Triazole resolvin analogs compounds, methods and uses thereof

Abstract

The present application relates to triazole resolvin analogs being useful in the treatment or prevention of inflammatory diseases or disorders (such as arthritis, osteoarthritis, inflammatory bowel disease or disorder, or skin inflammatory diseases and disorders), as an antioxidant agent or for the inhibition of monocyte / macrophage differentiation. More specifically, the present application relates to compounds of formula (I)

Description

TRIAZOLE RESOLVIN ANALOGS COMPOUNDS, METHODS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority of co-pending U.S. Provisional Patent Application No.63 / 528,984, which was filed July 26, 2023, the content of which is incorporated herein by reference in its entirety. FIELD

[0002] The present application is in the field of anti-inflammatory and antioxidant compounds. More specifically, the present application relates to resolvin analogs having anti- inflammatory and antioxidant properties. BACKGROUND

[0003] Resolvins are a class of compounds derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs), and are classified based on the straight chain PUFA from which they are formed and / or a unique aspect of their structure. Sub-classes of resolvins include resolvin Ds, resolving Es and resolvin Ts.

[0004] One of these compounds, resolvin D1 (RvD1) has been studied and shown remarkable properties in resolving inflammation, promoting tissue repair, preserving tissue integrity, treatment of bone and cartilage disorders, and the like.

[0005] Another compound, resolvin D2 (RvD2), one of the members of the resolvin family, is produced from the ω3-polyunsaturated fatty acid, docosahexaenoic acid (DHA), as a result of a series of reactions catalysed by lipoxygenases. The anti-inflammatory and pro- resolution effects of RvD2 are mediated, at least in part, by the pertussis-sensitive G-protein- coupled receptor (GPCR), GPR18, by a signaling mechanism yet to be fully elucidated. The resolving action of RvD2 is accompanied by the activation of GSK3b, Akt, and SGK1. It has been reported that RvD1 treatment prevents alveolar bone loss via inhibiting RANKL-mediated osteoclast differentiation and reduced RANKL / OPG ratio.

[0006] However, similar to the majority of specialized proresolving mediator (SPM) members, both RvD1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) and RvD2 (7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid) are chemically unstable molecules that undergo a very fast transformation to inactive products 17- 1 8625002oxo-RvD1 and 8-oxo-RvD1. The RvD2 can be converted to yield 7-oxo-RvD2 or 16-oxo-RvD2 through the enzymatic action of eicosanoid oxidoreductase. In the recent years, a number of studies conducted in vitro and in vivo studying the biological effects of SPM have resulted in the development of a variety of analogues that were tested for their ability to restore tissue homeostasis and to inhibit inflammatory processes. Given the protective effects of RvD1 and RvD2 against inflammation and tissue damage, it would be desired to develop metabolically stable molecules with improved pharmacokinetic and pharmacodynamics properties to improve the mode of administration for preclinical and clinical applications.

[0007] As such, there is need to provide improved compounds with similar activities to RvD1 and RvD2, that would at least partially alleviate the disadvantages discussed above. SUMMARY

[0008] It has been surprisingly shown herein that compounds of the present application provide for improved stability, pharmacokinetic and pharmacodynamics properties. Comparable compounds did not display the same properties, highlighting the surprising results obtained with the compounds of the application.

[0009] Accordingly, the present application includes a compound of Formula (I): wherein:R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, CO2R7and C(O)NR7R7’, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; 2 8625002R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8or R6is -OR7, -NR7R7’, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; n is an integer from 1 to 7; are independently absent or represent a bond, R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer, salt or solvate thereof.

[0010] The present application further includes a compound of Formula (IA):wherein: R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; 3 8625002R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; is absent or represents a bond, R5is absent when is a bond, or an enantiomer,or solvate thereof.

[0011] The present application also includes a compound of Formula (IB):wherein: R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms 4 8625002selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; n is an integer from 1 to 7; are independently absent or represent a bond, R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer, salt or solvate thereof.

[0012] Also provided is the compound of the present application, for use in treatment or prevention of an inflammatory disease or disorder.

[0013] Also included is the compound of the present application, for use in treatment or prevention of a bone disease or disorder or joint disease and disorder.

[0014] Further provided is the compound of the present application, for use as an anti- inflammatory agent or an antioxidant agent.

[0015] Also provided is the compound of the present application, for inhibiting monocytes / macrophages differentiation.

[0016] The present application further provides a pharmaceutical composition comprising a compound of the present application, and a pharmaceutically acceptable excipient, diluent or carrier.

[0017] Also provided is the use of the compound of the present application in treatment or prevention of an inflammatory disease or disorder.

[0018] Also provided is the use of the compound of the present application, in manufacture of a medicament for treating or preventing an inflammatory disease or disorder.

[0019] Also included is the use of the compound of the present application, in treatment or prevention of a bone disease or disorder or joint disease and disorder.

[0020] Further provided is the use of the compound of the present application, in manufacture of a medicament for treating or preventing a bone disease or disorder or joint disease and disorder. 5 8625002

[0021] Also provided is the use of a compound of the present application, as an anti- inflammatory agent or an antioxidant agent.

[0022] Also provided is the use of a compound of the present application, for inhibiting monocytes / macrophages differentiation.

[0023] Also provided is the use of a compound of the present application as an antioxidant for skin diseases and cosmetic applications.

[0024] The present application further includes a method for treating or preventing an inflammatory disease or disorder, comprising administering an effective amount of a compound of the present application in a subject in need thereof.

[0025] The present application further provides a method for treating or preventing a bone disease or disorder or joint disease and disorder, comprising administering an effective amount of a compound of the present application in a subject in need thereof.

[0026] In some embodiments, the inflammatory disease or disorder is selected from arthritis, osteoarthritis, inflammatory bowel disease or disorder, and skin inflammatory disease and disorder.

[0027] In some embodiments, the bone disease or disorder is selected from osteoporosis, and bone metastases and the joint disease or disorder is arthrosis.

[0028] Further included is a method for inhibiting monocytes / macrophages differentiation, comprising administering an effective amount of a compound of the present application in a subject in need thereof.

[0029] Also included is the use of a compound of the present application, as an antioxidant agent, a stabilizing agent or a preservative in a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

[0030] Further provided is the compound of the present application, for use as an antioxidant agent, a stabilizing agent or a preservative in a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

[0031] The present application also includes a method for stabilizing or preserving a composition, comprising adding an acceptable amount of a compound of the present application as an antioxidant agent, a stabilizing agent or a preservative, wherein the 6 8625002composition is a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

[0032] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole. BRIEF DESCRIPTION OF DRAWINGS

[0033] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0034] FIG.1A and FIG.1B show spectra for Compound I-2 according to exemplary embodiments of the present application, where FIG.1A is the1H NMR spectrum and FIG.1B is the13C spectrum.

[0035] FIG.2A and FIG.2B show spectra for Compound I-3 according to exemplary embodiments of the present application, where FIG.2A is the1H NMR spectrum and FIG.2B is the13C spectrum.

[0036] FIG.3A and FIG.3B show spectra for Compound I-5 according to exemplary embodiments of the present application, where FIG.3A is the1H NMR spectrum and FIG.3B is the13C spectrum.

[0037] FIG.4A and FIG.4B show spectra for Compound I-6 according to exemplary embodiments of the present application, where FIG.4A is the1H NMR spectrum and FIG.4B is the13C spectrum.

[0038] FIG.5 shows a graph of cell viability of Raw 264.7 macrophages incubated for 24 hours with RvD1 and compounds T1, T2, T3 and T4 at 10 ^M, according to exemplary embodiments of the present application.

[0039] FIG.6 shows a graph of enzymatic conversion of RvD1 and analogues T1, T2, T3 and T4 by eicosanoid oxidoreductase, showing % of residual compound over time of incubation of 10 ^g in 1 mM NAD and 1 mg of eicosanoid oxidoreductase in Tris buffer pH 7.4, enzymatic activity was measured by the formation rate of NADH (n=2), according to exemplary embodiments of the present application. 7 8625002

[0040] FIG.7A and FIG.7B show graphs of effect of RvD1 and analogues T1, T2, T3 and T4 on ROS neutralization, where FIG.7A shows relative MitoSox Red fluorescence intensity on Raw264.7 macrophages pre-incubated with RvD1 or analogues (T1-T4) (1 µM) for 1 hour and with 500 µM H2O2during 4 hours; where FIG.7B shows relative MitoSox Red fluorescence intensity on H2O2 and CuCl2 at 10 µM treated with RvD1 and analogues at 1 ^M; ROS generation was assessed with MitoSox Red (n=3) and ascorbic acid at 10 µM used as control, according to exemplary embodiments of the present application.

[0041] FIG.8 shows images of TRAP enzymatic staining on isolated human monocytes for compounds RvD1 and analogues T1, T2, T3 and T4 at 1 µM on osteoclasts differentiation (n=3), according to exemplary embodiments of the present application.

[0042] FIG.9 shows images of a Western blotting of COX-2 and iNOS protein expression in Raw 264.7 macrophages lysates for compound RvD1 and analogues T1, T2, T3 and T4, with macrophages pre-incubated with increasing concentrations (100, 200, 500, 1000, 5000 and 10000 nM) for 1 hour and with 100 ng / mL of LPS during 24 hours, according to exemplary embodiments of the present application.

