C-Glycosides as anti-inflammatory agents

Abstract

Novel compounds and methods of using these compounds are provided herein. The compounds include novel carbon analogs of pyranose derivatives that have been found to have Toll-like receptor 4 (Tlr4) inhibitory activity. The methods provide for treating infectious, inflammatory, and post-traumatic disorders.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 359,049, filed on July 7, 2022; U.S. Provisional Patent Application No. 63 / 426,704, filed on November 18, 2022; and U.S. Provisional Patent Application No. 63 / 443,835, filed on February 7, 2023, the contents of which are hereby incorporated by reference in their entirety.

[0002] Grant Information This disclosure was made with government support under grant numbers R01DK117186, R01DK083752, and R01GM078238 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] 1. Introduction The presently disclosed subject matter relates to novel carbon analogs of pyranose derivatives that have been found to have Tlr4 inhibitory activity. The disclosed subject matter further provides methods of using pyranose derivatives for treating infectious, inflammatory, and post - traumatic disorders.

Background Art

[0004] 2. Background of the Invention The Toll - like receptor 4 ( "Tlr4"), a pattern recognition receptor of the innate immune system, is recognized as a receptor on hematopoietic and non - hematopoietic cells for endotoxin (lipopolysaccharide, "LPS") and various endogenous molecules released in the body during inflammatory or infectious disorders. Since Tlr4 is the most upstream receptor in the inflammation - promoting LPS signaling cascade, by using inhibitors that weaken Tl4 signaling, one can act further downstream in the pathway and thus avoid the risks associated with other cytokine inhibitors that play less important roles.

Summary of the Invention

Problems to be Solved by the Invention

[0005] 3. Summary The objects and advantages of the disclosed subject matter will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the disclosed subject matter. The additional advantages of the disclosed subject matter will be realized and attained by means of the devices particularly pointed out in the specification and claims hereof as well as the appended drawings.

Means for Solving the Problems

[0006] To achieve these and other advantages and in accordance with the purpose of the disclosed subject matter, as embodied and broadly described, the disclosed subject matter includes carbon analogs of pyranose derivatives, and methods of using said derivatives for treating infectious, inflammatory and post-traumatic disorders, said derivatives having Tlr4 signaling inhibitory activity. Some of the compounds that can be used according to the present disclosure are shown in Table 1 below. In addition to the methods of treatment, the presently disclosed subject matter further provides pharmaceutical compositions comprising said compounds together with suitable pharmaceutical carriers. Since Tlr4 is the most upstream receptor in the inflammation-promoting LPS signaling cascade, the treatments of the disclosed subject matter that inhibit or attenuate the action of Tlr4 act further downstream in the pathway and thus avoid the risks associated with other cytokine inhibitors that play a less specific (and perhaps less important) role.

[0007] In some embodiments, the disclosed subject matter is of Formula I

[0008]

Chemical Formula

[0009] The disclosed subject matter also provides a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the pharmaceutical composition is selected from the group consisting of coated particles, micelles, liposomes, tablets, capsules, sachets, suppositories, liquid pharmaceutical compositions, and combinations thereof. In some embodiments, the pharmaceutical composition further comprises an antibiotic, a steroid, or a non-steroidal anti-inflammatory agent, or a combination thereof.

[0010] In some embodiments, the compound of Formula I has the following structure

[0011]

Chemical formula

[0012] The presently disclosed subject matter also provides a compound of Formula II

[0013]

Chemical formula

[0014] The disclosed subject matter further provides a pharmaceutical composition comprising a compound of Formula II. In some of these embodiments, the pharmaceutical composition is selected from the group consisting of coated particles, micelles, liposomes, tablets, capsules, sachets, suppositories, liquid pharmaceutical compositions, and combinations thereof. In some of these embodiments, the pharmaceutical composition further comprises an antibiotic, a steroid, or a non-steroidal anti-inflammatory agent, or a combination thereof.

[0015] According to some embodiments of the presently disclosed subject matter, the compound of Formula II has the following structure

[0016]

Chemical formula

[0017] In other embodiments, the disclosed subject matter is a method of treating an infectious or inflammatory disorder, the method comprising administering to a subject in need of such treatment an effective amount of a Toll-like receptor 4 inhibitor compound of Formula I

[0018]

Chemical formula

[0019] In another embodiment, the disclosed subject matter is a method of treating an infectious or inflammatory disorder, the method comprising administering to a subject in need thereof an effective amount of a Toll-like receptor 4 inhibitor compound of Formula II

[0020] [wherein, Z is O or NH, R1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R2 is H or COR3, where R3 is selected from R1, NHR1 or N(R1)2] or a stereoisomer thereof. In some embodiments of the method, the subject suffers from one or more of osteoarthritis, pancreatitis, metabolic syndrome, trauma-induced systemic inflammation, acute respiratory distress syndrome, and COVID-19-induced systemic inflammation. In a specific embodiment, the subject suffers from necrotizing enterocolitis.

[0021] According to the disclosed method, the Toll-like receptor 4 inhibitor is selected from the group consisting of

[0022] TIFF2025522637000013.tif217159, TIFF2025522637000014.tif229159, TIFF2025522637000015.tif70161, and combinations thereof.

[0023] [wherein, Z is O or NH, R1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R2 is H or COR3, where R3 is selected from R1, NHR1 or N(R1)2] TIFF2025522637000013.tif217159TIFF2025522637000014.tif229159TIFF2025522637000015.tif70161 and combinations thereof.

[0024] In an alternative embodiment, the Toll-like receptor 4 inhibitor is selected from the group consisting of

[0025] [wherein, Z is O or NH, R1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R2 is H or COR3, where R3 is selected from R1, NHR1 or N(R1)2] TIFF2025522637000017.tif26160 and combinations thereof.

[0026] The disclosed subject matter also provides a method of treating trauma in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a Toll-like receptor 4 inhibitor compound that reduces Toll-like receptor 4-induced post-traumatic injury. In some embodiments, the trauma is to an organ selected from the group consisting of the heart, liver, lung, kidney, intestine, brain, eye, and pancreas.

[0027] In some embodiments, the compound is administered to treat organ rejection after transplantation.

[0028] In some embodiments, the method comprises administering a compound of Formula I or Formula II to prevent necrotizing enterocolitis in a premature infant.

[0029] 4. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are included to illustrate some aspects of the present disclosure and should not be considered exclusive embodiments. The disclosed subject matter is capable of considerable modification, alteration, combination, and equivalents in form and function, without departing from the scope of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030]

Figure 1

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Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Mode for Carrying Out the Invention

[0031] 5. Detailed Description of the Invention The terms used in this specification generally have their ordinary meanings in the context of the present invention and in the specific context in which each term is used. Some terms are discussed below or elsewhere in the specification to provide further guidance to the practitioner in the description of the methods and compositions of the present invention, as well as their methods of manufacture and use.

[0032] As used in this specification, when used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" or "an" can mean "one", but it also conforms to the meanings of "one or more", "at least one", and "one or more than one". Further, the terms "having", "including", "containing", and "comprising" are interchangeable, and those skilled in the art recognize that these terms are non-limiting terms.

[0033] The term "about" or "approximately" means within an acceptable error range for a particular value determined by those skilled in the art, which will depend in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" can mean within 3 or more standard deviations according to the conventions of the art. Alternatively, "about" can mean a range up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or biological processes, this term can mean within one order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0034] The term "alkyl" is recognized in the art and includes saturated aliphatic groups including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Further, the term "alkyl" (or "lower alkyl") includes both "unsubstituted alkyl" and "substituted alkyl", and the latter of these refers to an alkyl moiety having substituents that replace hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted where appropriate. For example, substituents of substituted alkyl can include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as substituted and unsubstituted forms of ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0035] The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines. A primary amine has two hydrogens, a secondary amine has one hydrogen and another substituent, and a tertiary amine has two hydrogens substituted. The substituents for one or both hydrogens can be, for example, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, polycycle, etc. When both hydrogens are substituted by carbonyls, the nitrogen framed by the carbonyl forms an imide.

[0036] The term "alkylamine" includes the amine group defined above having a substituted or unsubstituted alkyl bonded thereto.

[0037] The term "aryl" is recognized in the art and includes 5-membered, 6-membered, 7-membered monocyclic aromatic groups that may contain 0 to 4 heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. These aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heterocyclic aromatic compounds". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic moiety or heterocyclic aromatic moiety, -CF3, -CN, etc. The term "aryl" also includes polycyclic ring systems having two or more rings (these rings are "fused rings") where two or more carbons are common to two adjacent rings (where at least one of the rings is aromatic, for example, the other ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl), or rings bonded by an acyclic moiety.

[0038] The terms "heterocyclyl" and "heterocyclic group" are recognized in the art and include 3- to about 10-membered ring structures, such as 3- to about 7-membered rings, and these ring structures contain 1 to 4 heteroatoms. The heterocycle may also be polycyclic. Examples of heterocyclyl groups include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthin, pyrrole imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, etc. The heterocycle may be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl aralkyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic moiety or heteroaromatic moiety, -CD3, -CN, etc.

[0039] The terms "polycyclyl" and "polycyclic group" are recognized in the art and include structures having two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl) in which two or more carbons are common to two adjacent rings, e.g., the rings are "fused rings". Rings that are joined by non-adjacent atoms, e.g., rings in which three or more atoms are common to both rings, are called "bridged" rings. Each ring of the polycycle can be substituted with such substituents as described above, e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic moiety or heteroaromatic moiety, -CD3, -CN, etc.

