Aromatic lipoxin b4 analogues and compositions and uses thereof

Abstract

The present application provides LXB4 analogues that have good metabolic stability compared to LXB4 and having sufficient biological activity to enable a neuroprotective and / or anti-inflammatory effect. The LXB4 analogues are compounds of having the structure of Formula (I). Also provided are pharmaceutical compositions, and methods and uses for providing neuroprotection, or for treating or preventing a disease or condition associated with neuroinflammation or neurodegeneration.

Description

AROMATIC LIPOXIN B4 ANALOGUES AND COMPOSITIONS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 574,493, filed April 4, 2024, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present application pertains to the field of natural product analogues. More particularly, the present application relates to analogues of lipoxin B4 and therapeutic uses thereof.BACKGROUND

[0003] Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin B4 (LXB4) is a non-classic eicosanoid and a member of the specialized pro-resolving mediator (SPM) family of polyunsaturated fatty acids, naturally derived from arachidonic acid (AA) through a series of oxidation steps by 5- lipoxygenase (5-LOX) and 12 / 15-LOX.[1,2]

[0004] Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) are associated with a variety of inflammatory conditions, and both demonstrate potent anti-inflammatory and pro-resolution processes since their initial discovery in 1984 (3). In the nervous system, LXA4 and LXB4exert an array of neuroprotective effects against neurological diseases, including ischemic or hemorrhagic stroke, neonatal hypoxia-ischemia encephalopathy, brain and spinal cord injury, Alzheimer's disease, multiple sclerosis, neuropathic pain and glaucoma. LXB4is a potent neuroprotectant (31 nM) in primary RGCs, cortical neurons, and neuronal cell lines.

[0005] The therapeutic potential of LXA4 and LXB4is compromised by their chemical instability and their rapid metabolic inactivation in vivo, for example by prostaglandin (PG) dehydrogenase-mediated oxidation and reduction.

[0006] Given the role of LXB4in resolution of inflammation and in neuroprotection, there has been significant interest in designing synthetic analogues having improved stability and similar or improved activity. To date, however, a need remains for synthetically accessible, active analogues of LXB4.

[0007] The above information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.SUMMARY OF THE INVENTION

[0008] An object of the present application is to provide LXB4analogues and compositions and uses thereof. It is an aim of the present application, amongst others, to provide a compound, composition, use and method that addresses at least one disadvantage of the prior art, whether identified here or elsewhere, or to provide an alternative to existing compounds, compositions, uses or methods. For instance, it may be an aim of the present application to provide a compound, or class of compounds, having improved metabolic stability compared to LXB4and having sufficient biological activity to enable a neuroprotective and / or anti-inflammatory effect.

[0009] In accordance with an aspect of the present application, there is provided an LXB4analogue, which is a compound having the structure of Formula Ior a salt, lactone, ester, or solvate form thereof, whereinA is: (i) a 5-membered, 6-membered, or fused bicyclic heterocycle, where the heterocycle is optionally substituted with one or more halo, hydroxy, C1- C3alkyl, C1- C3fluoroalkyl, C1- C3alkoxyl and / or -NR2substituent, wherein each R is independently H or a C1- C3alkyl, or(ii) benzene substituted with one or more non-chloro halo substituents, a C1-C3alkyl with a terminal heterocycle, a C1- C3heteroalkyl, comprising one heteroatom (e.g., O, N or S), with a terminal heterocycle, or a heterocycle that is optionally substituted with a C1- C3alkyl, a C3- C6cycloalkyl and / or a C1- C3fluoroalkyl; and the 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety of Formula I are each connected to A at an sp2-hybridized carbon of A, and wherein the two connected sp2-hybridized carbons are adjacent to one another or separated by one or two atoms of A.

[0010] In some embodiments, the compound of Formula I is not

[0011] In some embodiments, the compound of Formula I has the following stereochemistry:

[0012] In some embodiments, the compound of Formula I is in a salt comprising a counterion to the carboxylate, for example a Li+counterion.

[0013] In other embodiments, the compound of Formula I is in an ester form, where the ester is a compound having the structure of Formula laor a salt or solvate thereof, where R1is a C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl), substituted C1-6alkyl (e.g., a cycloalkyl-substituted or hydroxy-substituted C1-6 alkyl), C2-6alkylene, substituted C2-6alkylene, benzyl, substituted benzyl.

[0014] In some embodiments, the compound of Formula is partially or completely in its lactone form of Formula lb

[0015] In some embodiments, the LXB4analogue comprises A which is a 5-membered heterocycle, such as pyrazole, thiazole, or isoxazole, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.

[0016] In some embodiments, the LXB4analogue comprises A which is a 6-membered heterocycle, such as pyridine, pyrazine, or pyrimidine, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.

[0017] In some embodiments, the LXB4analogue comprises A which is a fused bicyclic heterocycle, such as imidazo[l,2-a]pyrazine or quinoline, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.

[0018] In some embodiments, the LXB4analogue comprises A which is benzene substituted with one or more non-chloro halo substituents, a C1- C3alkyl with a terminal heterocycle, aC1- C3heteroalkyl, comprising one heteroatom (e.g., O, N or S), with a terminal heterocycle, or a heterocycle that is optionally substituted with a C1- C3alkyl, a C3- C6cycloalkyl or a C1- C3fluoroalkyl.

[0019] The LXB4analogues of the present application are useful as a medicine, for example, for providing neuroprotection or for treatment or prevention of a neural disorder or condition or a disease or condition associated with neuroinflammation or neurodegeneration in a subject in need thereof.

[0020] In accordance with another aspect of the present application, there is provided a pharmaceutical composition comprising one or more LXB4analogue as described herein, in combination with a pharmaceutically acceptable diluent, excipient, carrier, or combination thereof.

[0021] In some embodiments, the pharmaceutical composition is formulated for parenteral, topical, intravenous, subcutaneous, intramuscular, intraorbital, ophthalmic, intraocular, intravitreal, intracameral, subtenon, subconjunctival, intraperitoneal, aerosol or oral administration. Optionally, the pharmaceutical composition is formulated for topical administration to an eye, for example, by incorporation in a sustained delivery device (e.g., a contact lens), topical gel or ointment, polymer, or intraocular gel or sustained delivery device implant, polymer, or nanoparticles.

[0022] In some embodiments, the composition is formulated for administration of the compound at an amount of at least 0.2 nM or at least 50 nM and, optionally, less than 1 mM.

[0023] In accordance with another aspect of the present application, there is provided a use or method for providing neuroprotection, optionally retinal neuroprotection, or treating or preventing a disease or condition associated with neuroinflammation or neurodegeneration in a subject, comprising administering an LXB4analogue as described herein to the subject.

[0024] In some embodiments, the neuroprotection is for and / or the neural disorder or condition is central nervous system neurodegeneration and / or neural cell loss and thesubject in need thereof is administered an amount of the compound such that neural degeneration and / or neuron cell loss is inhibited or prevented.

[0025] In some embodiments, the neural disorder or condition comprises hippocampal neuron, cortical neuron, optic neuron or retinal ganglion cell (RGC) neuron degeneration and / or cell loss. In other embodiments, the neural disorder or condition comprises vision loss, an acute retinal or brain injury, optionally angle closure glaucoma, retinal vein occlusions, macular edema, ischemic and hemorrhagic stroke, and traumatic brain injury or a chronic neurodegenerative retinal or brain disorder such as glaucoma including all forms of primary open angle glaucoma, normal tension glaucoma, as well as retinal ischemias, diabetic retinopathy and diabetic macular edema, age related macular degeneration, retinitis pigmentosa, and Alzheimer's disease (retinal pathology), multiple sclerosis, as well as neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the neural disorder or condition comprises vision loss (or reduced vision), optionally wherein the disorder or condition is glaucoma.DETAILED DESCRIPTION

[0026] Definitions

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0028] As used in the specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0029] The term "comprising", as used herein, will be understood to mean that the list following is non-exhaustive and may or may not include any other additional suitable items, for example one or more further feature(s), component(s) and / or ingredient(s) as appropriate.

[0030] Reference throughout this specification to "one embodiment," "an embodiment," "another embodiment," "a particular embodiment," "a related embodiment," "a certain embodiment," "an additional embodiment," or "a further embodiment" or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0031] The term "and / or" as used in a phrase such as "X and / or Y" herein is intended to include "X and Y", "X or Y", "X", and "Y".

[0032] As used herein, the term "alkyl," unless otherwise specified, refers to a straight or branched chain saturated hydrocarbon radical, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, sec-pentyl, t-pentyl, neopentyl, and the like. By way of example, the term "C1-C4-alkyl" as used herein refers to a saturated straight-chain or branched hydrocarbon having 1 to 4 carbon atoms. "Alkyl" is intended to embrace all structural isomeric forms of an alkyl group. In some embodiments, alkyl groups have from 1 to 20 carbon atoms, or from 1 to 12 carbon atoms, or from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. The term "cycloalkyl" as used herein, is also intended to have its accustomed meaning of a cyclic, saturated hydrocarbon, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or the like. In some embodiments, cycloalkyl groups have from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms, or from 3 to 6 carbon atoms, or 5 or 6 carbon atoms.

[0033] As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined above. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, sec-butoxy, t-butoxy and the like.

[0034] As used herein, the term "aryl," unless otherwise specified, is intended to mean an aromatic hydrocarbon system, for example, phenyl, naphthyl, phenanthrenyl, anthracenyl, pyrenyl, and the like. Included within the term "aryl" are heteroaryl groups including one or more heteroatom, such as oxygen, sulfur and / or nitrogen, in the aromatic system, forexample, pyridyl, furyl, and thienyl. In some embodiments, aryl groups have from 6 to 10 carbon atoms. A "substituted aryl" includes one or more substituent, as defined below. Preferably, a "substituted aryl" includes one or two substituents, as defined below.

[0035] As used herein, the term "fluoroalkyl" refers to an alkyl, as defined above, in which at least one of the hydrogen atoms is replaced with a fluorine atom. Fluoroalkyl includes, for example, -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CHF2, -CHFCHF2, CH2CHF2, - CF2CH2F, -CHFCH2F,

[0036] As used herein, the term "halo" or "halogen" alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. In some embodiments, a halo substituent is other than a chloro substituent.

[0037] The term "heterocyclic ring" or "heterocycle", as used herein refers to fourmembered to eight-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and / or nitrogen. These four-membered to eight-membered rings can be saturated, fully unsaturated or partially unsaturated. Non-limiting examples of heterocyclic rings include piperidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrimidinyl, piperazinyl, indolinyl, and the like.

[0038] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds describedherein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example of neuroinflammatory and neurodegenerative disorders, including, but not limited to glaucoma and / or Alzheimer's disease.

[0039] "Compound" as the term is used herein, refers to and encompasses the chemical compound itself, either named or represented by structure, and salt, lactone or ester form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt, lactone or ester forms are to be excluded. The term "compound" further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvate forms include those of the compound itself and its salt or ester form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; and when a compound can be associated with two or more solvent molecules, the two or more solvent molecules may be the same or different.

[0040] In some instances, a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not imply any solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above. Furthermore, when explicit reference to a salt, lactone, ester and / or solvate form of a compound is not made, that omission is not to be construed as excluding the salt, lactone, ester and / or solvate form(s) of the compound unless the context makes clear that such salt, lactone, ester and / or solvate forms are to be excluded.

[0041] As used herein, the phrase, "pharmaceutically acceptable", is used to reference any pharmaceutically acceptable salt, ester, salt of such ester, or solvate (including hydrate) of such compound, which, upon administration to a patient, is capable of providing (directly or indirectly) a compound having the structure of Formula I, as otherwise described herein, or a metabolite or residue thereof.

[0042] The phrase "salt thereof" as the phrase is used herein, refers to a salt form of a compound. A salt form of a compound is of one or more internal salt forms and / or involves the inclusion of another molecule such as an inorganic ion, an acetate ion, a succinate ion or other counterion. The counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more than one charged atom in its structure. In instances where multiple charged atoms are part of the salt form, multiple counter ions and / or multiple charged counter ions are present. Hence, a salt form of a compound typically has one or more charged atoms corresponding to those of the non-salt form of the compound and one or more counterions. In some aspects, the non-salt form of a compound contains at least one amino group or other basic moiety, and accordingly in the presence of an acid, an acid addition salt with the basic moiety is obtained. In other aspects, the non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and accordingly in the presence of a base, a carboxylate or other anionic moiety is obtained. Exemplary salts include, but are not limited to, sodium, lithium, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene- bis-(2-hydroxy-3-naphthoate)) salts. The present application covers all such salt forms of the compound of Formula I.

[0043] A pharmaceutically acceptable salt is a salt form of a compound that is suitable for administration to a subject as described herein and in some aspects includes countercations or counteranions, for example, as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley- VCH / VHCA, 2002.

[0044] The term "ester thereof" as used herein, refers to an ester form of a compound, which is typically an in vivo hydrolysable ester or an ester prodrug that is hydrolysable in vivo, to generate the active form of the compound. As used herein to reference the compounds of the present invention, the term "ester thereof" is understood as meaning anin vivo hydrolysable ester form of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include, but are not limited to, alkyl (e.g., a straight or branched alkyl, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl), substituted alkyl (e.g, hydroxy or cycloalkyl substituted), cycloalkyl, optionally substituted cycloalkyl, optionally substituted phenylalkyl, in particular benzyl esters, C1-C6alkoxymethyl esters(e.g. methoxymethyl), C1-C6alkanoyloxymethyl esters (e.g. pivaloyloxymethyl), phthalidyl esters, C1-C6cycloalkoxy- carbonyloxy- C1-C6alkyl esters (e.g., 1- cyclohexylcarbonyloxyethyl, l,3-dioxolen-2- onylmethyl esters, 5-methyl-l,3-dioxolen-2- onylmethyl), and C1-C6- alkoxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl), and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester form of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A non-limiting selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present application covers all such ester forms of the compound of Formula I.

[0045] The term "stable", as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0046] The term "neural disorder or condition", as used herein, includes any and all disorders and conditions that affect the eye and the central nervous system that involve neural degeneration and / or neural cell loss including but not limited to neural injuries associated with hippocampal or retinal ganglion cell (RGC) degeneration, acute retinal, brain injury, such as angle closure glaucoma, retinal vein occlusions, macular edema, ischemic andhemorrhagic stroke, and traumatic brain injury as well as chronic neurodegenerative retinal or brain disorders such as glaucoma including all forms of primary open angle glaucoma, normal tension glaucoma, as well as retinal ischemias, diabetic retinopathy and diabetic macular edema, age related macular degeneration, retinitis pigmentosa, and Alzheimer's disease (retinal pathology), multiple sclerosis, as well as neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).

[0047] The term "neuroprotection" as used herein means making a neuron more resistant to a stressor or injury and includes for example inhibiting degeneration, including neurite degeneration and / or further degeneration, promoting survival and / or inhibiting neural cell loss compared to the stressor or injury in the absence of the factor. For example, neurons that are provided one or more of the analogues of LXB4of the present application are more resistant to stress compared to similarly treated neurons not administered the one or more LXB4analogues. Neuroprotection may be desired when a subject is at risk of a neurodegenerative disease and under neural stress and includes prophylactic use for example use with subjects with ocular hypertension (risk for glaucoma), diabetes (risk for diabetic retinopathy, macular edema), or subjects with drusen or age-related macular degeneration (exudative or non-exudative forms), as well as for example subjects with a family history of dementia, Alzheimer's disease, Parkinson's disease, etc. Neuroprotection may be desired also after an injury or disease that affects neurons, to protect for example neighbouring neurons from degeneration including neurite degeneration.

[0048] The term "central nervous system neurodegeneration and / or neural cell loss" as used herein includes for example degeneration and / or loss of any neurons of the central nervous system including hippocampal neurons, optic neurons and / or retinal ganglion cell (RGC) neurons. Further, the phrase "inhibiting central nervous system neurodegeneration and / or neural cell loss" in the context of administering one or more compounds described herein, means decreasing the number of neurons affected by at least 10%, at least 20%, at least 30%, at least 40% or more compared to the number of neurons affected under similar conditions in the absence of administering the compound.

[0049] The term "subject" as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans.

[0050] 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. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more compounds described in the application and optionally consists of a single administration, or alternatively comprises a series of applications. For example, the compounds described herein may be administered at least once a week, about one time per week to about once daily for a given treatment or the compound may be administered one, two, three or four times daily, for example twice daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, the age of the patient, the concentration, the activity of the compounds described herein, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.

[0051] The present inventors have sought to overcome the instability of endogenously synthesized LXB4by replacing certain functionalities of the core structure of LXB4with alternative groups. As a result, the present inventors have surprisingly found that replacement of the tetraene moiety in LXB4with various heterocycles and substituted aromatics is effective in producing active compounds having improved stability in comparison to LXB4.