[0043] FIG.10 shows graphs of the effect of RvD1 and analogues T1, T2, T3 and T4 on PGE2 production, where Raw 264.7 macrophages were pre-incubated with increasing concentrations (100, 200, 500, 1000, 5000 and 10000 nM) for 1 hour and with 100 ng / mL of LPS during 24 hours, PGE2 levels determined by EIA assay (n=3), according to exemplary embodiments of the present application.

[0044] FIG.11 shows an image of protection of hyaluronic acid by RvD1 or analogues T1, T2, T3 and T4 at 1 µM against ROS-induced HA degradation (n=3), according to exemplary embodiments of the present application.

[0045] FIG.12 shows a graph of the effect of RvD1 and analogues T1, T2, T3 and T4 on lipid peroxidation in Raw264.7 cells, **p<0,01 (vs H2O2), according to exemplary embodiments of the present application.

[0046] FIG.13 shows a graph of the effect of RvD1 and analogues T1, T2, T3 and T4 on intracellular glutathione pool in Raw264.7 cells, *p<0,05, **p<0,01 (vs H2O2), according to exemplary embodiments of the present application. 8 8625002

[0047] FIG.14 shows a graph of the effect of RvD1 and analogues T1, T2, T3 and T4 on caspase-3 activation in Raw264.7 cells, *p<0,05, **p<0,01 (vs H2O2), according to exemplary embodiments of the present application.

[0048] FIG.15 shows images of Western blotting of Bcl2 and Nrf2 expression in Raw264,7 cells for RvD1 and analogues T1, T2, T3 and T4, according to exemplary embodiments of the present application.

[0049] FIG.16 shows image of Western blotting of NFATc1 phosphorylation and cathepsin K expression in human monocytes for RvD1 and analogues T1, T2, T3 and T4, according to exemplary embodiments of the present application. DETAILED DESCRIPTION I. Definitions

[0050] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0051] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0052] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0053] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0054] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% 9 8625002of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0055] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0056] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0057] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present. The term “and / or” with respect to enantiomers, prodrugs, salts and / or solvates thereof means that the compounds of the application exist as individual enantiomers, prodrugs, salts and hydrates, as well as a combination of, for example, a salt of a solvate of a compound of the application.

[0058] The term “compound of the application” or “compound of the present application” and the like as used herein refers to a compound of Formula (I) or salts, solvates and / or enantiomers thereof.

[0059] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds of the application.

[0060] The term “suitable” as used herein means that the selection of the particular composition or conditions would depend on the specific steps to be performed, the identity of the components to be transformed and / or the specific use for the compositions, but the selection would be well within the skill of a person trained in the art.

[0061] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency. 10 8625002

[0062] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C1-10alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0063] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”. For example, the term C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0064] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 10 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds).

[0065] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocyclic group containing from 3 to 20 carbon atoms and one or more rings.

[0066] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains 6 to 20 carbon atoms.

[0001] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring containing 5-20 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. Heteroaryl groups are optionally benzofused.

[0002] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups, contain one or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.

[0003] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0004] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between. 11 8625002

[0067] The term “triazole” as used herein refers to five-membered heterocyclic group comprising three nitrogen and two carbon atoms.

[0068] The term “aq.” as used herein refers to aqueous.

[0069] The term “rt” as used herein refers to room temperature.

[0070] The term “MS” as used herein refers to mass spectrometry.

[0071] The term “LCMS” as used herein refers to liquid chromatography-mass spectrometry.

[0072] The term “NMR” as used herein refers to nuclear magnetic resonance.

[0073] The term “TLC” as used herein refers to thin-layer chromatography.

[0074] The term “DMF” as used herein refers to dimethyl formamide.

[0075] The term “Ph” as used herein refers to phenyl.

[0076] The term “Et” as used herein refers to ethyl.

[0077] The term “Ac” as used herein refers to acetate.

[0078] The term “Me” as used herein refers to methyl.

[0079] The term “Bu” as used herein refers to butyl.

[0080] The term “TSA” as used herein refers to toluenesulfonic acid.

[0081] The term “DCM” as used herein refers to dichloromethane.

[0082] The term “PPTS” as used herein refers to pyridinium p-toluenesulfonate.

[0083] The term “THF” as used herein refers to tetrahydrofuran.

[0084] The term “DMSO” as used herein refers to dimethylsulfoxide.

[0085] The term “TEA” as used herein refers to triethylamine.

[0086] The term “EDTA” as used herein refers to ethylenediaminetetraacetic acid.

[0087] The term “SEM” as used herein refers to Standard Error of the Mean.

[0088] The term “MEM” as used herein refers to Minimum Essential Medium.

[0089] The term “AMEM” as used herein refers to Alpha Minimum Essential Medium.

[0090] The term “FBS” as used herein refers to fetal bovine serum. 12 8625002

[0091] The term “PBS” as used herein refers to phosphate-buffered serum.

[0092] The term “RPMI” as used herein refers to Roswell Park Memorial Institute growth medium.

[0093] The term “MTS” as used herein refers to [3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].

[0094] The term “ANOVA” as used herein refers to analysis of variance.

[0095] The term “RANKL” as used herein refers to receptor activator of nuclear factor kappa-β ligand.

[0096] The term “M-CSF” as used herein refers to macrophage colony-stimulating factor.

[0097] The term “TRAP” as used herein refers to tartrate-resistant acid phosphatase.

[0098] The term “TNF” as used herein refers to tumor necrosis factor.

[0099] The term “TBE” as used herein refers to Tris / Borate / EDTA buffer solution.

[0100] The term “RvD1” refers to resolvin D1, having the chemical structure: .

[0101] Thestructure:

[0102] as a cell or a plurality of cells and includes a cell either in a cell culture or in a subject. 13 8625002

[0103] The term “subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0104] The term “pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.

[0105] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0106] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0107] The term “solvate” as used herein means a compound, or a salt and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0108] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0109] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations. 14 8625002

[0110] “Palliating” a disease or disorder means that the extent and / or undesirable clinical manifestations of a disorder or a disease state are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0111] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition.

[0112] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell either in cell culture or in a subject.

[0113] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result. II. Compounds and Compositions of the Application

[0114] It has been shown herein that compounds of the present application provide for improved stability, pharmacokinetic and pharmacodynamics properties.

[0115] Accordingly, the present application includes a compound of Formula (I): wherein:R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, CO2R7and C(O)NR7R7’, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; 15 8625002R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8or R6is -OR7, -NR7R7’, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; n is an integer from 1 to 7; are independently absent or represent a bond, wherein R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer, salt or solvate thereof.

[0116] A compound of Formula (IA):wherein: 16 8625002R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; is absent or represents a bond, wherein R5is absent when is a bond,or an enantiomer, isomer, or solvate thereof.

[0117] A compound of Formula (IB):wherein: R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; 17 8625002R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; n is an integer from 1 to 7; are independently absent or represent a bond, R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer, salt or solvate thereof

[0118] In some embodiments, R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl and CO2R7, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8. In some embodiments, R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, CO2C1-8alkyl and CO2H. In some embodiments, R1is H, methyl, ethyl, propyl, CO2Me, CO2Et, CO2Pr or CO2H.

[0119] In some embodiments, R2, R3and R5are H, methyl, ethyl or propyl or an alcohol protecting group. A skilled person would appreciate which protecting group may be used. In some embodiments, when two alcohols are on adjacent carbons, the protecting group may be joined to form, together with the atom there between, an heterocyclyl group. In some embodiments, R2and R3may form an acetal protecting group.

[0120] In some embodiments, R4is H, C1-8alkyl, C2-10alkenyl or phenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and the alkyl, alkenyl and phenyl may be substituted with one or more group R8, In some embodiments, R4is H, methyl, ethyl, propyl or phenyl.

[0121] In some embodiments, R6is linear or branched C1-8 alkyl or C2-10alkenyl which may be substituted with one or more group R8. In some embodiments, R6is linear or branched C1-8 alkyl or C2-10alkenyl substituted with -CO2R7. In some embodiments, R6is C2-10alkenyl 18 8625002substituted with one or more group selected from halogen, CO2R7, -OR7, -N(R7R7’, and phenyl. In some embodiments, R6is linear or branched C2-10alkenyl, which may comprise 1 to 4 double bonds. In some embodiments, R6is pentyl, propyl, octyl or benzyl. In some embodiments, R6is propenyl, butenyl, pentenyl or octenyl.

[0122] In some embodiments, R7and R7’are independently H, methyl, ethyl, or propyl.

[0123] In some embodiments, each R8is independently selected from the group consisting of Cl, F, Br, C1-8alkyl, CO2C1-8alkyl, -CO2H, -OH, -OC1-8alkyl, -NH2, -NHC1-8alkyl and N(C1-8alkyl)2. In some embodiments, each R8is independently selected from the group consisting of C1-4alkyl, CO2C1-4alkyl, -CO2H, -OH, -OC1-4alkyl, -NH2, -NHC1-4alkyl and N(C1-4alkyl)2. In some embodiments, each R8is methyl, ethyl, or propyl, CO2Me, CO2Et, -CO2H, -OH, -OMe, -OEt or -OPr.

[0124] In some embodiments, R5is H and represents a single bond. In some embodiments, R5is absent and represents a double bond.