[0040] The term "carbocyclic ring" is recognized in the art and includes aromatic or non-aromatic rings in which each atom of the ring is carbon. The following terms recognized in the art have the following meanings. That is, "nitro" means -NO2, the term "halogen" represents -F, -Cl, -Br, or -I, the term "sulfhydryl" means -SH, the term "hydroxyl" or "hydroxy" means -OH, and the term "sulfonyl" means -SO2-.

[0041] The terms "amine" and "amino" are recognized in the art and include both unsubstituted amines and substituted amines. A primary amine has two hydrogens, a secondary amine has one hydrogen and another substituent, and a tertiary amine has two hydrogens substituted. The substituents for one or both hydrogens can be, for example, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocycle, polycycle, etc. When both hydrogens are substituted with carbonyls, the nitrogen framed by the carbonyl forms an imide.

[0042] The term "alkylamine" includes the amine group as defined above having a substituted or unsubstituted alkyl attached thereto.

[0043] The term "amide" is recognized in the art as an amino-substituted carbonyl.

[0044] The term "alkylthio" is recognized in the art and includes the alkyl group as defined above having a sulfur group attached thereto. In some embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, etc.

[0045] The term "carbonyl" is recognized in the art and includes the C=O structure. Carbonyl is involved in esters, carboxyl groups, formates, thiocarbonyls, thioesters, thiocarboxylic acids, thioformates, ketones, and aldehydes.

[0046] The terms "alkoxyl" and "alkoxy" are recognized in the art and include the alkyl group as defined above having an oxygen group attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, etc.

[0047] An "ether" is two hydrocarbons covalently bonded by oxygen. Thus, the substituent of the alkyl that makes it an ether is an alkoxyl or is similar to an alkoxyl and can be represented by one of, for example, -O-alkyl, -O-alkenyl, -O-alkynyl, etc.

[0048] The term "sulfonate" is recognized in the art and includes a moiety where the sulfur atom has two double-bonded oxygens and a single-bonded oxygen.

[0049] The term "sulfate" is recognized in the art and is similar to sulfonate but includes a moiety with two single-bonded oxygens.

[0050] The terms "sulfonamide", "sulfamoyl", "sulfonyl" and "sulfoxide" are recognized in the art and each may include various R group substituents as described herein.

[0051] The terms "phosphoramidite" and "phophonamidite" are recognized in the art.

[0052] The term "selenoalkyl" is recognized in the art and includes an alkyl group having a substituted seleno group attached thereto. Exemplary "selenoethers" that may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and the like.

[0053] Substitution may be effected on alkenyl and alkynyl groups, for example, to produce aminoalkenyl, aminoalkynyl, amidoalkenyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or carbonyl-substituted alkynyl.

[0054] It will be understood that "substituted" or "substituted with" includes the implicit condition that such substitution follows the acceptable valences of the substituted atoms and substituents and results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as transformation by rearrangement, cyclization, elimination, or other reactions.

[0055] The term "substituted" is also intended to include all acceptable substituents of an organic compound, such as the imide reagent of interest. In a broad aspect, acceptable substituents include acyclic and cyclic substituents, branched and unbranched substituents, carbocyclic and heterocyclic substituents, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, the substituents described herein. The acceptable substituents may be one or more and may be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom, such as nitrogen, may have any acceptable substituent of the organic compounds described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. The present invention is not intended to be limited in any way by the acceptable substituents of the organic compound.

[0056] As used herein, the term "enantiomer" refers to a pair of stereoisomers that cannot be superimposed on each other's mirror images. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used, where appropriate, to represent a racemic mixture.

[0057] As used herein, the term "diastereoisomer" refers to stereoisomers having at least two asymmetric atoms, which are not mirror images of each other. The absolute stereochemistry is specified by the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which the compound rotates plane-polarized light at the wavelength of the sodium D line. The compounds of the presently disclosed subject matter contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the point of view of absolute stereochemistry. The presently disclosed subject matter is meant to include all such possible isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques. When a compound contains a double bond, the substituents can be in the E or Z stereoconfiguration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have the cis- or trans-stereoconfiguration. All tautomeric forms are also intended to be included.

[0058] As used herein, the term "isomer" refers to different compounds having the same molecular formula but differing in the arrangement and configuration of atoms. Also as used herein, the term "stereoisomer" refers to any of the various stereoisomeric arrangements that can exist for a given compound of the presently disclosed subject matter and includes geometric isomers. Substituents are understood to be those that can be attached at the chiral centers of carbon atoms. Thus, the presently disclosed subject matter includes enantiomers, diastereomers, or racemates of the compounds. Also as used herein, the term "structural isomer" refers to different compounds having the same number of atoms and the same types of atoms but in which the atoms are joined by different bonds.

[0059] The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is co-administered. Such physiological carriers can be sterile liquids such as water, and oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Physiological saline as well as aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectables. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol and the like. The composition can also contain, if desired, minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0060] For the purposes of clarity and not limitation, the detailed description of the disclosed subject matter is divided into the following subsections. That is, 5.1 Tlr4 inhibitory compounds, 5.2 Pharmaceutical compositions, 5.3 Disorders, and 5.4 Methods of treatment as follows.

[0061] 5.1 Tlr4 inhibitory compounds The present disclosure provides carbon analogs of pyranose derivatives. In some embodiments, said compounds can be used to inhibit Tlr4.

[0062] In some embodiments, the present disclosure provides Formula I

[0063]

Chemical formula

[0064] In some embodiments, the present disclosure relates to Formula II

[0065]

Chemical formula

[0066] In some specific embodiments, the compounds of the present disclosure are shown in Table 1.

[0067]

Table 1

[0068] In some embodiments, a compound is considered to inhibit Tlr4 if the compound inhibits one or more signs or symptoms of inflammation, such as activation of the nuclear factor kappa-light-chain enhancer of activated B cells (“NFkB”), increased expression / levels of interleukins including but not limited to interleukin 1 (“Il1”) and interleukin 6 (“Il6”), increased expression / levels of tumor necrosis factor (“Tnf”), increased expression / levels of lipocalin 2 (“Lcn2”), increased erythrocyte sedimentation rate, increased C-reactive protein, fever, tachypnea, malaise, swelling, erythema, and / or pain. In some embodiments, the ability of a compound and / or a particular concentration of the compound to inhibit Tlr4 can be determined using an assay for Tlr4 activity that can evaluate one of the above signs or symptoms. For example, in some embodiments, Tlr4 inhibition can be assayed by a method of measuring the effect of the compound on NFkB activity, such as but not limited to, an NFkB luciferase reporter mouse model or HEK-Blue-4 cells (InvivoGen) stimulated with a Tlr4 ligand, such as LPS described in the following examples. Some other non-limiting examples of systems for testing a compound to determine Tlr4 inhibitory activity include CWT mice that can be treated with LPS and the test compound and observed for signs and symptoms of inflammation, and / or C3H / WT cells (InvivoGen) that can be treated with LPS and the test compound and tested for activation of NFkB, Il6 production, or other markers of the inflammatory process.

[0069] 5.2 Pharmaceutical Compositions In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I or formula II as described above in a suitable pharmaceutical carrier. The amount of the compound present in the composition can be calculated to provide an effective amount of the compound of formula I or formula II when administered to a subject in need of such treatment.

[0070] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of Formula I or Formula II, for example but not limited to, with a pharmaceutical carrier such as water or another physiological solvent. By the therapeutically effective amount, Tlr4 is inhibited.

[0071] In non-limiting embodiments, the compounds of Formula I or Formula II can be included in coated particles, micelles, liposomes, or similar structures.

[0072] In some embodiments, the pharmaceutical composition can be in liquid form, including the compound of Formula I or Formula II in a liquid pharmaceutical carrier such as, for example, water (aqueous carrier) or saline. In some embodiments, the liquid composition can optionally further contain one or more of a buffering agent or a preservative.

[0073] In some other embodiments, the pharmaceutical composition of the present disclosure can be in the form of a solid, such as a tablet, capsule, sachet or suppository, comprising a dosage of the compound of Formula I or Formula II that provides an effective amount of the compound of Formula I or Formula II to a subject in need of such treatment when administered according to a dosing regimen. In some embodiments, the solid pharmaceutical composition can further include one or more excipients such as, but not limited to, lactose, sucrose, mannitol, erythritol, carboxymethylcellulose, crystalline cellulose, hydroxypropylmethylcellulose, starch, polyvinylpyrrolidone, and the like.

[0074] In some embodiments, the pharmaceutical composition can include additional agents having antibacterial activity and / or anti-inflammatory activity. In some embodiments, such compounds include, but are not limited to, antibiotics, steroid agents, or non-steroidal anti-inflammatory agents. In some other embodiments, the pharmaceutical composition can include an analgesic. In some further embodiments, the pharmaceutical composition can include agents that improve cardiac function and / or reduce cardiac stress, such as, but not limited to, angiotensin-converting enzyme inhibitors, beta blockers, nitroglycerin or related nitrate compounds, digoxin or related compounds, or calcium channel blockers.