[0052] The compounds of the present application include a core moiety substituted with a 5-hydroxypentanoate group (optionally as a salt, and preferably as a lithium salt) and a non-l-ene-3,4-diol moiety, similar to the C1-C5 and C12-20 region of LXB4, respectively. The core moiety can be a 5-membered heterocycle, a 6-membered heterocycle, or bicyclic heterocycle. The core can also be a benzene with a heterocyclic substituent separated from the core by a 0, 1, 2, or 3 atom spacer.

[0053] LXB4Analogues

[0054] According to aspects of the present application there is provided analogues of LXB4, which are compounds having the structure of Formula Ior a salt, lactone, ester, hydrate, or solvate form thereof, where A is 5-membered heterocycle, a 6-membered heterocycle, a fused bicyclic heterocycle, or benzene substituted with a halogen, a heterocycle or a C1- C3alkyl with a terminal heterocycle, as defined above, wherein the C1- C3alkyl optionally includes a heteroatom, such as O, N or S. Non-limiting examples of the 5-membered heterocycle include pyrazine, thiazole, and isoxazole. Non-limiting examples of the 6-membered heterocycle include pyridine and pyrimidine. Non-limiting examples of the fused bicyclic heterocycle include imidazo[l,2-a]pyrazine and quinoline. The 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety are connected to the A moiety at two sp2-hybridized carbons of the A moiety, where the two sp2-hybridized carbons are adjacent to one another or separated by one or two atoms of the A moiety.

[0055] The term "LXB4analogue", as used herein, includes compounds having the structure of Formula I in free acid, salt, lactone, ester, or solvate (e.g., hydrate) form.

[0056] In some embodiments, the compound of Formula I has one of the following stereochemistries:

[0057] As detailed above compound of Formula I can be in a salt form. According to some embodiments, the compound of Formula I is in a salt form in which a counterion to the carboxylate group is present. In some embodiments, the counterion to the carboxylate group is Li+, Na+or K+.

[0058] In some embodiments, one or more of the heteroatoms in the compound of Formula I are charged and are associated with a counterion, as defined above in relation to salt forms.

[0059] In some embodiments, the compound of Formula I is in its ester form and has the structure of Formula la:or a salt or solvate thereof, where R is a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl), substituted C1-6alkyl (e.g., a cycloalkyl-substituted or hydroxy-substituted C1-6alkyl), C2-6alkylene, substituted C2-6alkylene, benzyl, substituted benzyl.

[0060] In some embodiments, the compound of Formula I can be partially or completely in a lactone form. The lactone form can be either an inter- or intramolecular lactone, however, most commonly the lactone form is an intramolecular lactone with a ring structure formed by elimination of a water molecule between the hydroxyl and the carboxylate of the 5-hydroxypenta noate moiety. This can occur spontaneously under certain conditions. In particular, the LXB4analogue can be wholly or partially in a lactone form having the structure of Formula lb:

[0061] In some embodiments, A is a 5-membered heterocycle, which is unsubstituted or substituted with one or more halo, hydroxy, C1- C3alkyl, C1- C3fluoroalkyl, C1- C3alkoxyl and / or -NR2substituent, wherein each R is independently H or a C1- C3alkyl. In the embodiment in which the substituted 5-membered heterocycle is substituted with more than one substituent, the substituents can be the same or different. In some embodiments, the 5-membered heterocycle is substituted with one or two substituents, which may be the same or different.

[0062] In some embodiments, the 5-membered heterocycle is aromatic.

[0063] Non-limiting examples of 5- membered heterocycles that can be incorporated as A in the LXB4analogue of Formula I include:, where R' is H or substituent as defined above (e.g., a C1- C3alkyl or C1- C3fluoroalkyl group) and the * indicates the position of the connection to the 5-hydroxypentanoate group and the non-1-ene-3,4-diol moiety of Formula I.

[0064] The LXB4analogues comprising the 5-membered ring at A, provide improved chemical and metabolic stability in comparison to LXB4. In addition, selection of the specific position of ring heteroatoms (N, S, O), and the identity and position of any substituents on the 5-membered ring (e.g., Cl, NR2), can be used to further tailor or confer physicalproperties to the LXB4analogue of Formula I, to further enable specific interactions with a biological target or a combination thereof.

[0065] In specific embodiments, there is provided an LXB4analogue that is:

[0066] In some embodiments, A is a 6-membered heterocycle, which is unsubstituted or substituted with one or more halo, hydroxy, C1- C3alkyl, C1- C3fluoroalkyl, C1- C3alkoxyl and / or -NR2substituent, wherein each R is independently H or a C1- C3alkyl. In the embodiment in which the substituted 6-membered heterocycle is substituted with more than one substituent, the substituents can be the same or different. In some embodiments,the 6-membered heterocycle is substituted with one or two substituents, which may be the same or different.

[0067] In some embodiments, the 6-membered heterocycle is aromatic.

[0068] Non-limiting examples of 6- membered heterocycles that can be incorporated as A in the LXB4analogue of Formula I include:, where the * indicates the position of the connection to the 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety ofFormula I.

[0069] The LXB4analogues comprising the 6-membered ring at A, provide improved chemical and metabolic stability in comparison to LXB4. In addition, selection of the specific position of ring heteroatoms (N, S, O), and the identity and position of any substituents on the 6-membered ring (e.g., Cl, NR2), can be used to further tailor or confer physical properties to the LXB4analogue of Formula I, to further enable specific interactions with a biological target or a combination thereof. For example, for pyridyl-containing analogues, N being ortho or meta to the hydroxypentanoate moiety would allow for specific hydrogen bonding interactions that would be different or impossible with N at the para position.

[0070] In specific embodiments, there is provided an LXB4analogue that is:lactone or solvate form thereof.

[0071] In some embodiments, A is a fused bicyclic heterocycle, which is unsubstituted or substituted with one or more halo, hydroxy, C1- C3alkyl, C1- C3fluoroalkyl, C1- C3alkoxyl and / or - NR2substituent, wherein each R is independently H or a C1- C3alkyl. In the embodiment in which the substituted, fused bicyclic heterocycle is substituted with more than one substituent, the substituents can be the same or different. In some embodiments, the 6-membered heterocycle is substituted with one or two substituents, which may be the same or different.

[0072] In some embodiments, the fused bicyclic heterocycle is aromatic.

[0073] Non-limiting examples of fused bicyclic heterocycles that can be incorporated as A in the LXB4analogue of Formula I include:, where the * indicates the position of the connection to the 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety of Formula I.

[0074] The LXB4analogues comprising the fused bicyclic heterocycle at A, provide improved chemical and metabolic stability in comparison to LXB4. In addition, selection of the specific position of ring heteroatoms (N, S, O), and the identity and position of any substituents on the 6-membered ring (e.g., Cl, NR2), can be used to further tailor or confer physical properties to the LXB4analogue of Formula I, to further enable specific interactions with a biological target or a combination thereof.

[0075] In specific embodiments, there is provided an LXB4analogue that is:lactone or solvate form thereof.

[0076] In some embodiments, A is benzene substituted with one or more non-chloro halo substituents (e.g, F), a C1- C3alkyl with a terminal heterocycle, a C1- C3heteroalkyl, comprising one heteroatom (e.g., O, N or S), with a terminal heterocycle, or a heterocyclethat is optionally substituted with a C1- C3alkyl, a C3- C6cycloalkyl and / or a C1- C3fluoroalkyl.

[0077] In some embodiments, the 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety of the LXB4analogue are connected to the benzene ring at two sp2-hybridized carbons that are adjacent to one another and the benzene comprises a substituent, as defined above, para to the 5-hydroxypentanoate group.

[0078] In some embodiments, the one or more substituent on the benzene is a 5- or 6- membered heterocycle, as defined above, which is optionally substituted with a C1- C3alkyl (e.g., methyl, ethyl, or t-butyl), a C3- C6cycloalkyl (e.g., cyclopropyl or cyclobutyl) and / or a C1- C3fluoroalkyl (e.g., trifluoromethyl).

[0079] In some embodiments, the one or more substituent on the benzene is -O-alkyl terminally substituted with a 5-membered heterocycle (e.g., pyrrole or pyrazole) or a 6- membered heterocycle (e.g, pyridine, pyrazine, pyrimidine, piperidine, morpholine).

[0080] In specific embodiments, there is provided an LXB4analogue that is:

[0081] Compositions and Methods of Use

[0082] Also provided are compositions comprising one or more LXB4analogue, which, as described above, is the compound of Formula I in free acid, salt, lactone, ester, hydrate, or solvate form, in a suitable diluent or excipient.

[0083] In some embodiments, there is provided a pharmaceutical composition comprising an LXB4analogue in combination with a pharmaceutically acceptable diluent, excipient, carrier, or combination thereof.

[0084] In addition to having improved stability in comparison to LXB4, the LXB4analogues of the present application have been found to provide neuroprotective activity against oxidative stress. Accordingly, these LXB4analogues are useful in the treatment or preventionof diseases and / or conditions associated with neuroinflammation or neurodegeneration, for example, as a neuroprotective agent. Accordingly, there is also provided a method treating a subject susceptible to or having neuroinflammation or neurodegeneration by administering to the subject a compound having the structure of Formula I, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof.

[0085] An aspect of this application provides a method or use of providing neuroprotection comprising administering to a subject in need thereof an effective amount of one or more of the LXB4analogues as defined herein.

[0086] In an embodiment, the neuroprotection is for central nervous system neuroprotection, optionally hippocampal neuroprotection or cortical neuron protection. In another embodiment, the neuroprotection is retinal neuroprotection, optic nerve neuroprotection or RGC neuroprotection.

[0087] The neuroprotection can be provided to inhibit neurodegeneration including neurite degeneration and / or to prevent neural cell loss. A subject at risk of developing a disease or condition affecting the central nervous system, retinal neurons, optic nerve or RGC may be a suitable candidate for receiving an effective amount of one or more LXB4analogues of Formula I.

[0088] The neuroprotection can be provided to inhibit neuroinflammation.Neuroinflammation is comprised of inflammatory responses within nervous system tissues, characterized by changes in cytokines, chemokines, second messengers, reactive oxygen species, blood flow, and / or cellular infiltrates and glial cells in response to stress, injury, and / or infection

[0089] In an embodiment, the subject has sustained an ischemic and hemorrhagic stroke, or a brain injury such as a traumatic brain injury.

[0090] In an embodiment, the one or more LXB4analogue is administered to a subject with ocular hypertension (risk for glaucoma), diabetes (risk for diabetic retinopathy, macular edema), or subjects with drusen or age-related macular degeneration (exudative or non-exudative forms). In another embodiment, the one or more LXB4analogue is administered to a subject with a family history of dementia, Alzheimer's disease, Parkinson's disease, etc.

[0091] In a further embodiment, the method or use is for inhibiting or preventing RGC degeneration and / or cell loss, optionally resulting from acute injury, the method comprising administering to a subject in need thereof an effective amount of one or more LXB4analogues of Formula I such that degeneration and / or cell loss of RGCs is inhibited or prevented.

[0092] In an embodiment, the method or use is for treating vision loss, occurring for example related to an acute injury and / or chronic condition.

[0093] In an embodiment, the subject is afflicted with an acute retinal injury, such as angle closure glaucoma, retinal vein occlusions, or macular edema.

[0094] In an embodiment, the subject is afflicted with a chronic retinal disorder such as glaucoma.

[0095] Another aspect includes a method or use of treating a neural disorder or condition, the method comprising administering to a subject in need thereof an effective amount of one or more of the LXB4analogues as defined herein.

[0096] In an embodiment, the neural disorder or condition is a brain disorder, a retinal neural disorder or retinal neural injury associated with RGC degeneration and / or cell loss. In an embodiment, the neural disorder or condition is a chronic neurodegenerative retinal disorder.

[0097] In an embodiment, the chronic neurodegenerative retinal or brain disorder comprises, all forms of primary open angle glaucoma, normal tension glaucoma, retinal ischemias, diabetic retinopathy and macular edema, age related macular degeneration, retinitis pigmentosa, multiple sclerosis, and Alzheimer's disease (retinal pathology), as well as neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).

[0098] In some embodiments, a neurodegenerative disease, disorder or condition to be treated according to the methods and uses described herein is also associated with neuroinflammation. In such embodiments, the LXB4analogues as defined herein can be effective in treatment or prevention of one or both of the neurodegeneration and neuroinflammation.

[0099] Another aspect of this application provides a method or use of treating neuroinflammation, the method comprising administering to a subject in need thereof an effective amount of one or more of the LXB4analogues as defined herein.

[0100] In some embodiments, the neuroinflammation is associated with or triggered by traumatic brain injury, spinal cord injury, intracerebral hemorrhage, autoimmunity, toxic metabolites, ageing, or infection (e.g., viral).

[0101] Neuroinflammation comprises inflammation of neural tissues and can include one or more of intraocular and / or retinal inflammation, optic nerve inflammation, central nervous system inflammation, brain inflammation, and spinal cord inflammation.

[0102] To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in any way.EXAMPLES

[0103] EXAMPLE 1: Synthesis of LXB4Aromatic and Heterocyclic Analogues

[0104] General Procedures

[0105] General Procedure A: Aryl bromide (1.0 eq) and vinyl boronate 2 (1.3 eq) were dissolved in dioxane / water (4:1) mixture (0.15 M). The solution was sparged with argon for 20 minutes to degas. K3PO4 (3.0 eq) and Pd(PPhs)4 (0.05 eq) were added in one portion. The reaction flask was evacuated and backfilled with argon three times, then sealed and heated to 100 °C for 2 hours. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate andconcentrated on under reduced pressure. The resulting oil was purified by silica gel chromatography (Hex:EtOAc 10:0 8:2) to afford the desired product.

[0106] General Procedure B: Aryl chloride 5 (1.0 eq) and boronate (2.0 eq) were dissolved in dioxane / water (9:1) mixture (0.15 M). The solution was sparged with argon for 20 minutes to degas. CS2C03 (2.5 eq) and XphosG2 (0.1 eq) were added in one portion. The reactions flask was evacuated and backfilled with argon three times, then sealed and heated to 110 °C for 15 hours. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated on under reduced pressure. The resulting oil was purified by silica gel chromatography (Hex:EtOAc 10:0 4:6) to afford the desired product.

[0107] General procedure C: Triisopropylsilyl ether (TIPS) protected starting material (1.0 eq) was dissolved in THF (0.05 M) under argon at room temperature. TBAF (1.0 M solution in THF, 1.2 eq for each silyl group) was added dropwise. The reaction was stirred at room temperature overnight. THF was removed under reduced pressure and the resulting oil was redissolved in diethyl ether and extracted with saturated NH4CI. The aqueous was extracted twice more with ether. The combined organics were dried over sodium sulfate, and concentrated. The crude was purified by silica gel chromatography using a 100:095:5DCM:MeOH gradient to afford the expected product.

[0108] General procedure D: Ketone (1.0 eq) was dissolved in HPLC grade methanol (0.05 M), and NaBH4 was added in one portion (2.5 eq). The reaction was stirred under argon until TLC showed complete conversion (15 min - 3 h). The reaction was then quenched by the addition of water and extracted with Ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography using a 100:095:5 DCM:MeOH gradient. 5R- and 5S- diastereomers were partially separable by column chromatography, but were combined and carried forward as an epimeric mixture.

[0109] General procedure E: TIPS protected ketone (1.0 eq) was dissolved in THF (0.05 M) under argon at room temperature. TBAF (1.0 M solution in THF, 1.2 eq for each silyl group) was added dropwise. The reaction was stirred at room temperature overnight. THFwas removed under reduced pressure and the resulting oil was redissolved in diethyl ether and extracted with saturated NH4CI. The aqueous was extracted twice more with ether. The combined organics were dried over sodium sulfate, and concentrated. The crude oil was then dissolved in HPLC grade methanol (0.05 M), and NaBH4 was added in one portion (2.5 eq). The reaction was stirred under argon until TLC showed complete conversion (15 min - 3 h). The reaction was then quenched by the addition of water and extracted with Ethyl acetate. The combined organics were dried over sodium sulfate and concentrated. The crude was purified by silica gel chromatography using a 100:095:5 DCM:MeOH gradient.5R- and 5S- diastereomers were partially separable by column chromatography, but were combined and carried forward as an epimeric mixture.

[0110] General procedure F: Methyl ester (1.0 eq) was dissolved in a 3:1 mixture of THF and distilled, deionized water (0.2 M). LiOH (1.0 eq) was added in one portion. The mixture was stirred overnight. The reaction was then lyophilized to afford the expected lithium carboxylate salt as a white solid. If trace organic impurities are present, the product was triturated with a 1:1 mixture of DCM:Et2O and lyophilized.

[0111] General procedure G: Phenol (1.0 eq) and an aliphatic bromide (2.5 eq) were dissolved in anhydrous DMF (0.2 M). CS2CO3 (2.5 eq) was added in one portion. The reaction was stirred at room temperature overnight, and TLC showed spot to spot conversion. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (Hex:EtOAC 10:06:4) to obtain the alkylated product.