[0125] In some embodiments, the compound of Formula (I) is selected from the following: Compound Structure IUPAC Name I.D. I-1 methyl (Z)-6-((4S,5R)-5- ((E)-2-(4-((S,Z)-1- hydroxyhex-3-en-1-yl)-1- methyl-1H-1,2,3-triazol-5- yl)vinyl)-2,2-dimethyl-1,3- dioxolan-4-yl)hex-4- enoate I-2 (T1) methyl (4Z,7S,8R,9E)-7,8- dihydroxy-10-(4-((S,Z)-1- hydroxyhex-3-en-1-yl)-1- methyl-1H-1,2,3-triazol-5- yl)deca-4,9-dienoate 19 8625002I-3 (T2) (4Z,7S,8R,9E)-7,8- dihydroxy-10-(4-((S,Z)-1- hydroxyhex-3-en-1-yl)-1- methyl-1H-1,2,3-triazol-5- yl)deca-4,9-dienoic acid I-4 methyl (S,Z)-7-(5-((E)-2- ((4R,5R)-2,2-dimethyl-5- ((Z)-pent-2-en-1-yl)-1,3- dioxolan-4-yl)vinyl)-1- methyl-1H-1,2,3-triazol-4- yl)-7-hydroxyhept-4- enoate I-5 (T3) methyl (S,Z)-7-(5- ((1E,3R,4S,6Z)-3,4- dihydroxynona-1,6-dien-1- yl)-1-methyl-1H-1,2,3- triazol-4-yl)-7- hydroxyhept-4-enoate I-6 (T4) (S,Z)-7-(5- ((1E,3R,4S,6Z)-3,4- dihydroxynona-1,6-dien-1- yl)-1-methyl-1H-1,2,3- triazol-4-yl)-7- hydroxyhept-4-enoic acid III. Methods and Uses of the Application

[0126] The compounds of the application have been shown to inhibit TNFα production, inhibit monocytes / macrophages differentiation and protect against free radicals. Inflammation and oxidative stress are known to be involved in various diseases, such as arthritis, osteoarthritis, osteoporosis, etc. 20 8625002

[0127] Accordingly, the present application includes use of the compounds of the present application in treatment or prevention of an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is selected from arthritis, osteoarthritis, inflammatory bowel disease or disorder, and skin inflammatory disease or disorder. In some embodiments, inflammatory bowel disease or disorder may include Crohn’s disease and ulcerative colitis. In some embodiments, skin inflammatory disease or disorder may include eczema, psoriasis, urticaria, and the like.

[0128] Accordingly, also provided is a method for the treatment or prevention of skin oxidative stress or disorder by administering an effective amount of a compound of the present application.

[0129] Accordingly, also provided is a method for the treatment or prevention of an inflammatory disease or disorder by administering an effective amount of a compound of the present application.

[0130] The present application further includes use of the compounds of the present application in treatment or prevention of a bone disease or disorder or joint disease and disorder. In some embodiments, the bone disease or disorder is selected from osteoporosis and bone metastases, and the joint disease or disorder is osteoarthritis.

[0131] Accordingly, also provided is a method for the treatment or prevention of a bone disease or disorder or joint disease and disorder by administering an effective amount of a compound of the present application.

[0132] Further included is use of the compounds of the present application as an antioxidant agent, a stabilizing agent or a preservative.

[0133] Antioxidant agents have many industrial applications and have a wide range of use in the preparation of several formulations. Thus, antioxidant agents are generally used as preservatives and supplements with the ultimate goal of stabilizing and increasing the shelf life of industrial products. This includes food products, cosmetics and medical products and petrochemicals. Typical preservatives include natural antioxidants such as sorbitol, mannitol, ascorbic acid, tocopherols, as well as synthetic antioxidants generally including phenolic compounds such as butylhydroxytoluene (BHT), tertiary butylhydroquinone (BHQ) or even gallates.

[0134] Specifically, the antioxidant properties of the compounds of the present application have been demonstrated in hyaluronic acid formulations (see Example 12). 21 8625002

[0135] Accordingly, the compounds of the present application may be used as an antioxidant agent, a stabilizing agent or a preservative in a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

[0136] The present applicant further includes a method for stabilizing or preserving a composition, comprising adding an acceptable amount of a compound of the present application as an antioxidant agent, a stabilizing agent or a preservative, wherein the composition is an agri-food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition. IV. Methods of Preparing the Compounds and Compositions of the Application

[0137] The compounds of the present application can be prepared according to various synthetic routes within the purview of a skilled person in the art. In some embodiments, the compounds of the present application are prepared as described in the following Examples. EXAMPLES

[0138] The following non-limiting examples are illustrative of the present application. General Methods

[0139] Reagents and solvents were obtained from commercial suppliers (Sigma Aldrich, Combi-blocks, Alfa Aesar) and used without further purification, unless otherwise noted. All reactions that were moisture and air-sensitive were carried out in flame-dried glassware, under an argon atmosphere. Reaction progress was monitored by thin layer chromatography (TLC), using EMD silica gel 60 F254 aluminum plates. Spots were visualized with UV light (254 nm), followed by staining using a cerium ammonium molybdate (CAM) solution or a potassium- permanganate solution, followed by heating on a hot plate. SiliCycle® R10030B 230-400 mesh silica gel (Québec, QC, Canada) was used for flash chromatography. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 digital spectrometer (Billerica, MA, USA) at 400 MHz for 1H NMR. The following abbreviations were used to designate multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, m = multiplet, br = broad. Low-resolution mass spectra (MS) were recorded on a Shimadzu Prominence instrument (Kyoto, Japan) equipped with a Shimadzu LCMS-2020 mass spectrometer and an APCI (atmospheric pressure chemical ionization) probe. Molecule nomenclature (IUPAC) was generated using the ACD / name module of ACD / Labs software (Toronto, ON, Canada). 22 8625002Example 1 - Synthesis Scheme – compounds (IA)

[0140] Exemplary synthesis following the above general procedure according to embodiments of the present application is shown in Scheme 1.23 8625002Block A - azide block

[0141] Block A will be synthesized from methodology reported by Koronatov et al. (see ref.4) Block B - alkyne block

[0142] Block B will be synthesized from methodology reported by Tungen et al. (see ref.5). Block C - Methyl (4Z)-6-{(4S,5R)-2,2-dimethyl-5-[(E)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)ethenyl]-1,3-dioxolan-4-yl}hex-4-enoatefrom Gaetano et al. (ref: European Journal of Medicinal Chemistry, 2019,162, 80-108), as shown in Scheme 2.

[0144] D-deoxyribose was treated with 2-methoxyprop-1-ene in ethyl acetate in the presence of a catalytic amount of pyridinium p-toluenesulfonate (PPTS). The mixture was reacted at room temperature for 18h to afford intermediate 2-1. Intermediate 2-1 was treated with phosphonium salt 2-2 and benzoic acid in THF. The mixture was heated at 75ºC for 6h to 24 8625002give intermediate 2-2. Intermediate 2-3 was then treated with sulfur trioxide pyridine complex and DMSO, in the presence of TEA, and DCM at 0ºC. The mixture was allowed to warm to room temperature for about 1.5h to provide oxidated intermediate 2-4. Intermediate 2-4 was then treated with dimethyl(1-diazo-2-oxopropyl)phosphonate in methanol in the presence of K2CO3and reacted at room temperature for 16h to give intermediate 2-5. Finally, intermediate 2-5 was treated with pinacolborane, TEA and Schwartz’s reagent (zirconocene hydrochloride) to afford the boronate compound – Block C. Between each step, reactions were quenched and compounds isolated and / or purified before proceeding to following step.1H NMR data were in full agreement with that reported in the literature. Example 2 - Synthesis Scheme – compounds (IB)

[0145] Exemplary synthesis following the above general procedure according to embodiments of the present application is shown in Scheme 3. 25 8625002Scheme 3 Block A - azide block

[0146] Block A will be synthesized from methodology reported by Koronatov et al. (see ref.4) 26 8625002Block D - methyl (4Z,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}non-4-en-8-ynoate

[0147] The Block D was prepared following the seven steps synthetic sequence reported by Maltais et al (see ref.6), as shown in Scheme 4.Block E - 2-[(E)-2-{(4R,5S)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4-yl}ethenyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0148] The Block E was prepared following a five steps synthetic sequence adapted from Gaetano et al. (ref: European Journal of Medicinal Chemistry, 2019,162, 80-108), as shown in Scheme 5. 27 8625002, , Assembly of blocks A, B and C for the synthesis of I-2 and I-3 28 8625002

[0149] The assembly of Blocks A, B and C was performed according to Scheme 6 above, where Block B (tert-butyl(dimethyl){[(3S,5Z)-oct-5-en-1-yn-3-yl]oxy}silane) was synthetized from L-malic acid as previously reported by Maltais et al in JOC 2023 J. Org. Chem.2023, 88, 11, 7088–7095, and Block C (Methyl (4Z)-6-{(4S,5R)-2,2-dimethyl-5-[(E)-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethenyl]-1,3-dioxolan-4-yl}hex-4-enoate) was prepared from D-2-deoxyribose as previously reported by De Gaetano M et al European Journal of Medicinal Chemistry, 2019, 162, 80-108. 29 86250024-[(1S,3Z)-1-{[tert-butyl(dimethyl)silyl]oxy}hex-3-en-1-yl]-5-iodo-1- [(trimethylsilyl)methyl]-1H-1,2,3-triazole (Intermediate 6-1)

