Lipopeptide compounds, and use in modulating eosinophilia

Abstract

Provided herein are compounds of formula (I- A): or a salt thereof, including any isomers of the foregoing, wherein the variables are as defined herein. Such compounds may be suitable for use in methods for treating eosinophilic conditions, diseases or disorders. Such compounds may be orally administered. The compositions described herein may be useful to reduce eosinophil effector function.

Description

LIPOPEPTIDE COMPOUNDS, AND USE IN MODULATING EOSINOPHILIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 596,380 filed November 6, 2023, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure related generally to lipopeptides, and more specifically to the use of lipopeptide compounds suitable for treating eosinophilic conditions, diseases or disorders.BACKGROUND

[0003] Inflammation is an immunological conundrum. On the one hand, the physiological changes that accompany inflammation allow us to mount an acute response to external threats that would otherwise have wiped out the human species. On the other, chronic inflammation, where age or external stressors keep our immune system in overdrive, can contribute to many debilitating diseases ranging from Alzheimer’s to diabetes and bronchial asthma.

[0004] An eosinophil is a type of white blood cell stored in tissues throughout the body and continually replenished from the bone marrow. Eosinophils typically have a two-day lifespan in blood, but inflammatory conditions such as infections and allergic diseases will extend the lifespan up to two weeks by eosinophil-activating cytokines. See Park YM & Bochner BS, Allergy Asthma Immunol Res. 2010, 2:87-101. An eosinophil count is a blood test that measures the quantity of eosinophils in the human body. Elevated levels, usually measured during routine complete blood count testing, indicate an infection or allergy.

[0005] Activated eosinophils, which are promoted by eosinophil-activating cytokines under inflammatory conditions, are a major source of reactive oxygen species, cytotoxic proteins and proinflammatory cytokines. They signal the activation of resident tissue cells such as epithelial, endothelial and fibroblast cells, leading to the progression of inflammation and mucus secretion. Eosinophils are therefore potent activators and modulators of diseases such as bronchial asthma, atopic dermatitis5and colitis ulcerosa. See Hogan SP, IntArch Allergy Immunol. 2007,143(Suppl 1):3-14; Simon D et al., Allergy. 2004, 59:561-570; Wedemeyer J & Vosskuhle K., Best Pract Res Clin Gastroenterol. 2008, 22:537-549. Further, in asthmatics, levels of eosinophil granule proteins such as eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) largely correlate with asthma severity. See Parra A, et al., J Investig Allergol Clin Immunol. 1999; 9:27-34. Eosinophilic inflammation of the upper airways may also occur independent of allergy, as observed in chronic rhinosinusitis (CRS) subjects. See Hutcheson PS, et al., J Rhinol Allergy. 2010, 24:405-408. Such individuals represent a unique subgroup who are largely resistant to medical and surgical interventions and who could show immediate benefit by therapy that targets eosinophilic expansion and effector functions.BRIEF SUMMARY

[0006] In some aspects, provided is a compound of formula (I):or a salt thereof, including any isomers of the foregoing, wherein:R1is at least one optionally substituted amino acid;R2xis alkyl or alkenyl, optionally substituted with -OH, or -COOH;R2yis H or alkyl; orR2xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle;R3is alkyl or alkenyl; andZ is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl) 2.

[0007] In some aspects, provided is a compound of formula (I-A);(I-A), or a salt thereof, including any isomers of the foregoing, wherein:R2xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle;R3is alkyl or alkenyl; andR4is H or alkyl;R5is a hydrophobic side chain of Ala, Vai, lie, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R8is a hydrophobic side chain of Ala, Vai, lie, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R6is H or alkyl; andR7is -OH, -O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, -SH, or -S(C=O)alkyl; andZ is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl)2.

[0008] In some embodiments, provided is a compound of formula (I-B):or a salt thereof, including any isomers of the foregoing, wherein :R3is alkyl or alkenyl;R7ais H or -C(O)alkyl;Rbis H or -OH; andZ is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl)2,

[0009] In one aspect, provided is a compound selected from Table A or Table A’ herein, or a salt thereof, including any isomers of the foregoing.

[0010] In certain aspects, provided is a pharmaceutical composition comprising: any of the compounds described herein; and at least one pharmaceutically acceptable excipient.

[0011] In other aspects, provided herein eosinophilia modulating treatments, such as eosinophilic esophagitis and asthma treatments, using any of the compounds described herein. In some embodiments, the asthma is bronchial asthma. In certain embodiments, the treatments provided target a subgroup of patients (e.g., eosinophilic esophagitis and asthma patients) that are largely resistant to medical and surgical interventions, including steroid therapies,

[0012] In certain aspects, provided is a method for treating an inflammatory condition, disorder or disease in a human in need thereof, comprising: orally administering to the human an effective dose of any of the compounds described herein to treat the inflammatory condition, disorder or disease.

[0013] In certain aspects, provided is a method for treating an eosiniphilia condition, disorder or disease in a human in need thereof, comprising: orally administering to the human an effective dose any of the compounds described herein to treat the eosinophilic condition, disorder or disease.

[0014] In certain aspects, provided is a method for reducing eosinophil effector function in a human in need thereof, comprising administering to the human any of the compounds described herein to reduce eosinophil effector function.

[0015] In other aspects, provided is an article of manufacture, comprising: a container comprising any of the compounds described herein; and a label containing instructions for use of such compounds.

[0016] In yet other aspects, provided is a kit, comprising: a dosage form of any of the compounds described herein; and a package insert containing instructions for use of such composition. In some variations of the foregoing aspects, die dosage form is a syrup, chewable, capsule or soft gel. In other variations, the compositions provided herein Eire formulated for aerosol delivery.DETAILED DESCRIPTION

[0017] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0018] In some aspects, provided is a compound of formula (I):(I), or a salt thereof, including any isomers of the foregoing, wherein:R!is at least one optionally substituted amino acid;R2xis alkyl or alkenyl, optionally substituted with -OH, or -COOH;R2yis H or alkyl; orR2xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle;R3is aikyl or alkenyl; andZ is -OH, -OC(O)alkyl, -NH2, -NH(alkyl), or -N(alkyl)2.

[0019] In some variations of the foregoing aspect, the compound is other than: 1-(N-(O- acetyl-N-(N-(2,4-dimethyloctanoyl)-N-methylleucyl)threonyl)-N-methylvalyl)-4- hydroxypyrrolidine-2-carboxylic acid; or(12-isopropyl-8,l l-dimethyl-9-(4-methyl-2-(N-methyloctanamido)pentanamido)-10-oxo-2,5,7- trioxa- 11 - azatridecan- 13-oyl)proline;or a salt thereof, including any isomers of the foregoing.

[0020] In other variations of the foregoing aspect, when R3is alkyl, and Z is OH, then R* is other than -optionally substituted Leu - optionally substituted Thr - optionally substituted Vai-.

[0021] In some embodiments, R’ is a sequence of three optionally substituted amino acid moieties.

[0022] In certain embodiments, R!is -R,a-R1!’-Rk-, wherein:Rlais an optionally substituted amino acid moiety with a hydrophobic side chain;R,bis an optionally substituted amino acid moiety with a polar uncharged side chain; and Rk;is an optionally substituted amino acid moiety with a hydrophobic side chain.