[0112] General procedure H: A heatgun dried flask was charged with CuCN-2LiCI (1.0 M in THF, 1.5 eq) and cooled to -78 °C under argon. A solution of 4-Ethoxy-4-oxobutylzinc bromide (0.5 M in THF, 1.8 eq) was added dropwise. The reaction was stirred at -78 °C for 10 minutes. In a separate dried flask, aldehyde (1.0 eq) was dissolved in THF (0.8 M) under argon, and BFsOet (8.0 eq) was added dropwise. The aldehyde-BFs solution was then added dropwise to the organocuprate at -78 °C. The reaction was stirred at -78 °C for 10 minutes, then the dry ice-acetone bath was removed and the reaction was allowed to stir at RT overnight. A colour change from brown-grey to clear was observed after stirring overnight.TLC showed formation of a new spot and some residual starting material. The reaction was quenched by the addition of NH4CI and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated to afford a crude oil, which was purified by column chromatography (Hex:EtOAc 10:0 4:6).

[0113] General procedure I: Alcohol (1.0 eq) was dissolved in anhydrous DMF (1 M) under argon. Imidazole (3.0 eq) and dimethylamino pyridine (0.1 eq) were added in one portion. The reaction was cooled in an ice bath, then TIPS-CI (2.0 eq) was added dropwise. The reaction was warmed to room temperature overnight. After TLC, if necessary, another 1 eq of TIPS-CI was added and the reaction was stirred for another 2h. showed formation of a new spot and significant starting material. Another 150 uL of TIPS-CI was added. The reaction was stirred for another 2 hours. The reaction was then quenched by the addition of saturated NH4CI solution and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated to afford a crude oil, which was purified by column chromatography (Hex:EtOAc 10:0 8:2). The expected TIPS protected product was obtained after column chromatography.

[0114] General procedure J: A heatgun dried flask was charged with CuCN-2LiCI (1.0 M in THF, 1.1 eq) and cooled to -78 °C under argon. A solution of 4-ethoxy-4-oxobutylzinc bromide (0.5 M in THF, 1.5 eq) was added dropwise. The reaction was stirred at -78 °C for 10 minutes. In a separate dried flask, 4-bromo-l-methyl-lH-pyrazole-3-carbaldehyde (250 mg, 1.32 mmol, 1.0 eq) was dissolved in THF (2.1 mL) under argon, and BFs-Oet (1.50 g, 1.31 mL, 10.6 mmol, 8 eq) was added dropwise. The aldehyde-BFs solution was then added dropwise to the organocuprate at -78 °C. The reaction was stirred at -78 °C for 10 minutes, then the dry ice-acetone bath was removed and the reaction was allowed to stir at room temperature overnight. A colour change from brown-grey to clear was observed after stirring overnight. TLC showed formation of a new spot and some residual starting material. The reaction was quenched by the addition of NH4CI and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated to afford a crude brown oil which was not stable to chromatography. Instead, the crude oil was redissolved in DCM under argon and cooled in an ice bath. NaHCOs (133.1 mg, 1.58 mmol, 1.2 eq) was added, followed by Dess-Martin periodinane (1.2 eq). The reaction was warmed to room temperature over 3 h, when TLC showed full consumption of the starting material. Thereaction was evaporated to dryness and purified by column chromatography (Hex:EtOAc 10:0 7:3) to afford the expected product.

[0115] General procedure K: In a 100 mL round bottom flask equipped with a stir bar was added iodo-pyridine (1.0 eq.), cyclopentenyl boronic acid (1.2 eq.), Pd(dppf)Ch (0.1 eq.), and CS2CO3 (3.0 eq.) under argon atmosphere at room temperature. The solids were dissolved in a degassed mixture of dioxanes / HzO (0.1M, 9:1) under Ar. The flask was heated to 90 °C and stirred at 90 °C overnight until reaction was complete as indicated by TLC analysis. Upon completion, the reaction mixture was cooled to room temperature and diluted with EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was then purified by flash column chromatography on silica gel (hexanes / ethyl acetate 9:1) to afford the coupled product.

[0116] General procedure L: In a 50 mL round bottom flask equipped with a stir bar was added cyclopentene (1.0 eq.) and NalO4 (5.0 eq.) dissolved in CCU / MeCN / l-bO (0.15M, 3:3:4). Biphasic mixture was allowed to stir at room temperature for 15 minutes, then RuCL (0.05 eq.) was added in one portion at room temperature. The resulting mixture was allowed to stir at room temperature until starting material consumption as indicated by TLC analysis (ranges from 2-24 hours). Upon completion, the mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was concentrated in vacuo, then diluted again in EtOAc and H2O. The phases were then separated; the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was directly dissolved in HPLC-grade MeOH (0.5M) where H2SO4 (0.25 equiv.) was added in one portion at room temperature. The mixture was allowed to stir at room temperature overnight. Upon completion as indicated by TLC analysis, methanol was removed in vacuo and the residue was diluted with EtOAc and H2O. The phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was then purified by flash column chromatography on silica gel (hexanes / EtOAc 9:1) to afford the methyl ester ring-opened product.

[0117] General Characterization of Final Compounds: For all final compounds,1H and13C NMR spectra were recorded on a Bruker AV 300 MHz spectrometer using CDCI3, methanol-d4, or DMSO-d6as solvents. Chemical shifts (6) are reported in ppm and coupling constants (J) are expressed in Hertz (Hz). HPLC analysis was performed using a Dionex Ultimate 3000™ HPLC with a SiliaChrom SB™ C18 column (5 pM, 150 A, 4.6 x 250 mm) and a mobile phase of acetonitrile + 0.1% TFA (A) and MilliQ™ water + 0.1% TFA (B). Gradient (5:95 A:B a 95:5 A:B over 15 minutes) or isocratic (35:65 A:B) methods were used for separation and compound elution was detected by UV monitoring at 220, 254, and 280 nm. HRMS analysis was performed using a Waters ACQUITY™ Tandem Quadrupole UPLC / MS / MS System equipped with an electrospray ionization (ESI) probe. Data acquisition, processing, and reporting were performed using MassLynx™ Software. All compounds were formulated in DMSO and stored at -80 °C.

[0118] Synthesis of Intermediate Compound 2Scheme 1: Synthesis of 2, an intermediate in synthesis of LXB4analogues

[0119] Compound 1 was prepared according to literature procedure.

[0120] Compound 2 was prepared as follows. In a dry flask under argon atmosphere,2,2,6,6-tetramethylpiperidine (1.60 equiv.) was dissolved in anhydrous THF. The solution was cooled to -78 °C before addition of n-butyl lithium (1.65 equiv.) and the solution was stirred for ca. 5—10 min (yellow colour). The reaction was then warmed to 0 °C and a THF solution of bis(pinacolatoboronyl)methane (1.50 equiv.) was added to the flask and the mixture was stirred for ca. 5—10 min ('peach' colour). The reaction was then cooled to -78 °C before addition of a THF solution of aldehyde (1.00 equiv.) and stirred until complete allowing to warm slowly to room temperature. The reaction was concentrated under reduced pressure and the crude isolate was dissolved in hexanes. The solution was concentrated under reduced pressure and hexanes was again added / removed (three times total); each hexane addition generates increased turbidity of the solution. Finally, the crudeisolate was again taken up in hexanes and the turbid solution was allowed to stand in the freezer for ca. 20 min before filtration through a pad of Celite®. The filtrate was collected and concentrated under reduced pressure to give the desired vinyl boronate as a clear oil, and used without further purification.1H NMR (400 MHz, CDCI3): 6 (ppm) representative signals provided herein, full characterization not possible from spectrum. 6.62 (dd, 1H, J = 18.0, 6.4 Hz), 5.55 (dd, 1H, J = 18.0, 1.0 Hz), 4.21 (ddd, 1H, J = 6.4, 3.5, 1.0 Hz), 3.82—3.79 (m, 1H).

[0121] Synthesis of LXB4Analogues 7 and 8Scheme 2: Synthesis of 8 from commercially available starting materials

[0123] 2-Bromo-4-chloro-l-iodobenzene (5.00 g, 15.8 mmol mol, 1 eq.), 4-pentynoic acid (1.58 g, 16.1 mmol, 1.02 eq), and Pd( PPhs)4 (182.0 mg, 0.158 mmol, 0.01 eq) were dissolved in diethylamine (31.5 mL, 0.5 M) in a dry round bottom flask under argon. The mixture was degassed by sparging with argon for 30 minutes. Cui (600.1 mg, 3.15 mmol mol, 0.2 eq) was added in one portion. The reaction was monitored by TLC. When TLC showed consumption of the iodobenzene starting material (Rf = 0.9 2:1 Hexane:EtOAc) and formation of the product (Rf = 0.1), the reaction mixture was added to 500 mL of IM HCI. The mixture was filtered to obtain a tan precipitate. This precipitate was redissolved in refluxing DCM and filtered to remove insoluble impurities. The filtrate was concentrated and then recrystallized in DCM / Hexane (~10:l ratio). The desired product was obtained as a tan crystalline solid in 69% yield (3.28 g).1H NMR (300 MHz, CDCI3) 6 7.46 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.6, 2.5 Hz, 1H), 2.87 - 2.67 (m, 4H).

[0124] Intermediate 4

[0125] Alkyne 3 (3.27 g, 10.9 mmol, 1 eq) was dissolved in concentrated H2SO4 (20.5 mL) at room temperature and stirred for 15 minutes. The reaction was cooled in an ice bath, followed by the addition of 50 mL ice water. This mixture was then extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with ice water (50 mL), dried over Na2SO4, and concentrated by rotovap to afford a brown oil. This oil was dissolved in 50 mL of reagent grade methanol, to which was added 0.5 mL of H2SO4. The solution was stirred overnight, then concentrated under vacuum. The resulting oil was partitioned between ethyl acetate and water and the aqueous phase was washed with ethyl acetate (3 x 30 mL). The combined organic phases were dried over Na2SC>4 and evaporated. The crude product was purified by silica gel chromatography using a hexane:EtOAc gradient (10:06:4) to afford 2.77 g (79% yield) of 4 as a pale yellow oil. 1H NMR (300 MHz, CDCI3) 6 7.62 (s, 1H), 7.35 (d, J = 0.9 Hz, 2H), 3.68 (s, 3H), 2.98 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.04 (p, J = 7.2 Hz, 2H).

[0126] Intermediate 5

[0127] 81%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 67.52 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 8.3, 2.2 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.22 (dd, J = 16.2, 7.6 Hz, 1H), 4.30 (dd, J = 7.8, 2.4 Hz, 1H), 3.95 (ddd, J = 7 A, 5.1, 2.4 Hz, 1H), 3.67 (s, 3H), 2.91 (td, J = 7.1, 1.4 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.00 (p, J = 7.2 Hz, 2H), 1.37 - 1.24 (m, 8H), 1.10 - 1.03 (m, 42H), 0.90 - 0.86 (m, 3H).

[0129] 86%, prepared according to General Procedure B. 1H NMR (400 MHz, CDCI3)6 7.79 (s, 1H), 7.65 - 7.61 (m, 3H), 7.39 (dd, J = 8.1, 1.7 Hz, 1H), 7.05 (d, J = 16.0 Hz, 1H), 6.26 (dd, J = 16.0, 8.1 Hz, 1H), 4.31 (dd, J = 8.2, 2.2 Hz, 1H), 4.01 - 3.97 (m, 1H), 3.96 (s, 3H), 3.67 (s, 3H), 2.95 (td, J = 7.1, 2.8 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.02 (p, J = 7.2 Hz, 2H), 1.58 - 1.46 (m, 2H), 1.40 - 1.27 (m, 6H), 1.13 - 1.03 (m, 42H), 0.88 (t, J = 6.8 Hz, 3H).

[0131] 72%, prepared according to General Procedure E.XH NMR (400 MHz, MeOD)6 7.95 (s, 1H), 7.82 (s, 1H), 7.64 (s, 1H), 7.50 - 7.40 (m, 2H), 6.98 (d, J = 15.7 Hz, 1H), 6.26(dd, J = 15.7, 6.9 Hz, 1H), 4.99 (t, J = 6.0 Hz, 1H), 4.12 (ddd, J = 6.6, 4.8, 1.2 Hz, 1H), 3.91 (s, 3H), 3.67 - 3.58 (m, 4H), 2.39 - 2.29 (m, 2H), 1.79 - 1.52 (m, 6H), 1.49 - 1.26 (m, 6H), 0.91 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 175.8, 141.5, 137.3, 136.8, 132.9, 132.7, 130.1, 129.1, 127.3, 125.6, 124.3, 124.2, 77.2, 75.9, 70.7, 52.0, 38.9, 38.8, 34.6, 34.1, 33.1, 26.7, 23.8, 22.5, 14.5.

[0133] 97%, prepared according to General Procedure F.3H NMR (400 MHz, MeOD)6 7.96 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.1, 1.7 Hz, 1H), 7.00 (d, J = 15.6 Hz, 1H), 6.24 (dd, J = 15.7, 6.7 Hz, 1H), 5.01 (t, J = 6.0 Hz, 1H), 4.13 (t, J = 5.9 Hz, 1H), 3.92 (s, 3H), 3.60 (ddd, J = 8.7, 5.1, 3.2 Hz, 1H), 2.20 (t, J = 6.6 Hz, 2H), 1.78 - 1.55 (m, 6H), 1.49 - 1.29 (m, 6H), 0.92 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, MeOD) 6 182.7, 141.9, 137.3, 136.9, 133.1, 132.5, 130.0, 129.1, 127.4, 125.6, 124.3, 124.2, 77.1, 75.9, 70.9, 39.6, 38.9, 38.8, 34.1, 33.1, 26.7, 24.0, 23.8, 14.5. LCMS: [M-H], predicted 429.2399, found429.2399.

[0134] Synthesis ofLXB4Analogues 10 and 11Scheme 3: Synthesis of 11 from intermediate 5

[0136] 91%, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 69.24 (s, 1H), 8.95 (s, 2H), 7.72 (dd, J = 4.9, 3.1 Hz, 2H), 7.51 (dd, J = 8.1, 1.8 Hz, 1H), 6.97 (d, J = 16.1 Hz, 1H), 6.32 (dd, J = 16.0, 7.8 Hz, 1H), 4.32 (dd, J = 7.9, 2.2 Hz, 1H), 3.97 (ddd, J = 7.5, 5.0, 2.2 Hz, 1H), 3.67 (s, 3H), 2.97 (td, J = 7.1, 2.7 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.03 (p, J = 7.2 Hz, 2H), 1.56 - 1.46 (m, 2H), 1.38 - 1.24 (m, 6H), 1.05 (dd, J = 7.2, 4.5 Hz, 42H), 0.87 (t, J = 6.6 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 202.8, 173.6, 158.1, 155.0, 138.3, 137.5, 137.1, 135.3, 133.5, 129.3, 128.2, 126.2, 125.5, 78.2, 77.3, 51.7, 41.0, 35.0, 33.1, 32.3, 25.4, 22.7, 19.5, 18.4, 18.4, 18.3, 18.2, 14.1, 12.9, 12.6.

[0137] LXB4Analogue 10

[0138] 89%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 9.13 (s, 1H), 9.10 (s, 2H), 7.82 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 8.2, 1.8 Hz, 1H), 7.02 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 15.7, 6.7 Hz, 1H), 5.10 - 5.03 (m, 1H), 4.14 (t, J = 5.9 Hz, 1H), 3.64 (s, 3H), 3.64 - 3.59 (m, 1H), 2.36 (dd, J = 7.8, 5.7 Hz, 2H), 1.82 - 1.51 (m, 4H), 1.49 - 1.24 (m, 8H), 0.92 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 175.7, 157.8, 156.1, 144.7, 137.5, 135.8, 134.1, 134.0, 129.4, 128.0, 127.1, 126.2, 77.1, 75.9, 70.6, 52.0, 38.8, 34.6, 34.1, 33.1, 26.7, 23.8, 22.5, 14.4.

[0140] 98%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 9.13 (s, 1H), 9.10 (s, 2H), 7.82 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.64 (dd, J = 8.2, 1.8 Hz, 1H), 7.02 (d, J = 15.7 Hz, 1H), 6.34 (dd, J = 15.7, 6.7 Hz, 1H), 5.07 (t, J = 5.6 Hz, 1H), 4.14 (t, J = 5.9 Hz, 1H), 3.64 (s, 3H), 3.64 - 3.59 (m, 1H), 2.36 (t, J = 6.7 Hz, 2H), 1.83 - 1.54 (m, 6H), 1.49 - 1.26 (m, 6H), 0.92 (t, J = 6.1 Hz, 3H).13C NMR (101 MHz, MeOD) 6 175.7, 157.8, 156.1, 144.7, 137.5, 135.8, 134.1, 134.0, 129.4, 128.0, 127.1, 126.2, 77.1, 75.9, 70.6, 52.0, 38.8, 34.6, 34.1, 33.1, 26.7, 23.8, 22.5, 14.4. LCMS: [M-], predicted 427.2303, found427.2238.