[0075] Pharmaceutically acceptable salts are recognized in the art and include relatively non-toxic inorganic acid addition salts and organic acid addition salts of the compositions of the present invention, including but not limited to therapeutic agents, excipients, and other materials. Examples of pharmaceutically acceptable salts include those derived from mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Examples of suitable inorganic bases for forming salts include hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, etc. The salts can also be formed with suitable organic bases that are non-toxic and strong enough to form such salts. In this description, classes of such organic bases include monoalkylamines, dialkylamines, and trialkylamines such as methylamine, dimethylamine, and triethylamine; monohydroxyalkylamines, dihydroxyalkylamines, or trihydroxyalkylamines such as monoethanolamine, diethanolamine, and triethanolamine; amino acids such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenthylamine; (trishydroxymethyl)aminoethane, etc. may be included. See, for example, J. Pharm. Sci., 66:1-19 (1977).

[0076] 5.3 Disorder In some embodiments, the compounds, compositions and methods provided herein are for treating any disease / disorder (the "disorder") associated with activation of Tlr44, including but not limited to infectious and inflammatory disorders such as sepsis, necrotizing enterocolitis ("NEC"), autoimmune diseases, Crohn's disease, celiac disease, ulcerative colitis, rheumatoid arthritis, cardiovascular diseases including myocardial infarction, epilepsy, gram-negative bacterial infections, aspergillosis, periodontal diseases, Alzheimer's disease, tobacco smoke-mediated lung inflammation, viral hepatitis (including hepatitis C virus hepatitis), alcoholic hepatitis, insulin resistance in adipocytes, osteoarthritis, pancreatitis, metabolic syndrome, trauma-induced systemic inflammation, acute respiratory distress syndrome ("ARDS"), COVID-19-induced systemic inflammation, organ rejection after transplantation, etc. See, for example, U.S. Patent Application Publication No. 2008 / 0311112 (A1), published December 18, 2008. In non-limiting embodiments, the presently disclosed subject matter can also be used to treat post-traumatic conditions including ischemic injury and trauma to the heart, liver, lung, kidney, intestine, brain, eye and pancreas.

[0077] 5.4 Method of treatment In some embodiments, the present disclosure provides a method of treating an infectious or inflammatory disorder, comprising administering to a subject in need of treatment for the infectious or inflammatory disorder an effective amount of a compound of Formula I or Formula II that reduces one or more signs or symptoms of inflammation in the subject.

[0078] In some embodiments, the present disclosure provides a method of treating an inflammatory disorder of the intestine in a subject in need of treatment for the inflammatory disorder of the intestine, comprising administering to the subject an effective amount of a compound of Formula I or Formula II that reduces the inflammation of the intestine in the subject. In some particular embodiments, the inflammatory disorder of the intestine is necrotizing enterocolitis. In some embodiments, the present disclosure provides a method of treating and / or preventing necrotizing enterocolitis in premature infants.

[0079] In some embodiments, the present disclosure provides a method of treating an inflammatory lung disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or Formula II that reduces inflammation of the pulmonary airways in the subject.

[0080] In some embodiments, the present disclosure provides a method of treating an injury in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or Formula II that reduces Tlr4-induced post-injury damage. In some specific embodiments, the injury is to an organ selected from the group consisting of the heart, liver, lung, kidney, intestine, brain, eye, and pancreas.

[0081] In some embodiments, the present disclosure provides a method of treating one or more of osteoarthritis, pancreatitis, metabolic syndrome, trauma-induced systemic inflammation, acute respiratory distress syndrome (ARDS), COVID-19-induced systemic inflammation, organ rejection after transplantation, or other disorders of the gastrointestinal tract that may involve Tlr4 signaling, such as ulcerative colitis or Crohn's disease.

[0082] In some embodiments, the subject is a human subject or a non-human subject. In certain embodiments, the subject is a human subject. In some embodiments, the subject is a non-human subject.

[0083] In some embodiments, the compound of Formula I or Formula II can be administered by any standard route including, but not limited to, oral, intraperitoneal (i.p.), intravenous (i.v.), subcutaneous (s.c.), intradermal, intramuscular (i.m.), intra-articular, intrathecal, intra-arterial, intravaginal, rectal, nasal, and transpulmonary.

[0084] In some embodiments, the effective dosage can be determined using methods well known in the art (including, but not limited to, the Tlr4 activity assay described herein). In some embodiments, the effective dosage can be between about 0.01 micromoles and about 50 micromoles of a compound of Formula I or Formula II per kilogram of the subject's body weight, or between about 0.1 micromoles and about 20 micromoles of a compound of Formula I or Formula II per kilogram of the subject's body weight.

[0085] In some embodiments, the dosage of the compound of Formula I or Formula II can be between about 0.001 milligrams and about 100 milligrams per kilogram of the subject's body weight, between about 0.01 milligrams and about 10 milligrams per kilogram of the subject's body weight, between about 0.1 milligrams and about 10 milligrams per kilogram of the subject's body weight, or between about 0.5 milligrams and 5 milligrams per kilogram of the subject's body weight.

Example

[0086] 6. Example The presently disclosed subject matter will be better understood by reference to the following examples, which are provided as illustrations of the presently disclosed subject matter and are not limiting.

[0087] [Example 1] Exemplary Synthesis of a Carbon Analogue of a Pyranose Derivative This example provides the synthesis of a carbon analogue of a pyranose derivative according to some embodiments of the present disclosure.

[0088] All reactions were carried out under N2 atmosphere through a column of Drierite. All glassware was flame-dried under high vacuum overnight or dried in an oven before use and cooled under a stream of N2. The reactants were magnetically stirred using a Teflon-coated magnetic stir bar, the syringe needles were dried in an oven and cooled via Drierite in a desiccator cabinet. CH2Cl2 was freshly distilled over calcium hydride. All other materials were obtained from commercial sources and used as received. The reactions were observed by thin-layer chromatography (TLC) analysis on pre-coated silica gel 60 F254 plates (layer thickness 250 μm) and visualization was achieved by UV light (254 nm) and / or staining with KMnO4 solution (1.5 g of KMnO4 and 10 g of K2CO3 in 200 mL of water with 10% NaOH added), or PMA solution (10 g of phosphomolybdic acid in 100 mL of absolute ethanol). Flash chromatography was performed on silica gel 60 (230 - 400 mesh). Melting points were determined in open capillary tubes and recorded on a Mel-Temp II apparatus equipped with a Fluke 51 II digital thermometer; melting points are uncorrected. Nuclear magnetic resonance (NMR) spectra were obtained on Bruker instruments operating at 300 MHz, 400 MHz, 500 MHz, and 600 MHz at ambient temperature for 1 H and 13 C. Chemical shifts (δ) were reported in parts per million (ppm) using the residual solvent peak as an internal standard (CDCl3: 1 7.26 ppm for 1H NMR and 13 77.16 ppm for 13C NMR). 11H NMR is shown below. That is, chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad line), coupling constant, and number of protons. High-resolution mass spectrum (HRMS) was obtained with a Thermo Scientific Exactive Orbitrap LC-MS (ESI positive ion mode) coupled to a Thermo Scientific Accela HPLC system using a Waters 3.5 μM XTerra C18 column (2.1×50 mm, 10 minutes, gradient elution with MeCN / H2O / MeOH containing 0.1% formic acid, flow rate of 500 μL / min, from 3:92:5 at 0 - 0.5 minutes to 93:2:5 at 4.0 minutes, and back to 3:92:5 at 6.0 - 7.5 minutes).

[0089] This example provides the synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-propyltetrahydro-2H-pyran-3,4,5-triyl triacetate (7), (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl triacetate (8), (2R,3S,4R,5R,6R)-2-isobutyl-6-((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) (9), (2R,3R,4R,5S,6R)-2-(((3,3-dimethylbutanoyl)oxy)methyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl tris(3,3-dimethylbutanoate) (10), and (2R,3R,4R,5S,6R)-2-((benzoyloxy)methyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (11) as shown by the following Scheme I. Intermediates 3 and 4 were published by procedures previously reported in the literature.

[0090]

Chemical Structure

[0091] [Example 1.1] Synthesis of (2R,3S,4R,5R,6R)-2-(hydroxymethyl)-6-propyltetrahydro-2H-pyran-3,4,5-triol (5): A suspension of 3 and 20% Pd(OH)2 / C in anhydrous EtOH is stirred at room temperature under H2 (balloon). The reaction mixture is filtered through Celite®, the filter pad is washed with EtOH, the filtrate is concentrated under reduced pressure and dried under vacuum to obtain crude 5. This 5 was used in the subsequent step without further purification.

[0092] [Example 1.2] Synthesis of (2R,3S,4R,5R,6R)-2-(hydroxymethyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triol (6): A suspension of 4 (550 mg, 0.950 mmol) and 20% Pd(OH)2 / C (123 mg) in anhydrous EtOH (12 mL) was stirred at room temperature under H2 (balloon) for 16 h. The reaction mixture was filtered through Celite®, the filter pad was washed with EtOH, the filtrate was concentrated under reduced pressure and dried under vacuum to obtain 209 mg (100%, 0.96 mmol) of crude tetraol as a colorless solid. This tetraol was used in the subsequent step without further purification. 1 1H NMR (MeOD, 500 MHz) δ 4.02 - 3.98 (m, 1H), 3.76 (dd, J = 11.7, 2.3 Hz, 1H), 3.59 (dd, J = 11.7, 1.0 Hz, 1H), 3.51 (t, J = 8.7 Hz, 1H), 3.42 - 3.38 (m, 1H), 3.25 (t, J = 8.7 Hz, 1H), 1.82 - 1.78 (m, 1H), 1.72 - 1.66 (m, 1H), 1.38 - 1.33 (m, 1H), 1.18 (t, J = 7.0 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H).