[0023] In certain variations, Riais an optionally substituted amino acid moiety selected from the group consisting of Leu, Vai, and Gly; Ribis an optionally substituted amino acid moiety selected from the group consisting of Thr, Ser, and Cys; and R,cis an optionally substituted amino acid moiety selected from the group consisting of Vai, Leu, and Gly.

[0024] In certain embodiments, R!is -Rla-Rlt‘-Rlc-, wherein:Rlais an optionally substituted Phe;R,bis optionally substituted Thr; and Rk;is is optionally substituted Vai.

[0025] In certain embodiments, R!is:Phe-OAcThr-Val, wherein each Phe and Vai is N-methylated; or Phe -Thr -Vai, wherein each Phe and Vai is N-methylated.

[0026] It should be understood that in the foregoing variations, “OAc-amino acid moiety” refers to the amino acid moiety substituted with an acetyl group via the oxygen atom of the amino acid moiety (as the case may be). For example, “OAcThr” or “OAcSer” refers to threonine or serine, respectively, substituted with an acetyl group through the oxygen atom of the amino acid side chain.

[0027] In some embodiments, R2xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle. In certain variations, the heterocycle is pyrrolidine. In certain variations, the heterocycle is pyrrolidine substituted with one or more -OH. In certain variations, the heterocycle is 4-hydroxy-pyrrolidine.

[0028] In some variations, R3is a branched alkyl. In other variations, R3is C1-20 alkyl, Ci-io alkyl, or C5-10 alkyl, or C7-9 alkyl. In certain variations of the foregoing, the alkyl is unbranched or branched. In some variations, R3is:or-^^^r^XyA . In one variation, the alkyl is branched at the 1- and / or 3-position of the alkyl chain, referring to the following positions on the exemplary alkyl chain depicted below':

[0029] In some variations, R3is alkenyl. In certain variations, R3is C2-C30 alkenyl. In certain variationsincluding any cis- and / or trans- configurations of such moieties.

[0030] In yet other variations, R3is an omega-3 fatty acid, or a derivative thereof. In certain variations, R3is an eicosapentaenoic acid (EP A) moiety, or a docosahexaenoic acid (DHA) moiety, or a derivative of any of the foregoing.

[0031] In certain aspects, provided is a compound of formula (I-A):(kA), or a salt thereof, including any isomers of the foregoing, wherein:R2Xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5 -membered heterocycle;R3is alkyl or alkenyl; andR“ is H or alkyl;R5is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R8is a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R6is H or alkyl; andR7is -OH, -O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, -SH, or -S(C=O)alkyl; andZ is -OH, -OC(O)alkyl, -XH . -NH(alkyl), or -N( alkyl)2.

[0032] In certain variations, R5is the hydrophobic side chain of Leu. In certain variations, R5is the hydrophobic side chain of Phe.

[0033] In some variations, R6is alkyl. In certain variations, R6is Ci-io alkyl, or Chs alkyl, or C us alky 1.

[0034] In certain variations, R7is -OH. In other variations, R7is -O(C-O)alkyl. In one variation of the foregoing, the alkyl is methyl. In other variations, R?is or -O-alkyl-O-alkyl-O- alkyl. In one variation, R?ais -O-methyl-O-ethyl-O-methyl.

[0035] In certain variations, R6is methyl, and R7is OH.

[0036] The descriptions herein refer to the following abbreviations: “Ala” refers to alanine;‘'Vai” refers to valine; “He” refers to isoleucine; “Leu” refers to leucine; “Met” refers to methionine; “Phe” refers to phenylalanine; “Tyr” refers to tyrosine; “Trp” refers to tryptophan;“Gly” refers to glycine.

[0037] In certain aspects, provided is a compound of formula (I-B):(I-B), or a salt thereof, including any isomers of the foregoing, wherein:R3is alkyl or alkenyl;R7ais H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl;Rbis H or -OH; andZ is -OH, -OC(O)alkyi, -NH2, -NH(alkyl), or -N(alkyl)2.

[0038] In certain variations, the alkyl is C1-20 alkyl, Ci-15 alkyl, Ci-10 alkyl, or C1.5 alkyl, or C1-3 alkyl.

[0039] In certain variations, R7ais H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl. In certain variations, R7ais H, -C(O)CHs, or -methyl-O-ethyl-O-methyl.

[0040] In certain variations, Rbis H. In other variations, Rbis -OH.

[0041] In certain aspects, provided is a compound selected from the compounds of Table A or Table A’ below, or a salt thereof, including any isomers of the foregoing:Table A.Table A’.

[0042] In some embodiments, the compound of formula (I) is a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.

[0043] In some variations, the compositions described herein may include one or more isomers of the compounds described herein, including compounds of formulae (I), (I- A), and (I- B), as well as compounds of Tables A and A’. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that have the same sequence of bonding of their atoms but differ in the arrangement of their atoms in space are termed “stereoisomers.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory. The prefixes d and 1 or (+) and (-) are employed to designate thesign of rotation of plane-polarized light by the compound, with (-) or 1 meaning tha t the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is referred to as a “racemic mixture” or “racemate”.

[0044] In certain embodiments, the compositions described herein comprise a racemic mixture of a compound of formulae (I), (I- A), and (I-B), as well as compounds of Tables A and A’. In certain embodiments, the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer. In other embodiments, the compound is enriched by at least about 95%', 98%, or 99%' by weight with a single diastereomer or enantiomer.

[0045] In some variations, the compositions described herein may include one or more salts of the compounds described herein, including compounds of formulae (I), (I-A), and (I-B), as well as compounds of Tables A and A’. In certain variations, the salts are pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the tree bases or free acids, which are not biologically or otherwise undesirable.General Sy nthesis far Compounds

[0046] The compounds provided herein, including compounds of formulae (I), (I-A), and (I- B), as well as the exemplary compounds of Tables A and A’, may be synthesized according to General Scheme 1 below. The general scheme, as well as the reactions described in the Examples section below', can be readily adapted to prepare the compounds disclosed herein. For example, the synthesis of rum-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials.General Schemes

[0047] The compounds provided herein, including compounds of formulae (I), (I-A), and (I- B), and the exemplary compounds of Tables A and A’, may be synthesized according to General Scheme 1 below. The general scheme, as well as the reactions described in the Examples section below, can be readily adapted to prepare the compounds disclosed herein. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials.Scheme 1

[0048] The exemplary compounds of Tables A and A’, may be synthesized according toGeneral Scheme 1 wherein:R2Xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle;R3is alkyl or alkenyl; andR4is H or alkyl;R5is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R8is independently a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R6is H or alkyl; andR7is -OH, -O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, -SH, or -S(C=O)alkyl.

[0049] An exemplary procedure for general Scheme 1 is provided below:

[0050] Step 1 (Condensation of R3COOH). A coupling reagent (e.g, N,N'- carbonyldiimidazole (CDI)) is combined with a suitable solvent, such as dichloromethane. This solution is cooled. Separately, R1 is also combined with a suitable solvent, such as dichloromethane, to which a suitable base, such as diisopropyl ethylamine (DIPEA), is added. Once the suspension turns clear, it is added to the chilled CDI suspension. Once the resulting second suspension turns clear, the reaction continues under drying conditions (such as under a CaCh drying tube) and is continued until completion. Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgS(>4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).

