Methods for treating inflammatory diseases

Abstract

Disclosed are methods of treating inflammatory diseases with peptides and pharmaceutical compositions using peptides.

Description

[0001] METHODS FOR TREATING INFLAMMATORY DISEASES

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 620,408, filed on January 12, 2024, the content of which is hereby incorporated by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] The present invention relates to treating inflammatory diseases with peptides and pharmaceutical compositions.

[0006] BACKGROUND

[0007] Inflammation is a protective mechanism in mammals against invading pathogens. However, uncontrolled inflammation can cause tissue damage and is the cause of many diseases. Inflammatory diseases, either chronic or acute in nature, afflict many patients every day and present an important problem in the health care industry.

[0008] Subsets of CD4+ T cells have been identified as being involved in promoting inflammation via secretion of cytokines that activate and / or attract other cell types to the site of an infection, trauma, or allergens. Such cytokine secretion can lead to adverse inflammatory activity, damage to self-tissue, and autoimmune diseases or disorders.

[0009] New therapeutic methods for dampening T cell-mediated inflammatory activity are needed.

[0010] SUMMARY

[0011] In one aspect, provided herein are methods of preventing or treating a chronic inflammatory lung disease or disorder in a subject, comprising administering to the subject a compound disclosed herein.

[0012] In a further aspect, provided are methods of treating chronic obstructive pulmonary disease in a subject, comprising administering to the subject a compound disclosed herein.

[0013] In yet another aspect, provided are methods of increasing levels of IL-10-producing regulatory T cells in a subject in need thereof, comprising administering to the subject a compound disclosed herein.

[0014] In another aspect, provided are methods of increasing IL- 10 expression in a subject in need thereof, comprising administering to the subject a compound disclosed herein. In another aspect, provided are methods of preventing or treating a disease selected from scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a compound disclosed herein.

[0015] In another aspect, provided are methods of preventing or treating a disease selected from scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a compound disclosed herein.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a series of flow cytometry graphs showing the effect of YDE-048 treatment on Thl, Th2, and Thl7 cells. Four groups of cells were observed. The first group of cells were not contacted by any cytokine-production stimulant and not contacted with YDE-048 (Unstim- / No YDE-048). The second group of cells were contacted with the mature T cell stimulants anti-CD3 / CD28 and not contacted with YDE-048 (Stim- / No YDE-048). The third group of cells were contacted with the mature T cell stimulants anti-CD3 / CD28 and contacted with 10 nM YDE-048 (Stim+ / YDE-048 (10 nM)). The fourth group of cells were contacted with the mature T cell stimulants anti-CD3 / CD28 and contacted with 500 nM YDE-048 (Stim+ / YDE-048 (500 nM)).

[0018] FIG. 2 is a series of flow cytometry graphs showing the effect of YDE-048 treatment on an enriched cell population of Th 17 cells.

[0019] FIG. 3 is a series of flow cytometry graphs showing the effect of YDE-048 treatment on IL-10-expressing regulatory T cells.

[0020] FIG. 4A is a pair of graphs showing the effect of YDE-048 treatment on IL- 10 cytokine production by cells in mixed peripheral blood mononuclear cell (PBMC) populations from two donor samples (Donor A and Donor B).

[0021] FIG. 4B is a graph showing the effect of YDE-048 treatment on IL- 10 cytokine production by an Thl7 enriched cell population.

[0022] FIG. 5 is a series of graphs showing the effect of YDE-048 treatment on IL- 10 and TNFa cytokine production in mixed PBMC cell populations from two donor samples (Donor A and Donor B).

[0023] FIG. 6 is a series of graphs showing the effect of YDE-048 treatment on proliferation of fluorescently labeled cells from three separate blood samples. FIG. 7 is a series of graphs showing levels of TGFP 1 in culture supernatants from three separate PBMC donors.

[0024] FIG. 8 is a series of flow cytometry graphs showing the effect of YDE-048 treatment on levels of Thl7 cells expressing IL- 17 (top panel), IL- 10 (middle panel), and Loxp3 (bottom panel).

[0025] FIG. 9 is a series of graphs showing the effect of YDE-048 treatment on TGEP 1 expression (top panel) and IL- 10 expression (bottom panel) by PBMCs. Cytokine protein expression levels were measured using Luminex. TGPpi and IL- 10 fold change is shown compared to the fold change in baseline control conditions (i.e., no YDE-048).

[0026] FIG. 10 is a series of graphs showing the effect of YDE-048 treatment on IL- 10 expression (top panel) and Eoxp3 expression (bottom panel) by CCR6+ cells.

[0027] FIG. 11A is a Uniform Manifold Approximation and Projection (UMAP) plot showing gene expression clusters of Thl7 cells treated (Sample 2) and not treated (Sample 1) with YDE-048.

[0028] FIG. 11B is a UMAP plot showing gene expression clusters CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE-048.

[0029] FIG. 12A is a series of principal component analysis (PCA) plots for Thl7 cells treated Thl7 cells treated (Sample 2) and not treated (Sample 1) and CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE-048.

[0030] FIG. 12B is a series of PCA plots showing an overlay of gene expression clusters of Th 17 cells treated Th 17 cells treated (Sample 2) and not treated (Sample 1) and CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE-048.

[0031] FIG. 13A is a volcano plot showing expression of differentially expressed genes in Thl7 cells treated (Sample 2) and not treated (Sample 1) with YDE-048.

[0032] FIG. 13B is a heatmap from Sample 1 (Thl7 cells not treated with YDE-048) versus Sample 2 (Thl7 cells treated with YDE-048) showing upregulation and downregulation of a set of genes.

[0033] FIG. 14A is a volcano plot showing expression of differentially expressed genes in CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE-048.

[0034] FIG. 14B is a heatmap from Sample 3 (CD4-T cells not treated with YDE-048) versus Sample 4 (CD4-T cells treated with YDE-048) showing upregulation and downregulation of a set of genes. FIG. 15 is a diagram showing the overlap of genes differentially expressed in both Thl7 cells (Sample 1 versus Sample 2) and CD4-T cells (Sample 3 versus Sample 4) with and without YDE-048 treatment.

[0035] FIG. 16 is a series of lists of differentially expressed genes in Thl7 cells (Sample 1 versus Sample 2) and CD4-T cells (Sample 3 versus Sample 4) with and without YDE-048 treatment.

[0036] FIG. 17 is a series of scatter plots showing expression level of IFNy, CCL4, IL41, CTLA4, F0X01, and TGFBR2 in Th 17 cells treated (Sample 2) and not treated (Sample 1) with YDE-048 and in CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE- 048.

[0037] FIG. 18 is a bobble map showing differentially expressed genes in Th 17 cells treated (Sample 2) and not treated (Sample 1) with YDE-048 and in CD4-T cells treated (Sample 4) and not treated (Sample 3) with YDE-048. A “+” mark signifies upregulation of that gene following treatment with YDE-048. A mark signifies downregulation of that gene following treatment with YDE-048.

[0038] DETAILED DESCRIPTION OF THE INVENTION

[0039] Definitions

[0040] According to the convention used in the art, in the formulae herein is used to indicate that a moiety or substituent “R” is attached to a backbone structure.

[0041] “Alkyl” is a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 10 carbon atoms (i.e., C1-C10 alkyl), or 1 to 6 carbon atoms (i.e., Ci-Ce alkyl). Examples of a suitable alkyl group include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, - CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl- 1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -QCPEh), 1 -pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl-2-butyl (-QCPEhCthCPE), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l- butyl (-CH2CH2CH(CH3)2), 2-methyl- 1 -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3- methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3- dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CHTJVCH ’J, but it is not limited thereto.

[0042] “Alkoxy” refers to a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent compound via an oxygen atom. The alkyl moiety of the alkoxy group may have, for example, 1 to 20 carbon atoms (i.e., Ci-C2o alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C10 alkoxy), or 1 to 6 carbon atoms (i.e., Ci-Ce alkoxy). Examples of a suitable alkoxy group include methoxy (-0- CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu), but it is not limited thereto.

[0043] “Haloalkyl” is an alkyl group in which at least one of the hydrogen atoms of the alkyl group as defined above is replaced by a halogen atom. The alkyl moiety of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1- C12 haloalkyl), 1 to 10 carbon atoms (i.e., C1-C10 haloalkyl), or 1 to 6 carbon atoms (i.e., C1- C6 haloalkyl). Examples of a suitable haloalkyl group include -CF3, -CHF2, -CFH2, and - CH2CF3, but it is not limited thereto.

[0044] “Alkenyl” is a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one unsaturated region, i.e., a carbon-carbon sp2double bond. For example, an alkenyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of a suitable alkenyl group include vinyl (- CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (- CH2CH2CH2CH2CH=CH2), but it is not limited thereto.

[0045] “Alkynyl” is a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, and encompasses straight, branched, and cyclic groups, or a combination thereof, and having at least one carbon-carbon sp triple bond. For example, an alkynyl group may have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 12 carbon atoms (i.e., C2-C12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of a suitable alkenyl group include acetylenic (-C=CH) and propargyl (- CH2C=CH), but it is not limited thereto. “Alkylene” refers to a saturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moieties) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, an alkylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of a typical alkylene group include 1,2-ethylene (-CH2-CH2-), but it is not limited thereto.