[0093] [Example 1.3] Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-propyltetrahydro-2H-pyran-3,4,5-triyl triacetate (7): To a suspension of 5 (100 mg, 0.49 mmol) and acetic anhydride (0.23 mL, 2.4 mmol) in pyridine (0.2 mL), a catalytic amount of DMAP was added. The solution was stirred at room temperature for 16 h and diluted with ethyl acetate (10 mL). The organic phase was successively washed with 1 M HCl (3×5 mL), water (1×5 mL), saturated aq NaHCO3 (1×5 mL), and brine (5 mL×1). The obtained organic phase was dried (Na2SO4), concentrated, and the resulting residue was dried under vacuum to give a 4:1 ratio of α-pentaacetylated anomer and β-pentaacetylated anomer. Recrystallization from a hexane / EtOAc mixture gave 7 as white needles (137 mg, 75%, 0.366 mmol). M.P.; 102~103.5 °C. 1 H NMR (CDCl3, 500 MHz) δ 5.32 (t, J = 9.3 Hz, 1H), 5.07 (dd, J = 9.3, 5.8 Hz, 1H), 4.99 (t, J = 9.3 Hz, 1H), 4.24 (dd, J = 12.2, 5.3 Hz, 1H), 4.20 - 4.16 (m, 1H), 4.08 (dd, J = 12.2, 2.5 Hz, 1H), 3.83 - 3.80 (m, 1H), 2.09 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.03 (s, 3H), 1.81 - 1.74 (m, 1H), 1.50 - 1.41 (m, 2H), 1.35 - 1.29 (m, 1H), 0.97 (t, J = 7.1 Hz, 3H). 13 C NMR (CDCl3, 500 MHz) δ 170.8, 170.4, 169.8, 169.7, 72.6, 70.7, 69.1, 68.7, 62.5, 27.5, 20.9, 20.8, 18.4, 13.9. HRMS C 17 H 27 O9 [M + H] + Calculated value: 375.1650; Measured value: 375.1647.

[0094] [Example 1.4] Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl triacetate (8): To a solution of 6 (42 mg, 0.19 mmol) and a catalytic amount of DMAP in pyridine (0.65 mL) was added acetic anhydride (0.18 mL, 1.91 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc (5 mL). The organic phase was washed successively with 1 M HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 8:1) to give 8 as an amorphous solid (50 mg, 76%, 0.129 mmol). M.P.; 58.5 - 60 °C. 1 1H NMR (CDCl3, 400 MHz) δ 5.31 (t, J = 9.2 Hz, 1H), 5.06 (dd, J = 9.6, 5.8 Hz, 1H), 4.99 (t, J = 9.2 Hz, 1H), 4.30 - 4.24 (m, 1H), 4.24 (dd, J = 12.1, 5.1 Hz, 1H), 4.06 (dd, J = 12.1, 2.6 Hz, 1H), 3.84 - 3.80 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.82 - 1.78 (m, 2H), 1.27 - 1.18 (m, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H). 13 13C NMR (CDCl3, 400 MHz) δ 170.8, 170.4, 169.8, 169.7, 71.0, 70.7, 70.6, 69.1, 68.8, 62.5, 33.8, 24.2, 23.6, 21.5, 20.9. HRMS C 18 H 29 O9 [M + H] + Calculated value: 389.1806; Found: 389.1801.

[0095] [Example 1.5] Synthesis of (2R,3S,4R,5R,6R)-2-isobutyl-6-((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) (9): To a solution of 6 (50 mg, 0.23 mmol) and a catalytic amount of DMAP in pyridine (0.8 mL) was added pivaloyl chloride (0.28 mL, 2.23 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc (5 mL). The organic phase was successively washed with 1 M HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 18:1) to give 9 as an amorphous solid (81 mg, 64%, 0.146 mmol). M.P.; 123~124 °C. 1 H NMR (CDCl3, 600 MHz) δ 5.41 (t, J = 9.7 Hz, 1H), 5.06 (dd, J = 10.0 Hz, 1H), 5.01 (t, J = 9.7 Hz, 1H), 4.29 - 4.25 (m, 1H), 4.12 (dd, J = 12.0, 1.2 Hz, 1H), 4.00 (dd, J = 12.0, 6.4 Hz, 1H), 3.82 - 3.80 (m, 1H), 1.88 - 1.83 (m, 1H), 1.76 - 1.71 (m, 1H), 1.21 (s, 9H), 1.17 (s, 9H), 1.16 (s, 9H), 1.12 (s, 9H), 0.98 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). 13 C NMR (CDCl3, 600 MHz) δ 178.3, 177.3, 177.2, 176.8, 71.0, 70.9, 70.2, 68.9, 63.0, 39.0, 38.9 (2 signals), 33.4, 27.3 (2 signals), 27.2, 23.8 (2 signals), 21.3. HRMS C 30 H 53O9[M + H] + Calculated value: 557.3684; Measured value: 557.3680.

[0096] [Example 1.6] Synthesis of (2R,3R,4R,5S,6R)-2-(((3,3-dimethylbutanoyl)oxy)methyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl tris(3,3-dimethylbutanoate) (10): To a solution of 6 (50 mg, 0.23 mmol) and a catalytic amount of DMAP in pyridine (0.8 mL) was added 3,3-dimethylbutyryl chloride (0.32 mL, 2.27 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc (5 mL). The organic phase was successively washed with 1 M HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 20:1) to give 10 as an amorphous solid (118 mg, 85%, 0.146 mmol). M.P.; 83 - 84 °C. 1 H NMR (CDCl3, 500 MHz) δ 5.37 (t, J = 9.3 Hz, 1H), 5.03 (dd, J = 9.7 Hz, 1H), 4.98 (t, J = 9.1 Hz, 1H), 4.29 - 4.25 (m, 1H), 4.15 - 4.09 (m, 2H), 3.84 - 3.80 (m, 1H), 2.23 (s, 2H), 2.22 - 2.11 (m, 4H), 2.15 (s, 2H), 1.82 - 1.75 (m, 1H), 1.74 - 1.69 (m, 1H), 1.24 - 1.19 (m, 1H), 1.02 (s, 9H), 1.01 (s, 9H), 1.00 (s, 9H), 0.98 (s, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). 1313C NMR (CDCl3, 500 MHz) δ 172.0, 171.3, 171.1, 170.9, 70.9, 70.7, 69.8, 69.2, 69.0, 62.5, 47.8 (2 signals), 47.7, 47.6, 33.9, 30.9, 30.8, 30.7, 30.6, 29.7 (3 signals), 24.1, 23.7, 21.5. HRMS C 34 H 61 O9 [M + H] + Calculated value: 613.4310; Measured value: 613.4307.

[0097] [Example 1.7] Synthesis of (2R,3R,4R,5S,6R)-2-((benzoyloxy)methyl)-6-isobutyltetrahydro-2H-pyran-3,4,5-triyl tribenzoate (11): To a solution of 6 (34 mg, 0.154 mmol) and a catalytic amount of DMAP in pyridine (0.8 mL) was added benzoyl chloride (0.18 mL, 1.54 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc (5 mL). The organic phase was successively washed with 1 M HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 18:1) to give 11 as a white crystalline solid (73 mg, 82%, 0.127 mmol). M.P.; 129.5 - 131 °C. 11H NMR (CDCl3, 500 MHz) δ 8.04 (d, J = 7.2 Hz, 2H), 7.98 (d, J = 7.3 Hz, 2H), 7.93 (d, J = 7.3 Hz, 2H), 7.90 (d, J = 7.3 Hz, 2H), 7.57 - 7.38 (m, 8H), 7.35 - 7.31 (m, 4H), 5.99 (t, J = 9.0 Hz, 1H), 5.57 (t, J = 9.0 Hz, 1H), 5.50 (dd, J = 9.0, 5.7 Hz, 1H), 4.61 (m, 1H), 4.55 (d, J = 4.7 Hz, 1H), 4.31 - 4.28 (m, 1H), 2.09 - 2.03 (m, 1H), 1.87 - 1.81 (m, 1H), 1.40 - 1.35 (m, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H). 13 13C NMR (CDCl3, 500 MHz) δ 166.4, 166.0, 165.5 (2 signals), 133.6, 133.5, 133.4, 133.2, 130.0 (2 signals), 129.9, 129.3, 129.2, 129.1, 128.6, 71.6, 71.0, 70.7, 70.0, 69.7, 63.5, 34.4, 24.3, 23.7, 21.5. HRMS C 38 H 37 O9[M + NH4] + Calculated value: 654.2698; Measured value: 654.2684.

[0098] This example further provides the synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-isobutyl-5-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl acetate (14) and (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-5-((3,3-dimethylbutanoyl)oxy)-6-isobutyltetrahydro-2H pyran-3,4-diyldiacetate (15) as shown by Scheme II.