[0051] To this crude product, additional solvent, such as dichloromethane, is added. To this, RJCOOH, a coupling reagent, such as 1 -hydroxybenzotri azole hydrate (HOBt hydrate), and a catalyst, such as CuBr?.. Upon completion of the reaction, the reaction mixture undergoes a workup, involving quenching (e.g.with an aqueous solution of HO) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCOs), dried (e.g. over MgSCb), filtered and the solvent is removed to obtain a crude product (such as an oil) (Pl).

[0052] Step 2 (Condensation of Pl with R2). Pl is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd / C). The reaction is stirred under H?, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (Pl acid).

[0053] A coupling reagent (e.g. N,N' -carbonyldiimidazole (CDI)) is combined with a suitable solvent, such as dichloromethane. This solution is cooled. Separately, R2 is also combined with a suitable solvent, such as dichlorometh aneto which a suitable base, such as diisopropylethylamine (DIPEA), is added. Once the suspension turns clear, it is added to the chilled CDI suspension. Once the resulting second suspension turns clear, the reaction continues under drying conditions (such as under a CaCh drying tube) and is continued until completion. Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).

[0054] To this crude product, additional solvent, such as dichloromethane, is added. To this, Pl acid (from above), a coupling reagent, such as 1 -hydroxybenzo tri azole hydrate (HOBt hydrate), and a catalyst, such as CuBi2. Upon completion of the reaction, the reaction mixture undergoes a workup, involving quenching (e.g. with an aqueous solution of HCI) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSCb), filtered and the solvent is removed to obtain a crude product (such as an oil) (P2).

[0055] Step 3 (Condensation of P2 with R3). P2 is added to a suitable organic solvent, such as methanol, and a suitable catalyst, such as Pd / C. The reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (P2 acid).

[0056] A coupling reagent (e.g. N,N'-carbonyldiimidazole (CDI)) is combined with a suitable solvent, such as dichloromethane. This solution is cooled. Separately, R3 is alsocombined with a suitable solvent, such as dichloromethane to which a suitable base, such as diisopropylethyl amine (DIPEA), is added. Once the suspension turns clear, it is added to the chilled CDI suspension. Once the resulting second suspension turns clear, the reaction continues under drying conditions (such as under a CaCh drying tube) and is continued until completion. Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitable organic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).

[0057] To this crude product, additional solvent, such as dichloromethane, is added. To this, P2 acid (from above), a suitable coupling reagent, such as 1 -hydroxybenzotri azole hydrate (HOBt hydrate), and a suitable catalyst, such as CuBi2. Upon completion of the reaction, the reaction mixture undergoes a workup, involving quenching (e.g.with an aqueous solution of HC1) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSC>4), filtered and the solvent is removed to obtain a crude product (such as an oil) (P3).

[0058] Step 4 (Condensation of P3 with R4). P3 is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (P3 acid).

[0059] A coupling reagent (e.g. N,N’-carbonyldiimidazole (GDI)) is combined with a suitable solvent, such as dichloromethane. This solution is cooled. Separately, R4 is also combined with a suitable solvent, such as dichloromethane to which a suitable base, such as diisopropylethylamine (DIPEA), is added. Once the suspension turns clear, it is added to the chilled CDI suspension. Once the resulting second suspension turns clear, the reaction continues under drying conditions (such as under a CaCh drying tube) and is continued until completion. Upon completion, the reaction mixture undergoes a workup, involving extraction with a suitableorganic solvent, such as ethyl acetate, and the organic layer dried (e.g., over MgSO4), filtered and solvent is removed to obtain a crude product (such as a viscous oil).

[0060] To this crude product, additional solvent, such as dichloromethane, is added. To this, P3 acid (from above), a coupling reagent, such as 1 -hydroxybenzotri azole hydrate (HOBt hydrate), and a catalyst, such as CuBrj. Upon completion of the reaction, the reaction mixture undergoes a workup, involving quenching (e.g. with an aqueous solution of HC1) and extraction with a suitable organic solvent, such as dichloromethane, and the organic layer is washed with an aqueous solution (e.g. NaHCCh), dried (e.g. over MgSCh), filtered and the solvent is removed to obtain a crude product (such as an oil) (P4).P4

[0061] Step 5 (Deprotection of P4). P4 is added to an organic solvent (e.g. methanol) and a catalyst (e.g. Pd / C). The reaction is stirred under H2, then filtered and the solvent is removed to obtain a crude product (e.g. an oil) (Formula (P)).

[0062] The exemplary compounds of Tables A and A’, may be synthesized according to General Scheme 2 above, wherein:X is -OC(O)alkyl, -NH2, -NH(alkyl), or -Nfalkyl ) 2; and LG is H or a suitable leaving group.

[0063] An exemplary procedure for general Scheme 2 is provided below:

[0064] (Condensation of compounds of Formula P). In some embodiments, exemplary compounds of formula P are reacted with reagent R5, wherein LG is H or a suitable leaving group (e.g. halo, pTsOH, or Fmoc), in a condensation reaction, to form compounds of FormulaQ-

[0065] The reagents of Scheme 1 and / or Scheme 2, may be synthesized according to General Scheme 3 above, wherein:R6is H or alkyl;R7bis -O-alkyl-O-alkyl-O-alkyl; andLGais a suitable leaving group.

[0066] An exemplary procedure for general Scheme 3 is provided below:

[0067] In some embodiments, carboxylic acids of formula R2-1& are reacted with a suitable protecting reagent, such as BnBr in the presence of K2CO3, 0° to room temperature, to providecompounds of formula R2-lb. The hydroxyl group of compounds of formula R2-lb are selectively deprotected, for example where the protecting group is tBu the hydroxyl groups are deprotected using an acid such as TFA. Resulting alcohols of formula R2-lc are reacted with LGa-R?b, wherein LGais a suitable leaving group (e.g. halo), such as Cl -MEM, in a condensation reaction, to form reagents of formula R2-ld.

[0068] The general schemes, as well as any reactions described in the Examples section below, can be readily adapted to prepare the compounds disclosed herein. For example, in some variations, reagent R1 may be N-Methyl-L-leucine benzyl ester p-toluenesulf onate or may be substituted with other appropriate compounds to produce other moieties corresponding to variables R4and R5in formula (IV-A).Conditions, Diseases or Disorders

[0069] In some aspects, the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be used to treat inflammatory conditions, disorders or diseases, including respiratory conditions, disorders or diseases. In some embodiments, the conditions, disorders or diseases are inflammations of the respiratory tract. In some aspects, provided is a method for treating inflammatory conditions, disorders or diseases in a human in need thereof, comprising administering the compositions provided herein to the human.

[0070] In some aspects, the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be used to treat inflammatory conditions, disorders or diseases, including eosiniphilia conditions, disorders or diseases. In some embodiments, the conditions, disorders or diseases are inflammations of the respiratory tract. In some aspects, provided is a method for treating inflammatory conditions, disorders or diseases in a human in need thereof, comprising administering the compositions provided herein to the human.