[0046] “Alkenylene” refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moieties) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkene. For example, an alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of a typical alkenylene group include 1,2-ethenylene (-CH=CH-), but it is not limited thereto.

[0047] “Alkynylene” refers to an unsaturated hydrocarbon group that may be branched, straight, or cyclic (or may have a combination of branched, straight, or cyclic moieties) and has two valencies derived by a removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkyne. For example, an alkynylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to carbon atoms. Examples of a typical alkynylene radical include acetylenylene (-C=C), propargylene (-CH2C=C-), and 4- pentynylene , but it is not limited thereto.

[0048] “Aryl” refers to an aromatic hydrocarbon group. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Examples of a typical aryl group include a radical derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, and the like, but it is not limited thereto.

[0049] “Arylalkyl” refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, typically a terminal or other sp3carbon atom, is replaced by an aryl group. Examples of a typical arylalkyl group include benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2- naphthylethan-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto. An arylalkyl group may have 7 to 20 carbon atoms. For example, the alkyl moiety thereof may have 1 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.

[0050] “Arylalkenyl” refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3carbon atom, although an sp2 carbon atom may also be used, is replaced by an aryl group. The aryl moiety of the arylalkenyl may be, for example, any aryl group described herein, and the alkenyl moiety of the arylalkenyl may comprise, for example, any of the alkenyl groups described herein. An arylalkenyl group may have 8 to 20 carbon atoms. For example, the alkenyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.

[0051] “Arylalkynyl” refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or other sp3carbon atom, although an sp carbon atom may also be used, is replaced by an aryl group. The aryl moiety of the arylalkynyl may be, for example, any aryl group described herein, and the alkynyl moiety of the arylalkynyl may comprise, for example, any of the alkynyl groups described herein. An arylalkynyl group may have 8 to 20 carbon atoms. For example, the alkynyl moiety thereof may have 2 to 6 carbon atoms, and the aryl moiety thereof may have 6 to 14 carbon atoms.

[0052] “Cycloalkyl” refers to a saturated monocycle or polycycle that comprises only carbon atoms in the ring. A cycloalkyl group may have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. A monocyclic cycloalkyl has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. A bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Non-limiting examples of a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted).

[0053] The term “substituted” with respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, and the like, for example, “substituted alkyl,” “substituted alkylene,” “substituted aryl,” “substituted arylalkyl,” “substituted heterocyclyl,” and “substituted carbocyclyl (e.g., substituted cycloalkyl),” means that at least one hydrogen atom of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl, or carbocyclyl (e.g., cycloalkyl) is each independently replaced by a non-hydrogen substituent. Examples of the typical substituent include halo, haloalkyl, oxo, - CN, -NO2, =N-OH, -N3, -R, -OR, -SR, -N(R)2, -N(R)3+, =NR, -NHC(=O)R, -C(=O)R, - C(=O)N(R)2, -S(=O)2R, -OS(=O)2OR, -S(=O)2OR, -S(=O)2N(R)2, -S(=O)R, -OP(=O)(OR)2, - (alkylene)-C(=O)R, -C(=S)R, -C(=O)OR, -(alkylene)-C(=O)OR, -C(=S)OR, -C(=O)SR, - C(=S)SR, -(alkylene)-C(=O)N(R)2, -C(=S)N(R)2, and -C(-NR)N(R)2, and R is independently H, alkyl, aryl, arylalkyl, or heterocyclyl, but it is not limited thereto. The alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Those skilled in the art will understand that when a moiety such as “alkyl,” “aryl,” “heterocyclyl,” and the like is substituted with at least one substituent, they may optionally be referred to as a moiety of “alkylene,” “arylene,” “heterocyclylene,” or the like (that is, at least one hydrogen atom of the parent “alkyl,” “aryl,” or “heterocyclyl” moiety is replaced by the substituent as described herein). If the moiety of “alkyl,” “aryl,” “heterocyclyl,” or the like is described herein as “substituted” or depicted in the drawings as substituted (or optionally substituted, for example, the number of substituents is 0 or a positive number), the term “alkyl,” “aryl,” “heterocyclyl,” or the like should be understood to be interchangeable with “alkylene,” “arylene,” “heterocyclylene,” or the like.

[0054] Those skilled in the art will recognize that the substituents and other moieties of the compound of Formula I should be selected so as to provide a compound that is sufficiently stable as a pharmaceutically useful compound that can be formulated into an acceptably stable pharmaceutical composition. The compound of Formula I having such stability is to be understood to fall within the scope of the present invention.

[0055] “Heteroalkyl” refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom such as O, N, or S. For example, if a carbon atom of the alkyl group attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be an alkoxy group (e.g., -OCH3), an amine group (e.g., -NHCH3, -N(CH3)2, or the like), or a thioalkyl group (e.g., -SCH3), respectively. If a non-terminal carbon atom of the alkyl group that is not attached to a parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be an alkyl ether (e.g., -CH2CH2-O-CH3 or the like), an alkylamine (e.g., -CH2NHCH3, -CH2N(CH3)2, or the like), or a thioalkyl ether (e.g., - CH2-S-CH3), respectively. If the terminal carbon atom of the alkyl group is replaced by a heteroatom (for example, O, N, or S), the resulting heteroalkyl group may be a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2), or an alkylthiol group (e.g., -CH2CH2-SH), respectively. For example, a heteroalkyl group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Preferably, a heteroalkyl group has from 2 to 20, 2 to 10, or 2 to 6 total atoms in the chain (i.e., carbon atoms plus heteroatoms combined). A Ci-Ce heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0056] The term “heterocycle” or “heterocyclyl” used herein includes those described in the documents such as Paquette, Leo A., Principles of Modem Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), specifically Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, from 1950 to the present), specifically Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566, but it is not limited thereto. In a specific embodiment of the present invention, “heterocycle” includes carbocycle as defined herein in which at least one (e.g., 1,

[0057] 2, 3, or 4) carbon atom is replaced by a heteroatom (e.g., O, N, or S). The term “heterocycle” or “heterocyclyl” includes saturated, partially unsaturated, and aromatic rings (i.e., a heteroaromatic ring). Substituted heterocycle, for example, includes a heterocyclic ring substituted with any of the substituents disclosed herein, inclusive of a carbonyl group.

[0058] Exemplary heterocycles include pyridyl, dihydropyridyl, tetrahydropyridyl(piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocynyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phtheridinyl, 4aH-carbazolyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, and benzoxazolinyl (each of which may be substituted or unsubstituted), but it is not limited thereto.

[0059] As an example, a carbon-bonded heterocycle may be bonded at the 2, 3, 4, 5, or 6- position of pyrazine, at the 3, 4, 5, or 6-position of pyridazine, at the 2, 4, 5, or 6-position of pyrimidine, at the 2, 3, 5, or 6-position of pyrazine, at the 2, 3, 4, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, at the 2, 4, or 5-position of oxazole, imidazole, or thiazole, at the 3, 4, or 5-position of isoxazole, pyrazole, or isothiazole, at the 2 or 3-position of aziridine, at the 2, 3, or 4-position of azetidine, at the 2,

[0060] 3, 4, 5, 6, 7, or 8-position of quinoline, or at the 1, 3, 4, 5, 6, 7, or 8-position of isoquinoline, but it is not limited thereto. More typically, examples of a carbon-bonded heterocycle include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2- pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl (each of which may be substituted or unsubstituted).

[0061] As an example, a nitrogen-bonded heterocycle may be bonded at the 1 -position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, or IH-indazole, at the 2-position of isoindole or isoindoline, at the 4-position of morpholine, and at the 9-position of carbazole or P-carboline (each of which may be substituted or unsubstituted), but it is not limited thereto. More typically, examples of a nitrogen-bonded heterocycle include 1-aziridinyl, 1-azetidyl, 1 -pyrrolyl, 1 -imidazolyl, 1- pyrazolyl, and 1-piperidinyl (each of which may be substituted or unsubstituted).

[0062] “Heterocyclylalkyl” refers to an acyclic alkyl radical in which one hydrogen atom bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced by a heterocyclyl radical (i.e., a heterocyclyl-alkylene moiety). Examples of a typical heterocyclylalkyl group include heterocyclyl-Cth-, 2-(heterocyclyl)ethan-l-yl, and the like, but it is not limited thereto. The “heterocyclyl” moiety thereof used herein includes those described in the document such as “Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described above. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkyl moiety of the heterocyclylalkyl through a carbon-to-carbon bond or a carbon-to-heteroatom bond. A heterocyclylalkyl group may have 2 to 20 carbon atoms. For example, the alkyl moiety of the heterocyclylalkyl group may have 1 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms. Examples of the heterocyclylalkyl include a 5-membered heterocycle containing sulfur, oxygen, and / or nitrogen such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like; and a 6-membered heterocycle containing sulfur, oxygen, and / or nitrogen such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridazylmethyl, pyrimidylmethyl, pyrazinylmethyl, and the like (each of which may be substituted or unsubstituted), but it is not limited thereto.