[0150] A mixture of trimethylsilylmethyl azide (Block A) (130.4 mg, 0.65 mmol) and alkyne (Block B) (200 mg, 0.84 mmol), was dissolved under argon in dry THF (5 mL). To the solution were added CuI (160 mg, 0.84 mmol), NBS (179 mg, 1.0 mmol) and DIPEA (125 mL, 0.84 mmol), which was stirred for 2 hours. Water was added to the reaction mixture after which time it was extracted with EtOAc. The combined extracts were washed with brine and dried over sodium sulfate. After filtration, the solvents were evaporated and the residual oil was purified on silica gel eluting with 70% EtOAc in hexanes giving firstly 112 mg (35 %) of 1,4- disubstituted-5-iodotriazole 6-1 as a syrup then 160 mg of a more polar product which was identified as 5-deiodinated triazole.1H NMR (400 MHz, Acetone-d6) δ 5.43 – 5.23 (m, 2H), 4.87 (t, J = 7.1 Hz, 1H), 3.95 (s, 2H), 2.72 – 2.50 (m, 2H), 1.91-2.04 (m, 2H), 0.86 (s + t, 12H), 0.17 (s, 9H), 0.11 (s, 6H). Methyl (4Z)-6-{(4S,5R)-5-[(E)-2-{4-[(1S,3Z)-1-{[tert-butyl(dimethyl)silyl]oxy}hex-3-en-1- yl]-1-methyl-1H-1,2,3-triazol-5-yl}ethenyl]-2,2-dimethyl-1,3-dioxolan-4-yl}hex-4-enoate (Intermediate 6-2)30 8625002

[0151] In a MW-vial was introduces 5-iodotriazole 6-1 (80 mg, 0.16 mmol) and tetrakis(triphenylphosphine) palladium (15 mg, 0.005 mmol). The mixture was degassed by bubbling argon. After 5 min, boronate (Block C) (62 mg, 0.16 mmol) was added followed by potassium carbonate (45 mg, 0.32 mL) and water (0.3 mL). The flask was then sealed and irradiated in a microwave apparatus at 900C for 3 hours. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride. After extraction with EtOAc, the organic phase was washed with brine, dried over sodium sulfate. After concentration under vacuum, the residue was purified by flash chromatography on silica gel eluting with 50% EtOAC in hexanes yielding 46 mg (55 %) of 1,4,5-trisubstituted triazole 6-2.1H NMR (400 MHz, Acetone-d6) δ 6.80 (dd, J = 16.1, 1.2 Hz, 1H), 6.59 (dd, J = 16.1, 7.1 Hz, 1H), 5.54 – 5.23 (m, 4H), 5.02 (t, J = 7.3 Hz, 1H), 4.81 (t, J = 6.7 Hz, 1H), 4.34 – 4.27 (m, 1H), 4.06 (s, 3H), 3.60 (s, 3H), 2.65 (p, J = 6.8 Hz, 2H), 2.38 – 2.28 (m, 6H), 1.96-2.04 (m, 2H), 1.50 (s, 3H), 1.36 (s, 3H), 0.89 (d, J = 3.6 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 3H), -0.06 (s, 3H). Methyl (4Z)-6-{(4S,5R)-5-[(E)-2-{4-[(1S,3Z)-1-hydroxyhex-3-en-1-yl]-1-methyl-1H-1,2,3- triazol-5-yl}ethenyl]-2,2-dimethyl-1,3-dioxolan-4-yl}hex-4-enoate (Intermediate 6-3)

[0152] A solution of triazole 6-2 (46 mg, 0.087 mmol) in THF (2 mL) was stirred at room temperature for 1 hour in presence of TBAF (1M, 170 mL, 0.17mmol). The mixture was diluted with water, extracted with EtOAc. After washing with brine, drying over sulfate de sodium, the solution was concentrated to give quantitatively alcohol 6-3 (36 mg) which was used directly in the next step. Methyl (4Z,7S,8R,9E)-7,8-dihydroxy-10-{4-[(1S,3Z)-1-hydroxyhex-3-en-1-yl]-1-methyl- 1H-1,2,3-triazol-5-yl}deca-4,9-dienoate (Compound I-2) 31 8625002

[0153] A solution of protected diol 6-3 (35 mg, 0.087 mmol) in MeOH (2.5 mL) was stirred at room temperature in presence of p-TSA (30 mg). After 1 hour of stirring at room temperature, a saturated solution of sodium bicarbonate was added and the mixture extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate. After concentration under vacuum, the residue was purified by flash chromatography on silica gel eluting with EtOAC then acetone yielding 15.8 mg (49 %) of 1,4,5-trisubstituted triazole methyl ester I-2.1H NMR (500 MHz, MeOD-d4) δ 6.72 – 6.63 (m, 1H), 6.54 (dd, J = 16.3, 5.7 Hz, 1H), 5.62 – 5.53 (m, 1H), 5.51 – 5.42 (m, 1H), 5.40 (ddt, J = 12.3, 7.2, 1.5 Hz, 1H), 5.34 – 5.22 (m, 1H), 4.80 (t, J = 7.2 Hz, 1H), 4.19 (td, J = 5.4, 1.5 Hz, 1H), 4.04 (s, 3H), 3.64 (s, 3H), 2.81 – 2.68 (m, 2H), 2.47 – 2.40 (m, 1H), 2.40 – 2.34 (m, 4H), 2.31 – 2.22 (m, 1H), 2.09 – 1.95 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H).13C NMR (126 MHz, MeOH-d4) δ 176.2, 148.6, 140.8, 136.0, 134.8, 131.6, 129.2, 126.1, 116.6, 76.9, 76.5, 68.1, 52.9, 49.5, 36.7, 35.9, 35.6, 32.8, 24.9, 22.5, 15.4; MS (APCI pos) m / z 394.2 [M+H]. See FIG.1A and FIG.1B. (4Z,7S,8R,9E)-7,8-Dihydroxy-10-{4-[(1S,3Z)-1-hydroxyhex-3-en-1-yl]-1-methyl-1H-1,2,3- triazol-5-yl}deca-4,9-dienoic acid (Compound I-3)

[0154] An ice cooled solution of Triazolo-RVD1methy ester I-2 (13 mg, 0.033 mmol) in THF (2 mL) was stirred for 10 h in presence of LiOH (28 mg, 0.66 mmol). The mixture was quenched with a 10% aqueous solution of NaH2PO4, extracted twice with EtOAc. After washing 32 8625002with brine, the combined organic phases were dried over Na2SO4then evaporated under vacuum to give Triazolo-RVD1 analogue I-3 (8 mg, 66%).1H NMR (500 MHz, MeOH-d4) δ 6.68 (dd, J = 16.2, 1.5 Hz, 1H), 6.55 (dd, J = 16.3, 5.6 Hz, 1H), 5.62 – 5.46 (m, 2H), 5.46 – 5.37 (m, 1H), 5.34 – 5.26 (m, 1H), 4.81 (t, J = 7.3 Hz, 1H), 4.20 (td, J = 5.4, 1.5 Hz, 1H), 4.05 (s, 3H), 3.66 – 3.60 (m, 1H), 2.79 – 2.70 (m, 2H), 2.49 – 2.24 (m, 6H), 2.08 – 1.96 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H).13C NMR (126 MHz, MeOH-d4) δ 187.1, 148.1, 140.5, 135.8, 131.7, 128.6, 125.9, 116.3, 76.6, 76.3, 67.8, 50.4, 50.1, 49.9, 49.8, 49.6, 49.4, 49.3, 49.2, 49.1, 36.5, 35.7, 32.6, 24.8, 22.2, 15.1. MS (APCI pos) m / z 380.1 [M+H]. See FIG.2A and FIG.2B. Methyl (4Z,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}non-4-en-8-ynoate (Block D)

[0155] Block D was prepared according to Scheme 7:

[0156] Synthesis of (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pent-4-ynal 7-1 from L-malic acid has been previously reported by Maltais et al in JOC 2023 J. Org. Chem.2023, 88, 11, 7088–7095.

[0157] To a suspension of commercial (4-methoxy-4-oxobutyl) triphenylphosphonium bromide (5.7 g, 12.9 mmol) in dry THF (25 mL) cooled at -700C (dry ice-acetone bath) was added under argon potassium hexamethyldisilylazide (1M in THF, 11.4 mL, 11.4 mmol). The cooling bath was replaced by an ice bath and the resulting orange mixture was stirred for 1 hour. After cooling again to -700C, (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pent-4-ynal 7-1 (1.1 g, 5.2 mmol) was added via cannula to the ylide. The brown mixture was stirred for 20 min at -70 0C then at 50C for 2.5 hours thereafter quenched with saturated ammonium chloride. The aqueous phase was extracted twice with EtOAc and the resulting combined extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel flash chromatography eluting with 4 % EtOAc in hexanes yielding protected propargylic alcohol (Block D) as a yellow oil (0.7 g, 50 %).1H NMR (400 MHz, CDCl3) δ 5.55-5.47 (m, 2H), 4.35 (dt, J = 6.4, 2.1, 1H), 3.67 (s, 3H), 2.46 (d, J = 6.2 Hz, 2H), 2.41 – 2.37 (m, 2H), 1.57 (s, 1H), 0.92 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H). 33 86250022-[(E)-2-{(4R,5S)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4-yl}ethenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Block E)

[0158] Block E was prepared according to Scheme 8:Scheme 8 {(4R,5S)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4-yl}methanol (Intermediate 8-1)