[0071] In some embodiments, the compositions provided herein comprise a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a- 10a, 12a, 13a, and 15a of Table A’.

[0072] In some variations, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following:(i) decreasing one more symptoms resulting from the condition, disease or disorder;(ii) diminishing the extent of the disease and / or stabilizing the condition, disease or disorder (e.g., delaying the worsening of the condition, disease or disorder);(iii) delaying the spread of the condition, disease or disorder;(iv) delaying or slowing the recurrence of the condition, disease or disorder and / or the progression of the condition, disease or disorder;(v) ameliorating the disease state and / or providing a remission (whether partial or total) of the condition, disease or disorder and / or decreasing the dose of one or more other medications required to treat the condition, disease or disorder;(vi) increasing the quality of life; and / or(vii) prolonging survival.

[0073] In some embodiments, the compositions provided herein, including compositions comprising compounds of formulae (I), (I- A), and (I-B) may be used to treat asthma, pneumonia, bronchiectasis, emphysema, tuberculosis, lung collapse, lung fibrosis, fibrosing alveolitis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, chronic rhinosinusitis (CRS), and acute respiratory disease syndrome.

[0074] In some embodiments, the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and (I-B) may be used to treat eosinophilic respiratory conditions, diseases or disorders. In some variations, conditions, diseases or disorders may include allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, hypereosinophilic syndrome, eosinophilic leukemia,eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper- IgE syndrome.

[0075] In some embodiments, the condition, disease or disorder is a chronic inflammatory disorder. In certain embodiments, the chronic inflammatory disorder is a chronic inflammatory disorder of the airways. In certain variations, the condition, disease or disorder is an inflammatory lung disease. In some variations, the condition, disease or disorder involves narrowing and / or swelling of airways, thereby making breathing difficult and triggering coughing, wheezing and / or shortness of breath. In certain variations, the condition, disease or disorder is asthma. In certain variations, the asthma is bronchial asthma. In one variation, the condition, disease or disorder involves steroid treatment resistant asthma and airway constrictions.

[0076] In some embodiments, the condition, disease or disorder is a chronic inflammatory disorder. In certain embodiments, the chronic inflammatory disorder is a chronic inflammatory disorder of the esophagus. In certain variations, the condition, disease or disorder is an inflammatory gastrointestinal disease. In some variations, the condition, disease or disorder involves narrowing and / or swelling of esophagus, thereby making swallowing difficult and triggering coughing and pain. In certain variations, the condition, disease or disorder is eosinophilic esophagitis. In one variation, the condition, disease or disorder involves eosinophilic esophagitis and esophagus constrictions.

[0077] In other embodiments, the condition, disease or disorder is an allergy or an allergic inflammation.

[0078] In other embodiments, the condition, disease or disorder is a viral respiratory disease.In some variations, condition, disease or disorder is severe acute respiratory syndrome. In certain variations, the severe acute respiratory syndrome is caused by a coronavirus.

[0079] In some variations, the human in need thereof is a lung-compromised individual. In certain variations, the lung-compromised individual has fluid build-up in the alveoli in the lungs.This fluid can leak from the smallest blood vessels in the lungs into the alveoli due to the destruction of the protective membrane in the alveoli. The membrane which normally keeps thisfluid in the vessels may be destroyed because of a disruption in immune response due to severe disease or injury. The fluid enters the alveoli and keeps the lungs from filling with enough air, which means less oxygen reaches the bloodstream. This deprives organs of the oxygen that is needed to function, which can cause multiple organ failure resulting in death.

[0080] In one embodiment, provided is a method for treating hospitalized lung-compromised humans in need thereof, comprising administering the compositions provided herein, including compositions comprising compounds of formulae (I), (LA), and (LB) to the human to reduce or delay the need to provide the human with assisted respiration.

[0081] In some embodiments, the methods described herein comprise administering a composition comprising a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.

[0082] In some variations, “delaying” development of a condition, disease or disorder means to defer, hinder, slow, retard, stabilize and / or postpone development of the condition, disease or disorder. This delay can be of varying lengths of time, depending on the history of the condition, disease or disorder and / or individual being treated.

[0083] In other aspects, the compositions provided herein, including compositions comprising compounds of formulae (I), (LA), and (LB) improve anti-inflammatory efficacy via a reduction in eosinophil effector function. Thus, in certain embodiments, provided is a method for reducing eosinophil effector function in a human in need thereof, comprising administering the compositions provided herein, including compositions comprising compounds of formulae (I), (LA), and (LB) to the human to reduce eosinophil effector function.Sub-Patient Population

[0084] In some embodiments, the methods provided herein involve treating a human in need thereof. In certain embodiments, the human is largely resistant to medical and surgical interventions for treating the inflammatory conditions, disorders or diseases described herein. In one embodiment, the human exhibits or has resistance to steroid therapy. For example, in onevariation, the human has steroid treatment resistant asthma. In another example, the human has eosinophilic esophagitis.

[0085] In some variations of the foregoing, the human is a child. In certain variations, the human is less than 18 years old, less than 12 years old, less than 10 years old, less than 5 years old, less than 2 years old, or less than 1 year; or between 2 years old and 12 years old.Formulations

[0086] In some embodiments, the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and ( I B ) are formulated for oral administration. Forms suitable for oral administration may include, for example, tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, aerosols, or powders.

[0087] In certain embodiments, the pharmaceutical compositions described herein are in the form of syrups, capsules, and soft gels (including, for example, chewable gummies).

[0088] In some embodiments, the pharmaceutical compositions provided herein comprise a compound selected from compounds 1-6, 8-10, 12, 13, and 15 of Table A and compounds la-6a, 8a-10a, 12a, 13a, and 15a of Table A’.

[0089] Techniques for formulation and administration of the compositions can be found in Remington’ s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co, Easton, Pa., 1990. The pharmaceutical compositions described herein can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee -making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent.

[0090] In some variations, the compositions provided herein are administered to the human as a unit dosage, for example, in the form of syrups, capsules, and soft gels (including, for example, chewable gummies) as described herein. In one variation, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantityof the compositions provided herein, or compositions comprising biological active(s) isolated from the compositions provided herein, which may be in a pharmaceutically acceptable carrier.

[0091] As used herein, by “pharmaceutically acceptable” refers to a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably thus in some embodiments met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0092] In other variations, the compositions provided herein are formulated for aerosol delivery.Dosages

[0093] In some embodiments, the methods provided comprise administering to the human in need thereof an effective amount of the compositions provided herein, including compositions comprising compounds of formulae (I), (I-A), and (I-B). In some variations, an “effective amount” intends such amount of a composition or biological active of the invention which should be effective in a given therapeutic form. In certain variations, an effective amount of the composition provided herein is an amount sufficient to reduce eosinophil effector function in the human, and thereby treating the human suffering from the conditions, diseases or disorders described herein, or alleviating the existing symptoms of such conditions, diseases or disorders.

[0094] In some variations, exemplary dosage levels for a human may be between 0.01 mg / kg to lOOmg / kg weight of the human.