[0063] “Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom although an sp2carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a heterocyclyl- alkenylene moiety). The heterocyclyl moiety of the heterocyclylalkenyl group includes those described in the document such as “Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described herein. The alkenyl moiety of the heterocyclylalkenyl group includes any alkenyl group described herein. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkenyl moiety of the heterocyclylalkenyl via a carbon-to-carbon bond or a carbon-to- heteroatom bond. A heterocyclylalkenyl group may have 3 to 20 carbon atoms. For example, the alkenyl moiety of the heterocyclylalkenyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms.

[0064] “Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom although an sp carbon atom may also be used, is replaced by a heterocyclyl radical (i.e., a heterocyclyl- alkynylene moiety). The heterocyclyl moiety of the heterocyclylalkynyl group includes those described in the document such as “Principles of Modern Heterocyclic Chemistry” and any heterocyclyl group described herein. The alkynyl moiety of the heterocyclylalkynyl group includes any alkynyl group described herein. Those skilled in the art will understand that if the resulting group is chemically stable, the heterocyclyl group may be attached to the alkynyl moiety of the heterocyclylalkynyl via a carbon-to-carbon bond or a carbon-to- heteroatom bond. A heterocyclylalkynyl group may have 3 to 20 carbon atoms. For example, the alkynyl moiety of the heterocyclylalkynyl group may have 2 to 6 carbon atoms, and the heterocyclyl moiety thereof may have 2 to 14 carbon atoms.

[0065] “Heteroaryl” refers to an aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of a suitable heteroatom that may be contained in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of a heteroaryl ring include all of those enumerated in the definition of “heterocyclyl” herein, inclusive of pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, and the like (each of which may be substituted or unsubstituted).

[0066] “Carbocycle” or “carbocyclyl” refers to a saturated, partially unsaturated, or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. A monocyclic carbocycle has 3 to 7 ring atoms, more typically 5 or 6 ring atoms. A bicyclic cycloalkyl may have 7 to 12 ring atoms and may be a fused ring system, a spirocyclic ring system, or a bridged ring system. In exemplary cycloalkyl groups, the atoms are arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Nonl l limiting examples of a monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (each of which may be substituted or unsubstituted).

[0067] “Acyl” refers to -C(=O)-alkyl, -C(=O)-carbocycle (which is substituted or unsubstituted), and -C(=O)-heterocycle (which is substituted or unsubstituted), wherein the alkyl, carbocycle, or heterocycle moiety is as defined herein. Non-limiting examples of “acyl” include -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)C(CH3)3, -C(=O)- phenyl (which is substituted or unsubstituted), -C(=O)-cyclopropyl (which is substituted or unsubstituted), -C(=O)-cyclobutyl (which is substituted or unsubstituted), -C(=O)- cyclopentyl (which is substituted or unsubstituted), -C(=O)-cyclohexyl (which is substituted or unsubstituted), and -C(=O)-pyridyl (which is substituted or unsubstituted).

[0068] “Arylheteroalkyl” refers to a heteroalkyl as defined herein, wherein a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) is replaced by an aryl group as defined herein. If the resulting group is chemically stable, the aryl group may be attached to a carbon atom of the heteroalkyl group or the heteroatom of the heteroalkyl group. For example, an arylhetero alkyl group may have a formula of -alkylene-O-aryl, -alkylene-O- alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S- alkylene-aryl, or the like. In addition, any alkylene moiety in the above formulae may be further substituted with any of the substituents defined or exemplified herein.

[0069] “Heteroarylalkyl” refers to an alkyl group as defined herein, wherein a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl include -CH2-pyridinyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2- furanyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzothiophenyl, -CH2-carbazolyl, -CH2- imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH2-isothiazolyl, -CH2- quinolyl, -CH2-isoquinolyl, -CH2-pyridazyl, -CH2-pyrimidyl, -CH2-pyrazyl, -CH(CH3)- pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3)-oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, - CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, - CH(CH3)-pyridazyl, -CH(CH3)-pyrimidyl, -CH(CH3)-pyrazyl, and the like.

[0070] “Silyloxy” refers to the group -O-SiR3, wherein each R independently is alkyl, aryl (which is substituted or unsubstituted), or heteroaryl (which is substituted or unsubstituted). Non-limiting examples of silyloxy include -O-Si(CH3)3, -O-Si(CH3)2tBu, -O-Si(tBu)2CH3, - O-Si(tBu)3, -O-Si(CH3)2Ph, -O-Si(Ph)2CH3, and -O-Si(Ph)3. The term “optionally substituted” refers to a particular moiety (e.g., an optionally substituted aryl group) of the compound of Formula I that optionally has one, two, or more substituents.

[0071] The term “ester thereof’ refers to any ester of a compound wherein any -COOH functional group of the molecule is modified to be a -COOR functional group or any -OH functional group of the molecule is modified to be a -OC(=O)R. Here, the R moiety of the ester may be any carbon-containing group that forms a stable ester moiety, which includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof. Examples of the ester may also include an ester such as those described above of a “tautomeric enol” as described below.

[0072] The terms “treatment” or “treating” and their grammatical equivalents may refer to the medical management of a subject with an intent to cure, ameliorate, or ameliorate a symptom of, a disease, condition, or disorder. Treatment may include active treatment, that is, treatment directed specifically toward the improvement of a disease, condition, or disorder. Treatment may include causal treatment, that is, treatment directed toward removal of the cause of the associated disease, condition, or disorder. In addition, this treatment may include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, condition, or disorder. Treatment may include supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, condition, or disorder. In some embodiments, a condition may be pathological. In some embodiments, a treatment may not completely cure or prevent a disease, condition, or disorder. In some embodiments, a treatment ameliorates, but does not completely cure or prevent a disease, condition, or disorder. In some embodiments, a subject may be treated for 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, indefinitely, or life of the subject.

[0073] The terms “prevent” or “preventing” means delaying, forestalling, or avoiding the onset or development of a disease, condition, or disorder for a period of time. Prevent also means reducing risk of developing a disease, disorder, or condition. Prevention includes minimizing or partially or completely inhibiting the development of a disease, condition, or disorder. In some embodiments, a composition, e.g., a pharmaceutical composition, prevents a disorder by delaying the onset of the disorder for 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months,

[0074] 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, indefinitely, or life of a subject.

[0075] The term “effective amount” or “therapeutically effective amount” may refer to a quantity of a composition, for example a composition comprising any compound herein disclosed, that can be sufficient to result in a desired activity upon introduction into a subject.

[0076] Compounds

[0077] In certain embodiments, the invention provides a compound represented by Formula

[0078] (I): or a pharmaceutically acceptable salt thereof wherein:

[0079] R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;

[0080] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CFhORb, halo, hydroxyl, and hydroxyalkyl;

[0081] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

[0082] R6is hydrogen or substituted or unsubstituted alkyl; and

[0083] R7, R8, and R9are each independently hydrogen or alkyl, preferably wherein the compound comprises at least one D-amino acid residue.

[0084] In certain embodiments, the invention provides a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is not:

[0085] In certain embodiments, R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl; R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -0Rb, hydroxyalkyl, -CH20Rb, and halo;

[0086] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;

[0087] R6is hydrogen or substituted or unsubstituted alkyl; and

[0088] R7, R8, and R9are each independently hydrogen or alkyl.

[0089] In some embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -N02, =N-0H, -N3, -Ra, -0Ra, -SRa, -N(Ra)2, -N(Ra)3+, =NRa, -NHC(=O)RC, -C(=O)RC, -C(=0)N(Ra)2, -S(=O)2RC, -OS(=O)2ORa, -S(=O)2ORa, - S(=O)2N(Ra)2, -S(=O)RC, -OP(=O)(ORa)2, -(alkylene)-C(=O)Rc, -C(=S)RC, -C(=O)ORa, - (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, - C(=S)N(Ra)2, and -C(-NRa)N(Ra)2;

[0090] Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and

[0091] Rc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0092] In more particular embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -0Ra, -N(Ra)2, -N(Ra)3+, -NHC(=O)RC, -C(=O)RC, - C(=0)N(Ra)2, -C(=0)0Ra, -(alkylene)-C(=O)ORa, and -(alkylene)-C(=O)N(Ra)2;

[0093] Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and

[0094] Rc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0095] In certain such embodiments, Ra, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; and Rc, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

[0096] In certain embodiments, the compound has the structure of formula (I-10L): Alternatively, the compound may have the structure of formula (I-10D):

[0097] In certain embodiments, R1is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

[0098] More specifically, R1may be selected from substituted or unsubstituted alkyl,

[0099] Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0100] Exemplary R1groups include

[0101] In some preferred embodiments, alternative preferred embodiments,

[0102] In certain embodiments, the compound has the structure of formula (I- IL):

[0103] Alternatively, the compound may have the structure of formula (I- ID)

[0104] In certain embodiments, R2is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

[0105] In some embodiments, R2is selected from hydrogen, substituted or unsubstituted

[0106] Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0107] Preferably, R2is hydrogen.

