor. Alternatively, the method may include screening for the inhibition of the activity, presence or expression of a downstream cellular target or product or downstream effect, such as proliferation, differentiation, recruitment, activation and / or maturation of an immune cell (e.g. B cells, T cells, basophils, eosinophils, neutrophils, macrophages, leukocytes and the like) or the progression of an inflammatory condition or condition associated with an activity of a cytokine as described herein, for example, in a subject such as an animal model. Detecting such antagonism or inhibition may be achieved utilising techniques including, but not limited to, ELISA, a binding assay (e.g. a radio-ligand binding assay or fluorescence binding assay), surface plasmon resonance, immunofluorescence, western blots, immunoprecipitation, immunostaining, scintillation proximity assays, competitive inhibition assays, a colorimetric assay, a fluorescence-based assay, a luciferase reporterassay (e.g. the assay described in Okragly et al. (2021) Journal of Inflammation Research, 14: 3823-3835), a proliferation assay and the like. Commercially available kits and assays may also be used, such as the Human IL-4 / IL-4Ra Binding Assay (Catalogue no. BAH-IL4R-IL4-1; RayBiotech Life, Inc., Peachtree Corners, GA, USA), IL- 5[Biotinylated] : IL-5Rα Inhibitor Screening ELISA Kit (Catalogue no. EP128-C01;ACROBiosystems, Newark, DE, USA), or IL-13RA2 [Biotinylated]: IL-13 Inhibitor Screening ELISA Kit (Catalogue no. EP149-96; ACROBiosystems, Newark, DE, USA).EMBODIMENTS

[0238] Exemplary embodiments include, but are not limited to:1. A compound of Formula I, II, III, IV, V or VI:(II)(VI) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L1L3L4L6L7L8L9L10L11L12L13L15L16L17L18L19L20L21L22L23L24L25L26L28, L29, L30, L31and L32are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L2, L5, L14and L27are independently selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; X1, X2, X3, X4, X5, X6, X7, Xs, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18are independently selected from CH and N ; andR1is selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12alkenyl and optionally substituted C2-C12alkynyl.2. The compound according to embodiment 1, wherein X1-X18are CH.3. The compound according to embodiment 1 or embodiment 2, wherein L1, L3, L4, L6L7L8L9L10L11L12L13L15L16L17L18L19L20L21L22L23L24L25L26L28L29L30and L32are independently selected from optionally substituted C1-C3alkylene, optionally substituted C2-C3alkenylene and optionally substituted C2-C3alkynylene.4. The compound according to embodiment 3, wherein L1, L3, L4, L6, L7, L8, L9, L10,L11, L12, L13, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L28, L29, L30and L32are optionally substituted C1-C3alkylene.5. The compound according to embodiment 4, wherein L1, L3, L4, L6, L7, L8, L9, L10,L11, L12, L13, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L28, L29, L30and L32are methylene.6. The compound according to any one of embodiments 1-5, wherein L2and L31are independently selected from optionally substituted C2-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene.7. The compound according to embodiment 6, wherein L2and L31are each independently optionally substituted C2-C5alkylene.8. The compound according to embodiment 7, wherein L2and L31are propylene.9. The compound according to any one of embodiments 1-8, wherein L5is selected from optionally substituted C3-C6alkylene, optionally substituted C3-C6alkenylene and optionally substituted C6-C6alkynylene.10. The compound according to embodiment 9, wherein L5is optionally substituted C3-C6alkylene.11. The compound according to embodiment 10, wherein L5is butylene.12. The compound according to any one of embodiments 1-11, wherein L14and L27are independently selected from optionally substituted C2-C4alkylene, optionally substituted C2-C4alkenylene and optionally substituted C2-C4alkynylene.13. The compound according to embodiment 12, wherein L14is optionally substituted C2-C4alkylene.14. The compound according to embodiment 13, wherein L14is ethylene.15. The compound according to any one of embodiments 1-14, wherein L27is optionally substituted C2-C4alkylene.16. The compound according to embodiment 15, wherein L27is ethylene.17. The compound according to any one of embodiments 1-16, wherein R1is selected from optionally substituted C6-C10alkyl, optionally substituted C6-C10alkenyl and optionally substituted C6-C10alkynyl.18. The compound according to embodiment 17, wherein R1is optionally substituted C6-C10alkyl.19. The compound according to embodiment 18, wherein R1is octyl.20. The compound according to any one of embodiments 1-16, wherein R1is methyl.21. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula VII:(VII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.22. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula VIII:(VIII)or a pharmaceutically acceptable salt, solvate or prodrug thereof.23. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula IX:(IX) or a pharmaceutically acceptable salt, solvate or prodrug thereof.24. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula X:(X) or a pharmaceutically acceptable salt, solvate or prodrug thereof.25. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula XI:(XI) or a pharmaceutically acceptable salt, solvate or prodrug thereof.26. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula XII:(XII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.27. The compound according to any one of embodiments 1-20, wherein the compound is a compound of Formula XIII:(XIII) or a pharmaceutically acceptable salt, solvate or prodrug thereof.28. The compound according to any one of embodiments 1-27, wherein the compound is in the form of a salt and the salt is the sodium salt.29. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 and a pharmaceutically acceptable carrier or diluent.30. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 for use in therapy.31. A method of treating or inhibiting the development of an inflammatory condition in a subject, comprising, consisting or consisting essentially of administering a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 to the subject.32. The method according to embodiment 31, wherein the inflammatory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease (CORD), acute respiratory distress syndrome (ARDS), dermatitis, nasal polyposis, esophagitis, vasculitis, rhinosinusitis, pruritis, rhinitis, sinusitis, urticaria, inflammatory bowel disease, multiple sclerosis, fibrosis, hypersensitivity pneumonitis, arthritis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity, bronchial hypertrophy and psoriasis.33. The method according to embodiment 32, wherein the inflammatory condition is selected from the group consisting of asthma, COPD, ARDS, dermatitis, rhinitis and sinusitis.34. The method according to embodiment 32, wherein the inflammatory condition is asthma.35. The method according to embodiment 32, wherein the inflammatory condition is COPD.36. The method according to embodiment 32, wherein the inflammatory condition is ARDS.37. The method according to any one of embodiments 31-36, wherein the inflammatory condition is a chronic inflammatory condition.38. A method of treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, comprising, consisting or consisting essentially of administering a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 to the subject.39. The method according to embodiment 38, wherein the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33.40. The method according to any one of embodiments 30-39, wherein the compound is administered by oral, inhalation, intranasal, topical or intravenous administration.41. A method of antagonizing a cytokine, comprising, consisting or consisting essentially of contacting the cytokine with a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28.42. The method according to embodiment 41, wherein the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33.43. Use of a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 in the manufacture of a medicament for treating or inhibiting the development of an inflammatory condition in a subject.44. Use of a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 in the manufacture of a medicament for treating or inhibiting the development of a condition associated with the activity of a cytokine in a subject.45. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 for use in treating or inhibiting the development of an inflammatory condition in a subject.46. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of embodiments 1-28 for use in treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject.

[0239] In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples.EXAMPLES

[0240] All starting materials, reagents and equipment used are commercially available (e.g. from Sigma-Aldrich (Burlington, MA, USA) and the like) and were obtained from commercial sources unless otherwise indicated.

[0241] Unless stated otherwise, all reactions were conducted in an atmosphere of nitrogen. NMR spectra were collected using a Bruker Ultraspin 400 MHz spectrometer (1H 400 MHz;13C 100 MHz). Flash chromatography was conducted using Merck silica gel 60 μm. Reactions were monitored by thin layer chromatography (TLC) using Merck silica gel 60 μm TLC plates with aluminium backing and containing F254 fluorescent indicator. Compounds were visualized on the TLC plates using ultraviolet light followed by staining with potassium permanganate solution containing KMnO4(1.5 g), K2CO3(10 g), 10% NaOH solution (1.25 mL) diluted to 200 mL with deionized water or by staining with a solution containing 10% H2SO4in ethanol. All organic extracts were dried with anhydrous magnesium sulphate unless otherwise stated and filtered prior to removal of the solvent under reduced pressure.EXAMPLE 1 - Synthesis of 2,3,3',4',6-penta-O-acetvl sucralose (compound 1)1

[0242] To a stirred solution of sucralose (6.1 g, 15 mmol) in pyridine (80 mL) was added acetic anhydride (15 mL, 100 mmol). The mixture was then stirred at room temperature (r.t.) for 24 hours (h.) and concentrated by co-evaporating pyridine with toluene. The crude material was dissolved in ethyl acetate (EtOAc) (100 mL) and washed with IM HCI (2 x 100 mL), 5% aq. NaHCO3(100 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to obtain a glassy solid. The crude material was recrystallized from toluene to obtain 2,3,3',4',6-penta-o-acetyl sucralose 1 (8.5 g, 97%) as needle like crystals.1H NMR (CDC3, 400 MHz): 5.67 (d, 1H, J3-,4- = 6.4 Hz, H-3'), 5.65 (d, J1,2= 2.0 Hz, H-l), 5.29-5.27 (m, 2H, H-2, H-3), 4.58-4.52 (m, 2H, H-4, H-5), 4.27- 4.19 (m, 3H, H-5', H-6a, H-6b), 3.75 (dd, 2H, J5',6' = 6.2 Hz, J6-a,6-b = 0.7 Hz, H-6'a, H- 6'b), 3.69, 3.57 (ABq, 2H, J = 12. 1 Hz, H-l'), 2.12 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.07 (s, 3H, CH3);13C NMR (CDCH, 100 MHz): 170.4, 170.2, 170.0, 169.8, 169.6 (5 x COCH3), 104.4 (C-2'), 90.7 (C-l), 80.8 (C-5'), 77.2, 76.1 (C-4'), 75.9 (C-3'), 68.0 (C-2), 67.8 (C-4), 66.9 (C-3), 63.6 (C-6), 59.0 (C-5), 44.5 (C-l'), 43.9 (C-6'), 20.8, 20.7 (x2), 20.5 (5 x COCH3).2

[0243] 2,3,3',4',6-penta-O-acetyl sucralose 1 (prepared according to Example 1) (35 g, 57 mmol) was dissolved in dimethylsulfoxide (DMSO) (100 mL) followed by the addition of sodium azide (10 g, 154 mmol) and the resulting solution heated at 80°C for 48 h. The reaction was cooled to room temperature and partitioned between diethyl ether (Et2O) (300 mL) and water (300 mL). The organic layer was washed twice with water (2 x 400 mL) and all three water layers were re-extracted with Et2O (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting yellow gum was dissolved in a minimal amount of EtOAc (~50 mL) followed by a small amount of petrol until cloudy. The addition of a seed crystal and scratching yielded a precipitate that continued to form as more petrol was slowly added with scratching. The resulting precipitate was filtered and washed with 1:4 EtOAc / petrol to give 2,3,3',4',6-penta-O-acetyl-6'-azidc sucralose 2 as a white powder (20 g, 56%).1H NMR (CDCI3, 400 MHz): 5.68 (d, 1H, J3'-4- = 6.9 Hz, H-3'), 5.64 (d, 1H, J1,2= 3.6 Hz, H-l), 5.32 (dd, 1H, J2,3= 10.7 Hz, H-3), 5.32-5.29 (m, 1H, H-4'), 5.25 (dd, 1H, H-2), 4.58-4.49 (m, 2H, H-4, H-5), 4.24-4.20 (m, 2H, H-6a, H-6b), 4.15-4.08 (m, 1H, H-5'), 3.69, 3.58 (ABq, 2H, J = 12.1 Hz, H-l'), 3.64-3.56 (m, 1H, H-6'a), 3.50 (dd, 1H, J6a-,6b- = 4.1 Hz, J5,6b- = 13.3 Hz, H-6b'), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.05 (s, 3H, CH3);13C NMR (CDCI3, 100 MHz): 170.3, 170.1, 170.0, 169.9, 169.7 (5 x COCH3), 104.1 (C-2'), 90.8 (C-l), 80.0 (C-5'), 75.6 (C-3'), 75.1 (C- 4'), 67.9 (C-3), 67.7 (C-5), 67.0 (C-2), 63.4 (C-6), 58.9 (C-4), 52.5 (C-6'), 44.5 (C-l'), 20.7, 20.6, 20.6, 20.6, 20.4 (5 x COCH3); HRMS (ESI); m / z [M + Na]+calculated for C22H29Cl2N3O13Na; found 636.0994.EXAMPLE 3 - Synthesis of 1.2.3.4.6-penta-O-acetvl-D-mannppvranpse (compound 3)

[0244] Acetic anhydride (20.7 mL, 160 mmol) was added to a mixture of D- mannose (3.0 g, 10.6 mmol) and sodium acetate (1.6 g, 20 mmol). The reaction mixture was then stirred at 80°C for 4 h. and poured into cold saturated (sat.) NaHCO3solution (100 mL). The mixture was then stirred for 1 h., extracted with dichloromethane (DCM) (2 x 100 mL), dried (MgSO4) and concentrated under reduced pressure. 1, 2,3,4, 6-penta- O-acetyl-D-mannopyranose 3 (3.5 g, 85%, α / β 1:0.4) was obtained as a colorless oil. The crude material was used in the subsequent step without further purification.1H NMR (CDCI3, 400 MHz): 6.06 (d, 1H, J = 1.1 Hz), 5.84 (d, 0.4 H, J = 1.3 Hz), 5.46 (dd, 0.4H, J = 1.1 Hz, J = 3.3 Hz), 5.34-5.32 (m, 2H), 5.28 (d, 0.4H, J = 9.9 Hz), 5.25-5.22 (m, 1H), 5.11 (dd, 0.4H, J = 3.3 Hz, J = 10.0 Hz), 4.28 (dd, 0.4H, J = 5.4 Hz, J = 12.5 Hz), 4.26 (dd, 1H, J = 4.9 Hz, J = 12.3 Hz), 4.15-3.98 (m, 2.4H), 3.78 (ddd, 0.4H, J = 2.4 Hz, J = 5.3 Hz, J = 7.8 Hz), 2.19 (s, 1.2H, OCH3), 2.16 (s, 3H, OCH3), 2.15 (s, 3H, OCH3), 2.08 (s, 1.3H, OCH3), 2.07 (s, 4H, OCH3), 2.03 (s, 4H, OCH3), 1.99 (s, 4H, OCH3)4

[0245] Propargyl alcohol (1.1 mL, 19.2 mmol) was added to a stirred solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose 3 (prepared according to Example 3) (1.5 g, 3.8 mmol) in dry DCM (20 mL). The mixture was cooled to 0°C and BF3.OEt2(4.9 mL, 38.4 mmol) was added dropwise. The resulting mixture was stirred for 15 min, brought to r.t, and the stirring was continued for 24 h. The reaction mixture was diluted with DCM (100 mL) and poured into ice-cold sat. NaHCO3(100 mL) solution. The resulting mixture was stirred until bubbling seized. The organic phase was then separated and washed with (3 x 50 mL) sat. NaHCO3, water (100 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was then purified by recrystallizing with petroleum spirit (Pet. Sp.) / EtOAc (8: 1) to obtain propynyl 2,3,4,6-tetra-O-acetyl-o-D- mannopyranoside 4 (1.2 g, 85%) as colorless needle like crystals.1H NMR (CDCI3, 400 MHz): 5.33 (dd, 1H, J2,3= 3.2 Hz, J3,4= 9.8 Hz, H-3), 5.29 (d, 1H, J3,4= J4,5 = 9.3 Hz, H-4), 5.26 (dd, 1H, Ji,2 = 1.8 Hz, J2,3= 3.2 Hz, H-2), 5.01 (d, 1H, 3I,2= 1.8 Hz, H-l), 4.30-4.24 (m, 3H, H-6a, CH2C = CH), 4.09 (dd, Js.eb = 2.5 Hz, J6a,6b = 12.3 Hz, H-6b), 4.00 (ddd, 1H, J4,5 = 9.2 Hz, J5,6b = 2.5 Hz, J5,ea= 5.3 Hz, H-5), 2.45 (t, 1H, J = 2.4 Hz,CH2C = CH), 2.14 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.97(s, 3H, CH3);13C NMR (CDCb, 100 MHz): 170.6, 169.9, 169.8, 169.7 (4 x CH3CO), 96.3 (C-l), 77.9 (OCH2C=CH), 75.6 (OCH2C=CH), 69.3 (C-2), 69.0 (C-3), 68.8 (C-5), 66.1 (C-4), 62.3 (C-6), 55.0 (OCH2C=CH), 20.9, 20.7 (2 x), 20.6 (4 x CH3CO); HRMS (ESI); m / z [M + Na]+calculated for C17H22O10Na; found 409.1121.