[0095] The final dosage regimen is determined by the attending physician in view of good medical practice, considering various factors that modify the action of the salmonid oil composition, or composition comprising biological active(s) isolated from the salmonid oil compositions provided herein, the identity and severity of the disease state, the responsiveness ofthe subject, the age, condition, body weight, sex, and diet of the subject, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy. Further refinement of the dosage appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosage information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials.

[0096] An effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. In certain embodiments, the salmonid oil composition, or composition comprising biological active(s) isolated from the salmonid oil compositions provided herein, are administered once, twice, or three times daily. In certain embodiments, the composition provided herein are administered once or twice daily. In certain embodiments, the composition provided herein are administered once daily.Articles of Manufacture and Kits

[0097] The compositions provided herein, including compositions comprising compounds of formulae (I), (I- A), and (I-B), as well as the exemplary compounds of Tables A and A’, may be formulated in one or more pharmaceutically acceptable carriers, excipients or other ingredients can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, disease or disorder. Accordingly, in certain aspects, also provided is an article of manufacture, such as a container comprising a dosage form of salmonid oil composition, or composition comprising biological active(s) isolated from the compositions provided herein, and a label containing instructions for use of such compositions.

[0098] In some embodiments, the article of manufacture is a container comprising a dosage form of compositions provided herein, and one or more pharmaceutically acceptable carriers, excipients or other ingredients. In one embodiment of the articles of manufacture described herein, the dosage form is a syrup, capsule and soft gel (including, for example, chewable gummies).

[0099] In certain aspects, kits also are provided. For example, in some embodiments, a kit can comprise a dosage form of compositions provided herein, and a package insert containing instructions for use of the composition / active(s) in treatment of a condition, disease or disorder. The instructions for use in the kit may be for treating a respiratory inflammation or inflammation of the respiratory tract, including, for example, asthma. In one variation, the instructions for use in the kit may be for treating bronchial asthma. In another variation, the instructions for use in the kit may be for treating severe acute respiratory syndrome. In other variations, the instructions for use in the kit may be for treating a gastrointestinal inflammation or inflammation of the gastrointestinal tract, including, for example, eosinophilic esophagitis or asthma. In one variation, the instructions for use in the kit may be for treating eosinophilic esophagitis. In another variation, the instructions for use in the kit may be for treating asthma.

[0100] The labels and package inserts of the articles of manufacture and kits, respectively, contain instructions for treating any of the conditions, diseases or disorders described herein. In some embodiments, the label contain instructions for treatment of inflammatory conditions, disorders or diseases, including respiratory conditions, disorders or diseases. In some variations, the label contains instructions for treatment of a chronic inflammatory disorder of the airways. In one variation, the label contains instructions for treatment of asthma, such as bronchial asthma and / or steroid treatment resistant asthma. In other embodiments, the label contains instructions for treatment of a viral respiratory disease, such as severe acute respiratory syndrome (including, for example, severe acute respiratory syndrome caused by a coronavirus). In some embodiments, the label contains instructions for treatment of inflammatory conditions, disorders or diseases, including eosinophilic conditions, disorders or diseases. In some variations, the label contains instructions for treatment of a chronic inflammatory disorder of the esophagus. In one variation, the label contain instructions for treatment of eosinophilic esophagitis and asthma, such as bronchial asthma, steroid treatment resistant asthma, and / or eosinophilic esophagitis. In other embodiments, the label contains instructions for treatment of a viral eosinophilic condition.

[0101] Unless clearly indicated otherwise, the terms “a,” "an.” and the like, refer to one or more.

[0102] In some variations, “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, “about x” includes and describes “x” per se. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of + / - 2%.

[0103] In some variations, “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se. For example, description referring to “between x and y” includes description of “x” and “y” per se.ENUMERATED EMBODIMENTS

[0104] The following enumerated embodiments are representative of some aspects of the invention.

[0105] Embodiment 1. A compound of formula (I- A);or a salt thereof, including any isomers of the foregoing, wherein:R2Xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle;R3is alkyl or alkenyl; andR4is H or alkyl;R5is a hydrophobic side chain of Ala, Vai, He, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R8is independently a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R6is H or alkyl; andR7is -OH, -O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, -SH, or -S(C=O)alkyi; andZ is -OH, -OC(O )aikyl, -NH2, -NH(alkyl), or -N(alkyi )2.

[0106] Embodiment 2. The compound of Embodiment 1, wherein the compound is a compound of formula (I-B);(I-B) or a salt thereof, including any isomers of the foregoing, wherein:R7ais H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; and Rbis H or -OH.

[0107] Embodiment 3. A compound selected from the group consisting of:or a salt thereof, including any isomers of the foregoing.

[0108] Embodiment 4. The compound of Embodiment 3, wherein the compound is:or a salt thereof, including any isomers of the foregoing.

[0109] Embodiment 5. A pharmaceutical composition, comprising: at least one compound of any one of Embodiments 1 to 4, and at least one pharmaceutically acceptable excipient.

[0110] Embodiment 6. A method for treating an eosinophilic inflammatory condition, disorder or disease in a human in need thereof, comprising: administering to the human an effective dose of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to treat the eosinophilic inflammatory condition, disorder or disease.[01 I I] Embodiment 7. The method of Embodiment 6, wherein the eosinophilic inflammatory condition, disorder or disease is an inflammatory gastrointestinal disease.

[0112] Embodiment 8. The method of Embodiment 6 or 7, wherein the eosinophilic inflammatory condition, disorder or disease is a chronic inflammatory disorder of the esophagus.

[0113] Embodiment 9. The method of any one of Embodiments 6 to 8, wherein the eosinophilic inflammatory condition, disorder or disease is eosinophilic esophagitis.

[0114] Embodiment 10. The method of Embodiment 6, wherein the eosinophilic inflammatory condition, disorder or disease is a chronic inflammatory disorder of the airways.

[0115] Embodiment 11. The method of Embodiment 6 or 10, wherein the eosinophilic inflammatory condition, disorder or disease is asthma.

[0116] Embodiment 12. The method of any one of Embodiments 6 to 11, wherein the eosinophilic inflammatory condition, disorder or disease is bronchial asthma.

[0117] Embodiment 13. A method for treating an eosinophilic respiratory condition, disorder or disease in a human in need thereof, comprising: administering to the human an effective dose of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to treat the eosinophilic respiratory condition, disorder or disease.

[0118] Embodiment 14. The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is a viral respiratory disease.

[0119] Embodiment 15. The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is severe acute respiratory syndrome.

[0120] Embodiment 16. The method of Embodiment 13, wherein the severe acute respiratory syndrome is caused by a coronavirus.

[0121] Embodiment 17. The method of Embodiment 13, wherein the eosinophilic respiratory condition, disorder or disease is allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, hypereosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper- IgE syndrome.

[0122] Embodiment 18. The method of any one of Embodiments 13 to 17, wherein the human is largely resistant to medical and surgical interventions for treating the condition, disorder or disease.

[0123] Embodiment 19. The method of any one of Embodiments 13 to 17, wherein the human exhibits or has resistance to steroid treatments.

[0124] Embodiment 20. The method of any one of Embodiments 13 to 17, wherein the human has steroid treatment resistant asthma.