[0108] In certain embodiments, the compound has the structure of formula (I-2L): Alternatively, the compound may have the structure of formula (I-2D):

[0109] In certain embodiments, R3is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R3is selected from substituted or unsubstituted alkyl,

[0110] Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0111] In certain embodiments, the compound has the structure of formula (I-3L):

[0112] Alternatively, the compound may have the structure of formula (I-3D):

[0113] In certain embodiments, p is 1 or 2; and R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl.

[0114] In certain embodiments, p is 1 or 2; and R4, independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.

[0115] In certain preferred embodiments, R4is hydroxyl. In alternative preferred embodiments, R4is -CH3.

[0116] In any of the above embodiments, p may be 1.

[0117] In certain embodiments, the compound has the structure of formula (I-4Lg):

[0118] 4Lg).

[0119] In certain embodiments, the compound has the structure of formula (I-4La):

[0120] In certain embodiments, the compound has the structure of formula (I-4Lc): In certain embodiments, the compound has the structure of formula (I-4Lc), provided that R4is not hydroxyl.

[0121] In certain embodiments, the compound has the structure of formula (I-4Dg):

[0122] 4Da).

[0123] In certain embodiments, the compound has the structure of formula (I-4Db):

[0124] 4Db).

[0125] In certain embodiments, the compound has the structure of formula (I-4Dc): 4Dc).

[0126] In certain embodiments, the compound has the structure of formula (I-4Dc), provided that R4is not hydroxyl.

[0127] In certain embodiments, R4is oxo.

[0128] In certain embodiments, the compound has the structure of formula (I-4Ld):

[0129] 4Ld).

[0130] In certain embodiments, the compound has the structure of formula (I-4Le):

[0131] 4Le). In certain embodiments, the compound has the structure of formula (I-4Dd):

[0132] In certain embodiments, the compound has the structure of formula (I-4De):

[0133] 4De). In certain embodiments, R6is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH2. In certain embodiments, wherein R6is alkyl optionally substituted with one occurrence of -C(=O)NH2. For example, R6may be -CH3.

[0134] Alternatively, R6may In certain embodiments, the compound has the structure of formula (I-6L):

[0135] 6L).

[0136] Alternatively, the compound may have the structure of formula (I-6D): 6D).

[0137] In certain embodiments, R7is (Ci-Cio)alkyl, preferably

[0138] In certain embodiments, the compound has the structure of formula (I-7L):

[0139] 7L). Alternatively, the compound may have the structure of formula (I-7D):

[0140] 7D). In certain embodiments, the compound has the structure of formula (I-11L):

[0141] 11L).

[0142] Alternatively, the compound may have the structure of formula (1-1 ID):

[0143] 11D).

[0144] In certain embodiments, R8is -CH3 or -H, preferably -H.

[0145] In certain embodiments, R9is -CH3 or -H, preferably -H.

[0146] In certain embodiments, the compound comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight D-amino acid residues.

[0147] In certain embodiments, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

[0148]

[0149]

[0150] Hyp Gly Gin Leu Gly Leu Ala Gly Pro Leu

[0151] (2S,4R)

[0152] Hyp Gly Gin Leu Gly Leu Ala Gly Pro Gin

[0153] (2S,4R)

[0154] Hyp Gly Gin Leu Gly Leu Ala Gly Pro Nle(6-OH) (2S,4R)

[0155] D-Hyp Ala Gin Leu Gly Leu Ala Gly Pro Ala

[0156] (2R,4S)

[0157] The present invention also provides a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;

[0158] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CH2ORb, halo, hydroxyl, and hydroxyalkyl;

[0159] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

[0160] R6is hydrogen or substituted or unsubstituted alkyl; and

[0161] R7, R8, and R9are each independently hydrogen or alkyl; wherein at least one of:

[0162] (a) at least one of R1, R2, and R3is substituted or unsubstituted (C2-Cio)haloalkyl;

[0163] (b) at least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is substituted with one or more substituents selected from -Ra, -ORa, -SRa, -N(Ra)2, -N(Ra)3+, =NRa, -NHC(=O)RC, -C(=O)RC, -C(=O)N(Ra)2, -S(=O)2RC, -OS(=O)2ORa, -S(=O)2ORa, - S(=O)2N(Ra)2, -S(=O)RC, -OP(=O)(ORa)2, -(alkylene)-C(=O)Rc, -C(=S)RC, -C(=O)ORa, - (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, - C(=S)N(Ra)2, and -C(-NRa)N(Ra)2; and at least one occurrence of Raor Rcis heterocyclylalkyl, cycloalkyl, or (cy cloalky 1) alkyl ;

[0164] (c) the compound comprises at least one D-amino acid residue; or

[0165] (d) at least two occurrences of Ra; at least two occurrences of Rc; or at least one occurrence of Raand at least one occurrence of Rc; and at least one occurrence of Raand / or Rcdiffers from the other occurrences.

[0166] In certain embodiments, at least one of R1, R2, and R3is substituted or unsubstituted (C2-C10)haloalkyl.

[0167] In certain embodiments, at least one of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is substituted with one or more substituents selected from -Ra, -ORa, -SRa, -N(Ra)2, -N(Ra)3+, =NRa, -NHC(=O)RC, -C(=O)RC, -C(=O)N(Ra)2, -S(=O)2RC, -OS(=O)2ORa, -S(=O)2ORa, - S(=O)2N(Ra)2, -S(=O)RC, -OP(=O)(ORa)2, -(alkylene)-C(=O)Rc, -C(=S)RC, -C(=O)ORa, - (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, - C(=S)N(Ra)2, and -C(-NRa)N(Ra)2; and at least one occurrence of Raor Rcis heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0168] In certain embodiments, the compound comprises at least one D-amino acid residue.

[0169] In certain embodiments, the compound has: at least two occurrences of Ra; at least two occurrences of Rc; or at least one occurrence of Raand at least one occurrence of Rc; and at least one occurrence of Raand / or Rcdiffers from the other occurrences.

[0170] In certain embodiments:

[0171] R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl;

[0172] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -0Rb, hydroxyalkyl, -CthOR13, and halo;

[0173] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl;

[0174] R6is hydrogen or substituted or unsubstituted alkyl; and

[0175] R7, R8, and R9are each independently hydrogen or alkyl.

[0176] In some embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -N02, =N-0H, -N3, -Ra, -0Ra, -SRa, -N(Ra)2, -N(Ra)3+, =NRa, -NHC(=O)RC, -C(=O)RC, -C(=0)N(Ra)2, -S(=O)2RC, -OS(=O)2ORa, -S(=O)2ORa, - S(=O)2N(Ra)2, -S(=O)RC, -OP(=O)(ORa)2, -(alkylene)-C(=O)Rc, -C(=S)RC, -C(=O)ORa, - (alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)-C(=O)N(Ra)2, - C(=S)N(Ra)2, and -C(-NRa)N(Ra)2;

[0177] Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and

[0178] Rc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

[0179] In more particular embodiments, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -0Ra, -N(Ra)2, -N(Ra)3+, -NHC(=O)RC, -C(=O)RC, - C(=0)N(Ra)2, -C(=0)0Ra, -(alkylene)-C(=O)ORa, and -(alkylene)-C(=O)N(Ra)2; Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl; and Rc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl. In certain such embodiments, Ra, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl; and Rc, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

[0180] In certain embodiments, the compound has the structure of formula (I-10L): Alternatively, the compound may have the structure of formula (I-10D):

[0181] In certain embodiments, R1is substituted or unsubstituted (C2-Cio)haloalkyl.

[0182] In certain embodiments, R1is substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl. More specifically, R1may be selected from substituted or unsubstituted alkyl,

[0183] Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3. Exemplary R1groups include ,

[0184] In certain embodiments, the compound has the structure of formula (I- IL):

[0185] Alternatively, the compound may have the structure of formula (I- ID) In certain embodiments, R2is substituted or unsubstituted (C2-Cio)haloalkyl.

[0186] In certain embodiments, R2is H or substituted or unsubstituted alkyl, arylalkyl, or heterocyclylalkyl.

[0187] In some embodiments, R2is selected from hydrogen, substituted or unsubstituted Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3. Exemplary R2groups include

[0188] Preferably, R2is hydrogen.

[0189] In certain embodiments, the compound has the structure of formula (I-2L):

[0190] Alternatively, the compound may have the structure of formula (I-2D):

[0191] In certain embodiments, R3is substituted or unsubstituted (C2-Cio)haloalkyl.

[0192] In certain embodiments, R3is substituted or unsubstituted alkyl or arylalkyl. In some embodiments, R3is selected from substituted or unsubstituted alkyl,

[0193] Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

[0194] In certain embodiments, the compound has the structure of formula (I-3L):

[0195] Alternatively, the compound may have the structure of formula (I-3D):

[0196] In certain embodiments, p is 1 or 2; and R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl.

[0197] In certain embodiments, p is 1 or 2; and R4, independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.

[0198] In certain preferred embodiments, R4is hydroxyl. In alternative preferred embodiments, R4is -CH3.

[0199] In any of the above embodiments, p may be 1.

[0200] In certain embodiments, the compound has the structure of formula (I-4Lg):

[0201] 4Lg).