[0099] [Chemical formula]

[0100] [Example 1.8] Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-5-(benzyloxy)-6-isobutyltetrahydro-2H-pyran-3,4-diyl diacetate (12): A suspension of 4 (787 mg, 1.36 mmol) and 20% Pd(OH)2 / C (176 mg) in EtOH (17 mL) was stirred at room temperature under H2 (balloon) for 16 h. The reaction mixture was passed through Celite®, and the filter pad was washed with EtOH. The filtrate was concentrated and dried under vacuum to give 348 mg of a 2:1 mixture of tetraol and triol as a colorless solid. Anhydrous acetic acid (1.3 mL, 13.6 mmol) was added dropwise to a solution of the crude intermediate and a catalytic amount of DMAP. The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc (10 mL). The organic phase was washed successively with 1 M HCl (10 mL × 2), sat aq NaHCO3 (10 mL × 2), and brine (10 mL × 2 mL). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue obtained was purified on SiO2 (hexane / EtOAc, 4:1) to give 165 mg (28%, 0.378 mmol) of 12 as a white crystalline solid. 11H NMR (CDCl3, 500 MHz) δ 7.25 - 7.26 (m, 4H), 5.28 (t, J = 9.5 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.56 (d, J = 3.9 Hz, 2H), 4.25 (dd, J = 12.2, 4.9 Hz, 1H), 4.12 - 4.09 (m, 1H), 4.00 (dd, J = 12.2, 2.3 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.68 (dd, J = 9.7, 5.9 Hz), 2.06 (s, 3H), 2.01 (s, 6H), 1.80 - 1.65 (m, 2H), 1.43 - 1.40 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H). 13 13C NMR (CDCl3, 500 MHz) δ 170.9, 170.5, 170.0, 137.9, 128.6, 128.1, 127.9, 73.2, 72.5, 72.4, 69.5, 68.4, 62.7, 33.0, 24.3, 23.7, 21.5, 21.0, 20.9, 20.8.

[0101] [Example 1.9] Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-5-hydroxy-6-isobutyltetrahydro-2H-pyran-3,4-diyl diacetate (13): A solution of 12 (140 mg, mmol) and 20% Pd(OH)2 / C (31 mg) in EtOH (4 mL) was stirred at room temperature under H2 (balloon) for 16 h. The reaction mixture was passed through Celite®, and the filter pad was washed with EtOH. The filtrate was concentrated under reduced pressure to obtain 13 as a colorless solid (100 mg, 90%, 0.29 mmol). M.P.; 73 - 76 °C. 11H NMR (CDCl3, 400 MHz) δ 5.10 (t, J = 8.4 Hz, 1H), 4.94 (t, J = 8.4 Hz, 1H), 4.31 (dd, J = 12.1, 5.6 Hz, 1H), 4.17 - 4.12 (m, 1H), 4.07 (dd, J = 12.1, 5.6 Hz, 1H), 3.89 - 3.83 (m, 1H), 2.23 (d, J = 6.6 Hz, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 1.77 - 1.68 (m, 2H), 1.47 - 1.40 (m, 1H), 0.99 (d, J = 6.5, 3H), 0.95 (d, J = 6.5 Hz, 3H). 13 13C NMR (CDCl3, 500 MHz) δ 171.4, 170.9, 169.7, 73.7, 72.9, 70.2, 69.5, 68.7, 62.4, 33.7, 24.4, 23.7, 21.7, 21.1, 20.9 (2 signals). HRMS C 16 H 27 O8 [M + H] + Calculated value: 347.1700; Measured value: 347.1698.

[0102] [Example 1.10] (2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-6-isobutyl-5-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate (14): To a solution of 13 (48 mg, 0.14 mmol), pyridine (0.1 mL), and a catalytic amount of DMAP in anhydrous CH2Cl2 (1.5 mL) at room temperature was added pivaloyl chloride (0.042 mL, 0.346 mmol). The reaction mixture was stirred for 16 h and diluted with CH2Cl2 (5 mL). The organic phase was washed successively with 1 M aq HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 8:1) to give 14 as a colorless amorphous solid (19 mg, 32%, 0.044 mmol).1 1H NMR (CDCl3, 600 MHz) δ 5.35 (t, J = 9.3 Hz, 1H), 5.02 (dd, J = 10.1 Hz, 1H), 5.00 (t, J = 9.3 Hz, 1H), 4.30 - 4.28 (m, 1H), 4.26 (dd, J = 12.2, 5.2 Hz, 1H), 4.06 (dd, J = 12.2, 2.4 Hz, 1H), 3.83 (m, 1H), 2.09 (s, 1H), 2.03 (s, 1H), 2.00 (s, 1H), 1.82 - 1.77 (m, 1H), 1.73 - 1.68 (m, 1H), 1.19 - 1.14 (m, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H). 13 13C NMR (CDCl3, 600 MHz) δ 177.2, 170.9, 170.3, 169.8, 71.3, 70.5, 70.4, 69.1, 68.8, 62.6, 38.9, 33.6, 27.1, 24.3, 23.7, 21.6, 20.9, 20.8. HRMS C 21 H 35 O9[M + H] + Calculated value: 431.2276; Measured value: 431.2269.

[0103] [Example 1.11] (2R,3R,4R,5S,6R)-2-(Acetoxymethyl)-5-((3,3-dimethylbutanoyl)oxy)-6-isobutyltetrahydro-2H-pyran-3,4-diyl diacetate (15): A solution of 13 (48 mg, 0.14 mmol), pyridine (0.1 mL), and a catalytic amount of DMAP in anhydrous CH2Cl2 (1.5 mL) at room temperature was added to 3,3-dimethylbutyryl chloride (0.05 mL, 0.35 mmol). The reaction mixture was stirred for 16 h and diluted with CH2Cl2 (5 mL). The organic phase was washed successively with 1 M aq HCl (5 mL × 2), sat aq NaHCO3 (5 mL × 2), and brine (5 mL × 1). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified on SiO2 (hexane / EtOAc, 9:1) to give 15 as a colorless amorphous solid (29 mg, 47%, 0.065 mmol). 1 H NMR (CDCl3, 600 MHz) δ 5.34 (t, J = 9.5 Hz, 1H), 5.08 (dd, J = 9.5, 5.9 Hz, 1H), 4.98 (t, J = 9.5 Hz, 1H), 4.32 - 4.28 (m, 1H), 4.24 (dd, J = 12.2, 5.0 Hz, 1H), 4.06 (dd, J = 12.2, 2.3 Hz, 1H), 3.84 - 3.81 (m, 1H), 2.19 (s, 2H), 2.08 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.81 - 1.76 (m, 1H), 1.72 - 1.68 (m, 1H), 1.27 - 1.19 (m, 1H), 1.00 (s, 9H), 0.97 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H). 13 C NMR (CDCl3, 600 MHz) δ 171.1, 170.8, 170.4, 169.8, 71.2, 70.6, 70.3, 69.4, 68.6, 62.5, 47.8, 33.6, 30.9, 29.6, 24.2, 23.7, 21.5, 20.9 (2 signals), 20.8. HRMS C 22 H 37 O9[M + H] + Calculated for: 445.2432; Found: 445.2425.

[0104] This example further provides the proposed synthesis of (2R,3S,4R,5S,6R)-2-(acetoxymethyl)-6-isobutyl-5-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate (21), as shown by Scheme III.

[0105] [Chemical Structure]

[0106] [Example 1.12] Synthesis of (2R,3S,4R,5S,6R)-2-(acetoxymethyl)-5-(benzyloxy)-6-isobutyltetrahydro-2H-pyran-3,4-diyl diacetate (19): A suspension of 18 and 20% Pd(OH)2 / C in EtOH is stirred at room temperature under H2 (balloon). The reaction mixture is passed through Celite®, the filter pad is washed with EtOH, the filtrate is concentrated and dried under vacuum. Anhydrous acetic acid is added dropwise to a solution of the crude intermediate and a catalytic amount of DMAP. The reaction mixture is stirred at room temperature and diluted with EtOAc. The organic phase is washed successively with 1 M HCl, sat aq NaHCO3, and brine. The organic phase is dried (Na2SO4) and concentrated under reduced pressure to give 19 (see, for example, Cipolla, L., Lay, L., Nicotra, F. J. Org. Chem. 1997, 62(19), 6678 - 6681).

[0107] [Example 1.13] Synthesis of (2R,3S,4R,5S,6R)-2-(acetoxymethyl)-5-hydroxy-6-isobutyltetrahydro-2H-pyran-3,4-diyl diacetate (20): A solution of 19 and 20% Pd(OH)2 / C in EtOH is stirred at room temperature under H2 (balloon). The reaction mixture is passed through Celite®, the filter pad is washed with EtOH, and the filtrate is concentrated under reduced pressure to give 20.

[0108] [Example 1.14] (2R,3S,4R,5S,6R)-2-(Acetoxymethyl)-6-isobutyl-5-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate (21): Pivaloyl chloride is added to a solution of 20, pyridine, and a catalytic amount of DMAP in anhydrous CH2Cl2 at room temperature. The reaction mixture is stirred and then diluted with CH2Cl2. The organic phase is washed successively with 1 M aq HCl, sat aq. NaHCO3, and brine. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. The residue obtained is purified on SiO2 to give 21.

[0109] This example further provides the proposed synthesis of (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3,4-diyl diacetate (24) as shown by Scheme IV.

[0110] [Chemical formula]

[0111] [Example 1.15] Synthesis of (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3,4-diyl diacetate (24): 22. A suspension of acetic anhydride and montmorillonite K-10 is stirred to obtain 23. Then, a solution of 23, in-situ prepared 5% HCl, and propargyl alcohol is stirred at 65 °C. Acetic anhydride and pyridine are added to the solution. Then, the solution is stirred at room temperature to obtain 24 (see, for example, Wipf, P., Eyer, B. R., Yamaguchi, Y., Zhang, F., Neal, M. D., Sodhi, C. P., Good, M., Branca, M., Prindle, T., Jr., Lu, P., Brodsky, J. L., Hackam, D. J., Tetrahedron Letters. 2015, 56(23), 3097 - 3100).