[0246] A catalytic amount of sodium metal (~ 4 mg) was dissolved in methanol (MeOH) (50 mL). The resulting solution was added to a solution of propynyl 2, 3,4,6- tetra-O-acetyl-o-D-mannopyranoside 4 (prepared according to Example 4) (50.0 g, 130 mmol) in MeOH (500 mL), and the mixture was stirred at 45°C for 1 h. The reaction mixture was then neutralized with pre-washed acidic ion exchange resin (IR-120 H+), filtered and concentrated under reduced pressure. The residue was dissolved in a minimal amount of methanol. The product was precipitated by a portionwise addition of ethyl acetate. The mixture was filtered to give a light yellow / brown solid (25.5 g, 90%). The crude material was dissolved in anhydrous pyridine (200 mL) and toluenesulfonyl chloride (30 g, 157 mmol) was added to the reaction mixture and allowed to stand at room temperature for 18 h. Benzoyl chloride (50 mL, 60 g, 426 mmol) was added and allowed to stand at room temperature for 4 h. Water (50mL) was added to the reaction mixture and it evaporated to dryness. The crude residue obtained was dissolved in EtOAc (1000 mL) and washed with 1 M HCI (2 x 500 mL), sat. NaHCO3(500 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (15-35% EtOAc / Pet. Sp.) on silica gel to afford propynyl 2,3,4-tri-O-benzoyl-6-toluenesulfonyl-o-D-mannopyranoside 5 (7.3 g, 70%) as a colorless oil.1H NMR (CDCb, 400 MHz): 8.06 (dd, 2H, J = 1.1 Hz, J = 8.1 Hz, H-OBz), 7.90 (dd, 2H, J = 0.9 Hz, J = 8.1 Hz, H-OBz), 7.78 (dd, 2H, J = 1.2 Hz, J = 8.3 Hz, H- OBz), 7.62-7.18 (m, 8H, H-OBz), 7.13 (s, 2H, H-OTPS), 5.87 (dd, 1H, J2,3= 3.3 Hz, J3,4= 10.0 Hz, H-3), 5.75 (dd, 1H, J3,4= J4,5= 10.0 Hz, H-4), 5.67 (dd, 1H, J1,2= 1.8 Hz, J2,3= 3.3 Hz, H-2), 5.26 (d, 1H, J1,2= 1.8 Hz, H-l), 4.47-4.40 (m, 1H, H-5), 4.32 (t, 2H, J = 2.9 Hz, CH2C = CH), 4.29-4.25 (m, 2H, H-6), 4.08 (h, 2H, J = 6.9 Hz, J = 13.3 Hz, J =20.1 Hz, C / 7- / -pr), 2.86 (h, 1H, J = 6.9 Hz, J = 13.3 Hz, J = 20.1 Hz, CH- / -pr), 2.48 (t, 1H, J = 2.4 Hz, CH2C = CH), 1.22 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.18 (s, 3H, CH3), 1.17 (s, 3H, CH3), 1.15 (s, 3H, CH3);13C NMR (CDCh, 100 MHz): 165.5, 165.3, 165.2 (3 x C=O), 153. 8, 150.9, 133.5, 129.9, 129.8, 129.7, 128.6, 128.4, 128.2, 123.7 (Ar-OTPS), 95.9 (C-l), 77.9, 77.2 (OCH2C=CH), 75.8 (OCH2C = CH), 70.2 (C-2), 69.7 (C-3), 69.6 (C- 5), 67.8 (C-6), 67.0 (C-4), 55.1 (OCH2C=CH), 34.1 (CH- / -pr), 29.6 (CH-i-pr), 24.6, 24.5, 23.4 (6 x CH3); HRMS (ESI); m / z [M + Na]+calculated for C44H48O11Nas found 819.2844.10

[0247] The general synthetic scheme for compound 10 is shown below:PROCEDURE 1 FOR SYNTHESIS OF SO3.PY

[0248] To a solution of pyridine (4 mL) in DCM (20 mL) at 0°C, chlorosulfonic acid (1.6 mL) was added dropwise and the mixture stirred for 30 min. The reaction mixture was then filtered and the precipitate was washed with ice cold water (3 x 20 mL), ice cold sat. NaHCO3(2 x 10 mL), ice cold water (2 x 10 mL) (until the pH of the filtrate was 7), cold ethanol (EtOH) (2 x 20 mL), cold toluene (10 mL) and cold DCM (10 mL). The precipitated SO3.Py was then thoroughly dried under high vacuum and used within 24 h.GENERAL PROCEDURE 1 FOR CLICK REACTION

[0249] Sodium ascorbate [2 equivalents (equiv.)] and copper sulfate pentahydrate (1 equiv.) were added to a mixture of azide analogue (1 equiv.) and alkyne analogue in l,4-dioxane / H2O (3: 1). The reaction mixture was then stirred at roomtemperature for 18 h. and filtered over a pad of celite. The filtrate was concentrated under reduced pressure and the crude material was dissolved in EtOAc. The organic layer was washed with IM HCI, sat. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude material obtained was purified by flash column chromatography on silica gel to obtain the desired compound.GENERAL PROCEDURE 1 FOR ACETATE AND BENZOATE HYDROLYSIS

[0250] The oligosaccharide was dissolved in methanol followed by the portion wise addition of 30% aqueous (aq.) NH3over 10 minutes to ensure the starting material did not oil out of solution. The resulting solution was left to stand at room temperature (24-48 h) before being concentrated and pre-adsorbed onto silica. Flash chromatography to remove both acetamide and benzamide returned the polyols as foams.GENERAL PROCEDURE 1 FOR SULFATION AND DIALYSIS

[0251] The polyol (100 mg) was dissolved in dimethylformamide (DMF) (10 mL) followed by the addition of freshly prepared SO3.Py (10 equiv. per hydroxyl group). The reaction was allowed to stand at room temperature (5 days) before being quenched with 5M NaOH solution (2 equiv. per SO3.Py). The resulting yellow-brown mixture was partitioned between water (20 mL) and CH2CI2(50 mL). The aqueous layer was washed again with CH2CI2before being concentrated. The resulting residue was dissolved in Milli- Q water (5-10 mL) and dialysed using approximately 30 cm of Cellulose membrane tubing with a molecular weight cut-off (MWCO) of 0.5 kD. The dialysis tube was washed with Milli-Q water prior to use, and the ends secured with clips. The tubes were placed in 4 litres of 0.1 M NaCI solution for 2 h and then 4 litres of Milli-Q water overnight. The dialysis tube expanded significantly to hold approximately 150 mL from the overnight dialysis. The contents of the dialysis tube was removed, concentrated to ~5 mL and transferred to a Microsep Advanced tube with a 1 kD MWCO Omega membrane (Pall Corporation, New York, USA). The tube was spun at 5000-7000 g to concentrate to ~200 pL before washing twice with 3 mL of Milli-Q water. The retained material was then passed through a C18 Sep-Pak by eluting with water (3 mL) followed by methanol (3 mL) to remove the majority of color remaining. The desired product was present in the water fraction as determined by thin layer chromatography (t.I.c.) (see below) and was freeze dried to return the sulfated glycanic as a powder.

[0252] Click reaction of 2,3,3',4',6-penta-O-acetyl-6'-azido sucralose 2 (prepared according to Example 2) (8.0 g, 13.0 mmol) and propynyl 2,3,4-tri-O-benzoyl- 6-toluene sulfonyl-o-D-mannopyranoside 5 (prepared according to Example 5) (8.0 g, 11.7 mmol) via general procedure 1 (72 h.) led to a yellow foam that was dissolved in DMF (100 mL) followed by the addition of sodium azide (1.5 g, 23.0 mmol). The resulting mixture was heated at 60°C for 48 h. before being partitioned between EtOAc (300 mL) and water (300 mL). The aqueous was re-extracted with EtOAc (200 mL) and the combined organics washed with water (2 x 300 mL), dried (MgSO4), concentrated and subjected to flash chromatography (40% - 60% EtOAc / Pet. Sp.) to return the azide 6 as a colorless foam (12.0 g, 88 %).1H NMR (CDCI, 400 MHz): 6 = 8.11-8.07 (m, 2H), 7.97-7.93 (m, 2H), 7.85 (s, 1H), 7.82-7.78 (m, 2H), 7.64-7.57 (m, 1H), 7.55-7.46 (m, 3H), 7.44-7.34 (m, 3H), 7.28-7.21 (m, 2H), 5.93-5.84 (m, 2H), 5.75 (d, 1H, J = 7.4 Hz), 5.74-5.72 (m, 1H), 5.69-5.67 (m, 1H), 4.43 (t, 1H, J = 7.3 Hz), 5.37-5.32 (m, 2H), 5.25 (d, 1H, J = 1.7 Hz), 5.02 (d, 1H, J = 12.5 Hz), 4.89 (dd, 1H, J = 3.7 and 14.4 Hz), 4.87 (d, 1H, J = 12.5 Hz), 4.76 (dd, 1H, J = 9.1 and 14.4 Hz), 4.64-4.58 (m, 2H), 4.49 (ddd, 1H, J = 3.6, 7.2 and 8.9 Hz), 4.41-4.32 (m, 1H), 4.36 (dd, 1H, J = 4.3 and 11.8 Hz), 4.27 (dd, 1H, J = 6.9 and 11.8 Hz), 3.64 (d, 1H, 11.9 Hz), 3.55 (d, 1H, 11.9 Hz), 3.53 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H), 2.01 (s, 3H).

[0253] Click reaction of azide 6 (12.0 g, 10.3 mmol) and propynyl 2,3,4-tri-O- benzoyl-6-toluene sulfonyl-o-D-mannopyranoside 5 (prepared according to Example 5) (7.0 g, 10.2 mmol) via general procedure 1 (24 h.) led to a foam that was dissolved inDMF (100 mL) followed by the addition of sodium azide (1.5 g, 23.0 mmol). The resulting mixture was heated at 60°C for 24 h. before being partitioned between EtOAc (300 mL) and water (300 mL). The aqueous was re-extracted with EtOAc (200 mL) and the combined organics washed with water (2 x 300 mL), dried (MgSO4), concentrated and subjected to flash chromatography (50% - 80% EtOAc / Pet. Sp.) to return the azide 7 as a light yellow foam (13.5 g, 77 %).1H NMR (CDCh, 400 MHz): 6 = 8.09-7.98 (m, 7H), 7.95-7.89 (m, 2H), 7.82-7.74 (m, 5H), 7.67-7.57 (m, 2H), 7.56-7.45 (m, 6H), 7.44-7.32 (m, 6H), 7.26-7.20 (m, 2H), 5.93-5.73 (m, 6H), 5.66 (dd, 1H, J = 1.6 and 3.3 Hz), 5.61 (dd, 1H, J = 1.8 and 3.1 Hz), 5.42 (t, 1H, J = 7.3 Hz), 5.39 (dd, 1H, J = 3.5 and 10.7 Hz), 5.33 (dd, 1H, J = 3.3 and 10.8 Hz), 5.24-5.19 (m, 1H), 4.97 (d, 1H, J = 12.4 Hz), 4.88-4.56 (m, 10H), 4.47 (ddd, 1H, J = 3.6, 7.2 and 8.9 Hz), 4.37-4.30 (m, 1H), 4.33 (dd, 1H, J = 4.5 and 11.6 Hz), 4.26 (dd, 1H, J = 7.3 and 11.8 Hz), 3.65, 3.61 (ABq, 2H, J = 12.2 Hz), 3.65-3.44 (m, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 1.96 (s, 3H).

[0254] Click reaction of the azide 7 (5.0 g, 2.9 mmol) and 1,5-hexadiyne (50 % in pentane, 280 pL, 1.4 mmol) via general procedure 1 (48 h.) gave an incomplete reaction via t.I.c. A second portion of copper sulfate pentahydrate and sodium ascorbate was added and the reaction heated at 50°C for 4 h. t.I.c. indicated the reaction to be complete. A usual workup as per general procedure 1 followed by flash chromatography (80% - 100% EtOAc / Pet. Sp.) returned the dimer 8 as a light brown foam (3.0 g, 59%).1H NMR (CDCh, 400 MHz): 6 = 8.05-7.95 (m, 5H), 7.95-7.85 (m, 4H), 7.82-7.76 (m, 2H), 7.75-7.70 (m, 3H), 7.67-7.30 (m, 15H), 7.25-7.18 (m, 4H), 5.93-5.82 (m, 2H), 5.81-5.68 (m, 3H), 5.67-5.58 (m, 2H), 5.54 (dd, 1H, J = 1.6 and 3.1 Hz), 4.45-4.36 (m, 2H), 5.32 (dd, 1H, J = 3.3 and 10.9 Hz), 5.21 (d, J = 1.3 Hz), 5.15 (d, J = 1.3 Hz), 4.88- 4.51 (m, 13H), 4.50-4.42 (m, 1H), 4.33 (dd, 1H, J = 4.6 and 11.9 Hz), 4.24 (dd, 1H, J = 7.0 and 11.9 Hz), 3.68 (d, 1H, J = 12.0 Hz), 3.61 (d, 1H, J = 12.0 Hz), 3.09-3.01 (m, 2H), 2.15 (s, 3H), 2.07 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.95 (s, 3H).SYNTHESIS OF COMPOUND 9

[0255] Acetate hydrolysis of compound 8 (2.8 g, 0.8 mmol) using methanol (200 mL) and 30% aq. NH3(30 mL) according to general procedure 1 (24 h) gave, after flash chromatography (50% - 100% MeOH / EtOAc), the oligosaccharide 9 as a light brown foam (1.2 g, 81%);1H NMR (D2O, 400 MHz): 6 = 7.89 (bs, 2H), 7.79 (s, 1H), 5.46 (d, 1H, J = 4.1 Hz), 4.94-4.85 (m, 2H), 4.62-4.51 (m, 2H), 4.48-4.32 (m, 4H), 4.31-4.13 (m, 6H), 3.95 (dd, 1H, J = 10.3 and 4.0 Hz), 3.92 (dd, 1H, J = 3.4 and 1.6 Hz), 3.90-3.74 (m, 6H), 3.70 (s, 2H), 3.65 (dd, 1H, J = 9.5 and 3.4 Hz), 3.61-3.53 (m, 2H), 2.97 (s, 2H).SYNTHESIS OF COMPOUND 10

[0256] Sulfation of the deprotected octomer 9 (100 mg, 0.05 mmol) according to general procedure 1 followed by dialysis gave the octomer 10 as a colorless powder (20 mg, 9%);1H NMR (D2O, 400 MHz): 6 = 8.15 (s, 1H), 8.07 (s, 1H), 7.93 (bs, 1H), 5.88 (d, J = 3.6 Hz, 1H), 5.39 (d, J = 7.9 Hz, 1H), 5.30 (d, 1H, J = 1.9 Hz), 5.24 (d, 1H, J = 1.8 Hz), 5.17-5.05 (m, 2H), 5.05-4.85 (m, 8H), 4.78-4.61 (m, 4H), 4.59-4.21 (m, 11H), 4.00, 3.93 (ABq, 2H, J = 12.5 Hz).EXAMPLE 7 - Synthesis of propargyl maltotriose (compound 11)

[0257] The general synthetic scheme is shown below:

[0258] Boron trifluoride diethyl etherate (46 mL) was added dropwise to a mixture of peracetate maltotriose (prepared according to the procedure of Su et al. (2019) EurJ Med Chem, 182: 111622) (13.3 g, 13.8 mmol) and propargyl alcohol (8.5 mL, 137 mmol) in dry DCM (500 mL) at 0°C. The mixture was then stirred at r.t. for 48 h. Sat. NaHCO3(10 mL) was then added to the reaction mixture and stirred for a further 10 min. The organic layer was extracted, dried (MgSO4) and concentrated under reduced pressure. The crude material obtained was purified by flash column chromatography (3: 1 EtOAc: Pet. Sp.) to obtain propargyl maltotriose 11 (6.0 g, 45%) as a glassy solid.1H NMR (CDCI3, 400 MHz): 5.43-5.22 (m, 6H), 5.04 (t, 1H, J = 10.0 Hz), 4.86-4.76 (m, 3H), 4.71 (dd, 1H, J = 4.1 Hz, J = 10. 4 Hz), 4.51-4.39 (m, 2H), 4.33 (d, 2H, J = 2.3 Hz), 4.32-4.13 (m, 4H), 4.06-3.87 (m, 6H), 3.77-3.69 (m, 1H), 2.44 (t, 1H, J = 2.4 Hz), 2.15, 2.13, 2.07, 2.02, 2.02, 2.00, 1.98, 1.97 (x2) (s, 3H, 9 x CH3);13C NMR (CDCb, 100 MHz): 170.6 (x2), 170.5 (x2), 170.3, 170.1, 169.8, 169.7 (x2), 169.4, 97.5, 95.7 (x2), 77.2, 75.5, 75.2, 73.7, 72.5, 72.2, 71.8, 71.7, 70.4, 70.1, 69.4, 68.9, 68.5, 67.9, 62.8, 62.3, 61.4, 60.4, 55.8, 20.9, 20.8, 20.6, 20.5, 14.2; HRMS (ESI); m / z [M + Na]+calculated for C41H54O26Na; found 385.2792.12