[0202] In certain embodiments, the compound has the structure of formula (I-4La):

[0203] In certain embodiments, the compound has the structure of formula (I-4Lb):

[0204] In certain embodiments, the compound has the structure of formula (I-4Lc):

[0205] 4Lc).

[0206] In certain embodiments, the compound has the structure of formula (I-4Lc), provided that R4is not hydroxyl.

[0207] In certain embodiments, the compound has the structure of formula (I-4Dg):

[0208] 4Dg).

[0209] In certain embodiments, the compound has the structure of formula (I-4Da):

[0210] 4Da).

[0211] In certain embodiments, the compound has the structure of formula (I-4Db):

[0212] 4Db).

[0213] In certain embodiments, the compound has the structure of formula (I-4Dc):

[0214] 4Dc).

[0215] In certain embodiments, the compound has the structure of formula (I-4Dc), provided that R4is not hydroxyl.

[0216] In certain embodiments, R4is oxo.

[0217] In certain embodiments, the compound has the structure of formula (I-4Ld):

[0218] 4Ld).

[0219] In certain embodiments, the compound has the structure of formula (I-4Le): 4Le).

[0220] In certain embodiments, the compound has the structure of formula (I-4Dd):

[0221] In certain embodiments, the compound has the structure of formula (I-4De): 4De).

[0222] In certain embodiments, R6is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH2. In certain embodiments, wherein R6is alkyl optionally substituted with one occurrence of -C(=O)NH2. For example, R6may be -CH3.

[0223] Alternatively, R6may In certain embodiments, the compound has the structure of formula (I-6L):

[0224] 6L).

[0225] Alternatively, the compound may have the structure of formula (I-6D):

[0226] 6D).

[0227] In certain embodiments, R7is (Ci-Cio)alkyl, preferably

[0228] In certain embodiments, the compound has the structure of formula (I-7L): L).

[0229] Alternatively, the compound may have the structure of formula (I-7D): D). In certain embodiments, the compound has the structure of formula (I-11L):

[0230] 11L).

[0231] Alternatively, the compound may have the structure of formula (1-1 ID): 11D).

[0232] In certain embodiments, R8is -CH3 or -H, preferably -H.

[0233] In certain embodiments, R9is -CH3 or -H, preferably -H. In certain embodiments, the compound is pharmaceutically acceptable salt thereof.

[0234] In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me).

[0235] In certain such embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

[0236] The peptide may be a variant of a collagen type II al-derived peptide. The collagen type II al may be isolated from the extracellular matrix derived from animal chondrocytes.

[0237] The term “peptide” used in the present invention refers to a compound in which two or more amino acids are linked by a peptide bond. Further, it is classified into dipeptide, tripeptide, tetrapeptide, and the like according to the number of constituent amino acids. An oligopeptide has about 10 or fewer peptide bonds, and a polypeptide has a plurality of peptide bonds. In addition, a peptide in the present invention includes a mutated peptide in which its amino acid residue is substituted.

[0238] The term “HyP” used in the present invention refers to an amino acid called hydroxyproline, in which a hydroxyl group (-OH) is bonded to the carbon atom at the 4- position of proline. HyP has a structure of C5H9NO3 and may be depicted as follows: may include all isomers. In addition, HyP may be an isomer represented by the stereochemistry of “2S,4R” unless otherwise specified.

[0239] The term “homo-Ser” used in the present invention is called homoserine and refers to an a-amino acid having a hydroxyl group in the side chain. Homo-Ser is an intermediate present in the biosynthesis of threonine and methionine in microorganisms and plants. Homo-

[0240] HO

[0241] Ser may be depicted as follows:

[0242] The term “Asp(Me)” used in the present invention indicates an amino acid in which the hydrogen atom of the hydroxyl group (OH) bonded to the carbon atom at the 4-position of aspartic acid is substituted by a methyl group (CH3). Asp(Me) may be depicted as follows:

[0243] The term “Asn(Me)” used in the present invention indicates an amino acid in which the hydrogen atom of the amine group (NH2) bonded to the carbon atom at the 4-position of asparagine is substituted by a methyl group (CH3). Asn(Me) may be depicted as follows:

[0244] The term “(N-Me)Gly” used in the present invention indicates an amino acid in which the hydrogen atom of the amine group (NH2) bonded to the carbon atom at the 2-position of glycine is replaced by a methyl group (CH3). (N-Me)Gly may be depicted as follows:

[0245] In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Asp-Xaa-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xaa is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly.

[0246] In certain such embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

[0247] In certain embodiments, the compound is a peptide having an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Xaa; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xaa is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-0H). In certain such embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

[0248] In certain embodiments, the compound is a peptide having an amino acid sequence represented by Xaa-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xaa is selected from:

[0249] In certain such embodiments, at least one, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

[0250] In certain embodiments, the invention provides a compound having the following pharmaceutically acceptable salt thereof.

[0251] In certain embodiments, the invention provides a compound represented by Formula (V): or a pharmaceutically acceptable salt thereof; wherein: R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;

[0252] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;

[0253] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

[0254] R6is hydrogen or substituted or unsubstituted alkyl; and

[0255] R9is hydrogen or alkyl.

[0256] In certain embodiments, R1and R2are each independently H or substituted or unsubstituted alkyl;

[0257] R4for each occurrence is hydroxyl; p is 1;

[0258] R6is alkyl optionally substituted with one occurrence of -C(=O)NH2; and

[0259] R9is hydrogen.

[0260] In certain embodiments, R1is substituted or unsubstituted alkyl, such

[0261] In certain embodiments, the compound has the structure of formula (V-1L)

[0262] Alternatively, the compound may have the structure of formula (V-1D)

[0263] In certain embodiments, R2is H.

[0264] In certain embodiments, p is 1 and R4is hydroxyl.

[0265] In certain embodiments, the compound has the structure of formula (V-4La):

[0266] In certain embodiments, the compound has the structure of formula(V-4Lb):

[0267] In certain embodiments, the compound has the structure of formula (V-4Da):

[0268] In certain embodiments, the compound has the structure of formula (V-4Db):

[0269] In certain embodiments, R6is alkyl substituted with one occurrence of -C(=O)NH2, such

[0270] In certain embodiments, the compound has the structure of formula (V-6L): Alternatively, the compound may have the structure of formula (V-6D):

[0271] In certain embodiments, R9is -H.

[0272] In certain embodiments, the compound is selected from the following: pharmaceutically acceptable salt thereof.

[0273] In certain embodiments, the invention provides a compound represented by Formula (VI): or a pharmaceutically acceptable salt thereof; wherein:

[0274] R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl

[0275] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;

[0276] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

[0277] R6is hydrogen or substituted or unsubstituted alkyl;

[0278] R7is hydrogen or alkyl; and

[0279] R9is hydrogen or alkyl. In certain embodiments, the invention provides a compound represented by Formula

[0280] (VI), wherein the compound is not:

[0281] Hyp Gly Gin Leu Gly Leu D-Hyp Gly D-GIn D-Leu Gly D-Leu

[0282] (2S,4R) or <2R-4S)

[0283] In certain embodiments: R1and R2are each independently H or substituted or unsubstituted alkyl;

[0284] R4for each occurrence is hydroxyl; p is 1;

[0285] R6is alkyl optionally substituted with one occurrence of -C(=0)NH2; and R9is hydrogen. In certain embodiments, R1is substituted or unsubstituted alkyl, such

[0286] In certain embodiments, the compound has the structure of formula (VI- IL)

[0287] Alternatively, the compound may have the structure of formula (VI- ID)

[0288] In certain embodiments, R2is H.

[0289] In certain embodiments, p is 1 and R4is hydroxyl.

[0290] In certain embodiments, the compound has the structure of formula (VI-4La):

[0291] In certain embodiments, the compound has the structure of formula(VI-4Lb):

[0292] In certain embodiments, the compound has the structure of formula (VI-4Da):

[0293] In certain embodiments, the compound has the structure of formula (VI-4Db):

[0294] In certain embodiments, R6is alkyl substituted with one occurrence of -C(=O)NH2, such

[0295] In certain embodiments, the compound has the structure of formula (VI-6L): Alternatively, the compound may have the structure of formula (VI-6D):

[0296] In certain embodiments, R9is -H.

[0297] In certain embodiments, R7is (Ci-Cio)alkyl, such

[0298] In certain embodiments, the compound has the structure of formula (VI-7L): Alternatively, the compound may have the structure of formula (VI-7D):

[0299] In certain embodiments, the invention provides a compound represented by Formula (VII): or a pharmaceutically acceptable salt thereof; wherein:

[0300] R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;

[0301] R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CH20Rb, halo, hydroxyl, and hydroxyalkyl;

[0302] Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;

[0303] R6is hydrogen or substituted or unsubstituted alkyl;

[0304] R7is hydrogen or alkyl; and

[0305] R9is hydrogen or alkyl.

[0306] In certain embodiments:

[0307] R1and R2are each independently H or substituted or unsubstituted alkyl;

[0308] R4for each occurrence is hydroxyl;

[0309] P is 1;

[0310] R6is alkyl optionally substituted with one occurrence of -C(=O)NH2; and

[0311] R9is hydrogen.