[0141] Synthesis ofLXB4Analogues 15 and 16Scheme 4: Synthesis of 16 from intemediate 5

[0142] Intermediate 12

[0143] Aryl chloride 5 (700 mg, 0.988 mmol, 1 eq), Xphos G2 (38.9 mg, 0.0494 mmol, 0.05 eq), bis(pinacolato)diboron (501.7 mg, 1.98 mmol, 2 eq), and KOAc (242.4 mg, 2.47 mmol, 2.5 eq) were added to a vial flushed with argon. The vial was evacuated and backfilled with argon three times. 1,4-dioxane (5.9 mL) was added and the resulting solution was stirred at 110 °C for 1.5 hours. TLC showed full consumption of the starting material (Rf = 0.5 in 2:1 Hex:Et2O) and formation of a new spot (Rf = 0.4). The reaction was quenched by adding 25 mL of water, then extracted with ethyl acetate (3 x 25 mL). The combined organic phase was dried over sodium sulfate, concentrated on the rotovap, and purified by a silica gel column (Hex:Et2O 10:06:4). The boronic ester 12 was obtained in 96% yield (18.5 mg). When repeated on a 0.5 mmol scale, the product was found to be contaminated with excess bis(pinacolato)diboron and carried forward as the crude.

[0144] Intermediate 13

[0145] Boronate 12 (760 mg, 0.949 mmol, 1 eq) was dissolved in THF (47 mL) and cooled in an ice bath. H2O2(7.2 mL of a 30% solution) was added dropwise. The reaction was allowed to warm to RT over 30 minutes. At this time, TLC showed spot to spot conversion of the starting material (Rf = 0.5 in 3:2 Hex:Et2O) to product (Rf = 0.3). The reaction was quenched by the addition of water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was dried over sodium sulfate and concentrated on the rotovap. The crude was purified by a silica gel column (Hex:Et2O 10:07:3). The desired product 13 was obtained in 42% yield (276.3 mg).

[0146] Intermediate 14

[0147] 94%, prepared according to General Procedure G.1H NMR (400 MHz, CDCI3) 67.64 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 16.0 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.81 (dd, J = 8.7, 2.6 Hz, 1H), 6.18 (dd, J = 16.0, 8.1 Hz, 1H), 4.30 (dd, J = 8.2, 1.8 Hz, 1H), 4.14 (t, J = 5.5 Hz, 2H), 3.99 - 3.93 (m, 1H), 3.74 (t, J = 4.7 Hz, 4H), 3.67 (s, 3H), 2.92 (td, J = 7.1, 1.4 Hz, 2H), 2.82 (t, J = 5.6 Hz, 2H), 2.65 - 2.51 (m, 4H), 2.40 (t, J = 7.3 Hz, 2H), 2.00 (p, J = 7.3 Hz, 2H), 1.55 - 1.44 (m, 3H), 1.27 (d, J = 17.2 Hz, 7H), 1.12 - 1.01 (m, 40H), 0.88 (t, J = 6.7 Hz, 3H).

[0148] LXB4Analogue 15

[0149] 24%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 7.37 (dd, J = 8.6, 3.3 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 6.96 (d, J = 15.8 Hz, 1H), 6.87 (dd, J = 8.6, 2.3 Hz, 1H), 6.18 (dd, J = 15.7, 6.9 Hz, 1H), 4.94 (t, J = 4.5 Hz, 3H), 4.16 (t, J = 5.4 Hz, 2H), 4.10 (t, J = 6.1 Hz, 1H), 3.75 - 3.68 (m, 4H), 3.63 (s, 3H), 3.63 - 3.56 (m, 1H), 2.81 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 4.7 Hz, 4H), 2.37 - 2.28 (m, 2H), 1.76 - 1.52 (m, 6H), 1.35 (d, J = 6.7 Hz, 6H), 0.92 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 175.8, 159.2, 137.7, 135.9, 132.9, 130.0, 128.2, 115.0, 113.0, 77.1, 75.8, 70.5, 67.6, 66.4, 58.8, 55.2, 52.0, 38.9, 34.6, 34.0, 33.1, 26.7, 23.8, 22.5, 14.4.

[0151] 99%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 7.37 (d, J = 8.5 Hz, 1H), 7.02 (s, 1H), 7.01 - 6.92 (m, 1H), 6.85 (dd, J = 8.6, 2.6 Hz, 1H), 6.22 - 6.10 (m, 1H), 4.97 - 4.93 (m, 1H), 4.15 (t, J = 5.5 Hz, 2H), 4.10 (q, J = 6.5 Hz, 1H), 3.72 (t, J = 4.7 Hz, 4H), 3.63 - 3.53 (m, 1H), 2.81 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 4.8 Hz, 4H), 2.18 (t, J = 7.2 Hz, 2H), 1.77 - 1.52 (m, 6H), 1.47 - 1.25 (m, 6H), 0.92 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, MeOD) 6 177.6, 159.1, 137.8, 136.3, 133.0, 130.0, 128.2, 114.9, 112.9, 77.0, 75.8, 70.7, 67.6, 66.3, 58.8, 55.1, 39.6, 38.7, 34.0, 33.1, 26.7, 26.7, 24.0, 23.8, 14.5. LCMS: [M-], predicted 479.2883, found 479.2881.

[0152] Synthesis ofLXB4Analogues 18 and 19

[0154] 86%, prepared according to General Procedure G.3H NMR (400 MHz, CDCI3) 68.61 (d, J = 5.0 Hz, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.5, 4.9 Hz, 2H), 7.13 (d, J = 2.6 Hz, 1H), 7.09 (d, J = 15.9 Hz, 2H), 6.88 (dd, J = 8.7, 2.6 Hz, 1H), 6.16 (dd, J = 16.0, 8.0 Hz, 1H), 5.24 (s, 2H), 4.31 (dd, J = 8.0, 2.3 Hz, 1H), 3.94 (ddd, J = 7.6, 4.6, 2.3 Hz, 1H), 3.66 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.99 (p, J = 7.2 Hz, 3H), 1.52 (ddd, J = 13.6, 9.5, 4.2 Hz, 2H), 1.42 - 1.27 (m, 8H), 1.06 (dd, J = 6.1, 4.3 Hz, 42H), 0.91 - 0.84 (m, 3H).13C NMR (101 MHz, CDCI3) 6 201.3, 173.8, 160.7, 156.6, 149.5, 140.4, 137.0, 134.0, 131.1, 130.1, 129.6, 122.9, 121.5, 113.8, 113.1, 78.1, 77.5, 70.7, 51.7, 40.2, 34.9, 33.3, 31.1, 25.4, 22.8, 19.9, 18.5, 18.4, 18.4, 18.3, 14.2, 13.0, 12.6.

[0156] 89%, prepared according to General Procedure E.1H NMR (400 MHz, CDCI3) 68.55 (d, J = 5.0 Hz, 1H), 7.71 (td, J = 7.7, 1.9 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.22 (dd, J = 7.5, 4.9 Hz, 1H), 7.00 (t, J = 2.3 Hz, 1H), 6.92 (d, J = 15.7 Hz, 1H), 6.84 (ddd, J = 9.1, 7.1, 2.7 Hz, 1H), 6.16 - 6.03 (m, 1H), 5.11 (d, J = 4.5 Hz, 2H), 4.90 (dt, J = 11.6, 6.2 Hz, 1H), 4.22 (t, J = 4.9 Hz, 1H), 3.78 - 3.69 (m, 1H), 3.64 - 3.60 (m, 3H), 3.60 - 2.74 (br m, 3OH), 2.41 - 2.22 (m, 2H), 1.75 - 1.26 (m, 10H), 0.87 (t, J = 5.7 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 174.5 (app d), 157.3 (app d), 149.0, 137.1, 136.4, 134.8, 134.6, 130.9 (app d), 129.5 (app d), 127.0 (app d), 122.8, 121.6 (app d), 114.1, 112.9 (app d), 75.6 (app d), 74.5 (app d), 70.5 (app d), 70.1, (app d) 51.7 (app d), 37.4 (app d), 33.5 (app d), 32.5, 31.9, 25.7, 22.7, 21.4, 14.1.

[0158] 98%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.54 (d, J = 6.0 Hz, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.12 - 7.06 (m, 1H), 6.96 (dd, J = 15.4, 10.3 Hz, 1H), 6.91 (dd, J = 8.6, 2.7 Hz, 1H), 6.21 - 6.09 (m, 1H), 5.19 (s, 2H), 4.95 (t, J = 6.1 Hz, 1H), 4.10 (q, J = 6.5 Hz, 1H), 3.62 - 3.52 (m, 1H), 2.18 (t, J = 6.7 Hz, 2H), 1.75 - 1.53 (m, 6H), 1.47 - 1.27 (m, 6H), 0.92 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, MeOD) 6 182.7, 158.6 (app d), 149.8, 139.0, 137.9, 136.8 (app d), 133.2,130.6, 129.9, 128.3 (app d), 124.4, 123.4, 115.2, 113.3, 77.1 (app d), 75.8, 71.1, 70.7 (app d),39.6, 38.8 (app d), 34.0, 33.1, 26.7, 24.1, 23.8, 14.5. LCMS: [M+Na], predicted 480.2362, found 480.2361.

[0159] Synthesis ofLXB4Analogues 24 and 25Scheme 6: Synthesis of 25 from commercial starting materials

[0160] Intermediate 20

[0161] 63%, prepared according to General Procedure H.1H NMR (400 MHz, CDCI3) 67.41 (d, J = 0.9 Hz, 1H), 4.93 (dd, J = 7.6, 4.7 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.37 (td, J = 6.7, 3.0 Hz, 2H), 1.88 - 1.66 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 173.7, 147.4, 138.7, 135.9, 67.9, 60.7, 38.5, 33.7, 20.7, 14.4.

[0162] Intermediate 21

[0163] 27%, prepared according to General Procedure 1.1H NMR (400 MHz, CDCI3) 67.34 (s, 1H), 5.06 (dd, J = 7.1, 4.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.87 - 1.72 (m, 2H), 1.63 - 1.54 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.12 - 0.94 (m, 27H).13C NMR (101 MHz, CDCI3) 6 173.2, 141.5, 138.1, 128.0, 69.2, 63.7, 40.3, 34.0, 26.2, 20.1, 18.1, 18.1, 12.3.

[0164] Intermediate 23

[0165] 48%, prepared according to General Procedure A.3H NMR (400 MHz, CDCI3) 67.45 (s, 1H), 6.65 (dd, J = 16.1, 6.5 Hz, 1H), 6.50 (dd, J = 16.2, 7.5 Hz, 1H), 5.03 (dt, J = 6.8, 4.3 Hz, 1H), 4.29 (dd, J = 7 A, 3.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.92 (q, J = 5.9 Hz, 1H), 2.27 (t, J= 7.2 Hz, 2H), 1.91 - 1.80 (m, 2H), 1.61 - 1.54 (m, 4H), 1.38 - 1.16 (m, 9H), 1.13 - 0.90 (m, 63H), 0.90 - 0.84 (m, 3H).13C NMR (101 MHz, CDCI3) 6 173.4, 166.7, 154.4, 143.4, 138.8, 125.0, 83.1, 78.9, 69.2, 60.5, 60.4, 40.4, 34.7, 34.2, 32.3, 24.9, 24.7, 22.8, 18.3, 18.3, 17.8, 14.3, 14.1, 12.4.

[0167] 18%, prepared according to General Procedure C.1H NMR (400 MHz, MeOD)6 7.57 (s, 1H), 6.82 (dd, J = 15.9, 1.3 Hz, 1H), 6.70 (dd, J = 16.0, 5.6 Hz, 1H), 4.92 (s, 4H), 4.11 (q, J = 7.1 Hz, 3H), 3.55 (ddd, J = 8.8, 5.4, 3.1 Hz, 1H), 2.37 (t, J = 6.9 Hz, 2H), 1.88 - 1.53 (m, 4H), 1.45 - 1.27 (m, 6H), 1.24 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 175.1, 168.4, 145.2, 139.7, 138.7, 124.9, 76.0, 75.5, 68.3, 61.5, 39.5, 34.6, 34.0, 33.1, 26.6, 23.7, 22.2, 14.6, 14.4.

[0169] 58%, prepared according to General Procedure F.1H NMR (400 MHz, D2O) 67.53 (s, 1H), 6.71 (d, J = 15.9 Hz, 1H), 6.53 (dd, J = 16.0, 6.4 Hz, 1H), 4.90 (t, J = 6.8 Hz, 1H), 4.24 - 4.13 (m, 1H), 3.67 - 3.58 (m, 1H), 2.09 (t, J = 7.4 Hz, 2H), 1.77 - 1.67 (m, 2H), 1.59 - 1.39 (m, 2H), 1.10-1.23 (m, 6H), 0.73 (q, J = 5.9 Hz, 3H).13C NMR (101 MHz, D2O) 6 183.1, 167.1, 142.7, 139.0, 135.4, 124.4, 74.4, 73.9, 67.1, 37.8, 36.9, 31.6, 30.9, 24.6, 22.0, 21.8, 13.3. LCMS: [M-H], predicted 356.1537, found 356.1545.

[0170] Synthesis ofLXB4Analogues 29 and 30Scheme 7: Synthesis of Analogue 30

[0171] Intermediate 27

[0172] 65%, prepared according to General Procedure J.1H NMR (400 MHz, CDCI3) 67.44 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.03 (t, J = 7.2 Hz, 2H), 2.39 (q, J = 7.4 Hz, 2H), 2.01 (p, J = 7.3 Hz, 2H), 1.22 (t, J = 7.1 Hz, 2H).13C NMR (101 MHz, CDCI3) 6 194.4, 173.8, 145.9, 133.1, 94.5, 60.3, 40.2, 38.2, 33.5, 19.1, 14.3.

[0174] 33%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 67.44 (s, 1H), 6.96 (d, J = 16.4 Hz, 1H), 6.03 (dd, J = 16.5, 8.4 Hz, 1H), 4.21 (dd, J = 8.5, 2.8 Hz,1H), 4.12 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.91 - 3.87 (m, 1H), 3.04 (t, J = 7.3 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.48 (dt, J = 13.7, 5.4 Hz, 2H), 1.40 - 1.18 (m, 9H), 1.11 - 0.99 (m, 42H), 0.87 (t, J = 6.9 Hz, 4H).13C NMR (101 MHz, CDCI3) 6 196.4, 173.9, 146.3, 131.9, 128.3, 122.8, 121.3, 77.8, 77.6, 60.4, 39.8, 38.5, 34.9, 33.8, 33.5, 32.3, 25.2, 22.7, 19.4, 18.4, 18.4, 18.4, 18.3, 18.3, 18.2, 14.3, 14.2, 13.0, 12.6.

[0176] 71%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 7.68 (s, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.00 (dd, J = 16.0, 7.2 Hz, 1H), 4.75 (t, J = 6.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 1H), 4.00 (ddd, J = 7.3, 4.7, 1.1 Hz, 1H), 3.82 (s, 3H), 3.64 (s, 1H), 3.58 - 3.50 (m, 1H), 2.38 - 2.28 (m, 2H), 1.92 - 1.73 (m, 2H), 1.59 - 1.52 (m, 5H), 1.39 - 1.14 (m, 9H), 0.91 (t, J = 3.5 Hz, 3H).

[0178] 99%, prepared according to General Procedure F.3H NMR (400 MHz, MeOD)6 7.66 (s, 1H), 6.61 (dd, J = 16.0, 4.5 Hz, 1H), 5.99 (dd, J = 16.0, 7.3 Hz, 1H), 4.77 (t, J = 7.0 Hz, 1H), 3.99 (t, J = 6.1 Hz, 1H), 3.81 (s, 3H), 3.57 - 3.51 (m, 1H), 2.18 (t, J = 7.5 Hz, 2H), 1.94 - 1.49 (m, 6H), 1.39 - 1.28 (m, 6H), 0.91 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 182.7, 153.3, 130.2, 128.7, 122.9, 118.9, 77.5, 75.8, 68.8, 38.9, 38.7, 38.1, 33.9, 33.1, 26.7, 24.1, 23.7, 14.5. LCMS: [M-H], predicted 353.2082, found 353.2079.

[0179] Synthesis ofLXB4Analogues 37 and 38Scheme 8: Synthesis of Analogue 38

[0180] Intermediate 3232

[0181] 65%, prepared according to literature procedure.1H NMR (400 MHz, CDCI3) 68.30 (d, J = 2.3 Hz, 2H), 7.83 (d, J = 2.3 Hz, 2H).