[0259] To a solution of propynyl 2,3,4,6-tetra-O-acetyl-o-D-mannopyranoside 4 (prepared according to Example 4) (5.0 g, 13 mmol) in MeOH (50 mL), a catalytic amount of sodium metal (~ 4 mg) was added and the mixture was stirred at r.t. for 2 h.The reaction mixture was then neutralized with pre-washed acidic ion exchange resin (IR-120 H+), filtered and concentrated under reduced pressure. The crude material was dissolved in anhydrous pyridine (50 mL) and cooled to 0°C. 2,4,6-triisopropylbenzene sulfonyl chloride (4.7 g, 16 mmol) was added to the reaction mixture and allowed to warm up to r.t., and stirred for 18 h. The reaction mixture was then cooled to 0°C and benzoyl chloride (5.0 mL, 47 mmol) was added and stirred at r.t. for 24 h. The reaction mixture was concentrated under reduced pressure by co-evaporating the pyridine with toluene. The crude residue obtained was dissolved in EtOAc (100 mL) and washed with 1 M HCI (2 x 50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Pet. Sp. / EtOAc 3: 1) on silica gel to afford propynyl 2,3,4-tri-O-benzoyl-6-2,4,6- triisopropylbenzene sulfonyl-o-D-mannopyranoside 12 (7.3 g, 70%) as a colorless oil.1H NMR (CDCb, 400 MHz): 8.06 (dd, 2H, J = 1.1 Hz, J = 8.1 Hz, H-OBz), 7.90 (dd, 2H, J = 0.9 Hz, 7 = 8.1 Hz, H-OBz), 7.78 (dd, 2H, J = 1.2 Hz, J = 8.3 Hz, H-OBz), 7.62-7.18 (m, 8H, H-OBz), 7.13 (s, 2H, H-OTPS), 5.87 (dd, 1H, J2,3= 3.3 Hz, J3,4= 10.0 Hz, H-3), 5.75 (dd, 1H, J3,4= J4,5= 10.0 Hz, H-4), 5.67 (dd, 1H, J1,2= 1.8 Hz, J2,3= 3.3 Hz, H-2), 5.26 (d, 1H, J1,2= 1.8 Hz, H-l), 4.47-4.40 (m, 1H, H-5), 4.32 (t, 2H, J = 2.9 Hz, CH2C = CH), 4.29-4.25 (m, 2H, H-6), 4.08 (h, 2H, J = 6.9 Hz, J = 13.3 Hz, J = 20.1 Hz, CH- / -pr), 2.86 (h, 1H, J = 6.9 Hz, J = 13.3 Hz, J = 20.1 Hz, CH- / -pr), 2.48 (t, 1H, J = 2.4 Hz, CH2C = CH), 1.22 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.18 (s, 3H, CH3), 1.17 (s, 3H, CH3), 1.15 (s, 3H, CH3);13C NMR (CDCb, 100 MHz): 165.5, 165.3, 165.2 (3 x C = O), 153. 8,150.9, 133.5, 129.9, 129.8, 129.7, 128.6, 128.4, 128.2, 123.7 (Ar-OTPS), 95.9 (C-l),77.9, 77.2 (OCH2C=CH), 75.8 (OCH2C=CH), 70.2 (C-2), 69.7 (C-3), 69.6 (C-5), 67.8 (C- 6), 67.0 (C-4), 55.1 (OCH2C = CH), 34.1 (CH- / -pr), 29.6 (CH- / -pr), 24.6, 24.5, 23.4 (6 x CH3); HRMS (ESI); m / z [M + Na]+calculated for C44H48O1NaS; found 819.2844.EXAMPLE 9 - Synthesis of compound 20 (G22)20

[0260] The general synthetic scheme for compound 20 is shown below.PROCEDURE 2 FOR SYNTHESIS OF SO3-PY

[0261] To a solution of pyridine (4 mL) in DCM (20 mL) at 0°C, chlorosulfonic acid (1.6 mL) was added dropwise and the mixture stirred for 30 min. The reaction mixture was then filtered and the precipitate was washed with ice cold water (3 x 20 mL), ice cold sat. NaHCO3(2 x 10 mL), ice cold water (2 x 10 mL) (until the pH of the filtrate was 7), cold EtOH (2 x 20 mL), cold toluene (10 mL) and cold DCM (10 mL). The precipitated SO3.Py was then thoroughly dried under high vacuum and used within 24 h.GENERAL PROCEDURE 2 FOR CLICK REACTION

[0262] Sodium ascorbate (2 equiv.) and copper sulfate pentahydrate (1 equiv.) were added to a mixture of azide analogue (1 equiv.) and alkyne analogue (1 equiv. per Na) in l,4-dioxane / H2O (3: 1). The reaction mixture was then stirred at r.t. for 18 h and filtered over a pad of celite. The filtrate was concentrated under reduced pressure and the crude material was dissolved in EtOAc. The organic layer was washed with IM HCI, sat. NaHCOa, dried (MgSO4) and concentrated under reduced pressure. The crude material obtained was purified by flash column chromatography on silica gel to obtain the desired compound.GENERAL PROCEDURE 2 FOR ACETATE AND BENZOYL ESTER HYDROLYSIS

[0263] A solution of 30% aq. NHa (3-5 mL) and oligosaccharide in methanol (20 mL) was stirred at r.t. for 48 h. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ultra-pure water (5-10 mL) and washed with EtOAc (5 x 10 mL). The aqueous layer was concentrated to obtain the pure compound.GENERAL PROCEDURE 2 FOR SULFATION

[0264] Freshly prepared SO3.Py (10 equiv. per OH) complex was added to a solution of the starting material in dry DMF (10 mL) kept under nitrogen atmosphere. The reaction mixture was stirred at r.t. for 2 days and made basic using 5 M NaOH (2 equiv. per SO3.Py). The mixture was then concentrated under reduced pressure and the crude material was dissolved in ultra-pure water (10-20 mL) and dialyzed according to the general procedure.GENERAL PROCEDURE 2 FOR DIALYSIS

[0265] Commercially available Cellulose membrane dialysis tubing with MWCO of 0.5 kD, lkD and 2 kD were used for dialysis. The dialysis tubing was washed with mil liQ water before use (approximately 5-10 mins of washing). One end of the dialysis tube was knotted and the sample was loaded into the tube. The tube was then closed using a clip, leaving little room for bubbles. A 3 L flask equipped with a stirrer bar was filled with milliQ water and placed on a magnetic stirring plate at room temperature. The stirring was set such that the dialysis bag slowly float around the top of the solution in the flask. After 2 h., the water was replaced with fresh milliQ water and dialysis continued for 2 days with the dialysis water being changed after every 18 h. The dialysis bag was then removed from the flask and the content of the bag was collected and freeze dried.SYNTHESIS OF OCTYL 2,3,4,6-TETRA-O-ACETYL-ALPHA-D-MANNOPYRANOSIDE (COMPOUND 13)13

[0266] Octanol (4.0 mL, 25.5 mmol) was added to a stirred solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose 3 (prepared according to Example 3) (5.6 g, 14.3 mmol) in dry DCM (100 mL). The mixture was cooled to 0°C and Boron trifluoride diethyl etherate (BF3.OEt2) (16.0 mL, 112.0 mmol) was added dropwise. The resulting mixture was stirred for 15 min, brought to r.t., and the stirring was continued for 24 h. The reaction mixture was diluted with DCM (100 mL) and poured into ice-cold sat. NaHCO3(100 mL) solution. The resulting mixture was stirred until bubbling seized. The organic phase was then separated and washed with (3 x 50 mL) sat. NaHCO3, water (100 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was then dissolved in MeOH (50 mL) and a catalytic amount of sodium was added to the mixture. The reaction was stirred at r.t. for 2 hours and neutralized with pre-washed acidic ion exchange resin (IR-120 H+), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc / MeOH 3: 1) to obtain 13 (2.5 g, 60%) as colorless oil.SYNTHESIS OF OCTYL 2,3,4-TRI-O-ACETYL-6-2,4,6-TRIISOPROPYLBENZENE SULFONYL- ALPHA-D-MANNOPYRANOSIDE (COMPOUND 14)

[0267] The crude material from above 13 (880 mg, 3.00 mmol) was dissolved in anhydrous pyridine (50 mL) and cooled to 0°C. 2,4,6-triisopropylbenzene sulfonyl chloride (1.18 g, 3.9 mmol) was added to the reaction mixture and allowed to warm up to r.t., and stirred for 18 h. The reaction mixture was then cooled to 0°C and acetic anhydride (2 mL) was added and stirred at r.t. for 24 h. The reaction mixture was concentrated under reduced pressure by co-evaporating the pyridine with toluene. The crude residue obtained was dissolved in EtOAc (100 mL) and washed with 1 M HCI (2 x 50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Pet. Sp. / EtOAc 3: 1) onsilica gel to afford the mannopyranoside 14 (1.7 g, 89%) as a colorless oil.1H NMR (CDCI3, 400 MHz): 7.18 (s, 2H, Ar-OTPS), 5.33 (dd, 1H, J2,3= 3.5 Hz, J3,4= 10.0 Hz, H-3), 5.19 (dd, 1H, J1,2= 1.7 Hz, J2,3= 3.5 Hz, H-2), 5.11 (t, 1H, J3,4= J4,5= 10.0 Hz, H-4), 4.72 (d, 1H, J1,2= 1.7 Hz, H-l), 4.17-4.05 (m, 5H, H-5), 3.69-3.62 (m, 1H, H-6a), 3.41-3.33 (m, 1H, H-6b), 2.91 (h, 1H, J = 6.9 Hz, J = 13.7 Hz, J = 20.1 Hz, CH- / -pr), 2.09 (s, 3H, CH3), 1.98 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.67-0.69 (m, 36H, 7 x CH2, CH3, OCH3);13C NMR (CDCI3, 100 MHz): 170.0, 169.8 (x2), 153.8, 150.9, 129.2, 123.7, 97.2 (C-l), 69.7 (C-2), 67.0 (C-3), 68.6 (C-5), 68.5 (C-6), 67.7, 66.7 (C-4), 34.2, 31.8, 29.7, 29.6, 29.3, 29.2, 29.1, 26.0, 24.7, 24.6, 23.5, 22.6, 20.8, 20.6, 20.5, 14.1.SYNTHESIS OF OCTYL 2,3,4-TRI-O-ACETYL-6-AZIDO-ALPHA-D-MANNOPYRANOSIDE (COMPOUND 15)15

[0268] To a solution of 14 (2.5 g, 3.7 mmol) in dry DMF (20 mL), NaN3(800 mg, 20 mmol) was added and the mixture was stirred at 60°C for 24 h. The reaction mixture was then decanted and the residue left in the flask was washed with EtOAc (3 x 5 mL). The combined organic layer was then concentrated under reduced pressure. The crude material was dissolved in EtOAc (100 mL) and washed with IM HCI (2 x 50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Pet. Sp. / EtOAc 1: 1) to obtain the azide 15 (quant.) as colorless oil.1H NMR (CDCI3, 400 MHz): 5.32 (dd, 1H, J = 3.5 Hz, J = 10.0 Hz, H-3), 5.23-5.15 (m, 2H, H-2, H-4), 4.79 (br-s, 1H, H-l), 3.96-3.88 (m, 1H, J = 2.5 Hz, J = 6.9 Hz, J = 9.6 Hz, H-5), 3.73-3.65 (m, 1H, J = 6.6 Hz, J = 9.4 Hz), 3.48-3.40 (m, 1H, J = 6.5 Hz, J = 9.4 Hz), 3.34 (dd, 1H, J = 6.7 Hz, J = 13.2 Hz, H- 6a), 3.24 (dd, 1H, J = 2.3 Hz, J = 13.1 Hz, H-6b), 2.13 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.96 (s, 3H, CH3), 1.67-0.71 (m, 18H, 7 x CH2, CH3);13C NMR (CDCI3, 100 MHz): 171.0, 170.0, 169.8, 97.3, 69.9, 69.6, 68.9, 68.6, 67.3, 60.3, 51.1, 31.7, 29.2, 29.1, 26.0, 22.6, 20.9, 20.8, 20.6, 14.1; HRMS (ESI); m / z [M + Na]+calculated for C20H33O3N3Na; found 466.2168.SYNTHESIS OF COMPOUND 16

[0269] Click reaction of 12 (prepared according to Example 8) (2.5 g, 3.10 mmol) and mannose azide 15 (2.0 g, 3.10 mmol) via general procedure 2 gave the disaccharide as a glassy solid. To a solution of the disaccharide in dry DMF (20 mL), sodium azide (500 mg, 7.40 mmol) was added and the mixture was stirred at 60°C under a nitrogen atmosphere for 18 h. The reaction mixture was then concentrated under reduced pressure and the crude material obtained was suspended in EtOAc (75 mL). The organic layer was washed with HCI (2 x 75 mL), sat. NaHCO3, dried (MgSO4) and concentrated. The crude material was then purified by flash column chromatography to obtain 16 (700 mg, 19%).1H NMR (CDCh, 400 MHz): 8.12-8.06 (m, 2H, Ar-H), 7.98- 7.91 (m, 2H, Ar-H), 7.85 (s, 1H, H-9), 7.82-7.77 (m, 2H, Ar-H), 7.66-7.59 (m, 1H, Ar- H), 7.55-7.47 (m, 3H, Ar-H), 7.46-7.35 (m, 3H, Ar-H), 7.29-7.22 (m, 2H, Ar-H), 5.93- 5.86 (m, 1H, H-4), 5.83 (dd, 1H, J2,3= 3.2 Hz, J3,4= 10.0 Hz, H-3), 5.67 (dd, 1H, Ji,2= 1.7 Hz, 3.2 Hz, H-2), 5.37 (dd, 1H, J2-,3- = 3.5 Hz, Jy, 4- = 10.0 Hz, H-3'), 5.24 (dd, 1H, Jr,2' = 1.8 Hz, Jy,3- = 3.4 Hz, H-2'), 5.21 (d, 1H, Jr,2- = 1.7 Hz, H-l'), 5.17 (t, 1H, J3-,4- = J4',5' = 10.0 Hz, H-4'), 5.04, 4.82 (ABq, 2H, J = 12.2 Hz, H-7), 4.77 (d, 1H, JI, 2 = 1.6 Hz, H-l), 4.67 (dd, 1H, J5-,6-a = 2.4 Hz, J6-a,6-b = 14.3 Hz, H-6'a), 4.43 (dd, 1H, J5-,6-b = 9.0 Hz, J6-a, 6-b= 14.3 Hz, H-6'b), 4.37-4.31 (m, 1H, H-5), 4.19 (ddd, 1H, J5-,6-a = 2.3 Hz, J6-a,6-b = 9.2 Hz, J = 12.0 Hz, H-5'), 3.52 (d, 2H, J = 4.4 Hz, H-6), 3.23 (dd, 2H, J = 1.5 Hz, J = 6.5 Hz, J = 8.1 Hz, H-7'), 2.17 (s, 3H, OCH3), 2.13 (s, 3H, OCH3), 1.99 (s, 3H, OCH2(CH2)6CH3), 1.48-1.37 (m, 2H, OCH2(CH2)6CH3), 1.27-1.14 (m, 8H, OCH2(CH2)6CH3), 1.13-1.07 (m, 2H, OCH2(CH2)6CH3), 0.86 (t, 3H, J = 6.8 Hz, OCH2(CH2)sC / 73);13C NMR (CDCh, 100 MHz): 171.1, 170.2, 169.9, 169.7, 165.5, 165.4 (x2), 143.4 (C-8), 133.6 (x2), 133.2, 129.8 (x2), 129.7, 129.1, 128.9, 128.7, 128.6, 128.5, 128.3, 124.7 (C-9), 97.4 (C-l'), 96.9 (C-l), 70.6 (C-5), 70.2 (C-2), 69.6 (C-3), 69.6 (C-2'), 69.1 (C-5'), 68.8 (C-3'), 68.5 (OCH2(CH2)6CH3), 67.7 (C-4), 67.5 (C-4'), 61.3 (C-7), 51.2 (C-6), 51.1 (C-6'), 31.7 (OCH2(CH2)6CH3), 29.2 (OCH2(CH2)6CH3), 29.1 (x2) (OCH2(CH2)6CH3), 26.0 (OCH2(CH2)6CH3), 21.0 (OCH2(CH2)6CH3), 20.8 (x2) (2 x OCH3), 20.6 (OCH3), 14.2 (OCH2(CH2)6CH3), 14.0 (OCH2(CH2)6CH3).SYNTHESIS OF COMPOUND 17