[0112] This example further provides the synthesis of (2R,3S,4R,5S,6S)-2-(acetoxymethyl)-5-pivalamido-6-propyltetrahydro-2H-pyran-3,4-diyl diacetate (28) as shown by Scheme V.

[0113] [Chemical formula]

[0114] [Example 1.16] N-((2R,3S,4R,5S,6R)-2-allyl-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)pivalamide (26): At room temperature, pivaloyl chloride (0.082 mL, 0.67 mmol) was added in one portion to a solution of 25 (265 mg, 0.560 mmol) and a catalytic amount of DMAP in an 8:1 mixture of CH2Cl2 and pyridine (3 mL). After 6 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by chromatography on SiO2 (hexane / EtOAc, 4:1) to obtain 26 (194 mg, 62%) as a colorless solid. Mp 32 - 34 °C, HRMS m / z C 35 H 44 O5N ([M + 1] +) Calculated value 558.3214, measured value 558.3213; 1 H NMR (500 MHz, CDCl3) δ 7.35 - 7.20 (m, 15 H), 6.79 (d, J = 9.5 Hz), 5.83 - 5.78 (m, 1 H), 5.10 - 5.02 (m, 2 H), 4.63 - 4.57 (m, 2 H), 4.52 (s, 2 H), 4.49 - 4.43 (m, 2 H), 4.34 - 4.32 (m, 1 H), 3.95 - 3.93 (m, 1 H), 3.88 (dd, J = 7.0, 10.0 Hz), 3.73 (dd, J = 7.0, 10.0 Hz), 3.65 (bs, 1 H), 3.58 - 3.57 (m, 1 H), 2.25 - 2.10 (m, 1 H), 1.04 (s, 9 H).

[0115] [Example 1.17] N-((2R,3R,4R,5S,6R)-4,5-Dihydroxy-6-(hydroxymethyl)-2-propyltetrahydro-2H-pyran-3-yl)pivalamide (27): A slurry of 26 (134 mg, 1.14 mmol) and 20% Pd(OH)2 / C (30 mg) in EtOH (3.5 mL) was stirred in a Parr reactor at room temperature under H2 (100 psi) for 48 h. The reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure to give 27 (66 mg, 0.23 mmol, 96%) as a colorless solid. This 27 was used in the subsequent step without further purification.

[0116] [Example 1.18] (2R,3S,4R,5S,6R)-2-(Acetoxymethyl)-5-pivalamido-6-propyltetrahydro-2H-pyran-3,4-diyl diacetate (28): A solution of 27 (32 mg, 0.11 mmol) and acetic anhydride (0.08 mL, 0.83 mmol) in pyridine (0.65 mL) was added with a catalytic amount of DMAP. The solution was stirred at room temperature for 16 h and diluted with ethyl acetate (7.5 mL). The organic phase was successively washed with 1 M HCl (3 × 5 mL), water (1 × 5 mL), saturated aq NaHCO3 (1 × 5 mL), and brine (5 mL × 1), then dried (Na2SO4) and concentrated under reduced pressure. The obtained residue was purified by chromatography on SiO2 (hexane / EtOAc, 4:1) to give 28 as a colorless amorphous solid (34 mg, 0.082 mmol, 74%). HRMS m / z C 20 H 34 O8N ([M+1] + ) calcd for 416.2279, found 416.2309; 1 H NMR (400 MHz, CDCl3) δ 6.06 (d, J = 8.0 Hz, 1 H), 5.05 - 5.01 (m, 1 H), 4.98 - 4.94 (m, 1 H), 4.36 (dd, J = 12.0, 6.4 Hz, 1 H), 4.24 - 4.20 (m, 1 H), 4.17 - 4.01 (m, 2 H), 3.86 - 3.84 (m, 1 H), 2.09 (s, 3 H), 2.08 (s, 3 H), 2.07 (s, 3 H), 1.65 - 1.55 (m, 2 H), 1.35 - 1.25 (m, 2 H), 1.18 (s, 9 H), 0.93 (t, J = 7.2 Hz, 3 H).

[0117] This example further provides the proposed syntheses of (2R,3S,4R,5S,6R)-6-allyl-2-((butyryloxy)methyl)-5-pivalamidotetrahydro-2H-pyran-3,4-diyl dibutyrate (31), (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-isobutyl-5-pivalamidotetrahydro-2H-pyran-3,4-diyl diacetate (32), (1S,2S,4S,6S)-2-acetoxy-4-(acetoxymethyl)-6-propoxycyclohexyl pivalate (33), N-((2S,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-isopropyltetrahydro-2H-pyran-3-yl)pivalamide (34), (2R,3S,4R,5S,6R)-6-allyl-2-((benzoyloxy)methyl)-4-(2-phenylacetoxy)-5-pivalamidotetrahydro-2H-pyran-3-yl benzoate (35), and (2R,3S,4R,5S,6R)-2-(((azetidine-1-carbonyl)oxy)methyl)-5-pivalamido-6-propyltetrahydro-2H-pyran-3,4-diyl bis(azetidine-1-carboxylate) (36) as shown by Scheme VI.

[0118] [Chemical formula]

[0119] [Example 1.19] (2R,3S,4R,5S,6R)-6-allyl-2-((butyryloxy)methyl)-5-pivalamidotetrahydro-2H-pyran-3,4-diyl dibutyrate (31): Starting from 25, 31 is obtained using a synthesis similar to Scheme V. The alkene can be retained in the debenzylation step using deprotection conditions (see, for example, Cavedon, C., Sletten, E. T., Madani, A., Niemeyer, O., Seeberger, P. H., Pieber, B., Org. Lett., 2021, 23(2), 514 - 518).

[0120] [Example 1.20] (2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-isobutyl-5-pivalamidotetrahydro-2H-pyran-3,4-diyl diacetate (32): Starting from 29, use a synthesis similar to Scheme V. Further steps using the product of step 3 can be achieved using selective deprotection at C-6 hydroxyl using methods disclosed in methods such as Filice et al. (Filice, M., Guisan, J. M., Terreni, M., Palomo, J. M., Nature Protocols., 2012, 7(10), 1783 - 1796) to obtain 32.

[0121] [Example 1.21] (2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-5-pivalamido-6-propyltetrahydro-2H-pyran-3,4-diyl diacetate (33): Starting from 25, use a synthesis similar to Scheme V. Further steps using the product of step 3 can be achieved using selective deprotection at C-6 hydroxyl using methods disclosed in methods such as Filice et al. (Filice, M., Guisan, J. M., Terreni, M., Palomo, J. M., Nature Protocols., 2012, 7(10), 1783 - 1796) to obtain 33.

[0122] [Example 1.22] N-((2S,3R,4R,5S,6R)-4,5-Dihydroxy-6-(hydroxymethyl)-2-isopropyltetrahydro-2H-pyran-3-yl)pivalamide (34): Starting from 30, use a synthesis similar to steps 1 - 2 of Scheme V to obtain 34 (see, for example, Wipf, P., Pierce, J. G., Zhuang, N., Org. Lett., 2005, 7(3), 483 - 485).

[0123] [Example 1.23] (2R,3S,4R,5S,6R)-6-Allyl-2-((benzoyloxy)methyl)-4-(2-phenylacetoxy)-5-pivalamidotetrahydro-2H-pyran-3-yl benzoate (35): Starting from 25, a synthesis similar to Scheme V is used. The alkene can be retained in the debenzylation step using deprotection conditions (see, for example, Cavedon, C., Sletten, E. T., Madani, A., Niemeyer, O., Seeberger, P. H., Pieber, B., Org. Lett., 2021, 23(2), 514 - 518). Further steps using the product of step 3 can be achieved by selective deprotection at C-6 hydroxyl followed by selective protection at C-6 hydroxyl using methods disclosed in, for example, Filice et al. (Filice, M., Guisan, J. M., Terreni, M., Palomo, J. M., Nature Protocols., 2012, 7(10), 1783 - 1796) to obtain 35.

[0124] [Example 1.24] (2R,3S,4R,5S,6R)-2-(((azetidine-1-carbonyl)oxy)methyl)-5-pivalamido-6-propyltetrahydro-2H-pyran-3,4-diyl bis(azetidine-1-carboxylate) (36): Starting from 25, a synthesis similar to Scheme V is used. Step 3 is achieved using 1-azetidinecarbonyl chloride using methods disclosed in, for example, WO 2017 / 023631 A1 to obtain 36.

[0125] This example further provides the synthesis of (1R,2S,3S)-5-(((3,3-dimethylbutanoyl)oxy)methyl)-3-propoxycyclohexane-1,2-diyl bis(3,3-dimethylbutanoate) (42) as shown by Scheme VII.

[0126] [Chemical formula]

[0127] [Example 1.25] Methyl (3aR,7S,7aR)-7-(allyloxy)-2,2-dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (38): To a solution of 37 (230 mg, 1.01 mmol) dissolved in toluene (3.6 mL) at room temperature was added TlOEt (0.1 mL). After 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in MeCN (3.6 mL). The solution was treated with allyl iodide (0.3 mL) and stirred in the dark. After 16 hours, the solid was removed by filtration through Celite®, the filter pad was washed with CH2Cl2, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on SiO2 (hexane / EtOAc, 2:3) to give 38 as an orange oil (46 mg). 1 H NMR (CDCl3, 400 MHz) δ 7.04 (s, 1 H), 6.01 - 5.91 (m, 1 H), 5.34 - 5.29 (m, 1 H), 5.25 - 5.22 (dd, J = 10.4, 1.2 Hz, 1 H), 4.67 - 4.64 (m, 1 H), 4.62 - 4.59 (m, 1 H), 4.30 - 4.25 (m, 1 H), 4.20 - 4.14 (m, 1 H), 3.87 - 3.85 (m, 1 H), 3.77 (s, 3 H), 3.03 (d, J = 16.3 Hz, 1 H), 1.94 - 1.84 (m, 1 H), 1.32 (s, 3 H), 1.31 (s, 3 H); 13 C NMR (CDCl3, 400 MHz) δ 166.2, 140.8, 134.4, 129.0, 118.3, 109.2, 75.7, 75.2, 73.0, 71.1, 52.1, 27.5, 26.0, 24.3; HRMS m / z C 14 H 21 O5([M + H] +) Calculated value 269.1407, measured value 269.1407 (see, for example, Mohanrao, R., Asokan, A., Sureshan, K. M., Chem. Commun., 2014, 50(51), 6707 - 6710).