[0125] Embodiment 21. The method of any one of Embodiments 13 to 17, wherein the human has eosinophilic esophagitis.

[0126] Embodiment 22. The method of any one of Embodiments 13 to 21, wherein the administration of the composition to the human reduces or delays the need to provide the human with assisted respiration.

[0127] Embodiment 23. A method for reducing eosinophil effector function in a human in need thereof, comprising: administering to the human at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5, to reduce eosinophil effector function.

[0128] Embodiment 24. The method of any one of Embodiments 6 to 23, wherein the composition is administered as a syrup, chewable, capsule or soft gel, or the composition is formulated for aerosol administration.

[0129] Embodiment 25. An article of manufacture, comprising: a container comprising at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5: and a label containing instructions for use of such composi tion.

[0130] Embodiment 26. The article of manufacture of Embodiment 25, wherein the composition is provided in a dosage form.

[0131] Embodiment 27. The article of manufacture of Embodiment 25 or 26, wherein the dosage form is a syrup, chewable, capsule or soft gel.

[0132] Embodiment 28. The article of manufacture of Embodiment 25 or 26, wherein the container is an aerosol container.

[0133] Embodiment 29. A kit, comprising: a dosage form of at least one compound of any one of Embodiments 1 to 4, or a pharmaceutical composition of Embodiment 5; and a package insert containing instructions for use of such composition.

[0134] Embodiment 30. The kit of Embodiment 29, wherein the dosage form is a syrup, chewable, capsule or soft gel, or the dosage form is in aerosol form.EXAMPLES

[0135] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.Synthetic Examples

[0136] Structure verification was carried out by obtaining the expectedion on all final analogs synthesized . The purity of compounds was determined by LCMS & HPLC. Mass spectra were determined by using Shimadzu LCMS 2020 with N- Series DUIS, system using positivenegative switching. HPLC spectra were determined by using Agilent 1200 series.

[0137] Abbreviations used are those conventional in the art. The following examples are intended to be illustrative only and not limiting in any way.CTC-Resin : 2-Chloro trityl chlorideDCM : Di chloromethaneDMF : DimethylformamideDIPEA : N, N-DiisopropylethylamineEPA acid : Eicosapentaenoic acidFmoc : FluorenylmethyloxycarbonylFmoc-Pro-OH : Fmoc-Proline-OHFmoc-N-Me Val-OH : Fmoc-N Methyl Valine-OHFmoc-Thr(tBu)-OH : Fmoc- Threonine(tBu) — OHFmoc-N-Me Phe-OH : Fmoc-N Methyl Phenylalanine-OH HATH : (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphateCOMU : (l-Cyano-2-ethoxy-2-oxoethylidenaminooxy) di methyl ami no- morpholino-carbenium hexafluorophosphateMeOH : MethanolTFA : Tri fluoroacetic acidTIPS : TriisopropylsilaneH2O : Water niL : millilitreExample AlSynthesis and Characterization of Compound la

[0138] This example describes the synthesis and characterization of Compound la. These compounds were produced according to the scheme provided below. Synthesis of Compound la was performed on solid phase peptide synthesis. The below method, sequence and resins were used for the synthesis.

[0139] Structure verification is carried out by obtaining the expected M+ ion on all final analogs synthesized. All mass resolution LC / MS data was obtained.

[0140] Procedure: 2-chlorotritylchloride resin (4.5 g) was swollen in dry DCM (45 mL) for1 h in a glass sintered vessel equipped with a frit. The dry DCM solution was filtered. The Fmoc- Pro-OH (3.2 g, 3.0 eq) is dissolved in DCM (50 mL) in presence of DIPEA (2.2ml, 6.0 eq) and added to the resin. The reaction mixture was allowed for 3 h on an orbital shaker at room temperature. The solution was drained and the resin was washed with DMF: DCM (3 times each). The Fmoc -Pro-OH coupled resin is treated with 20% piperidine in DMF solution for 20 min. The mixture was filtered, and the peptidyl resin was washed with DMF: DCM: DMF (3 x 45 mL) and next couplings continued with Amino acid (3 eq), Fmoc- NMeVal-OH, Fmoc- NMeVal-OH, Fmoc- NMePhe-OH, EP A acid and HATU / DIPEA (3 eq) using a coupling reagent in DMF. A kaiser test performed on the beads to confirm the presence of free amine.

[0141] Capping: Capping is performed with MeOH / DIPEA / DCM (24 / 2, ''24).Table Al.

[0142] Finally, the above peptidyl resin was washed by DMF: DCM (3 x 40 mL) each followed by methanol (40 mL) and diethyl ether (2 x 40 mL). Finally, the resin was dried overnight under vacuum.

[0143] Globa! deprotection: The cleavage of the peptide from the solid support was achieved by treating the peptidyl resin (6.0 g) with reagent cocktail (95% TFA / 2.5% TIPS / 2.5% H2O) at cooling condition 0-5 °C for 1 h and 1 h at room temperature. The precipitated peptide was centrifuged (4000 rpm) and supernatant ether was removed. Fresh ether was added to the peptide and re-centrifuged. This process was repeated 3 times. The precipitated peptide (Compound la) was lyophilized under high vacuum for 16 h to obtain the product as a white solid. HPLC and LCMS analysis was used to confirm the quality and identify the desired peptide.

[0144] Purification: The crude was dissolved in acetonitrile and methanol. The dissolved crude was purified by Agilent Prep HPLC 1200 series with diode array detector capable of monitoring at 210 nm wavelength. Method:

[0145] Product (Compound la): Total crude weight: 3.5 g, Total recovery: 400 mg. M+=773.5.Biological ExamplesExample BlPercent eosinophil apoptosis in allergic human purified peripheral blood eosinophils

[0146] In triplicate, Allergic Human Eosinophils were placed in RPMI 1640 medium supplemented with IL- 5 (50 pM), 1% FBS and PenStrep in the presence of 5 nM Fevipiprant (positive control), 10 nM test compounds, and formulation vehicle (negative control). The test compounds include Compound la, which was obtained in accordance with the synthesis procedures described in Example Al above. Aliquots were removed after 18 hr incubation, washed twice in PBS, and resuspended in binding buffer. The eosinophil cells were stained using the Annexin V-FITC Apoptosis Detection Kit I (Sigma Aldrich) and immediately analyzed by flow cytometry. Each sample was acquired for 1 min, and the total number of eosinophils gated on a forward scatter / side scatter plot and the percentage of live cells (annexin Vneg) and apoptotic cells (annexin Vpos) was recorded. (Standard deviation in the assay is + / - 2.3%). See results in Table 1 below.Table 1.* In triplicate, Allergic Human Eosinophils used as before but with fevipiprant as control to match the in-vivo assay control. (SD in the assay is + / - 2.1%)Example B2CDllb change (100% as baseline) on PMNL surface stimulated by 2.5 nra CCL11

[0147] PMNL cells were pretreated with 5 nM Fevipiprant (positive control), 10 nM test compounds, and formulation vehicle (negative control) for 30 minutes and incubated with serial dilutions of CCL11 for 30 minutes at 37°C. Samples were stained with anti-CD16-PE-Cy5 and anti-CD 11 b~PE (ICRF44) antibodies. Eosinophils were identified as CD 16 negative cells.CD1 ib upregulation was analyzed by flow cytometry and reported above. (Standard deviation in the assay is + / - 2%). See results in Table 2 below.Table 2.* In triplicate, Normal Polymorphonuclear Leukocyte (PMNL) cells used as before. (SD in the assay is + / - 3%)Example B3Eosinophil and other leucocyte and cytokine modulating properties of Exemplary Compounds in House Dust Mite (HDM) extract-induced murine asthma model

[0148] This Example was performed to determine Eosinophil and other leucocyte and cytokine modulating properties of exemplary compounds described herein (30 and 150 pg / animal / day) at low and high doses in House Dust Mite (HDM) extract-induced murine asthma model. For the same purpose, no treatment as eosinophilia control and, fevipiprant (5 pg / animal / day) as a positive control.