[0270] Click reaction of disaccharide 16 (700 mg, 0.60 mmol) and 5-hexyn-l-ol (0.09 mL, 0.90 mmol) via general procedure 2 gave the disaccharide as a glassy solid. To a solution of the crude material in anhydrous DCM (20 mL), triethylamine (0.6 mL, 4.5 mmol) and methanesulfonyl chloride (0.07 mL, 0.90 mmol) were added and stirred at r.t. for 18 h. The reaction mixture was washed with 1 M HCI (2 x 30 mL), sat. NaHCO3(30 mL), dried (MgSO4) and concentrated under reduced pressure. To a solution of the crude material in anhydrous DMF (20 mL), NaN3(100 mg, 1.7 mmol) was added and stirred at 60°C for 18 h. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in EtOAc (100 mL) and washed with 1 M HCI (50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (1.5: 1 EtOAc / Pet. Sp. to EtOAc) to obtain the azide 17 (370 mg, 58%).1H NMR (CDCb, 400 MHz) : 8.04-7.92 (m, 4H, Ar-H), 7.79-7.74 (m, 3H, Ar-H, H-9), 7.66-7.56 (m, 2H, Ar-H, H-10), 7.55-7.44 (m, 3H, Ar-H), 7.44-7.34 (m, 3H, Ar-H), 7.26-7.19 (m, 2H, Ar-H), 5.82 (dd, 1H, J2-,3- = 3.4 Hz, J3-,4- = 10.0 Hz, H-3'), 5.73 (t, 1H, J3-,4- = J4',5' = 9.7 Hz, H-4'), 5.59 (dd, 1H, J2-,3- = 1.7 Hz, Jr,2- = 3.3 Hz, H-2'), 5.35 (dd, 1H, J2,3= 3.5 Hz, J3,4= 10.0 Hz, H-3), 5.23 (dd, 1H, J1,2= 1.7 Hz, J2,3= 3.5 Hz, H-2), 5.15 (d, 1H, Jr, 2' = 1.7 Hz, H-l'), 5.14 (t, 1H, J3,4= J4,5 = 10.0 Hz, H-4), 4.77 (d, 1H, J1,2= 1.6 Hz), 4.76-4.67 (m, 1H, H-6'a ), 4.66-4.55 (m, 3H, H- 6'b, H-6a, H-5'), 4.60, 4.51 (ABq, 2H, H-7), 4.42 (dd, 1H, Js,6b = 8.2 Hz, J6a,6b = 14.4 Hz, H-6b), 4.22-4.15 (m, 1H, H-5), 3.27-3.19 (m, 4H, OCH2(CH2)SCH3, triazole- (CH2)3C / 72N3), 2.78-2.65 (m, 2H, triazole-(CH2)3CH2N3), 2.15 (s, 3H, OCH3), 2.11 (s, 3H, OCH3), 1.98 (s, 3H, OCH3), 1.76-1.65 (m, 2H, triazole-(CH2)3CH2N3), 1.65-1.54 (m, 2H, triazole-(C / 72)3CH2N3), 1.46-1.34 (m, 2H, OCH2(CH2)6CH3), 1.21-1.10 (m, 8H, OCH2(CH2)6CH3), 0.83 (t, 3H, OCH2(CH2)6CH3);13C NMR (CDCb, 100 MHz): 170.0, 169.9, 169.7, 165.7, 165.2 (x2), 147.5 (C-9), 143.0 (C-ll), 133.7, 133.6, 133.2, 129.8 (x2), 129.6, 129.0, 128.7, 128.6, 128.5, 128.2, 124.7 (C-9), 122.5 (C-10), 97.3 (C-l), 96.5 (C-l'), 70.2 (C-2'), 69.6 (C-5'), 69.5 (C-3', C-2), 68.9 (C-5), 68.8 (C-3), 68.4 (OCH2(CH2)6CH3), 67.9 (C-4'), 67.6 (C-4), 60.7 (C-7), 51.0 (C-6, triazole-(CH2)3CH2N3), 50.9 (C-6'), 31.7 (OCH2(CH2)6CH3), 29.2 (OCH2(CH2)6CH3), 29.1 (OCH2(CH2)6CH3) , 28.2(triazole-(CH2)3CH2N3), 26.4 (triazole-(CH2)3CH2N3), 26.0 (OCH2(CH2)6CH3), 25.0(triazole-(CH2)3CH2N3), 22.5, 20.8 (OCH3), 20.7 (OCH3), 20.6 (OCH3), 14.0 (OCH2(CH2)6CH3).SYNTHESIS OF COMPOUND 1818

[0271] Click reaction of azide 17 (130 mg, 0.12 mmol) and propargyl maltotriose 11 (prepared according to Example 7) (120 mg, 0.10 mmol) via general procedure 2 gave the oligosaccharide 18 (120 mg, 53%) as a glassy solid ;1H NMR (CDCI3, 400 MHz): 6 = 8.04-7.91 (m, 4H), 7.81-7.74 (m, 3H), 7.68-7.59 (m, 2H), 7.57- 7.46 (m, 4H), 7.46-7.35 (m, 3H), 7.26-7.20 (m, 2H), 5.83 (dd, 1H, J = 3.3 Hz, J = 10.0 Hz), 5.72 (m, 1H, J = 9.8 Hz), 5.60 (dd, 1H, J = 1.7 Hz, J = 3.3 Hz), 5.43-5.30 (m, 4H), 5.29-5.20 (m, 3H), 5.17-5.02 (m, 3H), 4.95-4.39 (m, 17H), 4.39-4.11 (m, 6H), 4.05 (dd, 1H, J = 2.2 Hz, J = 12.4 Hz), 4.01-3.87 (m, 4H), 3.79-3.70 (m, 1H), 3.24 (t, 2H, J = 6.4 Hz), 2.81-2.71 (m, 2H), 2.19-1.92 (10 x s, 30H), 1.76-1.64 (m, 2H), 1.47-1.36 (m, 2H), 1.30-1.11 (m, 10H), 0.84 (t, 3H, J = 6.8 Hz);13C NMR (CDCI3, 100 MHz): 6 = 170.6 (x2), 170.5, 170.4, 170.3, 170.1, 170.0, 169.9, 169.8, 169.7 (x2), 169.6, 169.4, 165.7, 165.3, 165.2, 146.9, 143.8, 143.0, 133.8, 133.7, 133.3, 129.9, 129.8, 129.7, 129.0, 128.8, 128.7, 128.5 (x2), 128.3, 124.8, 123.0, 122.9, 99.5, 97.3, 96.5, 95.7, 95.6, 77.2, 75.2, 73.7, 72.5, 72.3, 72.0, 71.7, 70.4, 70.2, 70.0, 69.6, 69.5, 69.4, 69.0,68.9, 68.8, 68.5, 67.9, 67.6, 62.9, 62.8, 62.3, 61.4, 60.8, 51.1 (x2), 50.0, 31.8, 29.5,29.2, 29.1, 26.1, 26.0, 24.6, 22.6, 20.9, 20.8 (x2), 20.6, 20.5 (x2), 14.1.SYNTHESIS OF COMPOUND 1919

[0272] Acetate and benzoyl ester hydrolysis of compound 18 (120 mg, 0.05 mmol) according to general procedure 2 gave the oligosaccharide 19 (47 mg, 73%)1H NMR (D2O, 400 MHz): 6 = 7.93 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 5.32 (t, 2H, J = 4.2 Hz), 4.93-4.74 (m, 5H), 4.54-4.37 (m, 3H), 4.33 (t, 2H, J = 7.0 Hz), 4.21, 4.14 (ABq, 2H, J = 12.1 Hz), 3.95-3.48 (m, 26H), 3.37 (t, 1H, J = 9.6 Hz), 3.31-3.19 (m, 2H), 2.99-2.90 (m, 1H), 2.69 (t, 2H, J = 7.4 Hz), 1.86-1.76 (m, 2H), 1.61-1.50 (m, 2H), 1.29-0.83 (m, 12H), 0.79 (t, 3H, J = 7.0 Hz);13C NMR (D2O, 100 MHz): 6 = 147.7, 143.4, 142.8, 125.9, 125.1, 124.2, 101.3, 99.9, 99.8, 99.6, 99.0, 77.2, 77.0, 76.1, 74.6, 73.3, 72.9 (x2), 72.7, 71.8 (x2), 71.5, 71.2, 70.6, 70.5, 70.0, 69.8, 69.3, 68.1 (x2), 67.9, 61.9, 60.7, 60.5, 58.9, 51.3, 51.1, 50.0, 31.0, 28.6, 28.4, 28.3, 28.2, 25.5, 25.3, 23.8, 22.1, 13.5.SYNTHESIS OF COMPOUND 2020

[0273] Sulfation of the deprotected oligosaccharide 19 (55 mg, 0.04 mmol) according to general procedure 2 followed by dialysis gave the oligosaccharide 20 (30 mg, 26%) as a white powder;1H NMR (D2O, 400 MHz): 6 = 8.16 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 5.75-5.66 (m, 1H), 5.64-5.55 (m, 1H), 8.26 (s, 1H), 5.23-4.88 (m, 10H), 4.88-4.66 (m), 4.66-4.31 (m, 15H), 4.30-4.12 (m, 5H), 4.06 (t, 1H, J = 10.0 Hz), 3.45- 3.36 (m, 1H), 2.06-1.90 (m, 2H), 1.78-1.62 (m, 2H), 1.44-0.96 (m, 10H), 0.89 (t, 3H, J = 7.0 Hz);13C NMR (CDCI3, 100 MHz): 6 = 125.9, 125.6, 124.3, 99.4, 97.1, 96.3, 94.3,93.6, 76.3, 75.5, 75.2, 74.7, 73.7, 73.5, 73.0, 72.7, 72.6, 71.6, 71.4, 70.7, 70.6, 69.8,67.8, 66.5, 65.9, 62.1, 59.8, 51.1, 50.9, 50.1, 31.0, 28.8, 28.4, 28.2, 28.1, 25.6, 25.2,24.0, 22.1, 13.5.EXAMPLE 10 - Synthesis of compound 25 (G19)25

[0274] The general synthetic scheme for compound 25 is below.PROCEDURE 3 FOR SYNTHESIS OF SO3.PY

[0275] To a solution of pyridine (4 mL) in DCM (20 mL) at 0°C, chlorosulfonic acid (1.6 mL) was added dropwise and the mixture stirred for 30 min. The reaction mixture was then filtered and the precipitate was washed with ice cold water (3 x 20 mL), ice cold sat. NaHCO3(2 x 10 mL), ice cold water (2 x 10 mL) (until the pH of the filtrate was 7), cold EtOH (2 x 20 mL), cold toluene (10 mL) and cold DCM (10 mL). The precipitated SO3.Py was then thoroughly dried under high vacuum and used within 24 h.GENERAL PROCEDURE 3 FOR CLICK REACTION

[0276] Sodium ascorbate (2 equiv.) and copper sulfate pentahydrate (1 equiv.) were added to a mixture of azide analogue (1 equiv.) and alkyne analogue (1 equiv. per N3) in l,4-dioxane / H2O (3: 1). The reaction mixture was then stirred at r.t. for 18 h. and filtered over a pad of celite. The filtrate was concentrated under reduced pressure andthe crude material was dissolved in EtOAc. The organic layer was washed with IM HCI, sat. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude material obtained was purified by flash column chromatography on silica gel to obtain the desired compound.GENERAL PROCEDURE 3 FOR ACETATE ESTER HYDROLYSIS

[0277] A solution of 30% aq. NH3(3-5 mL) and oligosaccharide in methanol (20 mL) was stirred at r.t. for 48 h. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ultra-pure water (5-10 mL) and washed with EtOAc (5 x 10 mL). The aqueous layer was concentrated to obtain the pure compound.GENERAL PROCEDURE 3 FOR SULFATION

[0278] Freshly prepared SO3.Py (10 equiv. per OH) complex was added to a solution of the starting material in dry DMF (10 mL) kept under nitrogen atmosphere. The reaction mixture was stirred at r.t. for 2 days and made basic using 5 M NaOH (2 equiv. per SO3.Py). The mixture was then concentrated under reduced pressure and the crude material was dissolved in ultra-pure water (10-20 mL) and dialyzed according to the general procedure.GENERAL PROCEDURE 3 FOR DIALYSIS

[0279] Commercially available Cellulose membrane dialysis tubing with MWCO of 0.5 kD, lkD and 2 kD were used for dialysis. The dialysis tubing was washed with mil I iQ water before use (approximately 5-10 mins of washing). One end of the dialysis tube was knotted and the sample was loaded into the tube. The tube was then closed using a clip, leaving little room for bubbles. A 3 L flask equipped with a stirrer bar was filled with milliQ water and placed on a magnetic stirring plate at room temperature. The stirring was set such that the dialysis bag slowly float around the top of the solution in the flask. After 2 h., the water was replaced with fresh milliQ water and dialysis continued for 2 days with the dialysis water being changed after every 18 h. The dialysis bag was then removed from the flask and the content of the bag was collected and freeze dried.SYNTHESIS OF COMPOUND 21

[0280] Click reaction of sucralose azide 2 (prepared according to Example 2) (2.05 g, 3.33 mmol) and 4-pentyn-l-ol (430 mg, 5.1 mmol) via general procedure 3 led to the compound 21 (2.00 g, 86%).1H NMR (CDCI3, 400 MHz): 6 = 7.47 (s, 1H, H-7'), 5.68-5.64 (m, 2H, H-l, H-3'), 5.36 (t, 1H, J = 7.2 Hz, H-4), 5.30-5.29 (m, 2H, H-4', H- 3), 4.76 (A part of ABX, 1H, J5,6a= 3.6 Hz, J6a,6b = 14.4 Hz, H-6a), 4.63 (B part of ABX, j5-6b= 8.7 Hz, J6a,6b = 14.4 Hz, H-6b), 4.60-4.54 (m, 2H, H-2, H-5'), 4.41-4.34 (m, 1H,H- 5), 4.28 (A part of ABX, J5-,6-a= 4.9 Hz, J6-a,6-b = 11.8 Hz, H-6'a), 4.21 (B part of ABX, J5',6'b = 6.7 Hz, J6-a,6-b = 11.8 Hz, H-6'b), 3.67 (t, 2H, Jio-,n- = 6.1 Hz, H-ll'), 3.61, 3.47 (ABq, 2H, J = 12.0 Hz, H-l'), 2.82 (t, 2H, J9-,io- = 7.3 Hz, H-9'), 2.11 (s, 3H, OCH3), 2.10 (s, 3H, OCH3), 2.07 (s, 6H, 2 x OCH3), 2.04 (s, 3H, OCH3), 1.96-1.87 (m, 2H, H-10');13C NMR (CDCI3, 100 MHz): 6 = 170.4, 170.2, 170.2 (x2), 169.6, 147.5 (C-8'), 122.6 (C- 7'), 103.9 (C-2'), 90.4 (C-l), 79.4 (C-5), 75.3 (C-4), 75.2 (C-2'), 68.1, 67.7, 67.0, 63.8 (C-6'), 61.5 (C-ll'), 58.9, 52.4 (C-6), 44.8 (C-9'), 31.7 (C-10'), 21.8, 20.7 (x2), 20.6 (OCH3), 20.5 (OCH3), 20.4 (OCH3).SYNTHESIS OF COMPOUND 2222

[0281] To a solution of the alcohol 21 (2.00 g, 2.86 mmol) in anhydrous DCM (20 mL), triethylamine (1.5 mL) and methanesulfonyl chloride (0.5 mL, 4.76 mmol) were added and stirred at r.t. for 18 h. The reaction mixture was washed with 1 M HCI (2 x 30 mL), sat. NaHCO3(30 mL), dried (MgSO4) and concentrated under reduced pressure. To a solution of the crude material in anhydrous DMF (20 mL), NaNs (304 mg, 4.76 mmol) was added and stirred at 60°C for 18 h. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in EtOAc (100 mL) and washed with 1 M HCI (50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (1.5: 1 EtOAc / Pet. Sp. to EtOAc) to obtain the azide 22 (1.24 g, 60%).1H NMR (CDCI3, 400 MHz): 6 = 7.43 (s, 1H, H-7'), 5.65-5.61 (m, 2H, H-l, H-3'), 5.34 (t, 1H, J = 7.2 Hz, H-4), 5.29-5.25 (2H, H-3, H-4'), 4.74 (A part of ABX, 1H, J5,6a= 3.6 Hz, J6a,6b = 14.3 Hz, H-6a), 4.60 (B part of ABX, J5,6b = 8.8 Hz, J6a,6b = 14.4 Hz, H-6b), 4.56-4.51 (m, 2H, H- 2, H-5'), 4.38-4.31 (m, lH,H-5), ), 4.25 (A part of ABX, J5-,6-a= 4.8 Hz, J6-a,6-b = 11.8 Hz, H-6'a), 4.17 (B part of ABX, J5', 6'b= 6.7 Hz, J6-a,6-b = 11.8 Hz, H-6'b), 3.58, 3.44 (ABq, 2H, J = 12.0 Hz, H-l'), 3.30 (t, 2H, J10-,11- = 6.7 Hz, H-ll'), 2.76 (t, 2H, J9-,io- = 7.4 Hz, H-9'), 2.08 (s, 3H, OCH3), 2.07 (s, 3H, OCH3), 2.03 (s, 6H, 2 x OCH3), 2.01 (s, 3H, OCH3),1.98-1.91 (m, 2H, H-10');13C NMR (CDCI3, 100 MHz): 6 = 170.2, 169.9 (x3), 169.5, 146.5, 122.3, 103.8, 90.3, 79.4, 75.2, 75.1, 68.0, 67.6, 66.8, 63.7, 58.8, 52.2, 50.5, 44.8, 28.3, 22.4, 20.6 (x2), 20.4, 20.3.SYNTHESIS OF COMPOUND 2323