[0159] To a cooled (-700C) suspension of propyltriphenylphosphonium bromide (14.1 g, 36.5 mmol) in toluene was added under argon sodium hexamethyldisilylazide (34.4 mL, 34.4 mmol). After 15 min, the flask was immerged in an ice bath and the mixture stirred for 1 hour. An orange red colour appeared which indicated the formation of an ylide. To this reagent was added at -700C, a solution of (D)-2-deoxyribose acetonide (3 g, 17.2 mmol) in toluene (15 mL). The cooling bath was removed and the mixture stirred for 2 hours during which it rose to room temperature. The orange solution was stirred for 2 hours then quenched with saturated 34 8625002ammonium chloride. The aqueous phase was extracted twice with EtOAc and the resulting combined extracts were washed with brine, dried over sodium sulfate then concentrated under vacuum. The residue was purified on silica gel flash chromatography eluting with 20 % EtOAc in hexanes yielding alcohol derivative 8-1 as a yellow oil (2.6 g, 70 %).1H NMR (400 MHz, CDCl3) δ 5.55-5.48 (m, 1H), 5.39 – 5.31 (m, 1H), 4.25 – 4.14 (m, 2H), 3.66 (d, J = 5.5 Hz, 2H), 2.44 – 2.34 (m, 1H), 2.34 – 2.24 (m, 1H), 2.12 – 2.00 (m, 2H), 1.49 (s, 3H), 1.37 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H). (4R,5S)-4-(2,2-dibromoethenyl)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolane (Intermediate 8-3)

[0160] To an ice-cooled solution of alcohol 8-1 (5 g, 23.4 mmol) in DCM (200 mL) was added sodium bicarbonate (8.9 g, 106 mmol) followed by Dess-Martin reagent (10.3 g, 24.3 mmol). After stirring at room temperature for 1 hour, the solution was treated with a mixture of saturated solution sodium bicarbonate and 10% solution of sodium thiosulfate. The organic phase was separated and washed several times with 10% NaOH until the aqueous phase becomes clear. After drying over sulfate sodium, filtration and evaporation the crude oily residue was purified on a silica gel column eluting with 5% EtOAc in hexanes to yield a smelly colourless oil (3.6 g, 72%). This aldehyde 8-2 was directly used in the next step without any characterization. To an ice-cooled solution of carbon tetrabromide (9.4 g, 28.3 mmol) in dry DCM (200 mL) was added under argon triphenylphosphine (14.8 g, 56.6 mmol). After stirring for 1 hour, a solution of aldehyde 8-2 (3 g, 14.2 mmol) in DCM (60 mL) containing triethylamine (2 mL, 14.2 mmol), was transferred via double-tip cannula to the red-orange mixture. The resulting brown mixture was stirred in the ice bath for 1 hour before being quenched with a saturated solution of sodium bicarbonate. The aqueous phase was extracted twice with DCM and the resulting combined extracts were washed with a 10% aqueous solution of thiosulfate, brine and dried over sodium sulfate. After concentration, the residue was purified on silica gel flash chromatography eluting with 5 % EtOAc in hexanes yielding gem-dibromo derivative 8-3 as a yellow oil (4 g, 80 %).1H NMR (400 MHz, CDCl3) δ 6.50 (d, J = 8.7 Hz, 1H), 5.59 – 5.47 35 8625002(m, 1H), 5.31 (dtt, J = 10.5, 7.1, 1.5 Hz, 1H), 4.75 (dd, J = 8.6, 5.9 Hz, 1H), 4.30 – 4.19 (m, 1H), 2.41 – 2.28 (m, 1H), 2.22 (dd, J = 14.7, 7.1 Hz, 1H), 2.06 (h, J = 7.1 Hz, 2H), 1.48 (s, 3H), 1.36 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H). (4R,5S)-4-ethynyl-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolane (Intermediate 8-4)

[0161] To a cooled (dry ice / acetone bath) solution of gem-dibromo 8-3 (3.8 g, 10.7 mmol) in dry THF (150 mL) was added under argon n-butyllithium (2.3 M in hexanes, 14 mL, 32 mmol). The orange solution was stirred for 2 hours then quenched with saturated ammonium chloride. The aqueous phase was extracted twice with EtOAc and the resulting combined extracts were washed with brine, dried over sodium sulfate then concentrated under vacuum. The residue was purified on silica gel flash chromatography eluting with 2 % EtOAc in hexanes yielding propargylic alcohol derivative 8-4 as a yellow oil (1.8 g, 80 %).1H NMR (400 MHz, Chloroform-d) δ 5.52 (dtt, J = 10.5, 7.2, 1.6 Hz, 1H), 5.41 – 5.30 (m, 1H), 4.74 (dd, J = 5.5, 2.2 Hz, 1H), 4.09 (td, J = 7.1, 5.4 Hz, 1H), 2.63 – 2.45 (m, 2H), 2.53 (d, J = 2.2 Hz, 1H), 2.17 – 2.04 (m, 2H), 1.54 (s, 3H), 1.34 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H). 2-[(E)-2-{(4R,5S)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4-yl}ethenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Block E)

[0162] In a MW tube were introduced under argon alkyne 8-4 (1.5 g, 7.1 mmol), pinacoldiborane (1.8 g, 14.1 mmol) and Schwartz reagent (183 mg, 0.71 mmol). After sealing, 36 8625002the tube was placed in an oil bath preheated at 60-70oC for 36 hours. The flash was cooling to room temperature before opening, and poured into crushed ice. After extraction with EtOAc (2X), the combined extracts were washed with brine, dried over sodium sulfate and finally concentrated under vacuum. The residue was purified on silica gel flash chromatography eluting with 2 % EtOAc in hexanes yielding boronate ester derivative (Block E) as a yellow oil (1.4 g, 61 %).1H NMR (400 MHz, CDCl3) δ 6.54 (dd, J = 18.0, 6.6 Hz, 1H), 5.73 (d, J = 18.0 Hz, 1H), 5.54 – 5.43 (m, 1H), 5.39 – 5.27 (m, 1H), 4.57 (t, J = 6.5 Hz, 1H), 4.21 (q, J = 6.3 Hz, 1H), 2.28 (dt, J = 14.4, 7.2 Hz, 1H), 2.18 (dt, J = 14.5, 7.0 Hz, 1H), 2.04 (p, J = 7.4 Hz, 2H), 1.50 (s, 3H), 1.36 (s, 3H), 1.26 (s, 12H), 0.96 (t, J = 7.5 Hz, 3H). Assembly of blocks A, D and E for the synthesis of I-5 and I-6

[0163] Blocks A, D and E were used as shown in Scheme 9:37 8625002Methyl (4Z,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-7-{5-iodo-1-[(trimethylsilyl)methyl]-1H- 1,2,3-triazol-4-yl}hept-4-enoate (Intermediate 9-1)

[0164] Cu- azide (Block A) and alkyne (Block D) was achieved as described for preparation of triazole intermediate 6-1. Thus, a mixture of alkyne (Block D) (200 mg, 0.72 mmol), trimethylsilylmethyl azide (Block A) (112 mg, 0.65 mmol), CuI (137 mg, 0.72 mmol), NBS (139 mg, 0.78 mmol) and DIPEA (0.1 mL, 0.72 mmol) in THF (5 mL) was stirred for 2 hours. After purification on silica gel eluting with 5% acetone in hexanes, 93 mg (25 %) of 1,4-disubstituted-5-iodotriazole 9-1 was obtained as a syrup then 162 mg (56%) of a more polar product which was identified as deiodinated 1,4- dialkylated-triazole.1H NMR (400 MHz, MeOH-d4) δ 5.43 – 5.27 (m, 2H), 3.97 (s, 2H), 3.65 (s, 3H), 2.63 (ddt, J = 21.0, 13.9, 7.1 Hz, 2H), 2.34 – 2.22 (m, 5H), 0.85 (s and t, 12H), 0.15 (s, 6H), 0.09 (s, 9H). Methyl (4Z,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-7-{5-[(E)-2-{(4S,5R)-2,2-dimethyl-5- [(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4-yl}ethenyl]-1-methyl-1H-1,2,3-triazol-4-yl}hept-4- enoate (Intermediate 9-2) 38 8625002

[0165] 4,5-disubstituted triazole 9-2 was synthetized by Suzuki coupling between boronate (Block E) and 4-iodotriazole 9-1 as described for intermediate 6-2.

[0166] Thus, a mixture of iodotriazole 9-1 (70 mg, 0.13 mmol), boronate (Block E) (66 mg, 0.19 mmol), Pd(PPh3)4 (10 mg) in 1:1 DMF / 2M aq K2CO3 mixture was heated at 1150C for 1 hour. After work-up and purification of the crude mixture on silica gel column eluting with 10% acetone in hexanes, 42 mg (60%) of compound 9-2 was isolated as a yellow oil.1H NMR (400 MHz, MeOH-d4) δ 6.74 (dd, J = 16.1, 1.0 Hz, 1H), 6.61 (dd, J = 16.1, 6.8 Hz, 1H), 5.53 – 5.29 (m, 4H), 5.01 – 4.93 (m, 1H), 4.80 – 4.75 (m, 1H), 4.31 (dt, J = 8.2, 5.9 Hz, 1H), 4.04 (s, 3H), 3.63 (s, 3H), 2.78 – 2.58 (m, 2H), 2.31 – 2.14 (m, 6H), 2.07 – 1.93 (m, 2H), 1.52 (s, 3H), 1.39 (s, 3H), 0.92 (d, J = 7.6 Hz, 3H), 0.86 (s, 9H), 0.10 (s, 6H). Methyl (4Z,7S)-7-{5-[(E)-2-{(4S,5R)-2,2-dimethyl-5-[(2Z)-pent-2-en-1-yl]-1,3-dioxolan-4- yl}ethenyl]-1-methyl-1H-1,2,3-triazol-4-yl}-7-hydroxyhept-4-enoate (Intermediate 9-3)39 8625002