[0182] Intermediate 33

[0183] 88%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.45 (d, J = 2.2 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 6.61 (p, J = 2.3 Hz, 1H), 2.86 (tq, J = 7.3, 2.3 Hz, 2H), 2.60 (tq, J = 7.6, 2.6 Hz, 2H), 2.12 - 1.93 (m, 2H).

[0184] Intermediate 34

[0185] 34%, prepared according to General Procedure L.1H NMR (400 MHz, CDCI3) 68.51 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 3.68 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.05 (p, J = 7.3 Hz, 2H).

[0186] Intermediate 35

[0187] 95%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 68.44 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.21 (d, J = 16.2 Hz, 1H), 6.27 (dd, J = 16.1, 7.8 Hz, 1H), 4.33 (dd, J = 7.7, 2.4 Hz, 1H), 3.97 (d, J = 5.3 Hz, 1H), 3.67 (s, 3H), 3.19 (td, J = 7.2, 2.1 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.00 (q, J = 7.3 Hz, 2H), 1.35 - 1.21 (m, 8H), 1.06 (dd, J = 10.2, 3.9 Hz, 42H), 0.89 (t, J = 6.6 Hz, 3H).

[0189] 78%, prepared according to General Procedure C.

[0190] LXB4Analogue 37

[0191] 98%, prepared according to General Procedure D.1H NMR (400 MHz, CDCI3) 68.46 - 8.38 (m, 1H), 7.86 - 7.73 (m, 1H), 6.86 - 6.67 (m, 1H), 6.40 - 6.21 (m, 1H), 4.98 (d, J = 10.1 Hz, 1H), 4.32 (d, J = 29.9 Hz, 1H), 3.81 (d, J = 21.2 Hz, 1H), 3.65 (apparent d, J = 3.7 Hz, 3H), 2.51 - 2.21 (m, 2H), 1.80 (s, 4H), 1.50 (dd, J = 16.5, 9.5 Hz, 2H), 1.32 (s, 6H), 0.97 - 0.82 (m, 3H).

[0193] 99%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.35 (t, J = 1.9 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 6.96 - 6.85 (m, 1H), 6.31 (ddd, J = 15.3, 8.6, 6.3 Hz, 1H), 4.96 (dd, J = 7.7, 4.8 Hz, 1H), 4.09 (dt, J = 10.9, 5.7 Hz, 1H), 3.53 (t, J = 5.5 Hz, 1H), 2.14 (t, J = 6.7 Hz, 2H), 1.80 - 1.47 (m, 7H), 1.33 (d, J = 19.4 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H). LCMS: [M+H], predicted 386.1734, found 386.1737.

[0194] Synthesis ofLXB4Analogues 44 and 45Scheme 9: Synthesis of 45

[0195] Intermediate 39

[0196] 47%, prepared according to literature procedure.1H NMR (400 MHz, CDCI3) 68.70 (s, 1H), 7.65 (s, 1H).

[0197] Intermediate 40

[0198] 88%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.20 (s, 1H), 7.56 (s, 1H), 6.12 (p, J = 2.3 Hz, 1H), 2.74 (tq, J = 7.2, 2.3 Hz, 2H), 2.62 - 2.48 (m,4H), 2.10 - 1.93 (m, 2H).

[0199] Intermediate 41

[0200] 45%, prepared according to General Procedure L.1H NMR (400 MHz, CDCI3) 68.46 (s, 1H), 7.65 (s, 1H), 3.68 (s, 3H), 3.03 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 2.16 -2.01 (m, 2H).

[0202] 58%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 68.65 (s, 1H), 7.43 (s, 1H), 7.00 (d, J = 16.1 Hz, 1H), 6.46 (dd, J = 16.1, 7.4 Hz, 1H), 4.38 - 4.31 (m, 1H), 3.97 (t, J = 6.3 Hz, 1H), 3.68 (s, 3H), 2.97 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.04 (d, J = 5.9 Hz, 2H), 1.51 (t, J = 7.5 Hz, 2H), 1.29 (d, J = 10.2 Hz, 6H), 1.06 (dd, J = 7.5, 4.0 Hz, 42H), 0.88 (q, J = 5.1 Hz, 3H).

[0204] 67%, prepared according to General Procedure C.1H NMR (400 MHz, CDCI3) 68.64 (s, 1H), 7.44 (s, 1H), 7.06 (dd, J = 15.9, 1.3 Hz, 1H), 6.39 (dd, J = 15.9, 6.1 Hz, 1H), 4.36 -4.28 (m, 1H), 3.81 (dt, J = 8.1, 4.1 Hz, 1H), 3.68 (s, 3H), 2.99 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 6.9Hz, 2H), 2.04 (p, J = 7.1 Hz, 2H), 1.51 - 1.36 (m, 2H), 1.35 - 1.23 (m, 6H), 0.89 (q, J = 4.8 Hz, 3H).

[0205] LXB4Analogue 44

[0206] 83%, prepared according to General Procedure D.XH NMR (400 MHz, CDCI3) 68.39 (d, J = 15.9 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 18.2, 15.9 Hz, 1H), 6.46 - 6.29 (m, 1H), 4.94 (q, J = 6.2 Hz, 1H), 4.31 (dt, J = 10.7, 4.3 Hz, 1H), 3.81 (dt, J = 7.9, 4.0 Hz, 1H), 3.65 (d, J = 2.2 Hz, 3H), 2.46 - 2.26 (m, 2H), 1.75 (td, J = 13.2, 6.4 Hz, 2H), 1.48 (dt, J = 9.0, 5.0 Hz, 2H), 1.31 (s, 6H), 0.89 (t, J = 6.3 Hz, 3H).

[0207] LXB4Analogue 45

[0208] 99%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.37 (s, 1H), 7.48 (s, 1H), 6.90 (dd, J = 16.0, 11.8 Hz, 1H), 6.50 (ddd, J = 15.7, 13.0, 6.0 Hz, 1H), 4.96 (s, OH), 4.17 - 4.06 (m, 1H), 3.58 - 3.48 (m, OH), 2.17 (t, J = 5.8 Hz, 2H), 1.78 - 1.50 (m, 6H), 1.37 (d, J = 38.5 Hz, 6H), 0.89 (t, J = 6.1 Hz, 3H). LCMS: [M+H], predicted 386.1734, found 386.1778.

[0209] Synthesis of LXB4Analogues 50 and 51Scheme 10: Synthesis of 50 and 51

[0210] Intermediate 46

[0211] 62%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.61 (d, J = 6.4 Hz, 1H), 7.91 (d, J = 43.6 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J = 18.6 Hz, 1H), 6.29 (s, 1H), 2.88 - 2.79 (m, 2H), 2.72 (s, 2H), 2.09 (p, J = 8.3 Hz, 2H).

[0213] 19%, prepared according to General Procedure L.1H NMR (400 MHz, CDCI3) 69.90 (d, J = 1.9 Hz, 1H), 8.47 (s, 1H), 7.88 (d, J = 9.4 Hz, 1H), 7.72 (dd, J = 9.5, 1.9 Hz, 1H), 3.70(s, 4H), 3.03 (q, J = 7.4 Hz, 2H), 2.48 (t, J = 7.1 Hz, 2H), 2.12 (p, J = 7.2 Hz, 2H).

[0215] 43%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 69.55 (s, 1H), 8.36 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.69 (d, J = 9.4 Hz, 1H), 6.56 - 6.35 (m, 2H), 4.31 (dd, J = 6.9, 3.2 Hz, 1H), 4.01 - 3.90 (m, 1H), 3.69 (s, 3H), 3.01 (t, J = 7.3 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.13 (p, J = 6.9 Hz, 2H), 1.53 (d, J = 8.2 Hz, 2H), 1.40 - 1.21 (m, 6H), 1.06 (d, J = 4.3 Hz, 42H), 0.89 (t, J = 6.8 Hz, 3H).

[0217] 72%, prepared according to General Procedure C.1H NMR (400 MHz, CDCI3) 69.52 (s, 1H), 8.35 (s, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.66 (dd, J = 9.3, 1.7 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 6.6 Hz, 1H), 4.34 - 4.27 (m, 1H), 3.82 (t, J = 6.2 Hz, 1H), 3.69 (s, 3H), 3.00 (t, J = 7.3 Hz, 2H), 2.46 (t, J = 7.1 Hz, 2H), 2.11 (p, J = 7.1 Hz, 2H), 1.49 - 1.41 (m, 2H), 1.33 - 1.27 (m, 6H), 0.91 - 0.83 (m, 3H).

[0219] 90%, prepared according to General Procedure D.1H NMR (400 MHz, CDCI3) 68.43 (d, J = 34.1 Hz, 1H), 7.68 - 7.32 (m, 3H), 6.58 - 6.29 (m, 2H), 5.00 (s, 1H), 4.24 (s, 1H), 3.82 (s, 1H), 3.67 (d, J = 2.4 Hz, 3H), 2.51 - 2.39 (m, 2H), 2.00 (dd, J = 40.5, 9.2 Hz, 2H), 1.49 (s, 4H), 1.27 (d, J = 12.8 Hz, 6H), 0.93 - 0.81 (m, 3H).

[0221] 99%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.44 (s, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.54 - 7.42 (m, 2H), 6.69 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 15.9, 6.6 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.11 (t, J = 5.8 Hz, 1H), 3.67 - 3.54 (m, 1H), 2.27 (t, J = 7.3 Hz, 2H), 2.08 (d, J = 7.5 Hz, 2H), 1.91 - 1.52 (m, 6H), 1.34 (s, 6H), 0.92 (t, J = 6.7 Hz, 3H). LCMS: [M+H], predicted 391.2233, found 391.2224.

[0222] Synthesis ofLXB4Analogues 56 and 57Scheme 11: Synthesis of 56 and 57

[0223] Intermediate 52

[0224] 49%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.60 (d, J = 4.7 Hz, 1H), 8.07 - 7.95 (m, 3H), 7.69 (d, J = 4.8 Hz, 1H), 6.46 (t, J = 2.4 Hz, 1H), 2.88 (ddt, J = 10.1, 7.1, 2.3 Hz, 2H), 2.62 (ddd, J = 10.2, 5.0, 2.6 Hz, 2H), 2.11 (p, J = 7.5 Hz, 2H).

[0226] 25%, prepared according to General Procedure L.1H NMR (400 MHz, CDCI3) 68.81 (s, 1H), 8.77 (s, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 4.6 Hz, 1H), 3.70 (s, 3H), 3.25 (t, J = 7.0 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.20 - 2.12 (m, 1H).

[0228] 58%, prepared according to General Procedure A.XH NMR (400 MHz, CDCI3) 68.94 (d, J = 4.7 Hz, 1H), 8.75 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 6.69 (dd, J = 15.7, 7.0 Hz, 1H), 4.52 (d, J = 6.8 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.70 (s, 3H), 3.18 (t, J = 7.1 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.14 (p, J = 7.2 Hz, 2H), 1.60 (s, 4H), 1.35 - 1.29 (m, 4H), 1.20 - 1.00 (m, 42H), 0.90 (t, J = 6.8 Hz, 3H).

[0230] 83%, prepared according to General Procedure C.1H NMR (400 MHz, CDCI3) 68.94 (d, J = 4.7 Hz, 1H), 8.75 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.53 (d, J= 4.8 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 6.69 (dd, J = 15.7, 7.0 Hz, 1H), 4.52 (d, J = 6.8 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.70 (s, 3H), 3.18 (t, J = 7.1 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.14 (p, J = 7.2 Hz, 2H), 1.60 (s, 4H), 1.35 - 1.29 (m, 4H), 1.20 - 1.00 (m, 42H), 0.90 (t, J = 6.8 Hz, 3H).

[0231] LXB4Analogue 56

[0232] 99%, prepared according to General Procedure D.1H NMR (400 MHz, CDCI3) 68.67 (s, 1H), 8.03 (d, J = 11.0 Hz, 1H), 7.94 (s, OH), 7.68 (dd, J = 25.9, 8.8 Hz, 1H), 7.45 (s, 1H), 7.32 (dd, J = 15.7, 10.2 Hz, 1H), 6.77 - 6.61 (m, 1H), 4.98 - 4.76 (m, 1H), 4.50 - 4.37 (m, 1H), 3.97 - 3.87 (m, 1H), 3.65 (s, 3H), 2.36 (s, 2H), 1.79 (s, 2H), 1.56 (s, 2H), 1.28 (d, J = 25.0 Hz, 8H), 0.88 (t, J = 7.0 Hz, 3H).

[0233] LXB4Analogue 57

[0234] 99%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.70 (d, J = 4.7 Hz, 1H), 8.20 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 4.7 Hz, 1H), 7.46 (d, J = 15.8 Hz, 1H), 6.70 (dd, J = 15.8, 6.0 Hz, 1H), 4.23 (t, J = 5.8 Hz, 1H), 3.60 (dd, J = 9.2, 5.1 Hz, 1H), 2.18 (t, J = 7.4 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.75 - 1.53 (m, 2H), 1.53 - 1.25 (m, 8H), 0.89 (t, J = 6.6 Hz, 3H). LCMS: [M+H], predicted 402.2280, found402.2259.

[0235] Synthesis ofLXB4Analogues 62 and 63Scheme 12: Synthesis of 62 and 63

[0236] Intermediate 58

[0237] 81%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.50 (dd, J = 4.6, 1.5 Hz, 1H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 6.99 (dd, J = 8.0, 4.6 Hz, 1H), 6.64-6.44 (m, 1H), 2.91-2.86 (m, 2H), 2.62-2.58 (m, 2H), 2.05-1.98 (m, 2H).

[0238] Intermediate 59

[0239] In a 50 mL round bottom flask equipped with a stir bar was added cyclopentene (1.0 eq.) and NalC>4 (5.0 eq.) dissolved in CH2CI2 / CH3CN / H2O (0.15 M, 3:3:4). Biphasic mixture was allowed to stir at room temperature for 15 minutes, then RuCI3(0.05 equiv.) was added in one portion at room temperature. The resulting mixture was allowed to stir at room temperature until starting material consumption as indicated by TLC analysis (ca. 2 h). Upon completion, the mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated in vacuo, then diluted again in ethyl acetate and water. The phases were then separated; the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was directly dissolved in HPLC -grade MeOH (0.50 M) where SOCI2 (5.0 equiv.) was slowly added with stirring. Upon completion (< 30 min) as indicated by TLC analysis, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was then purified by flash column chromatography on silica gel (gradient elution, 5 ->50% ethyl acetate in hexanes) to afford the methyl ester ring-opened product (46%)1H NMR (400 MHz, CDCI3) 6 8.54 (dd, J = 4.6, 1.4 Hz, 1H), 7.96 (dd, J = 8.2, 1.4 Hz, 1H), 7.26 (dd, J = 8.2, 4.6 Hz, 1H), 3.65 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.3 Hz, 2H), 2.04 (p, J = 7.3 Hz, 2H).

[0240] Intermediate 60

[0241] 55%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 68.51 (dd, J = 4.6, 1.6 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (dd, J = 8.0, 4.6 Hz, 1H), 7.22 (d, J = 16.2 Hz, 1H), 6.27 (dd, J = 16.2, 8.0 Hz, 1H), 4.34-4.32 (dd, J = 8.4, 2.4 Hz, 1H), 3.98- 3.95 (m, 1H), 3.67 (s, 3H), 3.22 (td, J = 7 A, 2.4 Hz, 2H), 2.43 (t, J = 7.4 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H), 1.54-1.48 (m, 2H), 1.41-1.28 (m, 6H), 1.16-0.99 (m, 42H), 0.89 (t, J = 6.8 Hz, 3H).

[0242] Intermediate 61

[0243] 85%, prepared according to General Procedure C.1H NMR (400 MHz, CDCI3) 68.51 (dd, J = 4.6, 1.6 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.38 (dd, J = 8.0, 4.6 Hz, 1H), 7.25 (d, J = 16.1 Hz, 1H), 6.19 (dd, J = 16.1, 6.9 Hz, 1H), 4.29 (s, 1H), 3.79 (s, 1H), 3.65 (s, 3H), 3.23 (td, J = 7 A, 2.2 Hz, 2H), 3.06 (br s, 1H), 2.67 (br s, 1H), 2.41 (t, J = 7.4 Hz, 2H), 2.00 (p, J = 7.4 Hz, 2H), 1.60-1.18 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H).

[0244] LXB4Analogue 62

[0245] 63%, prepared according to General Procedure D.1H NMR (400 MHz, CDCI3):68.45-8.35 (m, 1H), 7.75-7.72 (m, 1H), 7.21-7.16 (m, 1H), 6.77-6.72 (m, 1H), 6.28-6.22 (m, 1H), 4.97 (br s, 1H), 4.97-4.93 (m, 1H), 4.33-4.25 (m, 1H), 3.83-3.75 (m, 1H), 3.63 + 3.62 (two singlets, diastereomeric methyl ester peaks, 3H), 3.38 (br s, 1H), 2.66 (br s, 1H), 2.44- 2.26 (m, 2H), 1.85-1.71 (m, 2H), 1.56-1.39 (m, 4H), 1.39-1.23 (m, 6H), 0.87 (apparent t, J = 6.8 Hz, 3H).