[0282] Click reaction of the azide 22 (500 mg, 0.70 mmol) and propargyl maltotriose 11 (prepared according to Example 7) (700 mg, 0.70 mmol) via general procedure 3 gave the oligosaccharide 23 (700 mg, 59%) as a glassy solid;1H NMR (CDCI3, 400 MHz): 6 = 7.57 (s, 1H), 7.47 (s, 1H), 5.67-5.60 (m, 2H), 5.36-5.21 (m, 6H), 5.21-5.12 (m, 2H), 4.97 (t, 1H, J = 10.0 Hz), 4.86-4.68 (m, 5H), 4.68-4.49 (m, 5H), 4.46-4.28 (m, 5H), 4.23 (dd, 2H, J = 4.4 Hz, J = 12.0 Hz), 4.19-4.07 (m, 3H), 3.96 (dd, 1H, J = 2.3 Hz, J = 12.4 Hz), 3.93-3.81 (m, 4H), 3.73-3.62 (m, 1H), 3.57, 3.47 (ABq, 2H, J = 12.1 Hz), 2.73-2.57 (m, 2H), 2.24 (t, 2H, J = 6.7 Hz), 2.08-1.87 (15 x s, 45H);13C NMR (CDCI3, 100 MHz): 6 = 170.8, 170.4, 170.3 (x2), 170.1 (x2), 169.9, 169.8, 169.6, 169.5, 169.4 (x2), 169.2, 147.9, 145.7, 143.8, 123.0, 122.8, 103.9, 99.2, 95.5, 95.4, 90.4, 79.4, 75.2, 75.0, 73.6, 72.4, 72.0, 71.8, 71.5, 70.2, 69.8, 69.1, 68.7, 68.3, 68.0, 67.7, 67.6, 66.7, 63.8, 62.7, 62.6, 62.1, 61.2, 58.8, 52.3, 48.9, 44.6, 29.4, 21.8, 20.8, 20.7, 20.6 (x2), 20.5 (x2), 20.4, 20.3 (x2), 20.2.SYNTHESIS OF COMPOUND 2424

[0283] Acetate ester hydrolysis of compound 23 (700 mg, 0.42 mmol) according to general procedure 3 gave the oligosaccharide 24 (412 mg, 93%);1H NMR (D2O, 400 MHz): 6 = 8.02 (s, 1H), 7.79 (s, 1H), 5.43-5.38 (m, 3H), 4.98, 4.85 (ABq, 2H, J = 12.6 Hz), 4.68 (d, 1H, J = 7.9 Hz), 4.54 (d, 1H, J = 3.8 Hz), 4.51-4.40 (m, 4H), 4.24-4.15 (m, 2H), 4.04-3.55 (m, 21H), 3.44 (t, 1H, J = 9.3 Hz), 3.37 (dd, 1H, J = 1.3 Hz, J = 9.4 Hz, 1H), 2.73 (t, 2H, 7 = 7.1 Hz), 2.31 (p, 2H, J = 7.2 Hz, J = 13.8 Hz);13C NMR (D2O, 100 MHz): 6 = 177.3, 146.6, 143.5, 125.2, 124.1, 103.4, 101.9, 101.4, 99.8,99.6, 99.3, 92.4, 79.5, 78.9, 77.1, 76.9, 76.1, 75.6, 74.8, 74.6, 73.3, 72.9 (x2), 72.7, 71.8, 71.5, 71.2, 70.6, 69.3, 68.0, 67.5, 63.1, 62.0, 61.8, 60.7, 60.5, 52.1, 49.6, 43.8,28.7, 21.6.SYNTHESIS OF COMPOUND 2525

[0284] Sulfation of the deprotected pentamer 24 (235 mg, 0.22 mmol) according to general procedure 3 followed by dialysis gave the pentamer 25 (102 mg, 17%) as a white powder;1H NMR (D2O, 400 MHz): 6 = 8.21 (s, 1H), 7.98 (s, 1H), 5.83 (d, 1H, J = 3.4 Hz), 5.76-5.69 (m, 1H), 5.63 (d, 1H, J = 2.9 Hz), 5.42 (d, 1H, J = 7.4 Hz), 5.21-4.87 (m, 11H), 4.93-4.61 (m, 7H), 4.62-4.14 (m, 17H), 4.04, 3.95 (ABq, 2H, J = 12.1 Hz), 2.47-2.29 (m, 2H);13C NMR (CDCI3, 100 MHz): 6 = 125.7, 124.7, 103.6, 99.4, 94.4, 93.7, 90.9, 79.5 (x2), 78.3, 76.3, 76.1, 74.7, 73.6, 73.0, 72.6, 72.4, 71.8, 71.6, 71.4, 70.2, 69.8, 68.4, 67.8, 66.5, 66.0, 62.0, 60.3, 52.7, 49.7, 44.0, 29.0, 21.6.EXAMPLE 11 - Synthesis of compound 33 (G20)

[0285] The general synthetic scheme for compound 33 is shown below.SYNTHESIS OF METHYL 2,3,4,6-TETRA-O-ACETYL-ALPHA-D-MANNOPYRANOSIDE (COMPOUND26)

[0286] Anhydrous methanol (2.0 mL) was added to a stirred solution of1,2,3,4,6-penta-O-acetyl-D-mannopyranose 3 (2.0 g, 5.1 mmol) in dry DCM (50 mL).The mixture was cooled to 0°C and BF3.OEt2(8 mL, 56.0 mmol) was added dropwise.The resulting mixture was stirred for 15 min, brought to r.t., and the stirring was continued for 24 h. The reaction mixture was diluted with DCM (100 mL) and poured into ice-cold sat. NaHCO3(100 mL) solution. The resulting mixture was stirred until bubbling seized. The organic phase was then separated and washed with (3 x 50 mL)sat. NaHCO3, water (100 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was then purified by recrystallizing with Pet. Sp. / EtOAc (1 : 1) to obtain 26 (1.7 g, 92%) as colourless needle like crystals.1H NMR (CDCI3, 400 MHz): 5.33 (dd, 1H, J2,3 = 3.4 Hz, J3,4= 10.0 Hz, H-3), 5.30, 5.26 (ABq, 1H, J3,4= 9.9 Hz, H-4), 5.23 (dd, 1H, J1,2= 1.7 Hz, J2,3= 3.3 Hz, H-2), 4.71 (d, 1H, 3I,2= 1.7 Hz, H-l), 4.28 (A Part of ABX, 1H, J5.6a= 5.4 Hz, J6a,6b = 12.2 Hz, H-6a), 4.11 (B part of ABX, 1H, Js.eb = 2.4 Hz, J6a,6b = 12.4 Hz, H-6b), 3.96 (ddd, J5,6a = 2.4 Hz, J5,6b = 5.5 Hz, J4,5= 9.7 Hz, H-5), 2.15 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.98 (s, 3H, CH3);13C NMR (CDCI3, 100 MHz): 170.6, 170.0, 169.9, 169.7 (4 x CH3CO), 98.6 (C-l), 69.5 (C-2), 69.0 (C-3), 68.4 (C-5), 66.2 (C-4), 62.5 (C-6), 55.3 (OCH3), 20.8, 20.7, 20.6 (x2)(4 x CH3CO); ); HRMS (ESI); m / z [M + Na]+calculated for CI5H23OIO; found 363.1278.SYNTHESIS OF METHYL 2,3,4-TRI-O-BENZOYL-6-2,4,6-TRIISOPROPYLBENZENE SULFONYL- ALPHA-D-MANNOPYRANOSIDE (COMPOUND 27)

[0287] To a solution of mannopyranoside 26 (4.6 g, 12.9 mmol) in MeOH (50 mL), catalytic amount of sodium metal (~ 4 mg) was added and the mixture stirred at r.t. for 2 h. The reaction mixture was then neutralized with pre-washed acidic ion exchange resin (IR-120 H+), filtered and concentrated under reduced pressure. The crude material was dissolved in anhydrous pyridine (50 mL) and cooled to 0 °C. 2,4,6- triisopropylbenzene sulfonyl chloride (4.8 g, 25.2 mmol) was added to the reaction mixture and allowed to warm up to r.t., and stirred for 18 h. The reaction mixture was then cooled to 0°C and benzoyl chloride (5.2 mL, 47 mmol) was added and stirred at r.t. for 24 h. The reaction mixture was concentrated under reduced pressure by co- evaporating the pyridine with toluene. The crude residue obtained was dissolved in EtOAc (100 mL) and washed with 1 M HCI (2 x 50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Pet. Sp. / EtOAc 3: 1) on silica gel to afford the mannopyranoside 27 (5.2 g, 50%) as a colourless oil.1H NMR (CDCI3, 400 MHz): 8.09-8.04 (m, 2H, Ar-H), 7.95-7.88 (m, 2H, Ar-H), 7.83-7.77 (m, 2H, Ar-H), 7.65-7.32 (m, 7H, Ar-H), 7.29-7.21 (m, 2H, Ar-H), 7.13 (s, 2H, Ar-OTPS), 5.87 (dd, 1H, J2,3= 3.4 Hz, J3,4= 10.0 Hz, H-3), 5.73 (t, 1H, J3,4= J4,5= 10.0 Hz, H-4), 5.64 (dd, 1H, J1,2= 1.8 Hz, J2,3= 3.3 Hz, H-2), 4.94 (d, 1H, J1,2= 1.7 Hz, H-l), 4.46-4.38 (m, 1H, H-5), 4.32-4.22 (m, 2H, H-6), 4.11(sex, 1H, J = 6.9 Hz, J = 14.1 Hz, CH- / -pr), 3.49 (s, 3H, OCH3), 2.87 (h, 1H, J = 6.9 Hz, J = 13.7 Hz, J = 20.1 Hz, C / 7- / -pr), 1.23 (s, 3H, OCH3), 1.21 (s, 3H, OCH3), 1.19 (s, 3H, OCH3), 1.17 (s, 3H, OCH3), 1.16 (s, 3H, OCH3);13C NMR (CDCI3, 100 MHz): 165.6, 165.5, 165.3 (3 x C=O), 153.7, 150.9, 133.5, 133.1, 129.9, 129.8, 129.7, 129.2 (x2), 129.0, 128.7, 128.6, 128.4, 128.2, 123.7 (Ar-OTPS), 98.4 (C-l), 70.3 (C-2), 69.7 (C-3), 69.1 (C-5), 68.0 (C-6), 67.1 (C-4), 55.6 (OCH3), 34.2 (CH- / -pr), 29.6 (CH- / -pr), 24.7 (x2), 23.5 (6 x CH3).SYNTHESIS OF OCTYL 2,3,4-TRI-O-BENZOYL-6-AZIDO-ALPHA-D-MANNOPYRANOSIDE (COMPOUND 28)

[0288] To a solution of 27 (5.2 g, 6.61 mmol) in dry DMF (20 mL), NaNs (600 mg, 25 mmol) was added and the mixture was stirred at 60 °C for 24 h. The reaction mixture was then decanted and the residue left in the flask was washed with EtOAc (3 x 5 mL). The combined organic layer was then concentrated under reduced pressure. The crude material was dissolved in EtOAc (100 mL)and washed with IM HCI (2 x 50 mL), sat. NaHCO3(50 mL), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Pet. Sp. / EtOAc 1: 1) to obtain the azide 28 (3.0 g, 85%) as colourless oil.1H NMR (CDCI3, 400 MHz): 8.18 (m, 2H, Ar-H), 8.01-7.94 (m, 2H, Ar-H), 7.88-7.82 (m, 2H, Ar-H), 7.68-7.61 (m, 1H, Ar-H), 7.58-7.49 (m, 3H, Ar-H), 7.48-7.37 (m, 3H, Ar-H), 7.32-7.24 (m, 2H, Ar-H), 5.94-5.84 (m, 2H, H-3, H-4), 5.71 (dd, J1,2= 1.9 Hz, J2,3= 2.9 Hz, H-2), 5.03 (d, 1H, J1,2= 1.7 Hz, H-l), 4.32-4.24 (m, 1H, H-5), 3.59 (s, 3H, OCH3), 3.58-3.52 (m, 1H, H-6a), 3.48 (dd, 1H, J5,6b = 2.6 Hz, J6a, 6b = 13.3 Hz, H-6b);13C NMR (CDCI3, 100 MHz): 165.6, 165.6, 165.3, 133.5, 133.1, 129.9, 129.8, 129.7, 129.2, 129.0, 128.8, 128.6, 128.5, 128.2, 98.6 (C-l), 70.3 (C-2), 70.3 (C-5), 69.7 (C-3), 67.8 (C-4), 55.6 (OCH3), 51.3 (C-6); HRMS (ESI); m / z [M + Na]+calculated for C28H25O8N3Na; found 568.1686.SYNTHESIS OF COMPOUND 2929

[0289] Click reaction of mannopyranoside 12 (300 mg, 0.37 mmol) and mannose azide 28 (198 mg, 0.37 mmol) via general procedure 3 gave the disaccharide as a glassy solid. To a solution of disaccharide in dry DMF (20 mL), sodium azide (50 mg, 0.68 mmol) was added and the mixture stirred at 60°C under a nitrogen atmosphere for 18 h. The reaction mixture was then concentrated under reduced pressure and the crude material obtained was suspended in EtOAc (75 mL). The organic layer was washed with HCI (2 x 75 mL), sat. NaHCO3, dried (MgSO4) and concentrated. The crude material was then purified by flash column chromatography to obtain 29 (140 mg, 34%).1H NMR (CDCh, 400 MHz): 8.14-8.05 (m, 4H, Ar-H), 8.05-7.98 (m, 2H, Ar-H), 7.97-7.91 (m, 3H, Ar-H, H-tirazole), 7.86-7.77 (m, 4H, Ar-H), 7.67-7.58 (m, 2H, Ar-H), 7.58-7.46 (m, 6H, Ar-H), 7.46-7.33 (m, 6H, Ar-H), 7.30-7.21 (m, 4H, Ar-H), 5.93 (dd, 1H, J2,3= 3.3 Hz, J4,5= 9.9 Hz, H-3), 5.93-5.76 (m, 3H, H-4', H-4, H-3'), 5.68 (dd, 1H, 3I,2= 1.7 Hz, J2,3= 3.3 Hz, H-2), 5.65 (dd, 1H, Jr, 2' = 1.8 Hz, J2-,3- = 3.2 Hz, H-2'), 5.22 (d, 1H, Jr, 2' = 1.6 Hz, H- 1'), 4.99 (d, 1H, J1,2= 1.6 Hz, H-l), 4.99, 4.84 (ABq, 2H, J = 12.2 Hz, H-7), 4.88-4.79 (m, 1H, H-6a'), 4.64 (dd, 1H, J = 8.9 Hz, J = 14.1 Hz, H-6b'), 4.55 (ddd, 1H, J = 1.9 Hz, J = 9.5 Hz, H-5'), 4.37-4.30 (m, 1H, J = 4.9 Hz, J = 9.0 Hz, H-5), 3.54-3.49 (m, 2H, H- 6), 3.27 (s, 3H, OCH3);13C NMR (CDCb, 100 MHz): 165.9, 165.5, 165.4, 165.3 (x3), 165.2, 143.4 (C-8), 133.8, 133.6 (x2), 133.6, 133.2, 129.9 (x2), 129.8, 129.7, 129.6 (x2), 129.2, 129.1, 128.9, 128.7, 128.6, 128.5 (x2), 128.4, 128.2, 124.8 (C-9), 98.6 (C-l), 96.8 (C-l'), 70.5 (C-5), 70.3 (C-2), 70.2 (C-2'), 69.6 (C-5'), 69.5 (C-4) , 69.3 (C- 4'), 68.2 (C-3'), 67.6 (C-3), 61.2 (C-7), 55.5 (OCH3), 51.3 (C-6'), 51.2 (C-6).SYNTHESIS OF COMPOUND 30

[0290] Click reaction of azide 29 (2.6 g, 2.4 mmol) and 5-hexyn-l-ol (0.4 mL,3.6 mmol) via general procedure 3 gave the crude disaccharide that was dissolved in DCM (20 mL) followed by the addition of triethylamine (2.5 mL, 18 mmol) and mesyl chloride (0.27 mL, 3.6 mmol). After stirring at room temperature (3 h), the reaction was washed with IM HCI (100 mL), water (100 mL) with the organic dried and concentrated under reduced pressure. The crude mesylate was dissolved in dry DMF (70 mL) followed by the addition of sodium azide (0.5 g, 7.7 mmol). The resulting mixture was stirred at 60°C for 18 h. The reaction mixture was then concentrated under reduced pressure and the crude material obtained was suspended in EtOAc (75 mL). The organic layer was washed with HCI (2 x 75 mL), sat. NaHCO3, dried (MgSO4) and concentrated. The crude material was then purified by flash column chromatography (Pet. Sp. / EtOAc 1 :4 to 0:1) to obtain 30 (1.24 g, 43%).1H NMR (CDCh, 400 MHz): 8.14-7.75 (m, 13H, Ar-H), 7.70- 7.37 (m, 16H, Ar-H, H-tirazole), 7.31-7.24 (m, 6H, Ar-H), 5.92 (dd, 1H, , J = 3.5 Hz, J = 10.0 Hz), 5.85 (dd, 1H, , J = 3.3 Hz, J = 10.2 Hz), 5.82-5.72 (m, 2H), 5.67 (dd, 1H, J =1.7 Hz, J = 3.3 Hz), 5.59 (dd, 1H, J = 1.7 Hz, J = 3.3 Hz), 5.17, d, 1H, (dd, 1H, J = 1.5), 5.01, d, 1H, (dd, 1H, J = 1.6), 4.83 (dd, 1H, J = 2.1 Hz, J = 13.9 Hz), 4.78-4.70 (m, 1H), 4.68-4.49 (m, 6H), 3.28 (s, OCH3), 3.28-3.21 (m, 1H), 2.79-2.69 (m, 2H), 1.79- 1.67 (m, 3H), 1.67-1.56 (m, 2H);13C NMR (CDCh, 100 MHz): 165.9, 165.8, 165.4,165.3, 165.3, 165.2, 133.9, 133.8, 133.8, 133.7, 133.3, 133.2, 130.0, 129.9, 129.8, 129.7, 129.7, 129.2, 129.0, 129.0, 128.8, 128.7, 128.7, 128.6, 128.4, 128.3, 128.3, 98.6, 96.3, 77.3, 70.4, 70.3, 69.6, 69.5, 69.4, 68.2, 68.0, 60.5, 55.6, 51.5, 51.3, 51.0,28.3, 26.3, 24.6.SYNTHESIS OF COMPOUND 31