[0128] [Example 1.26] ((3aR,7S,7aR)-7-(allyloxy)-2,2-dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxol-5-yl)methanol (39): A solution of methyl 38 (0.040 g, 0.149 mmol, 1 eq) dissolved in THF (0.2 mL) was treated with DIBAL-H (0.298 mL in hexane, 0.298 mmol, 2 eq, 1 M) at -78 °C, warmed to room temperature over several hours, and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 39 (0.015 g, 0.062 mmol, 42%). This 39 was used in the subsequent step without further purification.

[0129] [Example 1.27] (1R,2R,3S)-3-(allyloxy)-5-(hydroxymethyl)cyclohex-4-ene-1,2-diol (40): A solution of 39 (0.038 g, 0.158 mmol) dissolved in TFA and water (80:20, 0.53 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo to give 40 (0.011 g, 0.055 mmol, 88%). This 40 was used in the subsequent step without further purification.

[0130] [Example 1.28] (1R,2R,3S)-3-(allyloxy)-5-(((3,3-dimethylbutanoyl)oxy)methyl)cyclohex-4-ene-1,2-diyl bis(3,3-dimethylbutanoate) (41): A solution of 40 (0.080 g, 0.400 mmol, 1 eq) dissolved in pyridine (1.33 mL) was treated with tert-butylacetyl chloride (0.566, 4.00 mmol, 10 eq) and the catalyst DMAP, and stirred overnight at room temperature. The reaction mixture was quenched by adding EtOAc (5 mL), extracted with 1 M HCl (2 × 5 mL) and brine (5 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by chromatography on SiO2 (8:1, hexane / EtOAc) to give 41 (0.087 g, 0.176 mmol, 71%) as a colorless oil. 1 H NMR (CDCl3, 300 MHz) δ 5.82-5.79 (m, 1 H), 5.66-5.61 (m, 2 H), 5.29-5.02 (m, 3 H), 4.49 (bs, 2 H), 4.19-4.11 (m, 2 H), 4.00-3.92 (m, 1 H), 2.38-2.31 (m, 2 H), 2.24 (s, 2 H), 2.22 (s, 2 H), 2.17 (s, 2 H), 1.03 (s 9 H), 1.02 (s, 9 H), 1.00 (s, 9 H).

[0131] [Example 1.29] (1R,2S,3S)-5-(((3,3-Dimethylbutanoyl)oxy)methyl)-3-propoxycyclohexane-1,2-diyl bis(3,3-dimethylbutanoate) (42): A solution of 41 (0.020 g, 0.04 mmol, 1 eq) dissolved in THF (0.2 mL) was treated with Pd / C (10%, 0.004 g, 0.004 mmol) and H2 gas, and stirred overnight at room temperature. The mixture was filtered through Celite®, and the solvent was removed under reduced pressure to give 42 as a 2:1 mixture of diastereomers.

[0132] This example further provides the proposed syntheses of (1S,2S,3S,4R,6S)-4-(acetoxymethyl)-6-propoxycyclohexane-1,2,3-triyl triacetate (43), (1S,2S,4S,6S)-2-acetoxy-4-(acetoxymethyl)-6-propoxycyclohexyl pivalate (44), and (1R,2R,4S,6S)-2-hydroxy-6-propoxycyclohexane-1,4-diyl bis(2,2-dimethylpropanoate) (45) as shown by Scheme VIII.

[0133] [Chemical Structure]

[0134] [Example 1.30] (1S,2S,3S,4R,6S)-4-(Acetoxymethyl)-6-propoxycyclohexane-1,2,3-triyl triacetate (43): Starting from 37, a synthesis similar to Scheme VII is used to obtain 43 (see, for example, Mohanrao, R., Asokan, A., Sureshan, K. M., Chem. Commun., 2014, 50(51), 6707 - 6710).

[0135] [Example 1.31] (1R,2R,4S,6S)-2-Hydroxy-6-propoxycyclohexane-1,4-diyl bis(2,2-dimethylpropanoate) (44): Starting from 37, a synthesis similar to Scheme VII is used to obtain 44 (see, for example, Mohanrao, R., Asokan, A., Sureshan, K. M., Chem. Commun., 2014, 50(51), 6707 - 6710).

[0136] [Example 1.32] (1S,2S,4S,6S)-2-Acetoxy-4-(acetoxymethyl)-6-propoxycyclohexyl pivalate (45): Starting from 37, use a synthesis similar to Scheme VII to obtain 45 (see, for example, Mohanrao, R., Asokan, A., Sureshan, K. M., Chem. Commun., 2014, 50(51), 6707 - 6710).

[0137] This example further provides the proposed syntheses of ((1S,3S,4S,5S)-3 - acetoxy - 5 - isobutoxy - 4 - pivalamidocyclohexyl)methyl acetate (47), ((1R,3R,4S,5S)-3 - acetoxy - 5 - phenethoxy - 4 - pivalamidocyclohexyl)methyl acetate (48), and (1R,2S,3S,5R)-2 - acetamido - 3 - isopropoxy - 5 - ((pivaloyloxy)methyl)cyclohexyl azetidine - 1 - carboxylate (49) as shown by Scheme VIII.

[0138] [Chemical formula]

[0139] [Example 1.33] ((1S,3S,4S,5S)-3 - acetoxy - 5 - isobutoxy - 4 - pivalamidocyclohexyl)methyl acetate (47): Starting from 46, use a synthesis similar to Scheme VII to obtain 47 (see, for example, Shie, J.-J., Fang, J.-M., Wang, S.-Y., Tsai, K.-C., Cheng, Y.-S. E., Yang, A.-S., Hsiao, S.-C., Su, C.-Y., Wong, C.-H., J. Am. Chem. Soc., 2007, 129(39), 11892 - 11893).

[0140] [Example 1.34] ((1R,3R,4S,5S)-3 - acetoxy - 5 - phenethoxy - 4 - pivalamidocyclohexyl)methyl acetate (48): Starting from 46, 48 is obtained using a synthesis similar to Scheme VII (see, for example, Shie, J.-J., Fang, J.-M., Wang, S.-Y., Tsai, K.-C., Cheng, Y.-S. E., Yang, A.-S., Hsiao, S.-C., Su, C.-Y., Wong, C.-H., J. Am. Chem. Soc., 2007, 129(39), 11892 - 11893).

[0141] [Example 1.36] (1R,2S,3S,5R)-2-Acetamido-3-isopropoxy-5-((pivaloyloxy)methyl)cyclohexyl azetidine-1-carboxylate (49): Starting from 46, 49 is obtained using a synthesis similar to Scheme VII (see, for example, Shie, J.-J., Fang, J.-M., Wang, S.-Y., Tsai, K.-C., Cheng, Y.-S. E., Yang, A.-S., Hsiao, S.-C., Su, C.-Y., Wong, C.-H., J. Am. Chem. Soc., 2007, 129(39), 11892 - 11893).

[0142] [Example 2] Compounds that control inflammatory and immune responses related to infection This example provides a means of controlling the inflammatory response according to some embodiments of the present disclosure.

[0143] Experimental methods and materials Mouse enteroids. Primary intestinal crypt cultures (enteroids) were prepared from the ileum of neonatal (p7 - p11) mice and maintained in Matrigel (Corning). Enteroids were digested weekly, passed through using TrypLE Express (Gibco), and passages 3 to 10 were used for all experiments. Enteroids were pretreated with a C34 analog (20 μM, overnight) and then treated with LPS (50 μg per mL) for 4 hours for further analysis. The relative mRNA expression levels of Toll-like receptor 4 (Tlr4) (Figure 1) and tumor necrosis factor (Tnf) (Figure 2) were shown.

[0144] Mouse. C57BL / 6J mice were purchased from the Jackson Laboratory, and all mice were housed in a specific pathogen-free environment (ambient temperature between 20 and 25 °C, humidity between 30 and 70%) on a 12-hour light / 12-hour dark cycle, with free access to water and standard rodent chow (Teklad global 18% protein rodent diets, Envigo).

[0145] Endotoxemia model. Endotoxemia was induced by intraperitoneal injection of 5 mg / kg lipopolysaccharide (LPS) into randomly assigned neonatal pups (p11 - p14) of either sex, and ileum samples were collected 6 hours after LPS treatment. C34 and C34 analogs were administered by oral gavage at a dose of 20 mg / kg body weight 1 day before LPS injection.