[0246] LXB4Analogue 63

[0247] 99%, prepared according to General Procedure F.1H NMR (400 MHz, CD3OD):68. 8.39 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 8.0, 5.1 Hz), 7.01-6.91 (m, 1H), 6.35-6.25 (m, 1H), 5.04-5.01 (m, 1H), 4.16-4.10 (m, 1H), 3.63-3.54 (m, 1H), 2.18 (t, J = 6.9 Hz, 2H), 1.84-1.50 (m, 6H), 1.50-1.24 (m, 6H), 0.90 (apparent t, J = 6.7 Hz, 3H).13C NMR (100 MHz, CD3OD): 6 (diastereomeric mixture, signals for resolved carbon atoms is reported; overlapping signals N.D.) 182.6, 182.5, 160.2, 160.2, 148.1, 148.1, 135.9, 135.8, 135.6, 135.6, 132.5, 132.4, 127.6, 127.3, 123.9, 77.0, 76.7, 75.8, 75.8, 71.8, 71.6, 38.8, 38.7, 38.3, 38.2, 34.2, 34.1, 33.1, 26.7, 26.6, 23.8, 23.7, 14.4. HRMS (ESI+) m / z: [M + H]+ calcd for C19H30NO5 352.2118; Found 352.2121.

[0248] Synthesis ofLXB4Analogues 68 and 69Scheme 13: Synthesis of 68 and 69

[0249] Intermediate 64

[0250] 65%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3) 68.39 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 7.7, 2.6 Hz, 1H), 6.51 (m, 1H), 2.90-2.80 (m, 2H), 2.60(m, 2H), 2.01 (m, 2H).

[0251] Intermediate 65

[0252] In a 50 mL round bottom flask equipped with a stir bar was added cyclopentene (1.0 eq.) and NalC>4 (5.0 eq.) dissolved in CH2CI2 / CH3CN / H2O (0.15 M, 3:3:4). Biphasic mixture was allowed to stir at room temperature for 15 minutes, then RuCH (0.05 equiv.) was added in one portion at room temperature. The resulting mixture was allowed to stir at room temperature until starting material consumption as indicated by TLC analysis (ca. 2 h). Upon completion, the mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated in vacuo, then diluted again in ethyl acetate and water. The phases were then separated; the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was directly dissolved in HPLC -grade MeOH (0.50 M) where SOCI2 (5.0 equiv.) was slowly added with stirring. Upon completion (< 30 min) as indicated by TLC analysis, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was then purified by flash column chromatography on silica gel (gradient elution, 5 ->50% ethyl acetate in hexanes) to afford the methyl ester ring-opened product (41%).1H NMR (400 MHz, CDCI3) 68.44 (dd, J = 2.5, 0.6 Hz, 1H), 7.76 (dd, J = 7.7, 2.5 Hz, 1H), 3.68 (s, 3H), 3.17 (t, J = 7.3 Hz, 2H),2.44 (t, J = 7.3 Hz, 2H), 2.05 (p, J = 7.3 Hz, 2H).

[0254] 44%, prepared according to General Procedure A.XH NMR (400 MHz, CDCI3) 68.34 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 9.6, 2.6 Hz, 1H), 7.28 (d, J = 16.2 Hz, 1H), 6.28 (dd, J = 16.2, 7.9 Hz, 1H), 4.34 (dd, J = 7.9, 2.2 Hz, 1H), 3.97 (m, 1H), 3.67 (s, 3H), 3.20 (td, J = 7 A, 1.3 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.01 (p, J = 7.4 Hz, 2H), 1.56-1.47 (m, 2H), 1.40-1.25 (m, 6H), 1.16-0.99 (m, 42H), 0.89 (t, J = 6.7 Hz, 3H).

[0256] 86%, prepared according to General Procedure C.XH NMR (400 MHz, CDCI3) 68.33 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 9.4, 2.7 Hz, 1H), 7.29 (d, J = 16.2 Hz, 1H), 6.23 (dd, J = 16.2, 6.7 Hz, 1H), 4.33-4.25 (m, 1H), 3.82-3.76 (m, 1H), 3.65 (s, 3H), 3.37 ( br s, 1H), 3.19 (td, = 7.3, 1.6 Hz, 2H), 2.86 (br s, 1H), 2.39 (t, J = 7.3 Hz, 2H), 1.97 (p, J = 7.3 Hz, 2H), 1.55-1.40 (m, 3H), 1.36-1.18 (m, 5H), 0.85 (t, J = 6.8 Hz, 3H).

[0257] LXB4Analogue 68

[0258] 83%, prepared according to General Procedure D.1H NMR (400 MHz, CDCI3):68.28-8.25 (m, 1H), 7.49-7.45 (m, 1H), 6.79-6.72 (m, 1H), 6.32-6.25 (m, 1H), 4.95-4.90 (m, 1H), 4.65-4.56 (m, 1H), 4.33-4.26 (m, 1H), 3.84-3.75 (m, 1H), 3.64 + 3.63 (two singlets, diastereomeric methyl ester peaks, 3H), 3.49-3.40 (m, 1H), 2.64-2.57 (m, 1H), 2.43-2.29 (m, 2H), 1.83-1.69 (m, 2H), 1.55-1.40 (m, 3H), 1.40-1.24 (m, 5H), 0.87 (apparent t, J = 6.7 Hz, 3H).

[0259] LXB4Analogue 69

[0260] 99%, prepared according to General Procedure F.1H NMR (400 MHz, CD3OD):68.29 (dd, J = 2.7, 1.5 Hz, 1H), 7.68 (dd, J = 10.0, 2.7 Hz, 1H), 7.01-6.93 (m, 1H), 6.40-6.31 (m, 1H), 5.01 (dd, J = 7.6, 4.9 Hz, 1H), 4.16-4.10 (m, 1H), 3.60-3.53 (m, 1H), 2.10 (apparent t, J = 7.0 Hz, 2H), 1.84-1.50 (m, 6H), 1.47-1.25 (m, 6H), 0.91 (apparent t, J = 6.7 Hz, 3H).13C NMR (100 MHz, CD3OD): 6 (diastereomeric mixture, signals for resolved carbon atoms is reported; overlapping signals N.D.)13C NMR (100 MHz, CD3OD) 6 182.5, 182.5, 160.4 (d, J = 253.0 Hz), 156.7, 137.2, 137.1, 136.0 (d, J = 24.5 Hz), 136.0 (d, J = 25.5 Hz), 134.2, 134.2, 134.2, 134.1, 126.5, 126.5, 126.2, 126.2, 121.8 (d, J = 18.9 Hz), 121.7 (d, J = 18.9 Hz), 76.8, 76.5, 75.8, 75.7, 71.5, 71.4, 38.8, 38.7, 38.2, 38.1, 34.2, 34.1, 33.1, 26.7, 26.6, 23.8, 23.8, 23.7, 14.4.19F NMR [3H,13C decoupled] (376 Hz, CD3OD) : 6 -132.1, -132.1. HRMS (ESI+) m / z: [M + H]+ Calcd for C19H29FNO5 370.2024; Found 370.2020.

[0261] Synthesis ofLXB4Analogues 74 and 75Scheme 14: Synthesis of 74 and 75

[0262] Intermediate 70

[0263] 25%, prepared according to General Procedure K.1H NMR (400 MHz, CDCI3):5 8.03 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.74-6.72 (m, 1H), 2.95-2.90 (m, 2H), 2.66-2.60 (m,2H), 2.05-1.97 (m, 2H).

[0264] Intermediate 71

[0265] In a 50 mL round bottom flask equipped with a stir bar was added cyclopentene (1.0 eq.) and NalC>4 (5.0 eq.) dissolved in CH2CI2 / CH3CN / H2O (0.15 M, 3:3:4).Biphasic mixture was allowed to stir at room temperature for 15 minutes, then RuCH (0.05 equiv.) was added in one portion at room temperature. The resulting mixture was allowed to stir at room temperature until starting material consumption as indicated by TLC analysis (ca. 2 h). Upon completion, the mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was concentrated in vacuo, then diluted again in ethyl acetate and water. The phases were then separated; the organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was directly dissolved in acetone (0.20 M) where potassium carbonate (2.5 equiv.) and iodomethane (2.0 equiv.) were added. The reaction was stirred overnight at room temperature then filtered through a pad of Celite® and washed with acetone. The filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel (gradient elution, 5 ->50% ethyl acetate in hexanes) to afford the methyl ester ring-opened product (31%).XH NMR (400 MHz, CDCI3) 6 8.19 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 3.68 (s, 3H), 3.20 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.07 (p, J = 7.2 Hz, 2H).

[0266] Intermediate 72

[0267] 58%, prepared according to General Procedure A.1H NMR (400 MHz, CDCI3) 68.02 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 16.2 Hz, 1H), 6.38 (dd, J = 16.2, 7.9 Hz, 1H), 4.35 (dd, J = 8.0, 2.1 Hz, 1H), 3.98 (m, 1H), 3.68 (s, 3H), 3.25 (td, J = 7.3, 3.2 Hz, 2H), 2.44 (t, J = 7.3 Hz, 2H), 2.04 (p, J = 7.3 Hz, 2H), 1.55-1.48 (m, 2H), 1.41-1.28 (m, 6H), 1.16- 0.99 (m, 42H), 0.89 (t, J = 6.8 Hz, 3H).

[0268] Intermediate 73

[0269] 53%, prepared according to General Procedure C.1H NMR (400 MHz, CDCI3) 68.04 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 6.6 Hz, 1H), 4.33 (s, 1H), 3.81 (s, 1H), 3.67 (s, 3H), 3.27 (td, J = 7.3, 1.8 Hz, 2H), 2.81 (s, 1H), 2.47 (s, 1H), 2.43 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.3 Hz, 2H), 1.58-1.40 (m, 2H), 1.38-1.22 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).

[0271] 78%, prepared according to General Procedure D. 1H NMR (400 MHz, CDCI3):6 7.91-7.89 (m, 1H), 7.58-7.54 (m, 1H), 6.85-6.78 (m, 1H), 6.40-6.33 (m, 1H), 5.03-4.98 (m, 1H), 4.53-4.44 (m, 1H), 4.38-4.29 (m, 1H), 3.86-3.77 (m, 1H), 3.64 + 3.63 (two singlets, diastereomeric methyl ester peaks, 3H), 3.52-3.40 (m, 1H), 2.63-2.49 (m, 1H), 2.49-2.30 (m, 2H), 1.90-1.76 (m, 2H), 1.57-1.40 (m, 4H), 1.40-1.22 (m, 6H), 0.87 (apparent t, J = 6.6 Hz, 3H).

[0273] 99%, prepared according to General Procedure F.1H NMR (400 MHz, CD3OD):6 8.07 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 15.8, 10.8 Hz, 1H), 6.49-6.36 (m, 1H), 5.05 (dd, J = 7.9, 4.5 Hz, 1H), 4.20-4.10 (m, 1H), 3.60-3.54 (m, 1H), 2.25-2.12 (m, 2H), 1.99-1.51 (m, 6H), 1.47-1.22 (m, 6H), 0.91 (apparent t, J = 6.6 Hz, 3H).19F NMR H,13C decoupled] (376 Hz, CD3OD) : 6 -69.2. HRMS (ESI+) m / z: [M + H]+ Calcd for C20H29F3NO5 420.1992; Found 420.2007.

[0274] Synthesis ofLXB4Analogues 78 and 79Scheme 15: Synthesis of 78 and 79

[0275] Intermediate 76

[0276] 39%, prepared according to General Procedure K. 1H NMR (400 MHz, CDCI3)6 7.88 (s, 1H), 6.53 (p app, J = 2.3 Hz, 1H), 3.12 (s, 6H), 2.90 - 2.80 (m, 2H), 2.63 - 2.54 (m, 2H), 1.96 (p app, J = 7.5 Hz, 1H).

[0278] In a vial equipped with a stir bar, the cyclopentene intermediate (1.0 equiv) and NalC>4 (5 equiv) were dissolved in CHzCL / MeCN / HzO (0.15 M, 3:3:4) followed by the addition of RuCH (0.05 equiv). After vigorously stirring for 2h at room temperature, the starting material was no longer observable by TLC. The miture was filtered through Celite®, rinsing with EtOAc. The resulting filtrate was washed once with H2O, then dried over Na2SO4, filtered and condensed to a brown oil. The crude residue was dissolved in acetone (0.05M), then K2CO3 (2.5 equiv) and methyl iodide (2.0 equiv) were added and the solutionstirred for 18h. The crude mixture was filtered to remove solids, then the solvent was removed in vacuo. Purification by flash chromatography (SiC , 0100% EtOAc / hexanes) gave the methyl ester intermediate (10%) in sufficient purity to carry forward.1H NMR (400 MHz, CDCI3) 6 7.84 (s, 1H), 3.63 (s, 3H), 3.19 (s, 6H), 3.07 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 1.98 (p app, J = 7.3 Hz, 2H).

[0279] LXB4Analogue 78

[0280] 9%, prepared according to General Procedures A and E.1H NMR (400 MHz,MeOD) 6 7.94 (d, J = 1.6 Hz, 1H), 7.07 (dd app, J = 5.8, 14.8 Hz, 1H), 6.99 (dd app, J = 4.7, 15.4 Hz, 1H), 4.96 (t app, J = 6.7 Hz, 1H), 4.20 (t, J = 5.4 Hz, 1H), 3.66 (s, 3H), 3.61 (m,lH), 3.16 (s, 6H), 2.36 (t app, J = 7.3 Hz, 2H), 1.92 - 1.27 (m, 12H), 0.93 (t, J = 6.7 Hz, 5H).

[0281] LXB4Analogue 79

[0282] 95%, prepared according to general procedure F.1H NMR (400 MHz, MeOD)6 7.92 (s, 1H), 7.09 - 6.93 (m, 2H), 4.97 (t, J = 6.8 Hz, 1H), 4.18 (m, 1H), 3.57 (m, 1H), 3.14 (s, 6H), 2.18 (t, J = 7.4 Hz, 2H), 1.84 (q, J = 7.1 Hz, 2H), 1.74 - 1.50 (m, 4H), 1.47 - 1.30 (m, 6H), 0.91 (t, J = 6.5 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.2, 153.4, 144.2, 144.2, 140.2, 136.4, 136.4, 127.1, 127.0, 125.4, 125.2, 75.5, 75.3, 74.4, 69.3, 69.2, 37.6, 37.5, 36.7, 36.3, 36.2, 32.5, 32.4, 31.7, 29.4, 25.3, 25.2, 22.6, 22.3, 13.0 HRMS m / z: [M + H]+ Calcd for C20H34N3O5 396.2493; Found 396.2497.

[0283] Synthesis ofLXB4Analogues 81 and 82Scheme 16: Synthesis of 81 and 82

[0284] Intermediate 80

[0285] 88%, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 67.66 (d, J = 1.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.40 (dd, J = 1.6, 8.1 Hz, 1H), 7.09 (d, J = 16.0 Hz, 1H), 6.97 (s br, 1H), 6.65 (t, J = 2.4 Hz, 1H), 6.47 (t, J = 2.2 Hz, 1H), 6.24 (dd, 1 = 8.2, 16.0 Hz, 1H), 4.32 (d br, 1 = 8.2 Hz, 1H), 3.98 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 2.95 (dt, 1 = 2.0, 7.2 Hz, 2H), 2.41 (t, 1 = 7.3 Hz, 2H), 2.02 (p app, J = 7.2 Hz, 2H), 1.65 - 0.96 (m, 50), 0.88 (t, 1 =6.8 Hz, 3H).

[0287] 63%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 7.60 (d, J = 1.4 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.04 - 6.94 (m, 2H), 6.64 (t, J = 2.4 Hz, 1H), 6.40 (t, J = 2.0 Hz, 1H), 6.21 (ddd app, J = 1.9, 7.0, 15.7 Hz, 1H), 4.97 (m, 1H), 4.12 (m, 1H), 3.67 (s, 3H), 3.65 - 3.58 (m, 4H), 2.40 - 2.28 (m, 2H), 1.80 - 1.52 (m, 6H), 1.49 - 1.23 (m, 6H), 0.92 (t, J = 6.8 Hz, 3H).