[0149] The experimental design involved induction of asthmatic condition in mice using House Dust Mite (HDM) extract and simultaneous evaluation of the effects Compound la (30 and 150 pg / animal / day), and Fevipiprant! 5 pg / animal / day) as a positive control on Eosinophil modulation in mice.

[0150] On day 1 of the experiment, all 40 mice were anesthetized with isoflurane and sensitized intranasally with 1 pg HDM protein in 40 pL PBS. All mice were then challenged by intranasal application of 10 pg HDM protein in 40 pL PBS once daily from days 7 to 11. Mice also received the vehicle, test compounds, or Fevipiprant as per the respective groups once daily from days 7 to 14. On day 15 of the experiment, all the mice were anesthetized and Broncho-Alveolar Lavage (BAL) fluid was collected, centrifuged and cell pellet was stored at -20°C and dispatched to an external laboratory for eosinophilia analyses. In addition, from all these animals, spleen samples were collected, frozen and dispatched for eosinophilia analysis.

[0151] Observations on the animals encompassed mortality / morbidity, onset of any clinical signs / symptoms and monitoring of body weight. Eosinophilia analyses from the BAL fluid and spleen were carried out by an approved external laboratory.

[0152] No clinical signs or symptoms were observed in any of the animals of all the groups.

[0153] Animals across all the groups did not show any statistical variation in the body weight as well as in the % body weight change throughout the experimental period.Conclusion

[0154] Compound la was observed to have properties to modulate eosinophils and other leucocyte and cytokines which are markers for asthma, indicating its efficacy in House Dust Mite (HDM) extract-induced murine asthma model.Example CEosinophil and other leucocyte and cytokine modulating properties of Exemplary Compounds in House Dust Mite (HDM) extract-induced murine asthma model

[0155] The objective of this example was to determine the impact of Compound la at an intermediate dose of 90 pg / animal / day over 8 weeks of treatment on modulating eosinophils, other leucocytes, and cytokines and thereby lung histopathology in House Dust Mite (HOM) extract-induced murine asthma model. For the same purpose, no treatment (saline / vehicle) was used as eosinophilia control and, montelukast (60ug / animal / day) as a positive control.[01561 The experimental design involved induction of asthmatic condition in mice using House Dust Mite (HOM) extract and simultaneous evaluation of the effects Compound la (90 pg / animal / day), and Montelukast (60 pg / animal / day) as a positive control on Eosinophil modulation in mice. On day 1 of the experiment, all 30 mice were anesthetized with isoflurane and sensitized intranasally with 1 pg HOM protein in 40 pL PBS. All micewere then challenged by intranasal application of 10 pg HOM protein in 40 pL PBS once daily from days 7 to 15. Mice also received the vehicle, Compound la and Montelukast as per the respective groups once daily from days 7 to 56. On day 57 of the experiment, all the mice were anesthetized and Broncho- Alveolar Lavage (BAL) fluid was collected from the right lung (the left bronchus was tied off), centrifuged and cell pellet was stored at -20°C and dispatched to an external laboratory for eosinophilia analyses. In addition, from all these animals, spleen samples were collected, frozen and dispatched for eosinophilia analysis and the left lung was fixed in neutral buffered formalin to enable subsequent sectioning, staining and assessment of the extent of asthmatic changes including airway inflammation and obstruction.

[0157] Observations on the animals encompassed mortality / morbidity, onset of any clinical signs / symptoms and monitoring of body weight. Eosinophilia analyses from the BAL. fluid and spleen were carried out.

[0158] Mortality / Morbidity: All animals were observed twice daily (morning and evening) for any morbidity or mortality, throughout the acclimatization and the experimental period.

[0159] Clinical Signs or symptoms: Observations were made once daily to check for any clinical signs or symptoms throughout the acclimatization and treatment periods. These cage-side observations included (but were not limited to) changes in skin and fur, eyes and mucous membranes, as well as respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behavior patterns.

[0160] Body weight: Animals were weighed during randomization, on day 1, on day 7 and on day 15 of the experiment.

[0161] BAL. (Broncho- Alveolar Lavage) fluid, serum, lungs and spleen collection: On day 57, animals were anesthetized. Their trachea was exposed and one side of lung (left lung) was tied, a total of 3 ml of BAL. buffer (PBS containing 1 mM EDTA), divided into three parts, and was instilled into the lungs. BAL fluid and spleen were collected and stored on ice. The left lung was collected and fixed in 10%' neutral buffered formalin (NBF). Following the BAL fluid collection, the fluid was centrifuged (400 g at 4°C for 7 min) and the collected cell-pellets were frozen (at - 20°C) till they were sent for assay for airway eosinophilia. All the pellets from the BALF andspleen samples were collected from all animals and stored at -20°C until samples were dispatched for assay of systemic eosinophilia. Serum was separated from blood and stored in - 80°C till the estimation of IL4, IL5, IL6, IL10, II..13, IL17, IgE and IGgl performed using ELISA kits. The lung tissues were processed and one set of sections from all the animals were stained with Hematoxylin and Eosin stain for histopathological evaluation and the other set with PAS stain for the presence of mucus in the condition of asthma.

[0162] BAL fluid and spleen sample analysis: The cell pellets and spleen tissues collected were analyzed for eosinophilia. Total cell count was performed using hemocytometer. For the analysis of differential eosinophils count, 80p 1 of resuspended cell pellets were stained using methods and techniques known in the art.Results

[0163] Evaluation of Results / Statistical Analysis: Raw data were processed using commercially available statistical software. The mean and standard deviations were calculated using the software and all data were summarized in tabular forms. All continuous data were checked for their homogeneity using Shapiro-Wilk test. Ail homogenous data were analyzed using ANOVA and data showing significance in their variances were subjected to Dunnett's t- test. P values of less than or equal to 0.05 were accepted as being statistically significant.

[0164] Mortality / Morbidity: No mortality / morbidity was noted in any of the animals from all the 4 groups throughout the experimental period.

[0165] Clinical Signs of Taxicity: No treatment-related clinical signs were observed in any of the groups.

[0166] Body Weight and % Change in the Body weight: No statistical significant difference in mean body weights was observed in treatment groups as compared to Vehicle Control Group throughout the experimental period. Percent change in the body weight with respect to day 1 also showed no statistically significant difference in any of the groups throughout the experimental period.