[0291] Click reaction of azide 30 (400 mg, 0.33 mmol) and propargyl maltotriose 11 (320 mg, 0.33 mmol) via general procedure 3 gave oligosaccharide 31 (486 mg, 68%) as a glassy solid;1H NMR (CDCh, 400 MHz): 6 8.09-7.90 (m, 9H, Ar-H, H-triazole), 7.87 (s, 1H, H-triazole), 7.83-7.74 (m, 4H, Ar-H), 7.67-7.57 (m, 3H, Ar-H), 7.57-7.45 (m, 7H, Ar-H), 7.44-7.32 (m, 7H, Ar-H), 7.25-7.17 (m, 2H, Ar-H), 5.89 (dd, 1H, J = 3.4 Hz, J = 10.0 Hz), 5.82 (dd, 1H, J = 3.3 Hz, J = 10.0 Hz), 5.78-5.68 (m, 2H), 5.68-5.63 (m, 1H), 5.58-5.53 (m, 1H), 5.44-5.31 (m, 4H), 5.28-5.19 (m, 2H), 5.13 (br- s, 1H), 5.06 (t, 1H, J = 10.0 Hz), 4.98 (br-s, 1H), 4.91-4.40 (m, 18H), 4.36-3.86 (m, 13H), 3.78-3.67 (m, 2H), 3.25 (s, 3H), 2.77-2.65 (m, 2H), 2.15 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.93(s,3H), 1.73-1.61 (m, 2H);13C NMR (CDCh, 100 MHz): 6 = 170.6 (x2), 170.5, 170.4, 170.3, 170.0, 169.8, 167.7, 169.6, 169.4, 165.8, 165.7, 165.3, 165.2 (x2), 147.0,143.8, 143.0, 133.7 (x3), 133.3, 133.2, 129.9, 129.8 (x2), 129.7, 129.2, 129.0, 128.9,128.8, 128.7, 128.6, 128.5, 128.3, 125.0, 122.9, 99.4, 98.6, 96.2, 95.7, 95.6, 77.2,75.2, 73.7, 72.5, 72.2, 72.0, 71.7, 70.4, 70.3, 70.2, 70.0, 69.5, 69.4, 69.3, 68.9, 68.5,68.2, 68.0, 67.9, 67.0, 62.9, 62.8, 62.3, 61.4, 60.4, 60.3, 55.5, 51.2, 51.0, 50.0, 29.6,26.1, 24.7, 20.9, 20.8 (x3), 20.6 (x2), 20.5 (x2).SYNTHESIS OF COMPOUND 32

[0292] Acetate and benzoyl ester hydrolysis of compound 31 (486 mg, 0.22 mmol) according to general procedure 2 gave the oligosaccharide 32 (252 mg, quant.) 1H NMR (D2O, 400 MHz): 6 = 7.91 (s, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 5.33 (t, 2H, J = 4.5 Hz), 4.92-4.74 (m, 4H), 4.62-4.60 (m, 1H), 4.55-4.42 (m, 3H), 4.30 (t, 2H, J = 6.9 Hz), 4.19 (ABq, 2H, J = 12.3 Hz), 3.95-3.45 (m, 23H), 3.37 (t, 1H, J = 9.4 Hz), 3.28 (dd, 1H, J = 8.0 Hz, J = 9.3 Hz), 2.96 (s, 3H), 2.68 (t, 2H, J = 7.1 Hz), 1.84-1.72 (m, 2H), 1.60-1.47 (m, 2H); );13C NMR (D2O, 100 MHz): 6 = 147.8, 143.4, 142.8, 125.9,125.1, 124.3, 101.4, 100.9, 99.8, 99.6, 99.0, 98.8, 77.1, 76.9, 76.1, 74.6, 73.3, 72.9, 72.7, 71.8, 71.5, 71.2, 71.0, 70.5 (x2), 69.8, 69.3, 68.0, 61.9, 60.7, 60.5, 58.8, 54.4,51.1, 51.0, 50.0, 28.5, 25.5, 23.8.SYNTHESIS OF COMPOUND 33

[0293] Sulfation of the deprotected oligosaccharide 32 (88.4 mg, 0.08 mmol) according to general procedure 3 followed by dialysis using general procedure 3 gave the oligosaccharide 33 (78.1 mg, 36%) as a white powder;1H NMR (D2O, 400 MHz): 6 = 8.16 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 5.78-5.69 (m, 1H), 5.67-5.60 (s, 1H), 5.26 (s, 1H), 5.23-4.88 (m, 11H), 4.89-4.62 (m), 4.63-4.34 (m, 15H), 4.34-4.09 (m, 8H), 3.06 (s, 3H), 2.07-1.91 (m, 2H), 1.79-1.62 (m, 2H);13C NMR (CDCh, 100 MHz): 6 = 147.9, 143.7, 142.9, 126.0, 125.5, 124.4, 99.3, 98.0, 96.0, 94.4, 93.7, 76.3, 75.3, 75.2, 74.8,73.6 (x2), 73.0, 72.8 (x2), 72.6, 71.8, 71.6, 70.6, 70.1, 69.8, 67.8, 66.5, 66.0, 62.1,59.5, 54.9, 51.1, 50.9, 50.1, 28.7, 25.6, 23.8.EXAMPLE 12 - Synthesis of compound 39 (G21)

[0295] Click reaction of propargyl mannose 12 (2.4 g, 3.00 mmol) and sucralose azide 34 (1.8 g, 2.9 mmol) via general procedure 3 led to the trisaccharide(3.7 g, 93%). To a solution of trisaccharide (1.0 g, 0.6 mmol) in dry DMF (50 mL), sodium azide (400 mg, 6.30 mmol) was added and the mixture stirred at 60°C under a nitrogen atmosphere for 18 h. The reaction mixture was then concentrated under reduced pressure and the crude material obtained was suspended in EtOAc (100 mL).The organic layer was washed with HCI (2 x 100 mL), sat. NaHCO3, dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography (1: 1 EtOAc / Pet. Sp.) on silica gel to obtain the azide 35 (1.7 g, 56%) as a glassy solid.1H NMR (CDCb, 400 MHz): 6 = 8.11 - 8.07 (m, 2H, H-Bz), 7.98 - 7.93 (m, 2H, H-Bz), 7.87 (s, 1H, triazole), 7.83 - 7.78 (m, 2H, H-Bz), 7.64 - 7.59 (m, 1H, H-Bz), 7.55 - 7.34 (m, 6H, H-Bz), 7.28 - 7.21 (m, 2H, H-Bz), 5.93 - 5.83 (m, 2H, H-3", H-4"), 5.77 - 5.71 (m, 2H, H-3, H-l), 5.68 (dd, 1H, J = 2.9 Hz, 1.8 Hz, H-3'), 5.42 (t, 1H, J = 7.2 Hz, H-4), 5.38 - 5.32 (m, 2H, H-2, H-2"), 5.25 (d, 1H, J = 1.8 Hz, H-l"), 5.04 (d, 1H, J = 12.5 Hz, H-7"a), 4.90 (m, 2H, H-7"b, H-6a), 4.77 (dd, 1H, J = 14.3 Hz, 9.0 Hz, H-6b), 4.66 - 4.59 (m, 2H, H-4', H-5'), 4.49 (m, 1H, H-5), 4.41 - 4.32 (m, 2H, H-5", H-6'b), 4.28 (dd, 1H, J = 11.8, 7.0 Hz, H-6'a), 3.65 (d, 1H, J = 12.0 Hz, H-l'a), 3.59 - 3.48 (m, 3H, H- l'b, H-6"a, H-6"b), 2.16 - 2.01 (5x s, 15H, 5x OAc) ppm;13C NMR (CDCb, 100MHz): 6 = 170.63 - 169.70 (5x C=O), 165.79 - 165.38 (3x C=O), 143.76 (C, triazole) 133.70 (CH, Bz), 133.70 (CH, Bz), 133.28 (CH, Bz), 130.33 - 129.58 (CH, Bz), 129.38 (C, Ar), 129.23 (C, Ar), 128.95 (C, Ar), 128.86 - 128.25 (6CH, Bz), 124.82 (CH, triazole), 104.33 (C, C-2'), 97.06 (CH, C-l"), 90.79 (CH, C-l), 79.71 (CH, C-5), 75.63 (CH), 75.57 (CH), 70.73 (CH, C-5"), 70.46 (CH, C-3'), 69.83 (CH), 68.51 (CH), 67.95 (CH), 67.79 (CH), 67.15 (CH, C-2), 64.17 (CH2, C-6'), 61.28 (CH2, C-7"), 59.09 (CH), 53.01 (CH2, C- 6), 51.37 (CH2, C-6"), 44.88 (CH2, C-l'), 20.92 - 20.61 (CH3) ppm.SYNTHESIS OF COMPOUND 37

[0296] Click reaction of propargyl acarbose 36 (300 mg, 0.26 mmol) and azide 35 (300 mg, 0.26 mmol) via general procedure 3 gave compound 37 (300 mg, 54%) as a glassy solid;1H NMR (CDCb, 400 MHz): 6 = 8.03-7.93 (m, 3H), 7.88 (s, 1H), 7.79- 7.72 (m, 2H), 7.65-7.59 (m, 1H), 7.56-7.45 (m, 3H), 7.44-7.35 (m, 3H), 7.25-7.19 (m, 2H), 5.95 (d, 1H, J = 5.2 Hz), 5.87 (dd, 1H, J = 3.3 Hz, J = 9.9 Hz), 5.83-5.80 (m, 1H), 5.78-5.68 (m, 2H), 5.67-5.47 (m, 3H), 5.23 (dd, 1H, J = 4.1 Hz, J = 12.0 Hz), 5.20-5.15 (m, 2H), 5.10 (t, 1H, J = 10.2 Hz), 4.97-4.84 (m, 3H), 4.83-4.68 (m, 6H), 4.68-4.54 (m, 7H), 4.54-4.41 (m, 3H), 4.44-4.22 (m, 4H), 4.20-4.13 (m, 1H), 3.97 (t, 1H, J = 9.4 Hz), 3.93-3.86 (m, 2H), 3.77-3.58 (m, 4H), 3.58-3.48 (m, 1H), 2.39 (t, 1H, J = 10.1 Hz), 2.15 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.96 (x2) (s, 3H), 1.94 (s, 3H), 1.88 (s, 3H), 1.20 (d, 3H, J = 6.2 Hz);13C NMR (CDCb, 100 MHz): 6 = 170.9,170.7, 170.6, 170.5, 170.4, 170.3 (x2), 170.2 (x2), 170.1, 170.0, 169.8 (x2), 169.7,169.6, 165.7, 165.3, 165.2, 144.1, 143.2, 133.9, 133.7, 133.6, 133.1, 129.9, 129.8,129.6, 129.1, 128.9, 128.6, 128.5, 128.2, 127.9, 124.7, 124.6, 104.1, 99.4, 96.5, 95.8,95.6, 90.6, 79.4, 75.4, 75.3, 73.3, 72.2, 72.1 (x2), 72.0, 71.8, 71.1, 70.8, 70.6, 70.4, 70.3, 70.0, 69.7, 69.5, 69.1, 68.3, 68.0, 67.9, 66.7, 64.1, 63.0, 62.7, 62.4, 62.2, 61.1,60.7, 59.0, 52.7, 52.1, 51.0, 44.7, 20.8 (x2), 20.7, 20.6 (x3), 20.5 (x2), 18.1.SYNTHESIS OF COMPOUND 38

[0297] Acetate and benzoyl ester hydrolysis of compound 37 (300 mg, 0.13 mmol) according to general procedure 2 gave the oligosaccharide 38 (140 mg, 83%)1H NMR (D2O, 400 MHz): 6 = 8.18 (s, 1H), 8.02 (s, 1H), 5.94 (d, 1H, J = 5.2 Hz), 5.49 (d, 1H, J = 4.1 Hz), 5.39 (d, 1H, J = 3.9 Hz), 5.34 (d, 1H, J = 3.3 Hz), 5.03, 5.13 (ABq, 2H, J = 12.6 Hz), 4.98-4.95 (m, 1H), 4.87-4.82 (m, 1H), 4.65 (dd, 1H, J = 8.1 Hz, J = 14.6 Hz), 4.59-4.42 (m, 5H), 4.32-3.53 (m, 32H), 3.33 (dd, 1H, J = 8.2 Hz, J = 9.2 Hz), 2.60 (t, 1H, J = 9.3 Hz), 1.39 (d, 3H, J = 6.2 Hz); );13C NMR (D2O, 100 MHz): 6 = 143.5, 139.9, 126.5, 125.7, 122.6, 103.5, 101.1, 99.8, 99.6 (x2), 92.5, 79.5, 77.2 (x2), 76.1,75.5, 74.9, 74.6, 73.3, 72.8 (x2), 72.7, 72.4, 71.5, 71.2, 71.1, 71.0, 70.4, 70.3, 69.8, 69.0, 68.0, 67.8, 67.5, 64.7, 63.1, 61.9, 61.7, 61.6, 60.7, 60.5, 59.8, 56.1, 52.5, 51.0,43.6, 17.3.SYNTHESIS OF COMPOUND 39

[0298] Sulfation of the deprotected oligosaccharide 38 (88 mg, 0.04 mmol) according to general procedure 3 followed by dialysis according to general procedure 3 gave the oligosaccharide 39 (79 mg, 57%) as a white powder;1H NMR (D2O, 400 MHz): 6 = 8.22 (s, 1H), 8.00 (s, 1H), 6.05 (s, 1H), 5.81-5.77 (m, 1H), 5.61-5.56 (m, 1H), 5.54-5.44 (m, 2H), 5.29 (d, 1H), 5.25-5.21 (m, 1H), 5.17-3.94 (m, 44H), 3.465-3.33 (m, 1H), 1.52-1.40 (m, 2H);13C NMR (CDCI3, 100 MHz): 6 = 132.7, 103.4, 99.4, 96.5,94.0, 90.8, 79.4, 79.3, 78.1, 76.4, 75.6, 75.1, 74.1, 73.5, 73.2, 72.8, 72.4, 72.2, 71.8,71.3, 70.1, 69.9, 68.3, 68.2, 67.7, 67.6, 66.3, 62.1, 60.2, 60.0, 53.0, 51.8, 51.0, 43.8,18.3.EXAMPLE 13 - Synthesis of compound 44 (G23)N44

[0299] The general synthetic scheme for compound 44 is shown below:SYNTHESIS OF SUCRALOSE-MANNOSE-MANNOSE-SUCRALOSE (COMPOUND 42)

[0300] Click reaction of 1,5-hexadiyne 41 (20 mg, 0.26 mmol) and azide 40 (520 mg, 0.53 mmol) via general procedure 3 gave compound 42 (0.41 mg, 77%) as a glassy solid;1H NMR (CDCh, 400 MHz): 6 = 7.64 (s, 1H), 7.58, (s, 1H), 5.79 (d, J = 3.6 Hz, 1H), 5.73 (d, J = 7.6 Hz, 1H), 5.37-5.41 (m, 2H), 5.26-5.31 (m, 2H), 5.15-5.20 (m, 1H), 5.11 (dd, J = 6.0, 6.0 Hz, 1H), 4.82-4.86 (m, 2H), 4.70 (dd, J = 14.0, 9.2Hz, 1H), 4.57-4.63 (m, 2H), 4.51 (dd, J = 14.3, 2.5 Hz, 1H), 4.35-4.47 (m, 4H), 4.30 (dd, J = 11.7, 4.5 Hz, 1H), 4.19-4.26 (m, 2H), 3.67 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 3.11 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H) ppm;13C NMR (CDCh, 100 MHz): 6 = 170.4, 170.2, 170.2, 170.0, 169.9, 169.8, 169.7, 169.7, 169.7, 146.9, 143.2, 124.4, 122.9,104.1, 96.2, 90.7, 79.5, 75.1, 75.3, 69.4, 68.7,, 68.5, 68.3, 68.0, 67.4, 66.7, 66.1.64.1, 62.5, 60.3, 59.1, 52.8, 50.8, 44.7, 21.0-20.6 ppm.SYNTHESIS OF COMPOUND 43