[0289] Quantitative, prepared according to General Procedure F. 1H NMR (400 MHz, MeOD) 6 7.58 (s, 1H), 7.38 (s, 2H), 7.04 - 6.94 (m, 2H), 6.64 (t, J = 2.4 Hz, 1H), 6.39 (s br, 1H), 6.27 - 6.15 (m, 1H), 4.99 (t, J = 6.1 Hz, 1H), 4.12 (q app, J = 3.4 Hz, 1H), 3.71 - 3.56 (m, 4H), 2.20 (t, J = 6.7 Hz, 1H), 1.84 - 1.53 (m, 6H), 1.52 - 1.25 (m, 6H), 0.92 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, MeOD) 6 181.4, 181.4, 138.9, 138.8, 135.1, 135.1, 131.0, 130.9, 129.5, 129.3, 125.6, 125.5, 124.3, 123.6, 123.6, 122.3, 122.1, 118.3, 105.5, 76.0, 75.8, 74.5, 69.6, 69.6, 38.2, 37.5, 37.4, 34.9, 32.7, 32.7, 31.7, 25.3, 25.3, 22.7, 22.4, 13.1 HRMS m / z: [M + Na]+ Calcd for C25H35NO5Na 452.2407 ; Found 452.2405.

[0290] Synthesis ofLXB4Analogues 84 and 85Scheme 17: Synthesis of 84 and 85

[0291] Intermediate 83

[0292] 62%, prepared according to General Procedure B.TH NMR (400 MHz, CDCI3) 67.66 (d, J = 8.0 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.34 (dd, J = 1.6, 8.0 Hz, 1H), 7.18 (s, 1H), 6.99 (d,J = 16.0 Hz, 1H), 6.26 (dd, J = 8.0, 16.1 Hz, 1H), 4.32 (dd, J = 1.5, 8.0 Hz, 1H), 3.97 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.97 (dt, J = 1.7, 7.2 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.04 (p app, J = 7.2 Hz, 2H), 1.58 - 0.98 (m, 50H) 0.89 (t, J = 6.7 Hz, 3H).

[0293] LXB4Analogue 84

[0294] 21%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 7.70 (s, 1H), 7.59 (dd, J = 3.1, 8.0 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.38 (d br, J = 8.0 Hz, 1H), 7.07 - 6.96 (t, J = 13.5 Hz, 2H), 6.24 (ddd app, J = 2.2, 6.8, 15.7 Hz, 1H), 5.04 (q br, J = 5.1 Hz, 1H), 4.12 (m, 1H), 3.73 (s, 3H), 3.66 - 3.57 (m, 4H), 2.37 (m, 2H), 1.84 - 1.49 (m, 6H), 1.48 - 1.24 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H).

[0295] LXB4Analogue 85

[0296] Quantitative, prepared according to General Procedure F.1H NMR (400 MHz, MeOD) 6 7.69 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.05 - 6.95 (m, 2H), 6.28 - 6.16 (m, 1H), 5.06 (s br, 1H), 4.13 (q app, J = 6.7 Hz, 1H), 3.72 (s, 3H), 3.59 (m, 1H), 2.21 (m, 2H), 1.85 - 1.50 (m, 6H), 1.49 - 1.24 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.2, 142.6, 142.5, 138.9, 135.6, 135.6, 132.6, 132.5, 128.4, 128.1, 128.1, 127.2, 127.2, 126.2, 126.1, 125.9, 125.8, 75.8, 75.5, 74.4, 74.4, 69.4, 38.1, 38.1, 37.3, 37.2, 32.8, 32.7, 31.7, 31.6, 25.3, 25.2, 22.6, 22.4, 13.0 HRMS m / z: [M + H]+ Calcd for C24H35N2O5 431.2540; Found 431.2538.

[0297] Synthesis of LXB4Analogues 87 and 88Scheme 18: Synthesis of 87 and 88

[0299] 92%, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 67.80 (s, 1H), 7.68 (s, 1H), 7.66 - 7.60 (m, 2H), 7.40 (dd, J = 1.6, 8.1 Hz, 1H), 7.05 (d, J = 16.1 Hz, 1H), 6.26 (dd, J = 8.2, 16.1 Hz, 1H), 4.32 (d br, J = 8.1 Hz, 1H), 4.23 (q, J = 7.3 Hz, 2H), 3.98 (ddd, J = 2.3, 5.0, 7.6 Hz, 1H), 3.68 (s, 3H), 2.95 (dt, J = 3.0, 7.2 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.2 Hz, 2H), 1.60 - 0.97 (m, 53H), 0.88 (t, J = 6.8 Hz, 3H).

[0300] LXB4Analogue 87

[0301] 72%, prepared according to General Procedure E.1H NMR (400 MHz, MeOD)6 8.01 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.46 (m, 2H), 6.98 (d app, J = 15.8 Hz, 1H), 6.26 (ddd app, J = 2.4, 6.9, 15.7 Hz, 1H), 4.99 (m, 1H), 4.21 (q, J = 7.3 Hz, 2H), 4.12 (m, 1H), 3.66 - 3.59 (m, 4H), 2.40 - 2.27 (m, 2H), 1.82 - 1.53 (m, 6H), 1.51 - 1.27 (m, 9H), 0.92 (t, J = 6.8 Hz, 3H).

[0302] LXB4Analogue 88

[0303] Quantitative, prepared according to General Procedure F.XH NMR (400 MHz,MeOD) 6 8.00 (s, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.50 - 7.41 (m, 2H), 6.99 (dd app, J = 13.0, 15.4 Hz, 1H), 6.25 (dt app, J = 6.5, 15.5 Hz, 1H), 5.01 (t, J = 5.8 Hz, 1H), 4.20 (q, J = 7.3 Hz, 2H), 4.13 (q app, J = 5.5 Hz, 1H), 3.62 (m, 1H), 2.20 (t, J = 6.6 Hz, 2H), 1.83 - 1.53 (m, 6H), 1.52 - 1.25 (m, 9H), 0.92 (t, J = 6.7 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 140.6, 140.4, 135.8, 135.5, 135.5, 131.7, 131.7, 131.2, 131.2, 128.9, 128.7, 126.2, 126.0, 125.9, 124.2, 124.2, 122.8, 122.7, 75.9, 75.7, 74.5, 74.5, 69.5, 69.4, 46.6, 38.2, 37.4, 37.3, 32.8, 32.7, 31.7, 25.3, 25.3, 22.6, 22.4, 14.7, 13.1 HRMS m / z: [M + H]+ Calcd for C25H37N2O5445.2697; Found 445.2686.

[0304] Synthesis of LXB4Analogues 90 and 91Scheme 19: Synthesis of 90 and 91

[0305] Intermediate 89

[0306] 42%, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 67.89 (s, 2H), 7.70 - 7.60 (m, 3H), 7.44 (dd, J = 1.6, 8.1 Hz, 1H), 7.04 (d, J = 16.1 Hz, 1), 6.27 (dd, J = 8.1, 16.0 Hz, 1H), 4.32 (d, J = 6.2 Hz, 1H), 3.98 (m, 1H), 3.68 (s, 3H), 2.96 (dt, J = 2.4, 7.2 Hz, 2H), 2.42 (t, J = 7.3 Hz, 3H), 2.03 (p app, J = 7.2 Hz, 2H), 1.62 - 0.97 (m, 50H), 0.88 (t, J = 6.9 Hz, 3H).

[0307] LXB4Analogue 90

[0308] 34%, prepared according to General Procedure E.XH NMR (400 MHz, MeOD)6 7.97 (s br, 2H), 7.68 (s, 1H), 7.54 - 7.39 (m, 2H), 6.99 (d app, J = 15.8 Hz, 1H), 6.26 (ddd app, J = 2.5, 6.9, 15.7 Hz, 1H), 5.00 (m, 1H), 4.12 (m, 1H), 3.69 - 3.55 (m, 4H), 2.42 - 2.30 (m, 2H), 1.83 - 1.51 (m, 6H), 1.50 - 1.24 (m, 6H), 0.92 (t, J = 6.8 Hz, 3H).

[0309] LXB4Analogue 91

[0310] Quantitative, prepared according to General Procedure F.1H NMR (400 MHz, MeOD) 6 7.96 (s, 2H), 7.67 (s, 1H), 7.47 (s, 2H), 7.00 (t app, J = 14.5 Hz, 1H), 6.24 (dt app, J = 6.7, 15.8 Hz, 1H), 5.01 (t, J = 5.9 Hz, 1H), 4.13 (q app, J = 6.3 Hz, 1H), 3.61 (m, 1H), 2.20 (t, J = 6.7 Hz, 2H), 1.84 - 1.51 (m, 6H), 1.50 - 1.24 (m, 6H), 0.92 (t, J = 6.8 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 181.3, 140.5, 140.4, 135.5, 135.5, 131.7, 131.7, 131.3, 129.0, 128.7, 126.0, 125.9, 124.4, 124.3, 123.0, 122.1, 75.9, 75.7, 74.5, 74.5, 69.5, 69.4, 38.2, 37.4, 37.3, 32.8, 32.7, 31.7, 25.3, 25.3, 22.6, 22.4, 13.0 HRMS m / z: [M + H]+ Calcd for C23H33N2O5 417.2384; Found 417.2373.

[0311] Synthesis ofLXB4Analogues 93 and 94Scheme 20: Synthesis of 93 and 94

[0313] Quantitative, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 6 7.78 (s, 1H), 7.74 (s, 1H), 7.66-7.60 (m, 2H), 7.39 (dd, J = 1.6, 8.1 Hz, 1H), 7.05(d, J = 16.1 Hz, 1H), 6.26 (dd, J = 8.2, 16.1 Hz, 1H), 4.31 (dd, J = 1.6, 8.1 Hz, 1H), 3.98 (ddd, J = 2.0, 4.7, 7.4 Hz, 1H), 3.71 - 3.60 (m, 4H), 2.95 (dt, J = 3.2, 7.2 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.03 (p app, J = 7.2 Hz, 2H), 1.60 - 0.98 (m, 54H), 0.88 (t, J = 6.8 Hz, 3H).

[0314] LXB4Analogue 93

[0315] 63%, prepared according to General Procedure E.1H NMR (400 MHz, CDCI3) 67.80 - 7.64 (m, 2H), 7.51 - 7.34 (m, 3H), 6.97 (dd app, J = 15.8, 20.5 Hz, 1H), 6.18 (dd app, J =6.9, 15.7 Hz, 1H), 4.99 (s br, 1H), 4.26 (s br, 1H), 3.80 (s br, 1H), 3.67 - 3.57 (m, 4H), 3.13 -2.76 (m, 1H), 2.53 - 2.09 (4H ), 1.84 - 1.62 (m, 4H), 1.60 - 1.00 (m, 12H), 0.88 (t, J = 6.6 Hz,

[0316] LXB4Analogue 94

[0317] 90%, prepared according to General Procedure F.XH NMR (400 MHz, MeOD)6 8.04 (s, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 7.49 - 7.40 (m, 2H), 6.99 (t app, J = 14.6 Hz, 1H), 6.24 (dt, J = 15.5, 7.2 Hz, 1H), 5.01 (t, J = 5.6 Hz, 1H), 4.13 (q app, J = 5.9 Hz, 1H), 3.70 - 3.54 (m, 2H), 2.20 (t, J = 6.6 Hz, 3H), 1.82 - 1.52 (m, 6H), 1.50 - 1.25 (m, 6H), 1.17 - 1.01 (m, 4H), 0.92 (t, J = 6.7 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 181.3, 140.7, 140.5, 136.2, 136.1, 135.5, 135.5, 133.1, 131.8, 131.7, 131.0, 128.9, 128.6, 127.0, 126.9, 126.0, 125.9, 124.2, 123.1, 122.9, 122.6, 75.9, 75.7, 74.5, 69.5, 69.4, 38.2, 37.4, 37.3, 32.8, 32.7, 32.2, 31.7, 25.3,25.3, 22.6, 22.4, 13.1, 5.6 HRMS m / z: [M + H]+ Calcd for C26H37N2O5 457.2697; Found457.2698.

[0318] Synthesis ofLXB4Analogues 96 and 97Scheme 21: Synthesis of 96 and 97

[0319] Intermediate 95

[0320] Quantitative, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 6 7.81 (s, 1H), 7.71 (s, 1H), 7.65 - 7.60 (m, 2H), 7.41 (dd, J = 1.7, 8.1 Hz, 1H), 7.06 (d, J = 16.1 Hz, 1H), 6.26 (dd, J = 8.2, 16.1 Hz, 1H), 4.54 (s, J = 6.7 Hz, 1H), 4.31 (dd, J = 1.6, 8.1 Hz, 1H), 3.99 (ddd, J = 2.5, 5.0, 7.8 Hz, 1H), 3.68 (s, 3H), 2.95 (dt, J = 3.1, 7.2 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.03 (p app, J = 7.2 Hz, 2H), 1.63 - 1.00 (m, 56H), 0.88 (t, J = 6.8 Hz, 3H).

[0322] 81%, prepared according to General Procedure E.1H NMR (400 MHz, CDCI3) 67.76 (s, 1H), 7.69 (d app, J = 2.8 Hz, 1H), 7.53 - 7.37 (m, 3H), 6.98 (dd app, J = 15.2, 24.4 Hz, 1H), 6.19 (dd app, J = 6.7, 15.8 Hz, 1H), 5.00 (s br, 1H), 4.53 (s, J = 6.7 Hz, 1H), 4.29 (s br, 1H), 3.81 (s br, 1H), 3.65 (d app, J = 3.7 Hz, 3H), 3.11 - 2.69 (m, 1H), 2.49 - 2.27 (m, 3H), 2.26- 1.96 (m, 1H), 1.83 - 1.23 (m, 18H), 0.89 (t, J = 6.6 Hz, 3H).

[0324] 91%, prepared according to General Procedure F.TH NMR (400 MHz, MeOD)6 8.04 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.46 (m, 2H), 6.99 (dd app, J = 13.1, 15.5 Hz, 1H),6.25 (td app, J = 7.1, 15.6 Hz, 1H), 5.01 (t, J = 5.9 Hz, 1H), 4.55 (s, J = 6.7 Hz, 1H), 4.13 (q app, J = 6.13 Hz, 1H), 3.62 (m, 1H), 2.20 (t, J = 6.6 Hz, 2H), 1.83 - 1.51 (m, 12H), 1.50 - 1.25 (m, 6H), 0.92 (t, J = 6.7 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 140.5, 140.4, 135.5,135.5, 131.7, 131.7, 131.3, 129.0, 128.7, 126.0, 125.9, 124.4, 124.2, 122.8, 122.4, 75.9, 75.7,74.5, 69.5, 69.4, 53.9, 38.2, 37.4, 37.3, 32.8, 32.7, 31.7, 25.3, 25.3, 22.6, 22.4, 21.8, 13.1 HRMS m / z: [M + H]+ Calcd for C26H39N2O5 459.2853; Found 459.2841.

[0325] Synthesis ofLXB4Analogues 99 and 100Scheme 22: Synthesis of 99 and 100

[0326] Intermediate 98

[0327] Quantitative, prepared according to General Procedure B.XH NMR (400 MHz, CDCI3) 6 7.82 (s, 1H), 7.73 (s, 1H), 7.66 - 7.60 (m, 2H), 7.40 (dd, J = 1.7, 8.1 Hz, 1H), 7.05 (d, J = 16.1 Hz, 1H), 6.26 (dd, J = 8.2, 16.1 Hz, 1H), 4.80 (p app, J = 8.4 Hz, 1H), 4.31 (dd, J =1.5, 8.1 Hz, 1H), 3.99 (ddd, J = 2.3, 4.9, 7.8 Hz, 1H), 3.68 (s, 3H), 2.95 (dt, J = 3.0, 7.2 Hz, 2H), 2.66 - 2.47 (m, 4H), 2.42 (t, J = 7.3 Hz, 2H), 2.03 (p app, J = 7.2 Hz, 1H), 1.97 - 1.80 (m, 2H), 1.62 - 0.99 (m, 50H) 0.88 (t, J = 6.9 Hz, 1H).

[0328] LXB4Analogue 99

[0329] 82%, prepared according to General Procedure E.1H NMR (400 MHz, CDCI3) 67.77 (s, 1H), 7.71 (d, J = 3.8 Hz, 1H), 7.52 - 7.36 (m, 3H), 6.98 (dd app, J = 15.7, 22.2 Hz, 1H), 6.19 (dd app, J = 6.9, 15.5 Hz, 1H), 5.00 (s br, 1H), 4.79 (p app, J = 8.4 Hz, 1H), 4.28 (s br, 1H), 3.82 (s br, 1H), 3.65 (d app, J = 3.6 Hz, 3H), 3.08 - 2.76 (m, 1H), 2.65 - 2.26 (m, 7H), 2.21 - 2.07 (m, 1H), 2.00 - 1.20 (m, 14H), 0.89 (t, J = 6.7 Hz, 3H).