[0167] Estimation ofCXCL-1, JL4, ILG, IL10 and JL17'. The CXCL-1 concentrations in serum were found to be reduced considerably in the Compound la (G2), and positive control group (G3) as compared to the disease control group (Gl).

[0168] A decreasing trend of serum IL6 levels were found in Compound la (G2), and positive control group (G3).

[0169] The serum IL10 levels were found decreased in Compound la (G2), and positive control group (G3).

[0170] Serum IL 17 levels were found to be reduced in the treated groups of Compound la and positive control in comparison with the disease control group,

[0171] No statistically significant alterations were observed in serum IL4 levels.

[0172] IL 5 showed a considerable reduction in Compound la (G2), and positive control group (G3) and can be corroborated with the reduction in eosinophilia observed in the histopathological evaluation.

[0173] Serum IL- 13 was found comparable in the disease control (Gl, untreated). Compound la (G2, treated) and Monteluekast (G3, positive control) showing no effect on the IL- 13 expression due to treatment with Compound la and Monteluekast.

[0174] IgE levels did not show any significant difference between the disease control (Gl, untreated). Compound la (G2, treated) and Monteluekast (G3, positive control).

[0175] IgGl levels did not show any significant difference between the disease control (Gl , untreated). Compound la (G2, treated) and Monteluekast (G3, positive control).

[0176] BAL, (Broncho Alveolar Lavage) fluid and spleen cellularity were evaluated and the results are as follows. The total cell count, eosinophil count in BAL fluid and percent eosinophils in spleen tissues decreased significantly in all the treatment groups in comparison with Gl (disease control).

[0177] Hematoxylin and eosin staining: the histology of lungs with Hematoxylin and eosin stain clearly showed lesions typical of asthma in the Gl group: hypertrophy of goblet cells. smooth muscle hyperplasia and airway obstruction thereby elevating the congestion in the lungs during the diseased condition in Gl. The severity of these lesions was mild to moderately reduced after the treatment with Compound la (G2) and Montelukast (G3).

[0178] PAS staining: Inflammatory infiltration, epithelial desquamation, thickening of basement membrane, mucous production and enlargement of goblet cells was observed of various degrees of severity i.e. marked asthmatic changes in Gl with marked inflammation, impaired barrier function, airway remodeling and airways obstruction. The degree of severity was subsequently reduced in G2 and to some extent in G3.

[0179] IL13 marker with immunohistochemical staining technique was found to be markedly expressed in the Gl, G2 and G3 groups.

[0180] Overall, no adverse clinical signs or symptoms were observed in any of the animals of all the groups and all animals remained healthy. Animals across all the groups did not show any statistical variation in the body weight as well as in the % body weight change throughout the experimental period.Conclusion

[0181] The reduction in 11,-5, IL-10, CXCL-1, 11,6, IL- 17 and eosinophil exhibit the potential role of Compound la in suppression of asthma pathogenicity which was also demonstrated in the histopathology of lungs. The unaltered levels of IL-4, IL,- 13, IgG l and IgE indicate that Compound la may not trigger IL-4 and 11,-13 pathways, but instead triggers the IL-5 pathway and thereby helps to combat the inflammatory response.

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I- A):or a salt thereof, including any isomers of the foregoing, wherein:R2Xand R2yare taken together with the atoms to which they are attached to form an optionally substituted 5-membered heterocycle:R3is alkyl or alkenyl: andR4is H or alkyl:R5is a hydrophobic side chain of Ala, Vai, lie, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R8is independently a hydrophobic side chain of Ala, Vai, He, Leu, Met, Phe, Tyr, Trp, or Gly, wherein the hydrophobic side chain is optionally substituted;R6is H or alkyl; andR' is -OH, -O(C=O)alkyl, -O-alkyl-O-alkyl-O-alkyl, -SH, or -S(C=O)alkyl; andZ is -OH, -OC(O )alkyl, -NH2, -NH(alkyl), or -Nfalkyl )2.

2. The compound of claim 1, wherein the compound is a compound of formula (I-B):or a salt thereof, including any isomers of the foregoing, wherein:R?ais H, -C(O)alkyl, or -alkyl-O-alkyl-O-alkyl; and Rbis H or -OH.

3. A compound selected from the group consisting of:or a salt thereof, including any isomers of the foregoing.The compound of claim 3, wherein the compound is:or a salt thereof, including any isomers of the foregoing.

5. A pharmaceutical composition, comprising: at least one compound of any one of claims 1 to 4, and at least one pharmaceutically acceptable excipient.

6. A method for treating an eosinophilic inflammatory condition, disorder or disease, or for treating an eosinophilic respiratory condition, disorder or disease, or for reducing eosinophil effector function in a human in need thereof, in a human in need thereof, comprising:administering to the human an effective dose of at least one compound of any one of claims 1 to 4, or a pharmaceutical composition of claim 5.

7. The method of claim 6, wherein the eosinophilic inflammatory condition, disorder or disease is: an inflammatory gastrointestinal disease; or a chronic inflammatory disorder of the esophagus; or eosinophilic esophagitis; or a chronic inflammatory disorder of the airways; or asthma; or bronchial asthma.

8. The method of claim 6, wherein the eosinophilic respiratory condition, disorder or disease is: a viral respiratory disease; or severe acute respiratory syndrome, optionally wherein the severe acute respiratory syndrome is caused by a coronavirus; or allergic rhinitis, asthma, atopic dermatitis (or eczema), allergic gastroenteritis, eosinophilic esophagitis, eosinophilic folliculitis, eosinophilic gastritis, eosinophilic colitis, eosinophilic cellulitis, hypereosinophilic syndrome, eosinophilic leukemia, eosinophilic granulomatosis, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, and hyper-IgE syndrome.

9. The method of any one of claims 6 to 8, wherein the human is:(i) largely resistant to medical and surgical interventions for treating the condition, disorder or disease(ii) exhibits or has resistance to steroid treatments(iii) has steroid treatment resistant asthma(iv) has eosinophilic esophagitis or any combination of (i)-(iv).

10. The method of any one of claims 6 to 9, wherein the administration of the composition to the human reduces or delays the need to provide the human with assisted respiration.

11. The method of any one of claims 6 to 10, wherein the composition is administered as a syrup, chewable, capsule or soft gel, or the composition is formulated for aerosol administration.

12. An article of manufacture, comprising; a container comprising at least one compound of any one of claims 1 to 4, or a pharmaceutical composition of claim 5; and a label containing instructions for use of such composition.

13. The article of manufacture of claim 12, wherein the composition is provided in a dosage form.

14. The article of manufacture of claim 12 or 13, wherein the dosage form is a syrup, chewable, capsule or soft gel.

15. The article of manufacture of any one of claims 12 to 14, wherein the container is an aerosol container.

16. A kit, comprising: a dosage form of at least one compound of any one of claims 1 to 4, or a pharmaceutical composition of claim 5; and a package insert containing instructions for use of such composition, optionally, wherein the dosage form is a syrup, chewable, capsule or soft gel, or the dosage form is in aerosol form.

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