[0146] Mouse NEC model. The experimental NEC was induced in 7-day-old male or female mice randomly divided into a control group and a test group by gavage feeding neonatal mice with a formula containing Similac Advance (Abbott Nutrition) for infants: Esbilac (PetAg) for puppies, in a 2:1 ratio, supplemented with enteric bacteria prepared from a stock made from specimens obtained from infants with surgical NEC 5 times a day. Additionally, the mice were exposed to hypoxia (5% O2 - 95% N2) for 10 minutes in a hypoxia chamber (Billups-Rothenberg) twice a day for 4 days. The C34 analog was administered by oral gavage at a dose of 10 mg per kg of body weight per day at the time of NEC induction. Pups of mice fed age-matched breast milk were used as non-NEC controls. The relative mRNA expression levels of Toll-like receptor 4 (Tlr4) (Figure 3), interleukin 6 (Il6) (Figure 4), interleukin 1β (Il1b) (Figure 5), tumor necrosis factor (Tnf) (Figure 6), and lipocalin 2 (Lcn2) (Figure 7) were shown.

[0147] RNA isolation, cDNA synthesis, and qPCR. Total RNA was isolated using the RNeasy mini kit (Qiagen) according to the manufacturer's protocol, and complementary DNA was synthesized from 0.5 μg of RNA using the QuantiTect Reverse Transcription kit (Qiagen). mRNA quantification was performed on a Bio-Rad CFX96 Real-Time System (Bio-Rad) using iTaq (trademark) universal SYBR (registered trademark) Green supermix (Bio-Rad), and data from qRT-PCR were collected using Bio-Rad CFX Manager 3.1 software. The relative mRNA expression levels of Toll-like receptor 4 (Tlr4) (Figure 8), interleukin 6 (Il6) (Figure 9), interleukin 1β (Il1b) (Figure 10), tumor necrosis factor (Tnf) (Figure 11), and lipocalin 2 (Lcn2) (Figure 12) were normalized to the expression of ribosomal protein lateral stalk subunit P0 (Rplp0), a housekeeping gene.

[0148] Hematoxylin and eosin (H&E) staining. Before imaging using a Leica DMi8 microscope, 5-μm paraformaldehyde-fixed paraffin-embedded tissue sections were rehydrated, stained in hematoxylin solution (Sigma-Aldrich), differentiated in Epredia™ Richard-Allan Scientific™ differentiating solution (Fisher Scientific), treated with Epredia™ Signature Series™ bluing reagent (Fisher Scientific), stained in eosin Y solution (Sigma-Aldrich), dehydrated, and then mounted using Permount mounting medium (Fisher Chemical). Representative images of the H&E-stained non-NEC control group, NEC group, and NEC + C281 group were shown (Figure 13).

[0149] Statistical analysis. The transcriptional levels of inflammatory biomarkers were evaluated by performing multiple comparisons following one-way ANOVA statistical analysis. Statistical significance was indicated by p-values, where *p < 0.05, ***p < 0.001, and ****p < 0.0001. Data were represented as relative mRNA expression normalized to the housekeeping gene Rplp0. Each data point represents an individual mouse.

[0150] Results This example demonstrated the effectiveness of C34 analogs in controlling infection-related inflammatory and immune responses. In vitro tests were performed using primary intestinal crypt cultures, specifically enteroids. Pretreatment of enteroids with C34 analogs demonstrated the ability to control inflammation induced by lipopolysaccharide (LPS), as shown by the relative mRNA expression levels of Toll-like receptor 4 (Tlr4) (Figure 1) and tumor necrosis factor (Tnf) (Figure 2).

[0151] This example further evaluated the efficacy of C34 analogs in the control of inflammation in an endotoxemia mouse model. Endotoxemia was induced in neonates by administering lipopolysaccharide (LPS) via intraperitoneal injection. The effects of the C34 analogs were evaluated by pre-administering these C34 analogs via enteral tube feeding 1 day prior to LPS injection. Samples of the ileum were collected 6 hours after LPS treatment to evaluate the inflammatory response markers of Toll-like receptor 4 (Tlr4) (Figure 8), interleukin 6 (Il6) (Figure 9), interleukin 1β (Il1b) (Figure 10), tumor necrosis factor (Tnf) (Figure 11), and lipocalin 2 (Lcn2) (Figure 12).

[0152] Similarly, C34 analogs were evaluated in a mouse model of necrotizing enterocolitis. The inflammatory markers of Toll-like receptor 4 (Tlr4) (Figure 3), interleukin 6 (Il6) (Figure 4), interleukin 1β (Il1b) (Figure 5), tumor necrosis factor (Tnf) (Figure 6), and lipocalin 2 (Lcn2) (Figure 7) following the induction of NEC were evaluated by qRT-PCR analysis. In particular, the C281 analog demonstrated a strong response. Furthermore, treatment with the C281 analog demonstrated the ability to preserve the tissue structure of the inner layer of the intestine in NEC mice.

[0153] While the presently disclosed subject matter and its advantages have been described in detail, it should be understood that various changes, substitutions, and modifications can be made to the invention without departing from the spirit and scope of the presently disclosed subject matter. Further, the scope of this application is not intended to be limited to the specific embodiments of the processes, machines, manufactures, and compositions, methods, and procedures described herein. As would be readily understood by one of ordinary skill in the art, the presently disclosed subject matter can be used with processes, machines, manufactures, compositions, methods, or steps that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein, whether currently existing or later developed. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufactures, compositions, methods, or steps.

[0154] Various patents, patent applications, publications, product descriptions, protocols, and sequence accession numbers are cited throughout this application, and the disclosures of each of them are hereby incorporated by reference in their entirety for all purposes.

Claims

1. Equation I 【Chemistry 1】 [wherein, X is O, Z is O or NH, and Y is CH 2 or CH(R 1 ), R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 , where R 3 is R 1 , NHR 1 or N(R 1 ) 2 selected from, or, In the formula, X is CH 2 Z is either O or NH, and Y is O, R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 And here R 3 is R 1 NHR 1 Or N(R 1 ) 2 [Selected from] A compound of or its stereoisomer.

2. A pharmaceutical composition comprising the compound described in claim 1.

3. A pharmaceutical composition according to claim 2, selected from the group consisting of coated particles, micelles, liposomes, tablets, capsules, sachets, suppositories, liquid pharmaceutical compositions, and combinations thereof.

4. The pharmaceutical composition according to claim 2, further comprising an antibiotic, a steroid, or a nonsteroidal anti-inflammatory agent, or a combination thereof.

5. The compound, 【Chemistry 2】 【change】 【change】 【change】 The compound according to claim 1, selected from the group consisting of and combinations thereof.

6. Formula II 【Transformation 3】 [In the formula, Z is O or NH, and R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 And here R 3 is R 1 NHR 1 or N(R 1 ) 2 [Selected from] A compound of or its stereoisomer.

7. A pharmaceutical composition comprising the compound described in claim 6.

8. A pharmaceutical composition according to claim 7, selected from the group consisting of coated particles, micelles, liposomes, tablets, capsules, sachets, suppositories, liquid pharmaceutical compositions, and combinations thereof.

9. The pharmaceutical composition according to claim 7, further comprising an antibiotic, a steroid, or a nonsteroidal anti-inflammatory agent, or a combination thereof.

10. The compound, 【Chemistry 4】 The compound according to claim 6, selected from the group consisting of and combinations thereof.

11. A method for treating infectious or inflammatory disorders, wherein the subject requiring such treatment is given Formula I 【Transformation 5】 [In the formula, X is O, Z is either O or NH, and Y is CH] 2 Or CH(R 1 ) and R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 And here R 3 is R 1 NHR 1 , or N(R 1 ) 2 Selected from, or In the formula, X is CH 2 Z is either O or NH, and Y is O, R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 And here R 3 is R 1 NHR 1 Or N(R 1 ) 2 [Selected from] A method comprising administering an effective amount of a Toll-like receptor 4 inhibitor compound or a stereoisomer thereof.

12. A method for treating infectious or inflammatory disorders, wherein the subject requiring such treatment is given formula II 【Transformation 6】 [In the formula, Z is O or NH, and R 1 is alkyl, branched alkyl, cycloalkyl, aryl or substituted aryl, and R 2 is H or COR 3 And here R 3 is R 1 NHR 1 or N(R 1 ) 2 [Selected from] A method comprising administering an effective amount of a Toll-like receptor 4 inhibitor compound or a stereoisomer thereof.

13. The method according to claim 11 or 12, wherein the subject suffers from one or more of the following conditions: osteoarthritis, pancreatitis, metabolic syndrome, trauma-induced systemic inflammation, acute respiratory distress syndrome, and COVID-19-induced systemic inflammation.

14. The method according to claim 11 or 12, wherein the subject is suffering from necrotizing enterocolitis.

15. Toll-like receptor 4 inhibitors 【Transformation 7】 【change】 【change】 【change】 The method according to claim 11, selected from the group consisting of and combinations thereof.

16. Toll-like receptor 4 inhibitors 【Transformation 8】 【change】 The method according to claim 12, selected from the group consisting of and combinations thereof.

17. A method for treating trauma in a subject, comprising administering an effective amount of a Toll-like receptor 4 inhibitor compound according to claim 11 or 12 to a subject requiring such treatment, the compound being used to reduce Toll-like receptor 4-induced post-traumatic injury.

18. The method according to claim 17, wherein the trauma is to an organ selected from the group consisting of the heart, liver, lungs, kidneys, intestines, brain, eyes, and pancreas.

19. The method according to claim 11 or 12, wherein the compound is administered to treat organ rejection after transplantation.

20. The method according to claim 11 or 12, comprising administering a compound of formula I or formula II to prevent necrotizing enterocolitis in premature infants.

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