[0330] LXB4Analogue 100

[0331] 97%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.07 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.46 (m, 2H), 6.99 (dd app, J = 13.3, 15.2 Hz, 1H), 6.25 (dt app, J = 7.4, 15.7 Hz, 1H), 5.01 (t, J = 5.8 Hz, 1H), 4.84 (p, J = 8.4 Hz, 1H), 4.13 (q app, J = 5.6 Hz, 1H), 3.62 (m, 1H), 2.66 - 2.42 (m, 4H), 2.20 (t, J = 6.4 Hz, 2H), 1.93 - 1.83 (m, 2H), 1.81 - 1.53 (m, 6H), 1.51 - 1.26 (m, 6H), 0.92 (t, J = 6.7 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 181.3, 140.6, 140.5, 136.0, 135.5, 135.5, 131.7, 131.7, 131.2, 128.9, 128.7, 126.0, 125.9, 125.2, 124.2, 122.9, 122.6, 75.9, 75.7, 74.5, 74.5, 69.5, 69.4, 55.5, 38.2, 37.4, 37.3, 32.8, 32.7, 31.7, 30.0, 25.3, 25.3, 22.6, 22.4, 14.0, 13.1 HRMS m / z: [M + H]+ Calcd for C27H39N2O5 471.2853; Found 471.2849.

[0332] Synthesis ofLXB4Analogues 102 and 103

[0334] Quantitative, prepared according to General Procedure B.1H NMR (400 MHz, CDCI3) 6 8.08 - 8.03 (m, 2H), 7.69 - 7.64 (m, 2H), 7.44 (dd, J = 1.7, 8.1 Hz, 1H), 7.01 (d, J = 16.0 Hz, 1H), 6.29 (dd, J = 8.1, 16.1 Hz, 1H), 4.32 (dd, J = 1.5, 8.0 Hz, 1H), 3.99 (ddd, J = 2.1, 5.2, 7.5 Hz, 1H), 3.68 (s, 1H), 2.96 (dt, J = 3.9, 7.2 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.03 (p app, J = 7.3 Hz, 2H), 1.60 - 0.99 (m, 50H), 0.88 (t, J = 6.8 Hz, 1H).

[0336] 84%, prepared according to General Procedure E.1H NMR (400 MHz, CDCI3) 68.08 - 7.98 (m, 2H), 7.59 - 7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 6.98 (dd app, J = 15.7, 23.1 Hz, 1H), 6.20 (dd app, J = 7.2, 15.7 Hz, 1H), 5.03 (s br, 1H), 4.29 (s br, 1H), 3.83 (s br, 1H), 3.65 (d app, J = 3.9 Hz, 3H), 3.12 - 2.79 (m, 1H), 2.49 - 2.09 (m, 4H), 1.88 - 1.22 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H).

[0337] LXB4Analogue 103

[0338] 92%, prepared according to General Procedure F.1H NMR (400 MHz, MeOD)6 8.58 (s, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.54 (m, 2H), 7.01 (d, J = 15.6 Hz, 1H), 6.28 (dd app, J = 6.7, 15.6 Hz, 1H), 5.03 (t, J = 5.8 Hz, 1H), 4.14 (m, 1H), 3.60 (m, 1H), 2.20 (t, J = 6.6 Hz, 2H), 1.83 - 1.52 (m, 6H), 1.51 - 1.25 (m, 6H), 0.92 (t, J = 6.8 Hz, 3H).13C NMR (101 MHz, MeOD) 6 181.3, 142.0, 141.5, 135.8, 132.3, 128.9, 128.5, 128.2, 126.2, 125.7, 125.0, 124.7, 123.6, 119.6, 75.6, 74.5, 69.4, 69.3, 38.1, 37.4, 37.2, 32.8, 32.7, 31.7, 25.3, 22.6, 22.4, 13.0 HRMS m / z: [M + Na]+ Calcd for C24H31F3N2O5Na 507.2077; Found 507.2066.

[0339] EXAMPLE 2: Neuroprotective Activity of the LXB4analogues

[0340] Oxidative stress is associated with several diseases, particularly neurodegenerative diseases, commonly found in the elderly. Attenuation of oxidative stress is a therapeutic means for providing neuroprotection and for protecting against detrimental neurological effects of aging.

[0341] Glutamate has been shown to induce neuronal cell death through two mechanisms: glutamate receptor-induced cytotoxicity and ROS-mediated oxidative stress. HT22 mouse hippocampal neuronal cells are a useful model for studying the mechanisms of glutamate-induced oxidative stress, which leads to cell death, since this cell line lacks functional ionotropic glutamate receptors and, thus, do not exhibit glutamate receptor- induced cytotoxicity. HT22 cells are particularly susceptible to glutamate-induced toxicity, which mimics aspects of neuronal damage, for example, from neuroinflammation or neurodegeneration.

[0342] The LXB4analogues of the present application have been found to provide neuroprotective activity against oxidative stress. This activity was demonstrated in vitro using an HT22 metabolic stress assay as described below, with cell protection ranging fromabout 10% to 100%. The results of stress assays performed using represent example of LXB4analogues of the present application are summarized in Table 1. As shown, all the LXB4analogues used in the assay provided protection against oxidative stress.Table 1: HT22 Cell Viability in Presence of Glutamate StressorSEM = standard error of mean

[0343] Experimental

[0344] Metabolic Protection Assay: HT22 cells were seeded at 4xl03cells in triplicate wells in 100 pL of DMEM +10% FBS + 1% Penstrep on 96-well plates for 20 hours at 37°C and 5% CO2 atmosphere. Cells were then pretreated with 5 pL of LXB4or related analogues, or vehicle 1 hour prior to addition of 5 mM glutamate stressor as previously reported. [4,5] Cells were exposed for 16 hours, then evaluated for cell viability using an XTT (sodium 3'-[l-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate)-based colourimetric assay of cell viability, following the manufacturer's directions (Roche). Relative absorbance was read in a CLARIOstar™ plate reader under 490 nM excitation and analyzed in Microsoft Excel and Graphpad Prism™.

[0345] Data Analyses: Statistical analyses of results were performed using an unpaired Student's t-test or ANOVA, where a p-value less than 0.05 was considered significant. Unless otherwise stated, "n" values indicate biological replicates across at least three wells within an experiment.

[0346] Mouse acute neurotoxic RGC degeneration model: All experimental protocols are approved by the UHN Animal Use and Care Committee in accordance with applicable regulations. Male C57BL / 6 mice are anesthetized by intraperitoneal injection ofketamine / xylazine. Intravitreal injections with 10 mM kainic acid (KA) were performed as previously described [PMID: 24508229], Briefly, a 30-gauge needle is inserted tangentially into the vitreous and replaced with a Hamilton syringe to inject a volume of 2 pL KA, followed by application of ophthalmic antibiotic ointment (BNP, Vetoquinol). Mice are euthanized by CO2 asphyxiation 18 hrs following KA treatment and the eyes fixed in 4% paraformaldehyde for embedding and sectioning prior to confocal microscopy and image analyses. In all experiments n refers to the number of eyes tested.

[0347] References[1] C. N. Serhan, M. Hamberg, B. Samuelsson, Biochem. Biophys. Res. Commun. 1984, 118, 943-949.[2] C. N. Serhan, M. Hamberg, B. Samuelsson, Proc. Natl. Acad. U.S.A. 1984, 81, 5335- 5339.[3] For the role of lipoxins in inflammation, see a) J. Pirault, M. Back, Front. Pharmacol. 2018, 9, 1273; b) J. A. Chandrasekharan, N. Sharma-Wali, J. Inflamm. Res. 2015, 8, 181-192; c) M. Romano, E. Cianci, F. Simiele, A. Recchiuti, Ear. J. Pharmacol. 2015, 760, 49-63; d) C. N. Serhan, N. Chiang, J. Dalli, B. D. Levy, Cold Spring Harb. Perspect. Biol. 2015, 7, a016311; e) C. N. Serhan, Nature 2014, 510, 92-101; f) B. D. Levy, C. N. Serhan, Annu. Rev. Physiol. 2014, 76, 467-492; g) C. D. Russell, J. Schwarze, Immunology 2014, 141, 166-173; h) A. Recchiuti, C. N. Serhan, Front. Immunol. 2012, 3, 1-23; i) C. N. Serhan, Am. J. Pathol. 2010, 177, 1576- 1591; j) C. D. Duffy, P. J. Guiry, Medchemcomm 2010, 1, 249-265; k) C. I. Svensson, M. Zattoni, C. N. Serhan, J. Exp. Med. 2007, 204, 245-252; I) J. F Parkinson, Inflamm. Allergy - Drug Targets 2006, 5, 91-106; m) C. N. Serhan, Prostaglandins Leukot. Essent. Fat. Acids 2005, 73, 141-162; n) B. McMahon, C. Godson, Am. J. Physiol. - Ren. Physiol. 2004, 286, 189-201; o) A. Kantarci, T. E. Van Dyke, Crit. Rev. Oral Biol. Med. 2003, 14, 4-12; p) C.Godson, S. Mitchell, K. Harvey, N. A. Petasis, N. Hogg, H. R. Brady, J. Immunol. 2000, 164, 1663-1667.[4] Livne-Bar I, Wei J, Liu HH, Alqawlaq S, Won GJ, Tuccitto A, Gronert K, Flanagan JG, SivakJM. J Clin Invest. 2017 Dec l;127(12):4403-4414.[5] Frank Lee C, Brown CE, Nielsen AJ, Kim C, Livne-Bar I, Parsons PJ, Boldron C, Autelitano F, Weaver DF, Sivak JM, Reed MA. Chemistry. 2022 Jun 21;28(35):e202200360.[6] Guo X, Dason ES, Zanon-Moreno V, Jiang Q, Nahirnyj A, Chan D, Flanagan JG, Sivak JM. Am J Pathol. 2014 Apr;184(4):1017-1029.

[0348] All publications, patents and patent applications mentioned in this Specification are indicative of the level of skill of those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication, patent, or patent applications was specifically and individually indicated to be incorporated by reference.

[0349] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

We Claim:

1. A compound having the structure of Formula Ior a salt, lactone, ester, or solvate form thereof, wherein:A is: (i) a 5-membered, 6-membered, or fused bicyclic heterocycle, where the heterocycle is optionally substituted with one or more halo, hydroxy, C1- C3alkyl, C1- C3fluoroalkyl, C1- C3alkoxyl and / or -NR2substituent, wherein each R is independently H or a C1- C3alkyl, or(ii) benzene substituted with one or more non-chloro halo substituents, a C1-C3alkyl with a terminal heterocycle, a C1- C3heteroalkyl, comprising one heteroatom (e.g., O, N or S), with a terminal heterocycle, or a heterocycle that is optionally substituted with a C1- C3alkyl, a C3- C6cycloalkyl and / or a C1- C3fluoroalkyl; and the 5-hydroxypentanoate group and the non-l-ene-3,4-diol moiety of Formula I are each connected to A at an sp2-hybridized carbon of A, and wherein the two connected sp2-hybridized carbons are adjacent to one another or separated by one or two atoms of A, with the proviso that the compound is not:

2. The compound of claim 1, wherein Formula I has the following stereochemistry:

3. The compound of claim 1 or 2, which is a salt comprising a counterion to the carboxylate.

4. The compound of claim 3, wherein the counterion to the carboxylate is Li+.

5. The compound of claim 1 or 2, which is an ester of Formula laor a salt or solvate thereof, where R1is a C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t- butyl), substituted C1-6alkyl (e.g., a cycloalkyl-substituted or hydroxy-substituted C1-6alkyl), C2-6alkylene, substituted C2-6alkylene, benzyl, substituted benzyl.

6. The compound of any one of claims 1 to 5, wherein A is a 5-membered heterocycle, such as pyrazole, thiazole, or isoxazole, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.

7. The compound of claim 6, which is:

8. The compound of any one of claims 1 to 5, wherein A is a 6-membered heterocycle, such as pyridine, pyrazine, or pyrimidine, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.

9. The compound of claim 8, which is:form thereof.

10. The compound of any one of claims 1 to 5, wherein A is a fused bicyclic heterocycle, such as imidazo[l,2-a]pyrazine or quinoline, optionally substituted with one or more halo, C1- C6alkyl, C1- C3fluoroalkyl or C3- C6cycloalkyl substituent.form thereof.

12. The compound of any one of claims 1 to 5, wherein A is benzene substituted with one or more non-chloro halo substituents, a C1- C3alkyl with a terminal heterocycle, a C1- C3heteroalkyl, comprising one heteroatom (e.g., O, N or S), with a terminal heterocycle, or a heterocycle that is optionally substituted with a C1- C3alkyl, a C3- C6cycloalkyl or a C1- C3fluoroalkyl.or a lactone or solvate form thereof.

14. The compound of any one of claims 1 to 13, which is partially or completely in the lactone form of Formula lb15. The compound of any one of claims 1 to 14 for use as a medicine.

16. The compound for use according to claim 15, wherein the medicine is for neuroprotection, optionally retinal neuroprotection, or for treatment or prevention of a neural disorder or condition or a disease or condition associated with neuroinflammation or neurodegeneration in a subject in need thereof.

17. The compound for use according to claim 16, wherein the medicine is for inhibiting or preventing central nervous system neurodegeneration and / or neural cell loss in the subject in need thereof, optionally wherein the central nervous system neurodegeneration and / or neural cell loss is selected from hippocampal neuron, optic neuron and / or retinal ganglion cell neuron (RGC) degeneration and / or neural cell loss.

18. The compound for use according to claim 16 or 17, wherein the neural disorder comprises hippocampal neuron or optic neuron or retinal ganglion cell (RGC) neuron degeneration and / or cell loss.

19. The compound for use according to claim 16 or 17, wherein the neural condition is a neural injury associated with hippocampal or RGC degeneration and / or cell loss.

20. The compound for use according to claim 16 or 17, wherein the neural disorder comprises an acute retinal or brain injury, such as angle closure glaucoma, retinal vein occlusions, macular edema, ischemic and hemorrhagic stroke, and traumatic brain injury or a chronic neurodegenerative retinal or brain disorder such as glaucoma including all forms of primary open angle glaucoma, normal tension glaucoma, as well as retinal ischemias, diabetic retinopathy and diabetic macular edema, age related macular degeneration, retinitis pigmentosa, and Alzheimer's disease (retinal pathology), multiple sclerosis, as well as neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, and a pharmaceutically acceptable diluent, excipient, carrier, or combination thereof.

22. The composition according to claim 21, wherein the composition is formulated for parenteral, topical, intravenous, subcutaneous, intramuscular, intraorbital, ophthalmic, intraocular, intravitreal, intracameral, subtenon, subconjunctival, intraperitoneal, aerosol or oral administration.

23. The composition according to claim 21 or 22, wherein the composition is formulated for topical administration to an eye, for example, by incorporation in a sustained delivery device (e.g., a contact lens), topical gel or ointment, polymer, or intraocular gel or sustained delivery device implant, polymer, or nanoparticles.

24. The composition according to any one of claims 21 to 23, wherein the composition is formulated for administration of the compound at an amount of at least 0.2 nM or at least 50 nM and, optionally, less than 1 mM.

25. A method of providing neuroprotection, optionally retinal neuroprotection, or treating or preventing a disease or condition associated with neuroinflammation or neurodegeneration in a subject, comprising administering the compound of any one of claims 1 to 14 to the subject.

26. The method of claim 25 wherein the neuroprotection is for and / or the neural disorder or condition is central nervous system neurodegeneration and / or neural cell loss and the subject in need thereof is administered an amount of the compound such that neural degeneration and / or neuron cell loss is inhibited or prevented.

27. The method of claim 25 or 26, wherein the neural disorder or condition comprises hippocampal neuron, cortical neuron, optic neuron or retinal ganglion cell (RGC) neuron degeneration and / or cell loss.The method of claim 25 or 26, wherein the neural disorder or condition comprises vision loss, an acute retinal or brain injury, optionally angle closure glaucoma, retinal vein occlusions, macular edema, ischemic and hemorrhagic stroke, and traumaticbrain injury or a chronic neurodegenerative retinal or brain disorder such as glaucoma including all forms of primary open angle glaucoma, normal tension glaucoma, as well as retinal ischemias, diabetic retinopathy and diabetic macular edema, age related macular degeneration, retinitis pigmentosa, and Alzheimer's disease (retinal pathology), multiple sclerosis, as well as neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).

28. The method of any one of claims 25 to 28, wherein the neural disorder or condition comprises vision loss (or reduced vision), optionally wherein the disorder or condition is glaucoma.

29. The method of any one of claims 25 to 29, wherein the compound is administered by parenteral, topical, intravenous, subcutaneous, intramuscular, intraorbital, ophthalmic, intraocular, intravitreal, intracameral, subtenon, subconjunctival, intraperitoneal, aerosol or oral administration.

30. The method of any one of claims 25 to 30, wherein the compound is administered to an eye, optionally by a sustained delivery device, such as a contact lens, topical gel or ointment, polymer, or intraocular gel or sustained delivery device implant, polymer, or nanoparticles.

31. The method of claim 31, wherein the compound is administered topically to the eye.

32. The method of any one of claims 25 to 32, wherein the concentration of the compound administered is at least 0.2 nM or at least 50 nM and, optionally, less than 1 mM.

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