[0167] Compound 9-3 was prepared as described for compound 6-3. Thus, 40 mg (0.07 mmol) of triazole 9-2 was treated with TBAF (1M in THF, 0.11 mmol) for 2 hours at room temperature. After purification on silica gel eluting with 20 % acetone-hexanes, 27 mg (87%) of alcohol 9-3 was isolated.1H NMR (400 MHz, MeOH-d4) δ 6.70 (dd, J = 16.1, 1.1 Hz, 1H), 6.49 (dd, J = 16.1, 7.0 Hz, 1H), 5.51 – 5.34 (m, 4H), 4.83 – 4.74 (m, 2H), 4.30 (dt, J = 8.3, 5.9 Hz, 1H), 4.04 (s, 3H), 3.64 (s, 3H), 2.74 (dt, J = 9.0, 6.7 Hz, 2H), 2.35 – 2.19 (m, 6H), 2.07 – 1.96 (m, 2H), 1.51 (s, 3H), 1.39 (s, 3H), 0.92 (t, J = 7.5 Hz, 3H). Methyl (4Z,7S)-7-{5-[(1E,3S,4R,6Z)-3,4-dihydroxynona-1,6-dien-1-yl]-1-methyl-1H-1,2,3- triazol-4-yl}-7-hydroxyhept-4-enoate (Compound I-5)

[0168] Deprotection of acetonide was achieved as reported for synthesis of compound I-2. Thus, 25 mg (0.05 mmol) of previous compound 9-3 was stirred in MeOH in presence of p-TSA (12 mg). After purification on silica gel eluting with 2% MeOH in DCM we isolated 14.8 mg (71%) of triazolo-RVD2 methyl ester analog I-5.1H NMR (500 MHz, MeOH-d4) δ 6.68 (dd, J = 16.3, 1.4 Hz, 1H), 6.56 (dd, J = 16.3, 5.7 Hz, 1H), 5.56 – 5.45 (m, 2H), 5.39 (ddd, J = 5.4, 3.8, 1.8 Hz, 2H), 4.82 (t, J = 7.2 Hz, 1H), 4.20 (td, J = 5.5, 1.5 Hz, 1H), 4.05 (s, 3H), 3.65 (s, 3H), 2.82 – 2.72 (m, 2H), 2.46 – 2.37 (m, 1H), 2.28 (dtdd, J = 19.9, 16.5, 8.0, 5.6 Hz, 5H), 2.15 – 2.04 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).13C NMR (126 MHz, MeOH-d4) δ 176.1, 148.4, 140.8, 135.5, 134.8, 132.1, 128.3, 127.0, 116.6, 76.9, 76.7, 68.0, 52.9, 36.7, 36.0, 35.5, 32.8, 24.8, 22.6, 15.4. MS (APCI pos) m / z 394.2 [M+H]. See FIG.3A and FIG.3B. (4Z,7S)-7-{5-[(1E,3S,4R,6Z)-3,4-dihydroxynona-1,6-dien-1-yl]-1-methyl-1H-1,2,3-triazol- 4-yl}-7-hydroxyhept-4-enoic acid (Compound I-6) 40 8625002

[0169] To a solution of compound I-5 (9.4 mg, 0.02 mmol) in a 1 / 2 / 2 mixture of MeOH / THF / water (0.1 mL) was added under argon lithium hydroxide (5 mg, 0.12 mmol). The yellow mixture was stirred for 1h at room temperature, quenched with a 10% aqueous solution of NaH2PO4, extracted twice with EtOAc. After washing with brine, the combined organic phases were dried over Na2SO4 then evaporated under vacuum to leave Compound I-6 (6.2 mg, 81%).1H NMR (500 MHz, MeOH-d4) δ 6.68 (dd, J = 16.3, 1.4 Hz, 1H), 6.56 (dd, J = 16.2, 5.7 Hz, 1H), 5.53 – 5.45 (m, 2H), 5.45 – 5.36 (m, 2H), 4.82 (t, J = 7.2 Hz, 2H), 4.19 (td, J = 5.5, 1.4 Hz, 1H), 4.05 (s, 3H), 3.66 – 3.60 (m, 1H), 2.81 – 2.71 (m, 2H), 2.45 – 2.37 (m, 1H), 2.36 – 2.18 (m, 5H), 2.14 – 2.03 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).13C NMR (126 MHz, MeOH-d4) δ 177.8, 148.4, 140.9, 140.8, 135.5, 134.8, 132.4, 128.1, 127.0, 116.6, 76.9, 76.7, 68.0, 36.8, 36.0, 35.6, 32.9, 24.8, 22.6, 15.4. MS (APCI pos) m / z 380.1 [M+H]. See FIG.4A and FIG.4B. Cell Culture

[0170] Murine macrophage RAW 264.7 (ATCC, Manassas, VA, USA) were cultured with AMEM / 10% FBS and antibiotics at 37˚C in a humidified atmosphere with 5% CO2. Primary human monocytes were isolated from whole blood obtained from healthy volunteers. Briefly, blood was centrifuged on a Ficoll-Paque density gradient, according to the manufacturer’s recommendations. Isolated monocytes were then cultured in RPMI 1640 medium supplemented with 10% FBS, and antibiotics. All donors provided written, informed consent for the use of their blood for research purposes. Experimental protocols were approved by the Research Ethics Board of the “Hôpital du Sacré-Coeur de Montréal”. Example 4 - Cell Viability Assay

[0171] Raw264.7 cells were treated for 24 hours with increasing concentrations of RvD1 and analogues T1, T2, T3 and T4 at 10-µM. Cell viability was assessed with MTS assay 41 8625002kit (Promega Corporation, Madison, WI, USA), as described by the manufacturer. Absorbance was measured with the micro-ELISA Vmax photometer (Bio-Tek Instruments, Winooski, VT, USA). Cell viability was evaluated by 3-(4,5-dimethyl-thiazoyl)-2,5-diphenyl-SH-tetrazolium bromide assay. ANOVA test was performed to compare the results. Results are expressed as mean ± SEM for n=3. Results are shown in FIG.5. Example 5 - TRAP Staining

[0172] Isolated human monocytes were isolated as described previously, seeded in chambered cell culture slides at 8 x 104cells / well, and treated with 50 ng / ml RANKL and 10 ng / ml M-CSF in the presence or absence of 1 ^M of compounds RvD1 and analogues T1, T2, T3 and T4 for 14 days. Culture medium was changed every 3 days. TRAP staining performed as recommended by the manufacturer. Nuclei were counter stained with Gill’s hematoxylin and TRAP positive multinucleated osteoclasts staining (≥3 nuclei) was counted in 10 randomly selected high-power fields using digital EVOSTMlight microscopy (Electron Microscopy Sciences, Hatfield, PA, USA) at 20X magnification. and TRAP-positive cells were observed with an inverted microscope (× 200). Results are shown in FIG.8, R= RANKL; M=M-CSF. Example 6 – COX-2 expression

[0173] Raw264.7 cells were treated for 24 hours with increasing concentrations of RvD1 and analogues (0, 0.1, 0.2, 0.5, 1, 5, and 10 µM) in the presence or absence of LPS (100 ng / ml). The culture media was collected and COX-2 expression was measured in cell extracts by Western blot Results are shown in FIG.9. Example 7 - Protein detection by Western blotting

[0174] 20 µg of total proteins of Raw264.7 macrophages lysates, treated under the indicated conditions, were loaded for discontinuous 4-12% sodium dodecyl sulfate- polyacrylamide gel electrophoresis. They were then transferred electrophoretically onto nitrocellulose membranes (Bio-Rad Laboratories, Mississauga, ON, Canada) for protein immunodetection and semi-quantitative measurement. The primary antibodies deployed were rabbit anti-COX-2 (Cayman Chemical Company) and mouse anti-β-actine (Sigma). After serial washes, the primary antibodies were revealed by goat anti-mouse or anti-rabbit immunoglobulin G conjugated to horseradish peroxidase (Cell Signaling Technology, Inc.). Immunoreactive proteins were detected with SuperSignal blotting substrate (Pierce, Rockford, IL) and exposed to Kodak X-OmatTMfilm (Eastman Kodak Company, Rochester, NY). Results for RvD1 and analogues T1, T2, T3 and T4 are shown in FIG.9. 42 8625002Example 8 - Conversion of RvD1 and analogues by enzymatic action

[0175] RvD1 and analogues T1, T2, T3 and T4 (10 ^g) were taken to dryness under N2stream and incubated with recombinant human 15-PG-dehydrogenase / eicosanoid oxidoreductase (EOR; 0.5 U; Cayman Chemical) in 200 μL Tris-HCl buffer (50 mM, pH 7.4) containing NAD+(1.0 mM). The activity of EOR was monitored spectrophotometrically by the formation of NADH from NAD+at 340 nm. The results are shown in FIG.6. Example 9 - Effect of RvD1 and analogues on ROS generation

[0176] First, Raw264.7 cells were pre-incubated with or without RvD1 and analogues T1, T2, T3 and T4 at 1 µM for 1 hour and then after treated with 500 mM H2O2for another 4 hours. ROS generation was assessed with MitoSox Red MitoSox Red (n=3). Second, another experiment was designed in acellular environment. Briefly, ROS generation was induced by the addition of CuCl2and H2O2at 10 µM during 1 hour in presence or absence of RvD1 and analogues at 1 µM. Ascorbic acid (Asc) at 10 µM was used as positive control. ROS production was determined by MitoSox Red. Results are shown in FIG.7A and FIG.7B. Example 10 - Oxygen radical absorbance capacity (ORAC) assay