[0301] Acetate ester hydrolysis of compound 42 (410 mg, 0.30 mmol) according to general procedure 3 gave the oligosaccharide 43 (275 mg, 100%);1H NMR (D2O, 400 MHz): 6 = 7.90 (s, 1H), 7.8 (s, 1H), 5.46 (d, J = 4.0 Hz, 1H) 4.96-4.72 (m, 2H), 4.69 (dd, J = 14.8, 2.0 Hz, 1H), 4.55 (d, J = 3.6 Hz, 1H), 4.43-4.51 (m, 4H), 4.36 (d, J = 12.4 Hz, 1H) 4.18-4.27 (m, 4H), 3.91-3.99 (m, 2H), 3.75-3.88 (m, 4H), 3.72 (d, J = 11.6 Hz, 1H), 3.68 (d, J = 11.6 Hz, 1H), 3.58 (dd, J = 9.6, 9.6, 1H), 307 (s, 2H);13C NMR (D2O, 100 MHz): 6 = 149.4, 145.8, 128.0, 126.8, 106.0, 101.9, 95.0, 82.2, 78.0, 77.5, 74.0, 73.5, 73.0, 72.3, 70.6, 70.4, 70.0, 65.7, 64.5, 61.9, 55.1, 53.4, 46.2, 26.5.SYNTHESIS OF COMPOUND 44

[0302] Sulfation of the deprotected oligosaccharide 43 (315 mg, 0.23 mmol) according to general procedure 3 followed by dialysis according to general procedure 3 gave the oligosaccharide 44 (350 mg, 51%) as a white powder;1H NMR (D2O, 400 MHz):6 = 8.05 (br. s, 2H), 5.86 (d, J = 0.8 Hz, 1H), 5.37 (d, J = 7.6 Hz, 1H), 5.11 (d, J =14.0 Hz, 1H) 5.05-4.61 (m, 10H), 4.53 (m, 2H), 4.44 (m, 2H), 4.25-4.35 (m, 4H), 3.98(d, J = 12.4 Hz, 1H), 3.92 (d, J = 12.4 Hz, 1H), 3.15 (br. s, 2H) ppm.EXAMPLE 14 - Synthesis of compound 47 (G16)

[0303] The general synthetic scheme for compound 47 is shown below:SYNTHESIS OF COMPOUND 45

[0304] Click reaction of propargyl acarbose 36 (400 mg, 0.42 mmol) and sucralose azide 34 (105 mg, 0.17 mmol) via general procedure 3 gave oligosaccharide 45 (100 mg, 33%) as a glassy solid;1H NMR (CDCI3, 400 MHz): 6 = 7.65 (s, 1H), 5.93 (d, 1H, J = 5.4 Hz), 5.73-5.64 (m, 2H), 5.59-5.48 (m, 2H), 5.40-5.28 (m, 3H), 5.26- 5.16 (m, 3H), 5.07 (t, 2H, J = 10.1 Hz), 4.93-4.86 (m, 2H), 4.85-4.54 (m, 9H), 4.54-4.11 (m, 8H), 3.96 (t, 1H, J = 9.2 Hz), 3.92-3.85 (m, 2H), 3.77-3.65 (m, 2H), 3.62, 3.49 (ABq, 2H, J = 12.1 Hz), 3.54-3.45 (m, 1H), 2.36 (t, 1H, J = 9.9 Hz), 2.14 (s, 3H),2.12 (2, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.07 (s, 6H), 2.06 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.97 (x2) (s, 9H), 1.95 (x2) (s, 6H), 1.93 (s, 3H), 1.17 (d, 3H, J = 6.1 Hz) ppm;13C NMR (CDCI3, 100 MHz): 6 = 171.0, 170.9, 170.7, 170.6, 170.5, 170.3 (x2), 170.2, 170.1 (x2), 170.0, 169.8, 169.6 (x2), 169.5, 133.8, 127.9, 124.2, 104.1, 99.2, 95.8, 95.6, 90.5, 79.5, 77.2, 75.3, 75.2, 75.1, 73.4, 72.1 (x2), 71.9, 71.8, 71.0,70.8, 70.6, 70.4, 70.0, 69.7, 69.0, 68.2, 67.7, 66.8, 63.9, 63.0, 62.7, 62.6, 62.2, 61.1,58.9, 52.5, 52.1, 20.9, 20.8 (x2), 20.6 (x2), 20.5 (x2), 20.4, 18.1 ppm.SYNTHESIS OF COMPOUND 46

[0305] Acetate ester hydrolysis of compound 45 (150 mg, 0.08 mmol) according to general procedure 3 gave the oligosaccharide 46 (86 mg, 96%);1H NMR (D2O, 400 MHz): 6 = 8.05 (s, 1H), 5.88-5.81 (m, 1H), 5.42 (d, 1H, J = 4.1 Hz), 5.31 (d, 1H, J = 3.9 Hz), 5.26 (d, 1H, J = 3.9 Hz), 4.93, 4.85 (ABq, 2H, J = 12.7 Hz), 4.49 (dd, 1H, J = 0.9 Hz, J = 3.9 Hz), 4.48-4.35 (m, 3H), 4.23-4.07 (m, 5H), 4.05-4.00 (m, 1H), 3.94-3.82 (m, 4H), 3.82-3.63 (m, 12H), 3.63-3.45 (m, 5H), 3.28 (dd, 1H, J = 8.1 Hz, J = 9.4 Hz), 2.70 (t, 1H, J = 10.1 Hz), 1.31 (d, 3H, J = 6.3 Hz); );13C NMR (D2O, 100 MHz): 6 = 143.4, 141.8, 126.4, 120.5, 103.5, 100.9, 99.9, 99.6, 92.5, 79.5, 77.4, 77.1, 76.2, 75.6, 74.9, 74.6, 73.3, 72.8, 72.6, 72.5, 71.5, 71.3, 71.2, 71.0, 70.9, 69.3, 69.0,67.8, 67.5, 64.2, 63.1, 61.9, 61.7, 61.4, 60.7, 60.5, 56.1, 52.5, 43.6, 17.3.SYNTHESIS OF COMPOUND 47

[0306] Sulfation of the deprotected oligosaccharide 46 (41 mg, 0.04 mmol) according to general procedure 3 followed by dialysis using general procedure 3 gave the oligosaccharide 47 (63 mg, 59%) as a white powder;1H NMR (D2O, 400 MHz): 6 = 8.17 (s, 1H), 6.15 (s, 1H), 5.89 (d, 1H, J = 3.6 Hz), 5.72-5.52 (m, 3H), 5.40 (d, 1H, J = 7.8 Hz), 5.26-4.86 (m, 16H), 4.74-4.58 (m, 5H), 4.57-4.06 (m, 16H), 4.00, 3.93 (ABq, 2H, J = 12.2 Hz), 1.55 (d, 3H, J = 6.2 Hz).EXAMPLE 15 - Inhibition of cvtokine activityIL-5 mediated cell proliferation assay

[0307] The Ba / F3 cell line was transformed to be both IL-5 dependent and to express luciferase by co-transfection of the cells with pGL3 control vector (Promega, Madison, Wisconsin, USA) and pEE6hcmv-IL-5Ro. The control vector, pGL3 expresses a modified luciferase under the direct control of the SV40 promoter and enhancer, but contains no selectable marker. To prepare pEE6hcmv-hIL-5Ro a full length human IL-5 receptor a chain (hIL-5R-o) was cloned by RT PCR from HL60 cells. The preparation of the Ba / F-IL-5 cells has been described by Coombe et al. (1998) Journal of Immunological Methods, 215(1): 145-150. The Ba / F-IL-5 cells may be further modified by co- transfection with pPGK-puromycin-luciferase, a vector containing luciferase under the control of the SV40 promotor with the selectable marker puromycin.

[0308] After transfection, positive transfectants were selected in 3 pg / mL puromycin. The positive transfectants were then cloned to produce a line with detectable luciferase expression. The proliferation assays were carried out in 96-well microplates suitable for such assays (Falcon, Corning Inc., Corning, New York, USA). The wells were flat bottomed, with white sides and a clear bottom. Cells were washed to remove any cytokine in the growth medium and then resuspended in Roswell Park Memorial Park Institute medium (RPMI) / 5% w / v Fetal Calf Serum (FCS). The cells were counted and 1.6 x 104cells were added to microplate wells that contain either no IL-5 (negative control) or various dilutions of IL-5. When the effect of the test compounds was to be measured (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14), the wells also contained various concentrations of these compounds.

[0309] The cells proliferated for 24 hours at 37°C in a humidified atmosphere, after which the luciferase activity was measured by the addition of 50 pL of luciferase substrate buffer (50 mM Tris-HCI, pH 7.8, 15 mM MgS04, 33.3 mM dithiothreitol (DTT), 0.1 mM ethylenediaminetetraacetic acid (EDTA), 0.5 mM Na-luciferin, 0.5 mM ATP, 0.25 mM lithium Co A and 0.5% v / v Triton X-100). Immediately after the addition of the luciferase buffer the plate was assayed for luciferase activity. Light emissions were detected on a Multi-label plate reader.

[0310] The results are presented in Figures 1A and IB. The ICso values are presented in Table 1. It is clear that a number of the test compounds were effective inhibitors of IL-5 dependent Ba / F-IL-5 cell proliferation.TABLE 1INHIBITION OF CYTOKINE MEDIATED CELL PROLIFERATION (ICso)IL-13 mediated cell proliferation assay

[0311] These experiments utilize TF-1 cells that are grown in 2 ng / mL recombinant human (rh) GM-CSF. TF-1 cells were originally established from a bone marrow sample from a male with severe pancytopenia. These cells are dependent on IL- 3 or GM-CSF for long term growth and are responsive to a variety of human cytokines including IL-13.

[0312] Briefly, proliferation assays were carried out in 96-well microplates suitable for such assays. Routinely, the cells were cultured in low dose rhGM-CSF (0.1 ng / mL) for 24 hours before the assay. Cells were washed to remove any cytokine in the growth medium and then resuspended in RPMI / 5% w / v FCS and 2.5 x 104cells were added to microplate wells that contain either no rhIL-13 (negative control) or various dilutions of rhIL-13. Routinely rhIL-13 was titrated from a starting concentration of 25 ng / mL. When the effect of the test compounds (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14) was measured, the wells alsocontained various concentrations of these compounds and the rhIL-13 concentration was held constant at 4 ng / mL. The cells proliferated for 48 hours, after which the number of cells present was quantified by staining. 20 pL per well of the CellTiter 96 Aqueous One reagent (Promega, Madison, Wisconsin, USA) was incubated with TF1 cells for the last 3.5 to 4 hours of culture and then absorbance was read at 490 nm on an Enspire Multimode plate reader (PerkinElmer, Waltham, MA, USA).

[0313] The results are presented in Figures 2A and 2B. The ICso values are presented in Table 1. It is clear that a number of the test compounds were very effective inhibitors of IL-13 mediated cell proliferation.IL-4 mediated cell proliferation assay

[0314] These experiments utilize TF-1.8 cells. TF-1.8 cells are a subclone of the TF-1 cells that have been selected for growth in IL-4 or IL-5. TF-1 cells were originally established from a bone marrow sample from a male with severe pancytopenia. These cells are dependent on IL-3 or GM-CSF for long term growth and are responsive to a variety of cytokines including IL-4.

[0315] TF-1.8 cells were transfected with the firefly luciferase gene contained in the expression vector, pPGK-puromycin-luciferase (Coombe et al, 1998, supra). The positive transfectants were cloned to produce a line with good luciferase expression. The proliferation assays were carried out in 96-well microplates suitable for such assays (Falcon, Corning Inc., Corning, New York, USA). The wells were flat bottomed, with white sides and a clear bottom. Cells were washed to remove any cytokine in the growth medium and then suspended in RPMI / 5% w / v FCS. The cells were counted and 2.5 x 104cells were added to microplate wells that contain either no IL-4 (negative control) or various dilutions of IL-4. When the effect of the test compounds (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14) was measured, the wells also contained various concentrations of these compounds.

[0316] The cells proliferated for 48 hours at 37 °C in a humidified atmosphere, after which the luciferase activity was measured by the addition of 50 pL of luciferase substrate buffer (50 mM Tris-HCI, pH 7.8, 15 mM MgSO4, 33.3 mM DTT, 0.1 mM EDTA, 0.5 mM Na-luciferin, 0.5 mM ATP, 0.25 mM lithium Co A and 0.5% v / v Triton X-100). Immediately after the addition of the luciferase buffer the plate was assayed for luciferase activity. Light emissions were detected on a Multi-label plate reader.

[0317] The results are presented in Figures 3A and 3B. The ICso values are presented in Table 1. It is evident from this figure that a number of the test compounds markedly inhibit the IL-4 dependent proliferation of TF-1.8 cells.IL-33 mediated cell proliferation assay

[0318] These experiments utilized TF1.8 cells. TF1.8 cells are a sub-clone ofTF1 cells that were selected to respond to IL-5 and transfected with the luciferase reporter gene contained in the expression vector, pPGK-puromycin-luciferase (Coombe et al, 1998, supra), so proliferation can be determined by measuring luciferase activity. TF- 1 cells were originally established from a bone marrow sample from a male with severe pancytopenia and are dependent on IL-3 or GM-CSF for long term growth but are responsive to a variety of cytokines. The positive transfectants were cloned to produce a line with good luciferase expression and are routinely grown in 10 ng / mL rhIL-5.

[0319] The expression of ST2 on TF1.8 cells was confirmed using flow cytometry and the polyclonal goat anti-human ST2 / IL-1 R4 antibody (R8iD Systems, Minneapolis, Minnesota, USA). Titrations indicated that the use of 0.5 pg of R4 / test (or 10 pg / mL) was saturating as the signal achieved with TF1.8 cells did not increase with a higher antibody concentration.

[0320] Briefly, proliferation assays in the presence of IL-33 were carried out in 96-well microplates suitable for such assays. Routinely, TF1.8 cells that have been cultured for 2 days were split to 30 x 104 / mL in maintenance level 10 ng / mL rhIL-5 and cultured for 24 hours before the assay. Cells were washed to remove any cytokine in the growth medium and then resuspended in RPMI / 5% w / v FCS and 2.5 x 104cells were added to microplate wells that contain either no cytokine or various dilutions of rhIL-33. When the effect of the test compounds (G16, G19, G20, G21, G22, G23 and G24 , prepared in accordance with Examples 1-14) was measured, the cells were preincubated with various concentrations of these compounds (10 pg / mL and 2.5 pg / mL) for at least an hour at 37° C, followed by the addition of rhIL-33 at the desired concentration. The cells proliferated for 48 hours, after which the number of cells present was quantified by measuring luciferase activity. The luciferase activity was measured by the addition of 50 pL of luciferase substrate buffer (50 mM Tris-HCI, pH 7.8, 15 mM MgS04, 33.3 mM DTT, 0.1 mM EDTA, 0.5 mM D-luciferin, 0.5 mM ATP, 0.25 mM lithium Co A and 0.5% v / v Triton X-100). Immediately after the addition of the luciferase buffer the plate was assayed for luciferase activity (cell proliferation). Light emissions were detected using a 2300 EnSpire Multimode Plate Reader (PerkinElmer, Waltham, MA, USA).

[0321] The results are presented in Figures 4A and 4B. The IC50values are presented in Table 1. The test compounds were inhibitors of IL-33 mediated cell proliferation.IL-8 mediated chemotaxis assay

[0322] These experiments were performed using dimethylsulfoxide (DMSO) treated human promyelocytic HL-60 cells. These cells were derived from a patient withacute promyelocytic leukemia. The cells were treated with DMSO (1.2%) for 4 days before being used in the experiments. The chemotaxis assays were performed in 96-well Costar chemotaxis plates consisting of a bottom chamber to which was added the human IL-8 with or without the test compounds (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14) and then cells in RPMI and 1% v / v FCS were added to a top chamber and the plate was incubated at 37 °C for 1 hour to allow cells to move from the top chamber into the bottom. The number of cells migrating into the bottom chamber was quantified by labeling with CellTiter 96 Aqueous One reagent (20 pL / well) (Promega, Madison, Wisconsin, USA) for 1.75 hours before absorbance at 490 nm was read. IL-8 was used at a final concentration of 20 ng / mL and the test compounds were used at 50 pg / mL, % inhibition data are shown. Mean and upper and lower limits are represented.

[0323] The results are presented in Figure 5. The majority of the test compounds were inhibitors of IL-8 mediated chemotaxis.IL-2 cell proliferation assay

[0324] The murine cytotoxic T lymphocytic line (CTLL) is a subclone of T cells derived from a C57bl / 6 mouse. The cells require interleukin-2 (IL-2) for growth and are used to assay for its presence in conditioned media. The cells are responsive to both murine and human IL-2. CTLL cells were transfected with the firefly luciferase gene contained in the expression vector, pPGK-puromycin-luciferase (Coombe et al, 1998, supra). The positive transfectants were cloned to produce a line with good luciferase expression and these cells were called CTL-Luc. The proliferation assays were carried out in 96-well microplates suitable for such assays (Falcon, Corning Inc., Corning, New York, USA). The wells were flat bottomed, with white sides and a clear bottom. Cells were washed to remove any cytokine in the growth medium and then suspended in RPMI / 5% w / v FCS. The cells were counted with a Coulter Z2 Particle Counter and Size Analyzer (Coulter Electronics, England) and 1.6 x 104cells were added to microplate wells that contained either no rhIL-2 (negative control) or various dilutions of rhIL-2. When the effect of the test compounds (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14) was measured, the wells also contained various concentrations of these compounds.