[0312] In certain embodiments, R1is substituted or unsubstituted alkyl, such

[0313] In certain embodiments, the compound has the structure of formula (VII- IL)

[0314] Alternatively, the compound may have the structure of formula (VII- ID)

[0315] In certain embodiments, R2is H. In certain embodiments, p is 1 and R4is hydroxyl.

[0316] In certain embodiments, the compound has the structure of formula (VII-4La):

[0317] In certain embodiments, the compound has the structure of formula(VII-4Lb):

[0318] In certain embodiments, the compound has the structure of formula (VII-4Da):

[0319] In certain embodiments, the compound has the structure of formula (VII-4Db):

[0320] In certain embodiments, R6is alkyl substituted with one occurrence of -C(=O)NH2, such In certain embodiments, the compound has the structure of formula (VII-6L):

[0321] Alternatively, the compound may have the structure of formula (VII-6D): In certain embodiments, R9is -H.

[0322] In certain embodiments, R7is (Ci-Cio)alkyl, such

[0323] In certain embodiments, the compound has the structure of formula (VII-7L):

[0324] Alternatively, the compound may have the structure of formula (VII-7D):

[0325] In certain embodiments, the compound has the structure of formula (VII-10L):

[0326] Alternatively, the compound may have the structure of formula VII- 10D): The invention also provides a salt of a compound represented by Formula 8: [Formula s]; and a salt of a compound represented by Formula 10: [Formula 10]. Detailed experimental procedures outlining the synthesis and characterization of the compounds of the invention are found in WO 2018 / 225961 and WO 2020 / 099925, both of which are herein incorporated by reference in their entireties.

[0327] The table below provides a list of exemplary compounds useful in the methods of the invention.

[0328] [Table 1]

[0329]

[0330] In certain embodiments, the compound may be a prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, a carboxylic acid present in the parent compound is presented as an ester, or an amino group is presented as an amide. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

[0331] In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.

[0332] The compounds of the invention have more than one stereocenter. Accordingly, the compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de. In certain embodiments, the compounds of the invention have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configurations at the remaining stereogenic centers.

[0333] In certain embodiments, the enantiomeric excess of a given stereocenter in the compound is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 92% ee, 94% ee, 95% ee, 96% ee, 98% ee or greater ee.

[0334] As used herein, single bonds drawn without stereochemistry do not indicate the stereochemistry of the compound. The compound of formula (I) provides an example of a compound for which no stereochemistry is indicated. As used herein, hashed or bolded wedge bonds indicate absolute stereochemical configuration.

[0335] In certain embodiments, a therapeutic preparation of the compound of the invention may be enriched to provide predominantly one enantiomer of a compound. An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

[0336] In certain embodiments, a therapeutic preparation may be enriched to provide predominantly one diastereomer of the compound of the invention. A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.

[0337] Methods of Treatment

[0338] In certain aspect, provided herein are methods of preventing or treating a chronic inflammatory lung disease or disorder comprising administering to the subject a compound disclosed herein.

[0339] In some embodiments, the chronic inflammatory lung disease or disorder is chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, bronchiectasis, cystic fibrosis, pulmonary alveolar microlithiasis, coal worker’s pneumoconiosis, asbestosis, pneumoconiosis due to talc dust, silicosis, aluminosis of lung, bauxite fibrosis of lung, berylliosis, graphite fibrosis of lung, siderosis, stannosis, pneumoconiosis associated with tuberculosis, byssinosis, flax-dresser’s disease, cannabinosis, bagassosis, bird fancier’s lung, suberosis, malt worker’s lung, mushroom- worker’s lung, maple-bark- stripper’s lung, airconditioner lung, humidifier lung, cheese-washer lung, coffee- worker lung, fishmeal- worker lung, furrier lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, fumes and vapors, pneumonitis due to solids and liquids, radiation pneumonitis, fibrosis of lung following radiation, chronic drug-induced interstitial lung disorders, pulmonary permeability edema, high-altitude pulmonary edema, eosinophilic asthma, Loftier’ s pneumonia, tropical pulmonary eosinophilia, alveolar and parietoalveolar conditions, Hamman-Rich syndrome, abscess of lung with pneumonia, pyothorax, pleural plaque, pneumothorax, chylous effusion, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary insufficiency following surgery, chronic lung allograft dysfunction, chronic lung allograft dysfunction - bronchiolitis obliterans syndrome, lung ischemia reperfusion injury, primary graft dysfunction after lung transplantation, Mendelson’s syndrome, pulmonary collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensatory emphysema, mediastinitis, congenital pneumonia due to viral agent, congenital pneumonia due to Chlamydia, congenital pneumonia due to Staphylococcus, congenital pneumonia due to Streptococcus group B, congenital pneumonia due to Escherichia coli, congenital pneumonia due to Pseudomonas, congenital pneumonia due to Haemophilus influenzae, congenital pneumonia due to Klebsiella pneumoniae, congenital pneumonia due to Mycoplasma, neonatal aspiration of meconium, interstitial emphysema originating in the perinatal period, pneumothorax originating in the perinatal period, pneumomediastinum originating in the perinatal period, pulmonary hemorrhage originating in the perinatal period, or Wilson-Mikity syndrome.

[0340] In some preferred embodiments, the chronic inflammatory lung disease or disorder is emphysema, chronic bronchitis. In further preferred embodiments, the chronic inflammatory lung disease is COPD.

[0341] In some embodiments, administering a compound described herein increases the level of regulatory T cells in the subject.

[0342] In some embodiments, regulatory T cells include cells that are CD3+, CD8-, CD25+, and Foxp3+.

[0343] In some embodiments, administering the compound to the subject increases the level of IL-10-producing regulatory T cells in the subject.

[0344] In some embodiments, regulatory T cells include cells that are CD3+, CD8-, CD25+, Foxp3+, and IL-10+.

[0345] In some embodiments, administering the compound to the subject increases expression of IL- 10 in the subject.

[0346] In some embodiments, administering the compound to the subject decreases the level of effector T-cells in the subject.

[0347] In some embodiments, administering the compound to the subject decreases the level of Thl7 cells in the subject. In some embodiments, Thl7 cells include cells that are CD3+, CD8-, and IL-17+.

[0348] In some embodiments, administering the compound to the subject decreases the level of Th2 cells in the subject.

[0349] In some embodiments, Th2 cells include cells that are CD3+, CD8-, and IL-4+.

[0350] In some embodiments, administering the compound to the subject prevents and / or treats scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

[0351] In some preferred embodiments, administering the compound to the subject prevents and / or treats scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

[0352] In some embodiments, the subject has elevated levels of IL- la, IL-ip, IL-2, IL-6, IL- 8, TNF-α, MMP3, CCL-2, CCL-3, CCL-4, Fas, TIMP-1, or a Thl, Th2, and / or Thl7 derived cytokine or proinflammatory chemokine.

[0353] In another aspect, provided are methods of increasing levels of IL-10-producing regulatory T cells in a subject, in need thereof, comprising administering to the subject a compound disclosed herein.

[0354] In another aspect, provided are methods of preventing or treating chronic obstructive pulmonary disease in a subject comprising administering to the subject a compound disclosed herein.

[0355] In another aspect, provided are methods of increasing IL- 10 expression, in a subject in need thereof, comprising administering to the subject a compound disclosed herein.

[0356] In another aspect, provided are methods of preventing or treating a disease selected from scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a compound disclosed herein.

[0357] In another aspect, provided are methods of preventing or treating a disease selected from scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a compound disclosed herein.

[0358] Pharmaceutical Compositions

[0359] In certain embodiments, the invention provides a pharmaceutical composition comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for topical administration to the eye, e.g., as eye drops.

[0360] In certain embodiments at least 50%, 60%, 70%, 80%, or 90% of the compound is present as a salt. Preferably, at least 95% of the compound is present as a salt. Even more preferably, at least 99% of the compound is present as a salt.

[0361] In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any salt or compound of the invention, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.

[0362] Certain embodiments of the present invention provide a pharmaceutical kit comprising a salt or compound of the invention, or a pharmaceutically acceptable salt thereof, and optionally directions on how to administer the compound.

[0363] The compositions and methods of the present invention may be utilized to treat a subject or individual in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In certain preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection, or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0364] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0365] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non- toxic compatible substances employed in pharmaceutical formulations.

[0366] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0367] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0368] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0369] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0370] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0371] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0372] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

[0373] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ (e.g., wheat germ), olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0374] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0375] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0376] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0377] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0378] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0379] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0380] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0381] The ointments, pastes, creams, and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0382] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0383] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0384] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0385] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0386] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0387] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0388] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0389] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0390] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0391] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0392] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0393] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0394] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher el al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0395] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0396] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0397] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

[0398] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[0399] In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., a compound of formula I, V, VI, or VII) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

[0400] This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, oxalic, mandelic and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I, V, VI, or VII. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I, V, VI, or VII per molecule of tartaric acid.

[0401] In further embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0402] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0403] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0404] EXAMPLES

[0405] The following examples are offered to illustrate, but not to limit.