[0177] This part of experiment was performed to measure the antioxidant capacity of RvD1 and analogues. Briefly, RvD1 and analogues T1, T2, T3 and T4 (20 mL at different doses) were incubated in 120 ml of fluorescein 58 nM for 30 min at 37°C without shaking. Then after, 60 µl (40 mM) of AAPH were manually added and with a multi-channel-pipette and fluorescence (Ex. 485 nm, Em. 520 nm) was measured every 90 seconds for 80 cycles by fluorometer. Results are shown in Table 1. 43 8625002Example 11 - Prostaglandin E2 (PGE2) determination

[0178] PGE2 levels were assessed in cell culture supernatants by EIA, according to the manufacturer’s instructions. All assays were performed in duplicate. The absorbance was quantified with the micro-ELISA Vmax photometer at 405 nm (Bio-Tek Instruments, Winooski, VT, USA). Results are shown in FIG.10. Example 12 - Stability of hyaluronic acid (HA)

[0179] HA solubilized in PBS at 1 mg / mL was pretreated with RvD1 or analogues T1, T2, T3 and T4 at a concentration of 1 μM for 1 hour then treated with CuCl2 and H2O2 at 10 ^M for 24 hours.20 μg of HA were loaded into an agarose gel (1% prepared in TBE buffer). 44 8625002After 4 hours of migration at 40 volts, the HA was visualized after staining with Stains-All dissolved in 30% ethanol. Results are shown in FIG.11. Example 13 - Cellular level of HNE-protein adducts

[0180] Cell treatment: Raw264.7 cells were pre-treated with 10 µM of RvD1 or analogues (T1, T2, T3, T4) for 1 hours and then after with 0.5 mM H2O2for 24 hours. Isolated human monocytes were isolated as described previously, seeded in chambered cell culture slides at 8 x 104cells / well, and treated with 50 ng / ml RANKL and 10 ng / ml M-CSF (RM) in the presence or absence of 1 µM of compounds RvD1 and analogues for 14 days. Culture medium was changed every 3 days. In both cell type, culture media was removed and cells were lysed using commercial lysis buffer.

[0181] Total proteins were extracted using commercial lysis buffer and cellular levels of HNE-protein adducts were assessed by ELISA, as described previously. HNE-modified bovine serum albumin (HNE / BSA) (Sigma–Aldrich) served as standard. Results are shown in FIG.12. Example 14 - Glutathione (GSH) Assay

[0182] Culture medium of cultured Raw274.7 macrophages was collected and cells were commercial lysis buffer from Sigma. Reduced GSH and oxidized GSH (GSSG) were quantified in cellular extracts with a Glutathione Assay Kit (Cayman Chemical Compagny), according, to the manufacturer’s directions. Values were expressed as the GSSG / GSSG + GSH ratio levels. All assays were performed in duplicate. Absorbance was measured with the microELISA Vmax photometer (Bio-Tek Instruments, Winooski, VT, USA). Data are shown in FIG.13. Example 15 - Active caspase -3 assay

[0183] Cell extracts were subjected to an active caspase-3 ELISA (R & D Systems, Minneapolis, MN), following the manufacturer’s instructions. Absorbance was measured with the micro-ELISA Vmax photometer (BioTek Instruments, Winooski, VT, USA). Results are shown in FIG.14. Example 16 - Protein detection by Western blotting

[0184] 20 µg of total proteins of Raw264.7 macrophages and osteoclast lysates, treated under the indicated conditions, were loaded for discontinuous 4-12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. They were then transferred electrophoretically onto 45 8625002nitrocellulose membranes (Bio-Rad Laboratories, Mississauga, ON, Canada) for protein immunodetection and semi-quantitative measurement. The primary antibodies deployed were rabbit anti-Bcl2, Nrf2, pNFATc1, cathepsin K, and mouse anti-β-actin (Sigma). After serial washes, the primary antibodies were revealed by goat anti-mouse or anti-rabbit immunoglobulin G conjugated to horseradish peroxidase (Cell Signaling Technology, Inc.). Immunoreactive proteins were detected with SuperSignal blotting substrate (Pierce, Rockford, IL) and exposed to Kodak X-OmatTM film (Eastman Kodak Company, Rochester, NY). Results are shown in FIG.15 and FIG.16. Results Cytotoxicity in Raw 264.7 macrophages

[0185] This part of the experiment was designed to test the cytotoxic effect of compounds RvD1 and T1, T2, T3 and T4 on mouse Raw264.7 macrophages. As illustrated in FIG.5, the compounds did not alter the cell viability after 24 h of incubation. As such, it may be concluded that RvD1 and T1, T2, T3 and T4 were not cytotoxic in Raw 264.7 macrophages. Enzymatic conversion of RvD1 and analogues

[0186] Here, the purpose of this part of the present study was to investigate whether our analogues are resistant than RvD1 to the enzymatic action of eicosanoid oxidoreductase (EOR). To do so, 10 ^M RvD1 and T1, T2, T3 and T4 were incubated with recombinant 15- PG-dehydrogenase / eicosanoid oxidoreductase in the presence of NAD+. As illustrated in FIG.6, RvD1 was rapidly converted by the action of EOR as compared to T1, T2, T3, and T4. As such, it may be concluded that analogues T1, T2, T3 and T4 are more stable and resistant to the enzyme action. ROS generation:

[0187] This part of experiments was designed to investigate the antioxidant properties of RvD1 and analogues T1, T2, T3 and T4 using two models: isolated Raw264.7 cells and acellular environment. As illustrated in FIG.7A, the production of ROS by Raw264.7 cells was reduced RvD1 and analogues as compared to the control. The analogue T2 and T4 were potent than RvD1 and T1 and T3 and ascorbic acid (Asc). The same pattern was observed in acellular environment (FIG.7B) Oxygen radical absorbance capacity of RvD1 and analogues 46 8625002

[0188] In this part of the study, 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH) was used to measure the capacity of RvD1 and analogues T1, T2, T3 and T4 to scavenge AAPH. The Trolox was used as reference. The OARC assay is a standardized method for determining the antioxidant capacity of any substance. As indicated in Table 1, the antioxidant capacity of analogue T2, T3 and T4 are higher than Trolox (1.54-fold, 3.4-fold, and 5-fold). These results support the notion that T2, T3, and T4 are the most powerful antioxidant compounds. Osteoclast differentiation

[0189] Here, the impact of RvD1 and analogues T1, T2, T3 and T4 on treatment on human isolated monocytes / macrophages-RANKL / M-CSF-derived osteoclasts was evaluated, by measuring their phenotypic markers, namely TRAP. As shown in FIG.8, the addition of compounds RvD1 and T1, T2, T3 and T4 at 1 ^M to the cultured cells strongly prevent osteoclasts differentiation as compared to RANKL / M-CSF-treated cells. As such, it may be concluded that compounds RvD1 and T1, T2, T3 and T4 inhibit monocytes / macrophages differentiation. CuCl2 / H2O2-induced hyaluronic fragmentation

[0190] Here, the capacity of RvD1 and analogues T1, T2, T3 and T4 to protect hyaluronic acid (HA) against ROS-induced HA degradation was investigated. To do so, the polymer was treated RvD-1 and analogues and then after with CuCl2 / H2O2. As indicated in FIG.11, the addition of RvD1 and analogues protected preserve the integrity of HA, as compared to the untreated HA. COX-2 and iNOS protein expression

[0191] Here, the hypothesis whether RvD1 analogues have the ability to modulate COX-2 and iNOS protein expression was tested. Raw264.7 macrophages were pretreated with increasing doses of compound RvD1 and T1, T2, T3 and T4 (0, 0.1, 0.2, 0.5, 1, 5-, and 10- ^M) for 1 hour and treated then after with 100 ng / ml LPS for 24 hours. As shown in FIG.9, we revealed that compound RvD1 and T1, T2, T3 and T4 reduced LPS-induced COX-2 protein expression (n=3), suggesting the anti-inflammatory these compounds. Prostaglandin E2 determination

[0192] Prostaglandin E2 (PGE2) is a potent inflammatory mediator that is generated by cyclooxygenase 2 (COX2) conversion of arachidonic acid. Here, it was investigated whether 47 8625002changes in COX-2 protein expression was associated with changes in PGE2 production. As illustrated in FIG.10. Markers of oxidative stress

[0193] First, the effect of RvD1 and analogues on oxidative stress was conducted by determining the production of 4-hydroxynonenal (HNE), one of the most abundant and cytotoxic of the lipid peroxidation product. As illustrated in FIG 12, the cell treatment with RvD1 and analogues decreased the H2O2-induced HNE / protein adducts formation when compared to H2O2alone. Then after, another set of experiments were performed to establish whether RvD1 and analogues could potentially regulate the antioxidant system, via measuring the GSSG / GSSG+GSH ratio. FIG 13 shows that H2O2 alone reduced the GSH as determined by an increase in GSSG / GSSG+GSH ratio. However, the cell treatment with RvD1 and analogues increased increase the GSH by decreasing GSSG / GSSG+GSH ratio, demonstrating the antioxidant effects of RvD1 and analogues in Raw264.7 cells. Markers of apoptosis

[0194] This part of experiments was designed to investigate the protective effects of RvD1 and analogues on H2O2-induced apoptotic process in Raw264.7 cells, by measuring the active caspase-3, the anti-apoptotic factor Bcl2, and Nrf2, a key transcription factor involved in expressing antioxidant target genes as well as Bcl2. Our data indicated that the cell treatment with RvD1 and analogues blocked the activation of caspase-3 (FIG 14) and the protein expression of both Bcl2 and Nrf2 (FIG 15) by H2O2. Collectively, these findings strongly suggest the antiapoptotic effects of our compounds in Raw264.7 cells. Expression of markers of osteoclasts

[0195] To confirm the inhibition of osteoclast differentiation by RvD1 and analogues, we conducted addition experiments to determine the expression of their phenotypic markers, namely NFATc1 transcription factor and cathepsin K. As shown in FIG 16, the cell treatment with RvD1 or analogues reduced the phosphorylated NFATc1 (pNFATc1) and the protein expression of cathepsin K as compared to the positive control (RM). These results support the inhibition of osteoclasts differentiation by analogues.