[0325] The CTL-Luc cells proliferated for 24 hours at 37 °C in a humidified atmosphere, after which the luciferase activity was measured by the addition of 50 pL of luciferase substrate buffer (50 mM Tris-HCI, pH 7.8, 15 mM MgSCX M 33g.S3O4mM DTT, 0.1 mM EDTA, 0.5 mM Na-luciferin, 0.5 mM ATP, 0.25 mM lithium Co A and 0.5% v / v Triton X-100). Immediately after the addition of the luciferase buffer the plate was assayed forluciferase activity. Light emissions were detected on a Victor 1420 Multi-label counter (Wallac, Turku, Finland).

[0326] Experiments in which the CTL-Luc cells were cultured in the presence of either 10 pg / mL or 1 pg / mL of test compounds reproducibly have no effect on the proliferation of CTL-Luc cells obtained with 1.25 ng / mL of rhIL-2 (Figure 6). The results of these experiments with the IL-2 responsive cell line suggest that none of the test compounds interacted with IL-2 in a manner that affects the proliferative activity. These results also suggest that the test compounds are not toxic to cytokine dependent lymphocytic cell lines.GM-CSF dependent cell proliferation assay

[0327] Briefly, TF-1.8 cells, a subclone of TF-1 transfected with the pPGK- puromycin-luciferase expression vector (refer to Coombe et al, 1998, supra), were added to microplate wells that contained either no GM-CSF (negative control), GM-CSF, or GM- CSF plus various concentrations of test compounds (G16, G19, G20, G21, G22, G23 and G24, prepared in accordance with Examples 1-14). The cells were cultured for 48 hours at 37°C in a humidified 5% CO2incubator, after which the luciferase activity was measured by the addition of 50 μL of luciferase substrate buffer (50 mM Tris-HCI, pH 7.8, 15 mM MgSO4, 33.3 mM DTT, 0.1 mM EDTA, 0.5 mM Na-luciferin, 0.5 mM ATP, 0.25 mM lithium Co A and 0.5% v / v Triton X-100). Immediately after the addition of the luciferase substrate buffer the plate was assayed for luminescence on a Victor 1420 Multi-label counter (Wallac, Turku, Finland).

[0328] % of GM-CSF activity inhibition = (1 - (sample of interest 4- GM-CSF control)) x 100%, where both the "sample" and the "GM-CSF control" values have had the background fluorescence indicated by the negative control (cells only, no GM-CSF) removed.

[0329] The results are presented in Figure 7. The test compounds did not significantly inhibit GM-CSF mediated cell proliferation.EXAMPLE 16 - Effect of G24 and G16 in a guinea pig OVA model of allergic asthma

[0330] The aim of this experiment was to study the effects of G24 and G16 (prepared in accordance with Examples 6 and 14) in a guinea pig ovalbumin model of allergic asthma. The effect on the late phase, 8 h post challenge, allergic reaction was investigated. Readouts were compound effect on number of cells, and concentration of total protein in bronchoalveolar lavage (BAL).

[0331] At arrival, a health check was performed on the guinea pigs, and they were allowed an acclimatization period of 5 days. The GP was housed 2-5 / two cages with an opening between, size for one cage is 65(L)x47(W)x30(H) cm, with a constanttemperature with 12-hour light / dark cycles. All animals had free access to food, tap water and cage enrichment. Animal welfare was monitored throughout the study duration. Animals exhibiting any of the following criteria were terminated: reduced mobility, changed movement pattern, rough or unkept fur, tense or unkept fur, tense abdomen and / or abnormal posture.

[0332] Guinea pigs (GP) were weighed, and colour coded for identification. GP were sensitized at days 0 and 7 by a 0.5 mL intraperitoneal (i.p.) injection of 10 pgEndoFit Ovalbumin (OVA) (Catalogue no. vac-pova; InvivoGen, San Diego, CA, USA) together with 20 mg Imject Alum (Catalogue no. 77161; Pierce Biotechnology, Rockford,IL, USA) in saline (0.9% NaCI) (Catalogue no. 3626865, B Braun, Melsungen, Germany).

[0333] Day 28 post experimental start, 30 min prior to the OVA challenge, theGP (n = 5 for each group) were treated with test compound (i.e. G24, synthesised in accordance with Example 6) / vehicle (Dulbecco's phosphate buffered saline (PBS); catalogue no. 12037539, Fisher Scientific UK, Loughborough, Leicestershire, UK) by an intrathecal (i.t.) instillation. The test compound concentration can be found in Table 2.The activity of the compound was compared to internal standard H in PBS, the negative control (PBS only with no sensitisation or OVA challenge), the positive control (PBS only) and budesonide (BUD) in a steroid vehicle. The GP was anaesthetized using isoflourane(4 %) O2 (1.4 L / min) and NO2 (1.2 L / min). When the GP reached sufficient anesthetic depth, it was placed in a supine position on a board with approximately 45 degrees decline. The volume administered was 200 pL. The i.t. administration was done with a syringe connected to a blunt steel cannula (with a small marble at the top to prevent injury to the airways). The GP was allowed to wake up in the supine position before returned to its cage.TABLE 2TEST INFORMATION

[0334] Day 28 post experimental start, the GP were challenged with 0.1 % OVA aerosol for 1.25 min. The OVA aerosol challenge was delivered to the animals using an inhalation tower exposure system and the aerosol generated using a vibrating mesh nebulizer (Aerogen Pro, Aerogen, Dangan, Galway, Ireland) from a solution of OVA (refer to, for example, Wong (2007) Toxicol Pathol. 35(1): 3-14).

[0335] At 8 h post challenge the animals were terminated. At termination theGPs were terminated by an overdose of pentobarbital-Na administered by intraperitoneal administration. Blood was drawn by heart puncture using vacutainer tubes pre-coated with Na-citrate. The blood was centrifuged at 1500 x g for 5 min and the plasma was aliquoted into two Eppendorf tubes and stored at -80 °C.

[0336] BAL was performed according to the following protocol. The GP was tracheostomized and a small tube placed in the trachea. A 10 mL syringe with 8 mL PBS(Catalogue no. 12037539, Fisher Scientific UK, Loughborough, Leicestershire, UK) was connected to the tube. The lungs were filled with the PBS. The PBS was left in the lungs for approximately 30 seconds and then aspirated back into the syringe. The syringe was then disconnected from the tubing and the BAL fluid collected into a sterile tube.Another 8 mL PBS was drawn into the syringe, the syringe connected to the tubing and the procedure above repeated once. In total of approximately 12-15 mL BAL fluid was collected. The BAL fluid was centrifuged at 1000 x g for 10 min, and the supernatant saved in three aliquots and stored at -80 °C awaiting cytokine and total protein analysis.

[0337] The total number of cells in BAL was counted by manually and cytospin slides were prepared for differential counting of the different inflammatory cell populations.

[0338] To analyse the total protein content of the BAL, a total protein assay (Pierce BCA Protein Assay kit; Catalogue no. 23225; Pierce Biotechnology, Rockford, IL, USA) was run according to the manufacturer's instructions. The BAL was analysed undiluted in both assays.

[0339] Data on cell count and differential counts of macrophage, lymphocyte, neutrophil and eosinophil populations, and total protein in BAL was summarized both as individual data points and means for the group with standard error of mean (SEM). Statistical analysis performed was a nonparametric Mann-Whitney test without Bonferroni correction. All statistical analyses were performed using GraphPad Prism for Mac OS X.

[0340] The results are provided in Table 3.TABLE 3LEUKOCYTE, EOSINOPHIL, NEUTROPHIL AND TOTAL PROTEIN CONTENT OF GUINEA PIGS FOLLOWING ADMINISTRATION OF G24 AND THE COMPARATIVE COMPOUNDSData is presented as mean per group ± SEM.

[0341] All animals coped well with sensitisation, and only a slightly lower increase in weight can be seen compared to controls during the sensitization period (Figure 8).

[0342] Sensitisation and challenge with OVA according to the protocol led to a significant increase in leukocytes in BAL in this experiment. The number of leukocytes was twice as many in the OVA control group (i.e. the positive control) as in the negative control and this was mainly due to a significant increase in influx of eosinophils and neutrophils into the lung (Table 3). G16 reduced the number of eosinophils to a level comparable to the internal standard, and although the neutrophil levels were raised with G16 this was due to one sample that could be viewed as an outlier. G16 shows promise as an anti-asthmatic in this experiment.

[0343] Total protein levels in BAL were also analysed, the levels were detectable but there was no significant difference between the negative control group and the OVA control group (Table 3). G16 did not increase the total protein levels in the BAL.EXAMPLE 17 - Effect of G24 in a mouse model of experimental allergic asthma

[0344] The therapeutic effects of G24 (synthesised in accordance with Example 6) on the late phase of allergic inflammatory responses and airway hyperresponsiveness (AHR) in a mouse model of allergic asthma was investigated. The particular target is Th2 disease and eosinophils.

[0345] The mice (BALB / c) (6 mice / group) were sensitised intranasally on days 0, 1 and 2 with house dust mite (HDM) extract (50 pg in 50 pL saline), without adjuvant, and challenged with HDM extract intranasally daily on days 14-17 (5 pg in 50 pl saline).

[0346] Drugs were administered (50 pL) intranasally (100 pg / animal) in sterile PBS on days 0, 1 and 2 of the sensitisation phase and then again 30 min before each challenge. 7 doses of drugs were given. Endpoints were to be assessed 24 hours after last challenge.

[0347] The groups included:Baseline control: (sensitised with PBS, challenged with PBS and treated with PBS)Positive control: (sensitised with HDM, challenged with HDM and treated with PBS)Treated animals: (sensitised with HDM, challenged with HDM and treated with drug, e.g. G24 (also referred to as Gly-121) and low molecular weight heparin (LMWH) as a positive drug control).

[0348] The readouts of the experiment included :Airway hyperresponsiveness following challenge with aerosolized methacholine, increasing doses (1.25, 2.5, 5 and 10 mg / mL). Lung function was measured using a Scireq flexivent.Collected bronchoalveolar lavage fluid (BAL) and assessed airway inflammation by determining leukocyte infiltration into bronchoalveolar lavage fluid, initially only examined total leukocyte number.Collected lung tissue for histology: perfuse, inflate, fix (buffered formalin) then dehydrate through a series of increasing ethanol (EtOH) solutions, and embed within paraffin. The lung tissue blocks were stored for later histological analysis.

[0349] Further analyses were performed including, differential counts on leukocytes in BAL (eosinophils, neutrophils, basophils and alveolar macrophages).Histology was performed to examine collagen deposition and goblet cell (mucus secreting cell) numbers in the lung tissues. For collagen deposition detection in the sections, a Sirius Red and Fast Green staining technique was used. This dye combination was used to distinguish collagen from its surrounding materials. Sirius Red specifically binds the [Gly-X-Y]n helical structure of fibrillar collagens, regardless of collagen type or species, whereas Fast Green binds to non-collagenous proteins. This method is a simple semi- quantitative assay to determine the amounts of collagen and non-collagenous proteins in tissue sections.

[0350] The paraffin-embedded tissue sections were first de-paraffinised according to standard procedures involving xylene, xylene and ethanol, ethanol, then ethanol and water, finishing in distilled water. 0.2 - 0.3 mL Dye Solution was loaded onto each sample, enough to completely immerse the tissue section. The sample was then incubated at room temperature for 30 minutes, followed by washing. The samples were then observed under a microscope.

[0351] Goblet cells were revealed by the PAS (Periodic Acid Schiff) stain. This stain reveals the presence of mucopolysaccharides, glycoproteins, and / or glycogen.

[0352] Low molecular weight heparin (the internal standard) had no effect on airway inflammation (Figures 9A-9E), significantly reduced airway hyperresponsiveness / wheezing (Figures 10A and 10B), collagen deposition / fibrosis around the airways (Figures 12A and 12B) and mucus secreting cell numbers around the airways (Figures 13A and 13B).

[0353] G24 (Gly-121) caused a significant increase in airway inflammation (Figures 9A-9E) with increases in eosinophils with smaller increases in lymphocytes. This compound significantly reduced airway hyperresponsiveness / wheezing (Figures IDA and 10B) and collagen deposition / fibrosis around the airways (Figures 12A and 12B). However, it did not decrease mucus secreting cell numbers around the airways (Figures 13A and 13B).

[0354] The effects of the compounds on other lung function parameters are presented in Figures 11A-E.

[0355] The beneficial effects of G24 are on the most intractable features of chronic asthma, including airway hyperresponsiveness / wheezing and collagen deposition / fibrosis.

[0356] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0357] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0358] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:( )(VI) or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:L1L3L4L6L7L8L9L10L11L12L13L15L16L17L18L19L20L21L22L23L24L25, L26, L28, L29, L30, L31and L32are independently selected from optionally substituted C1-C5alkylene, optionally substituted C2-C5alkenylene and optionally substituted C2-C5alkynylene;L2, L5, L14and L27are independently selected from optionally substituted C2-C8alkylene, optionally substituted C2-C8alkenylene and optionally substituted C2-C8alkynylene; X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17and X18are independently selected from CH and N; andR1is selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12alkenyl and optionally substituted C2-C12alkynyl.

2. The compound according to claim 1, wherein X1-X18are CH.

3. The compound according to claim 1 or claim 2, wherein L1, L3, L4, L6, L7, |_8 |_9 |_10 |_U |_12 |_13 |_15 |_16 |_17 |_18 |_19 L20 |_21 L22 L23 |_24 |_25 L26 L28 L29 L30 and L32are optionally substituted C1-C3alkylene.

4. The compound according to claim 3, wherein L1, L3, L4, L6, L7, L8, L9, L10, L11, L12, L13, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L28, L29, L30and L32are methylene.

5. The compound according to any one of claims 1-4, wherein L2and L31are each independently optionally substituted C2-C5alkylene.

6. The compound according to claim 5, wherein L2and L31are propylene.

7. The compound according to any one of claims 1-6, wherein L5is optionally substituted C3-C6alkylene.

8. The compound according to claim 7, wherein L5is butylene.

9. The compound according to any one of claims 1-8, wherein L14is optionally substituted C2-C4alkylene.

10. The compound according to claim 9, wherein L14is ethylene.

11. The compound according to any one of claims 1-10, wherein L27is optionally substituted C2-C4alkylene.

12. The compound according to claim 11, wherein L27is ethylene.

13. The compound according to any one of claims 1-12, wherein R1is optionally substituted C6-C10alkyl.

14. The compound according to claim 13, wherein R1is octyl.

15. The compound according to any one of claims 1-12, wherein R1is methyl.

16. The compound according to any one of claims 1-15, wherein the compound is a compound of Formula VII, VIII, IX, X, XI, XII or XIII, or a pharmaceutically acceptable salt, solvate or prodrug thereof:(VII),(XIII).

17. The compound according to any one of claims 1-16, wherein the compound is in the form of a salt and the salt is the sodium salt.

18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 and a pharmaceutically acceptable carrier or diluent.

19. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 for use in therapy.

20. A method of treating or inhibiting the development of an inflammatory condition iinn a subject, comprising, consisting or consisting essentially of administering a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 to the subject.

21. The method according to claim 20, wherein the inflammatory condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease (CORD), acute respiratory distress syndrome (ARDS), dermatitis, nasal polyposis, esophagitis, vasculitis, rhinosinusitis, pruritis, rhinitis, sinusitis, urticaria, inflammatory bowel disease, multiple sclerosis, fibrosis, hypersensitivity pneumonitis, arthritis, allergic respiratory disease, subepithelial fibrosis in airway hyperresponsiveness, idiopathic pulmonary fibrosis (IPF), allergic bronchopulmonary aspergillosis in a cystic fibrosis patient, eosinophilic bronchitis, bronchiectasis, bronchospasm, bronchial constriction, bronchial hyperreactivity, bronchial hypertrophy and psoriasis.

22. The method according to claim 21, wherein the inflammatory condition is selected from the group consisting of asthma, CORD, ARDS, dermatitis, rhinitis and sinusitis.

23. The method according to claim 22, wherein the inflammatory condition is asthma.

24. The method according to claim 22, wherein the inflammatory condition is COPD.

25. The method according to claim 22, wherein the inflammatory condition is ARDS.

26. A method of treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject, comprising, consisting or consisting essentially of administering a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 to the subject.

27. A method of antagonizing a cytokine, comprising, consisting or consisting essentially of contacting the cytokine with a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17.

28. The method according to claim 26 or claim 27, wherein the cytokine is selected from the group consisting of IL-4, IL-5, IL-8, IL-13 and IL-33.

29. Use of a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 in the manufacture of a medicament for treating or inhibiting the development of an inflammatory condition in a subject.

30. Use of a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 in the manufacture of a medicament for treating or inhibiting the development of a condition associated with the activity of a cytokine in a subject.

31. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 for use in treating or inhibiting the development of an inflammatory condition in a subject.

32. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof according to any one of claims 1-17 for use in treating or inhibiting the development of a condition associated with an activity of a cytokine in a subject.

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