[0406] Example 1: Anti-inflammatory effect(s) of YDE-048 on human adaptive cell responses

[0407] CD4+ T cells, together with CD8+ T cells and B cells, form part of the adaptive immune cell response and are responsible for responding to insults (infections, trauma, allergens etc) via secretion of cytokines which, in turn, activate / attract other cells to the site of infection. These CD4+ T cells typically make up 70% of the total T cell population (the rest are CD8+ T cells) and are key effector cells in immunity. They generally exist in subsets which reflect their role(s), and these cells can also adapt their function either to better deal with an infection or to allow them to function in an adverse microenvironment.

[0408] T helper type 1 (Thl) and T helper type 17 (Thl7) cells are involved in inflammation where they target specific cells / tissues. Thl and Thl7 activity can lead to damage to the host tissues, as occurs in T cell-mediated autoimmune diseases (e.g., Rheumatoid Arthritis, Autoimmune thyroiditis, and relapsing-remitting Multiple Sclerosis). In order to regulate Thl and Thl7-mediated immune responses, another CD4+ T cell subset, regulatory T cells (Treg), inhibit CD4+ T cell proliferation, dampening responses via secretion of one or both immunoregulatory cytokines IL- 10 and TGF|3. These cytokines can activate cells and promote inflammation, but are specifically downregulatory for CD4+ T cells.

[0409] The various CD4+ T cell subsets are identified by their expression of various proteins. Thl cells express CD4 and intracellular interferon-gamma (IFNy). Th 17 cells express CD4 and interleukin- 17 (IL-17). Th2 cells express CD4 and interleukins-4 and -13 (IL-4 and IL- 13). Treg cells express CD4, CD25, and FoxP3.

[0410] To identify the target inflammatory cells for peptide YDE-048, the direct effects of YDE-048 were investigated. Human immune cell levels were examined upon contact with two different concentrations of YDE-048. Briefly, healthy adult fresh human bloods collected in anti-coagulant tubes (n = 4 donors) were obtained, and peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density centrifugation. Isolated PBMCs were subsequently placed in culture and stimulated with either: saline as a negative control, Anti-CD3 / CD28 (to stimulate all mature T cells), or PMA + ionomycin (to stimulate all cells) for 24hr.

[0411] One hour prior to stimulation, YDE-048 was added (at 10 nM and 500 nM concentrations). Brefeldin A was added 4 hours before harvesting to prevent cytokine release by the cells. Cells were harvested at 24 hours post stimulation for immunophenotyping using cell surface markers combined with intracellular cytokine and transcription factor staining (using flow cytometry) to measure relative levels of CD4 (Thl, Th2, Thl7, Treg) & CD8 (Tel, Tc2, Tcl7 etc) T cell subsets or B cells (CD19), in comparison with vehicle-treated cells as controls.

[0412] Results

[0413] Thl7 cells were downregulated in response to YDE-048

[0414] A decrease in % of Thl7 cells was observed (identified as CD3+, CD8", IL-17A+) following pre-treatment with YDE-048 and subsequent stimulation with either anti- CD3 / CD28 or with PMA+Ionomycin. Although the overall levels of Thl7 cells in healthy human PBMC cultures were relatively low (<7%), a reproducible decrease in levels of Thl7 cells in all bloods was observed, including in response to anti-CD3 / 28 (where only the T cells were stimulated), suggesting that Thl7 cells were being directly targeted (FIG. 1).

[0415] To confirm this, enriched cultures of Thl7 cells were prepared by addition of cytokines that favour Th 17 survival and expansion during a 5-day period. PBMCs were cultured for 5 days in the presence of anti-CD3 / 28 with TGFP and IL-6 to promote Thl7 cells (36%). The enriched cultures were also found be susceptible to the inhibitory effects of YDE- 048, with approx. 25% decrease in Thl7 levels (FIG. 2; Table 2), suggesting that Thl7 cells were a target.

[0416] Table 2, Effects of YDE-048 on immune cell types

[0417] Th2 cells were downregulated by YDE-048

[0418] Similarly, a significant decrease in % Th2 (CD3+, CD8", IL-4+) cells (FIG. 1 and Table 2) in response to YDE-048 in comparison with vehicle controls was identified. By enriching for Th2 cells, an even greater decrease in Th2 levels following YDE-048 treatment was observed (data not shown).

[0419] IL-10-expressing regulatory T cells (Tree) were increased in response to YDE-048

[0420] The majority of adaptive immune responses consist of a delicate balance between effector cells (Thl, Thl7, Th2) and downregulatory (Treg) cells, and these cells are highly adaptable to changes in their local microenvironment.

[0421] In PBMC cultures, the baseline levels of Treg were low. However, they were detectable at higher levels in enriched Th 17 cultures. While no overall differences in levels of Treg (CD3+CD8'FoxP3+) in response to treatment with YDE-048 were observed, significant increases in levels of effector Treg (z.e., those expressing IL- 10; see Table 2 and FIG. 3) in those cultures that had been enriched for Thl7 cells were detected. YDE-048 had no overall effect on the levels of Treg (CD4+CD25+FoxP3+) but there was a significant increase in the proportion of IL-10-expressing Treg following co-culture with YDE-048 (n=6; mean % increase from baseline = 21%; P<0.04).

[0422] Effect of YDE-048 in vitro on human T cell cytokine secretion

[0423] Purified human mixed PBMC, enriched Thl7 & enriched Th2 cell cultures were prepared, treated with YDE-048 and stimulated with anti-CD3 / 28 to collect the supernatants at 24-72 hr post stimulation to quantify cytokine levels by multiplex bead array (Luminex). The cytokines measured simultaneously were IL-6, IL-10, IL-13, IL-17, TNFoc & IFNy. As can be seen from the results (FIG. 4A), two healthy PBMC were used, and there is often a slight variation in levels between donors. For IL- 10 secretion, levels were overall fairly low due to the mixed cell populations present in the cultures. Nevertheless, IL-10 levels were increased in both PBMC populations in response to YDE-048 treatment. In addition, in Thl7- enriched cultures, an increase in IL- 10 levels were detected following treatment with YDE- 048 in two of three experiments (FIG. 4B). For comparison, those same PBMC demonstrated decreases in levels of TNFoc following treatment with YDE-048 in the same cultures (FIG. 5).

[0424] Effect of YDE-048 in vitro on human T cell proliferation

[0425] In parallel cultures, PBMCs were pre-labelled with CFSE, a fluorescent dye that is taken up by viable cells, and cells were monitored for proliferation in response to anti- CD3 / 28 over 5 days by flow cytometry, with and without the presence of YDE-048, to determine its effect on promoting T cell subset proliferation. As shown in FIG. 6, in three separate bloods, there was a slight decrease in proliferation of labelled cells in the presence of YDE-048 at 500 nM although this varied between donors and therefore was not significantly different from untreated cells.

[0426] The data of this study suggest that percentages of Th2, Thl7 and IL-10-expressing Treg were significantly affected by YDE-048 in vitro, with IL-10-expressing Treg increased in response to YDE-048. This correlated with increases in levels of IL- 10 protein secreted. Activation levels of other immune cells (B cells, CD8+T cells, monocytes) did not appear to change following treatment.

[0427] TGFB secretion by human PBMCs in response to YDE-048 Another cytokine known to be secreted by regulatory T-cells is TGF|3, which suppresses effector T cell function, thus downregulating inflammatory responses. We investigated the effect of YDE-048 on secretion of TGFP by human PBMCs in the culture supernatants by Luminex. Purified human PBMC cultures were prepared, treated with YDE- 048 and stimulated with anti-CD3 / 28 and supernatants harvested at 24-72hr post stimulation to quantify TGFP levels in multiplex bead arrays (Luminex). There was a significant increase in levels of TGFP produced following exposure to YP-P10 (FIG. 7).

[0428] Example 2: Effects of YDE-048 on human peripheral blood mononuclear cells

[0429] Investigating the effects of YDE-048 on healthy human PBMC led to application of an ex vivo model using enriched Th 17 cells to study the anti-inflammatory function of YDE- 048. PBMCs were exposed to enrichment condition (IL6, IL23, TGFP, anti-IL4, anti-IFNg) for Thl7 enrichment. After 5 days post-enrichment, cells were treated for YDE-048 (500 nM) or saline for an overnight and stimulated with PMA / Ionomycin.

[0430] Enriched Thl7 cells treated with YDE048 (500 nM) showed a reduction (5.5%) in IL- 17 expression (FIG. 8 top panel shows gating on IL17 indication of Thl7). An increase (about 21%) in the level of CD4+CD25+Foxp3+IL-10+T cells (FIG. 8 middle and bottom panels show enriched Thl7 cells gated for CD25 marker and plotted for IL10 and Foxp3) was also observed. In parallel an increase in secreted TGFP and IL- 10 protein levels in the culture supernatants obtained from PBMC treated with YDE-048 using Luminex was detected (FIG. 9).

[0431] Looking at CCR6 as a potential specific receptor for Thl7 cells and, to a lesser extent in Th2 and Treg cells, the Treg signature in CCR6+positive cells was investigated. Enriched Thl7 cells from a healthy donor, treated with YDE-048 or vehicle is shown in FIG. 10. The cells were gated for CD25 and CCR6 markers and then plotted for IL- 10 and Foxp3. An increase of approximately 30% in CD4+CD25+CCR6+IL10+Foxp3+ cells was observed in YDE-048 (500 nM) treated cells.