[0196] While the applicant's teachings described herein are in conjunction with various embodiments for illustrative purposes, it is not intended that the applicant's teachings be limited to such embodiments as the embodiments described herein are intended to be examples. On the contrary, the applicant's teachings described and illustrated herein encompass various 48 8625002alternatives, modifications, and equivalents, without departing from the embodiments described herein, the general scope of which is defined in the appended claims. REFERENCES 1) Gharpure SJ et al, European journal of organic chemistry, 2020, 6870-6886. (DOI: 10.1002 / ejoc.202000973) 2) Escudero-Casao M et al, Org. Biomol. Chem., 2018, 16, 7230. (DOI: 10.1039 / c8ob01867g) 3) De Gaetano M et al European Journal of Medicinal Chemistry, 2019, 162, 80-108. (DOI: 10.1016 / j.ejmech.2018.10.049) 4) A.N. Koronatov et al. Org. Lett., 2020, 22, 7958-63. (DOI : 10.1021 / acs.orglett.0c02893 5) J.E. Tungen et al. Chemistry - A European Journal, 2019, 25,1476-1480. (DOI: 10.1002 / chem.201806029) 6) R. Maltais et al. J. Org. Chem. 2023, 88, 11, 7088-7095. (DOI: / 10.1021 / acs.joc.3c00360) 49 8625002

Claims

CLAIMS 1. A compound of Formula (I): wherein:R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, CO2R7and C(O)NR7R7’, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8;, R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8or R6is -OR7, -NR7R7’, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; 50 8625002n is an integer from 1 to 7; are independently absent or represent a bond, wherein R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer,solvate thereof.

2. A compound of Formula (IA):wherein: R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R6is selected from the group consisting of linear or branched C1-10alkyl and linear or branched C2-10alkenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8, R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; 51 8625002each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; is absent or represents a bond, wherein R5is absent when is a bond, or an enantiomer,or solvate thereof.

3. A compound of Formula (IB):wherein: R2, R3and R5are independently selected from the group consisting of H, C1-8alkyl, and a suitable protecting group; wherein R2and R3may be joined to form, together with the atom therebetween, an heterocyclyl group; R4is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered cycloalkyl, 5- to 20-membered heteroaryl, 6- to 20- membered aryl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be substituted with one or more group R8; R7and R7’ are independently selected from the group consisting of H and C1-8alkyl; each R8is independently selected from the group consisting of halogen, -CO2R7, -OR7, -CF3, -CN, -NR7R7’, -SH, -SO2NHR7, -SO2NR7R7’, benzyl and phenyl; n is an integer from 1 to 7; are independently absent or represent a bond, 52 8625002wherein R5is absent when the between the carbon and the oxygen is a bond, or an enantiomer, isomer, salt or solvate thereof.

4. R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl and CO2R7, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and may be substituted with one or more group R8.

5. The compound of claim 1, wherein R1is selected from the group consisting of H, C1-8alkyl, C2-10alkenyl, CO2C1-8alkyl and CO2H.

6. The compound of claim 1, wherein R1is H, methyl, ethyl, propyl, CO2Me, CO2Et, CO2Pr or CO2H.

7. The compound of claim 1 or 2, wherein R6is linear or branched C1-8alkyl or C2-10alkenyl which may be substituted with one or more group R8.

8. The compound of claim 1 or 2, wherein R6is linear or branched C1-8 alkyl or C2-10alkenyl substituted with -CO2R7.

9. The compound of claim 1 or 2, wherein R6is C2-10alkenyl substituted with one or more group selected from halogen, CO2R7, -OR7, -N(R7R7’, and phenyl.The compound of claim 1 or 2, wherein R6is linear or branched C2-10 alkenyl, which comprises 1 to 4 double bonds.

10. The compound of claim 1 or 2, wherein R6is pentyl, propyl, octyl or benzyl.

11. The compound of claim 1 or 2, wherein R6is propenyl, butenyl, pentenyl or octenyl.

12. The compound of any one of claims 1 to 11, wherein R2, R3and R5are independently selected from the group consisting of H, methyl, ethyl, and propyl.

13. The compound of any one of claims 1 to 11, wherein R2and R3are joined to form, together with the atom therebetween, an acetal group.

14. The compound of any one of claims 1 to 11, wherein R2, R3and R5are each H. 53 862500215. The compound of any one of claims 1 to 14, wherein R4is H, C1-8alkyl, C2-10alkenyl or phenyl, wherein the alkyl and alkenyl may be interrupted by 1 to 3 heteroatoms selected from O, N and S, and the alkyl, alkenyl and phenyl may be substituted with one or more group R8.

16. The compound of any one of claims 1 to 14, wherein R4is H, methyl, ethyl, propyl or phenyl.

17. The compound of any one of claims 1 to 16, wherein R7is H, methyl, ethyl, or propyl.

18. The compound of any one of claims 1 to 17, wherein each R8is independently selected from the group consisting of Cl, F, Br, C1-8alkyl, CO2C1-8alkyl, -CO2H, -OH, -OC1-8alkyl, -NH2, -NHC1-8 alkyl and N(C1-8 alkyl)2.

19. The compound of any one of claims 1 to 17, wherein each R8is independently selected from the group consisting of C1-4 alkyl, CO2C1-4 alkyl, -CO2H, -OH, -OC1-4 alkyl, -NH2, - NHC1-4 alkyl and N(C1-4 alkyl)2.

20. The compound of any one of claims 1 to 17, wherein each R8is methyl, ethyl, or propyl, CO2Me, CO2Et, -CO2H, -OH, -OMe, -OEt or -OPr.

21. The compound of any one of claims 1 to 20, for use in treatment or prevention of an inflammatory disease or disorder.

22. The compound for use of claim 21, wherein the inflammatory disease or disorder is selected from arthritis, osteoarthritis, inflammatory bowel disease or disorder, and skin inflammatory disease and disorder.

23. The compound of any one of claims 1 to 20, for use in treatment or prevention of a bone disease or disorder or joint disease and disorder.

24. The compound for use of claim 23, wherein the bone disease or disorder is selected from osteoporosis, and bone metastases and the joint disease or disorder is arthrosis. 54 862500225. The compound of any one of claims 1 to 20, for use as an anti-inflammatory agent or an antioxidant agent.

26. The compound of any one of claims 1 to 20, for inhibiting monocytes / macrophages differentiation.

27. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 20, and a pharmaceutically acceptable excipient, diluent or carrier.

28. Use of the compound of any one of claims 1 to 20, in treatment or prevention of an inflammatory disease or disorder.

29. Use of the compound of any one of claims 1 to 20, in manufacture of a medicament for treating or preventing an inflammatory disease or disorder.

30. The use of claim 28 or 29, wherein the inflammatory disease or disorder is selected from is selected from arthritis, osteoarthritis, inflammatory bowel disease or disorder, and skin inflammatory disease and disorder.

31. Use of the compound of any one of claims 1 to 20, in treatment or prevention of a bone disease or disorder or joint disease and disorder.

32. Use of the compound of any one of claims 1 to 20, in manufacture of a medicament for treating or preventing a bone disease or disorder or joint disease and disorder.

33. The use of claims 31 or 32, wherein the bone disease or disorder is selected from osteoporosis, and bone metastases and the joint disease or disorder is arthrosis.

34. Use of a compound of any one of claims 1 to 20, as an anti-inflammatory agent or an antioxidant agent.

35. Use of a compound of any one of claims 1 to 20, for inhibiting monocytes / macrophages differentiation. 55 862500236. A method for treating or preventing an inflammatory disease or disorder, comprising administering an effective amount of a compound of any one of claims 1 to 20 in a subject in need thereof.

37. The method of claim 36, wherein the inflammatory disease or disorder is selected from arthritis, osteoarthritis, inflammatory bowel disease or disorder, and skin inflammatory disease and disorder.

38. A method for treating or preventing a bone disease or disorder or joint disease and disorder, comprising administering an effective amount of a compound of any one of claims 1 to 20 in a subject in need thereof.

39. The method of claim 38, wherein the bone disease or disorder is selected from osteoporosis, and bone metastases and the joint disease or disorder is arthrosis.

40. A method for inhibiting monocytes / macrophages differentiation, comprising administering an effective amount of a compound of any one of claims 1 to 20 in a subject in need thereof.

41. Use of a compound of any one of claims 1 to 20, as an antioxidant agent, a stabilizing agent or a preservative in a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

42. The compound of any one of claims 1 to 20, for use as an antioxidant agent, a stabilizing agent or a preservative in a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition.

43. A method for stabilizing or preserving a composition, comprising adding an acceptable amount of a compound of any one of claims 1 to 20 as an antioxidant agent, a stabilizing agent or a preservative, wherein the composition is a food composition, a cosmetic composition, a pharmaceutical composition, a petrochemical composition or a medicinal composition. 56 8625002

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