[0432] Example 3: Differential gene expression induced by YDE-048

[0433] To address the question of whether YDE-048 directly affects Thl7 cells or whether another cell (monocyte, T cell etc) is involved, we performed a scRNAseq experiment on purified Thl7 cells (Donor A) and purified CD4+T cells (Donor B) in the presence and absence of YDE-048. Study Design

[0434] The following cell types were prepared. 30 ml of purified Thl7 cells (IxlO6) from healthy PBMC donor (Donor A). Purified CD4 T cells (4xl06) from health PBMC donor (Donor B). Overnight treatment with YDE-048 (500 nM) or with vehicle control in the presence of stimulation (PMA / Iono). Sample 1 (purified Th 17 cells, vehicle control treatment) consisted of 2,828 cells. Sample 2 (purified Thl7 cells, treatment with 500 nM YDE-048) consisted of 4,743 cells. Sample 3 (purified CD4 T cells, vehicle control treatment) consisted of 1,505 cells. Sample 4 (purified CD4 T cells, treatment with 500 nM YDE-048) consisted of 2,873 cells. Single-cell RNAseq was performed using 10X Genomics Chromium platform. Analysis was performed using Cell Ranger and Partek Flow.

[0435] Protocol: Thl7 cells were isolated from a healthy donor PBMC (30 ml) applying EasySep™ Human Enrichment Kit II (StemCell Tech, CA). Isolated Thl7 cells (IxlO6) were cultured in immunoCult-XF in the presence of YDE-048 (500 nM) or saline for an overnight. Cells were harvested after overnight stimulation with PMA / ionomycin as performed in previous experiments, and then prepared for quality control. A frozen sample of purified CD4+T cells, obtained commercially, was cultured at a density of IxlO6cell / ml (day 0) overnight in a chemically defined medium (ImmunoCult-XF) to allow the cells to recover after defrosting. On day 1, cells were treated with YDE-048 (500nM) or saline (vehicle control) for Ihr prior to adding PMA / ionomycin overnight, as described above.

[0436] Results

[0437] UMAP plots of Thl7-T cells (Thl7 cells in the absence and presence of YDE-048; Sample 1 (SI) and Sample 2 (S2), respectively) and CD4-T cells (CD4-T cells in the absence and presence of YDE-048; Sample 3 (S3) and Sample 4 (S4), respectively), are shown in FIGs. 11A-11B. The UMAP plots show similarities (close populations with similar gene expression) and differences between each cell population based on the distance between the clusters.

[0438] Principal component analysis (PCA) visualisations of individual samples (FIG. 12A) and an overlay of all samples together (FIG. 12B) is based on the variables (including gene expression profiles) used to create the graphs shown in FIG 17. In 3-dimensional PCA the overall relatedness and similarity of several data sets (gene expression profile) and how the data sets can be separated into different categories is visualized. PCI score shows the maximum variance and PC3 shows the minimum variance. The percentages represent abstract relative values for each.

[0439] A volcano plot of the differentially expressed genes in Thl7 cells treated with 500 nM YDE-048 compared to vehicle control is shown in FIG. 13A and in Table 3 below. A heatmap showing differentially expressed genes in Th 17 vehicle control (Sample 1) versus Thl7 YDE-048 treated (sample 2) cells is shown in FIG. 13B. Of 155 differentially expressed-genes, 102 genes were upregulated by YDE-048 treatment and 53 were downregulated in those samples (FIGs. 13A-13B). Table 3. Genes Impacted by YDE-048 in purified Thl7 cells.

[0440] A volcano plot of the differentially expressed genes in CD4 T cells treated with 500 nM YDE-048 compared to vehicle control is shown in FIG. 14A and in Table 4 below. A heatmap showing differentially expressed genes in CD4 vehicle control treated cells (sample 3) versus CD4 YDE-048 treated (sample 4) cells is shown in FIG. 14B. Of 58 differentially expressed-genes genes, 24 were upregulated by YDE-048 treatment and 34 were downregulated in those samples. This analysis is based on those genes that were statistically significantly different following YDE-048 treatment (P<0.01). Table 4. Genes Impacted by YDE-048 in purified CD4 T cells.

[0441] Of note, when the level of significance was reduced to P<0.05, a total of 378 genes in the Thl7 heatmap were altered, and IL- 10 appeared in the list using the P<0.05 level of significance. The number of overlapping genes that were differentially expressed in both cell types is shown in FIG. 15. FIG. 16 shows lists of differentially expressed genes in Thl7 cells, CD 4 T cells, and in both cell types. Scatter plots of selected genes involved in T cell function are provided in FIG. 17 for Samples 1-4. Arrows refer to more profound effect in scatter plots. IFNy is a Th 1 type inflammatory cytokine. CCL4 is related to TGF-Beta pathways and is involved in Glucocorticoid Regulation. IL4I1 is downregulated by YDE-048 and is a Metabolic Immune Checkpoint that involves in Foxp3 regulation and Treg function. By IL41I downregulation, Foxp3 can be functional. CTLA4 is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in regulatory T cells. F0X01 is essential for the development and function of Foxp3-expressing Treg cell. A bobble map (FIG. 18) illustrating the differentially expressed genes where the spot is larger when a more significant gene expression difference was observed. The selected genes are shown with their levels of expression in samples 1, 2, 3 and 4.

[0442] Incorporation by Reference

[0443] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0444] Equivalents

[0445] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMSWhat is claimed is:

1. A method of preventing or treating a chronic inflammatory lung disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of: i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:(X-am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula (8) or (10) or a pharmaceutically acceptable salt and / or prodrug thereof:ormu a iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-0H); andXdd is selected from:iv) a peptide, or a pharmaceutically acceptable salt thereof, having any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

2. The method of claim 1, wherein the chronic inflammatory lung disease or disorder is chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, bronchiectasis, cystic fibrosis, pulmonary alveolar microlithiasis, coal worker’s pneumoconiosis, asbestosis, pneumoconiosis due to talc dust, silicosis, aluminosis of lung, bauxite fibrosis of lung, berylliosis, graphite fibrosis of lung, siderosis, stannosis, pneumoconiosis associated with tuberculosis, byssinosis, flax-dresser’s disease, cannabinosis, bagassosis, bird fancier’s lung, suberosis, malt worker’s lung, mushroom- worker’s lung, maple-bark-stripper’s lung, air-conditioner lung, humidifier lung, cheese- washer lung, coffeeworker lung, fishmeal- worker lung, furrier lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, fumes and vapors,pneumonitis due to solids and liquids, radiation pneumonitis, fibrosis of lung following radiation, chronic drug-induced interstitial lung disorders, pulmonary permeability edema, high-altitude pulmonary edema, eosinophilic asthma, Loffler’s pneumonia, tropical pulmonary eosinophilia, alveolar and parietoalveolar conditions, Hamman-Rich syndrome, abscess of lung with pneumonia, pyothorax, pleural plaque, pneumothorax, chylous effusion, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary insufficiency following surgery, chronic lung allograft dysfunction, chronic lung allograft dysfunction - bronchiolitis obliterans syndrome, lung ischemia reperfusion injury, primary graft dysfunction after lung transplantation, Mendelson’s syndrome, pulmonary collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensatory emphysema, mediastinitis, congenital pneumonia due to viral agent, congenital pneumonia due to Chlamydia, congenital pneumonia due to Staphylococcus, congenital pneumonia due to Streptococcus group B, congenital pneumonia due to Escherichia coli, congenital pneumonia due to Pseudomonas, congenital pneumonia due to Haemophilus influenzae, congenital pneumonia due to Klebsiella pneumoniae, congenital pneumonia due to Mycoplasma, neonatal aspiration of meconium, interstitial emphysema originating in the perinatal period, pneumothorax originating in the perinatal period, pneumomediastinum originating in the perinatal period, pulmonary hemorrhage originating in the perinatal period, or Wilson-Mikity syndrome.

3. The method of any one of claim 1 or 2, wherein the chronic inflammatory lung disease or disorder is emphysema, chronic bronchitis, or COPD.

4. The method of any one of claims 1-3, wherein the chronic inflammatory lung disease is COPD.

5. The method of any one of claims 1-4, wherein administering the compound to the subject increases the level of regulatory T cells in the subject.

6. The method of any one of claims 1-5, wherein administering the compound to the subject increases the level of IL-10-producing regulatory T cells in the subject.

7. The method of any one of claims 1-6, wherein administering the compound to the subject increases expression of IL- 10 in the subject.

8. The method of any one of claims 1-7, wherein administering the compound to the subject decreases the level of Thl7 cells in the subject.

9. The method of any one of claims 1-8 wherein administering the compound to the subject decreases the level of Th2 cells in the subject.

10. The method of any one of claims 1-9, wherein the subject has elevated levels of IL- la, IL-10, IL-2, IL-6, IL-8, TNF-α, MMP3, CCL-2, CCL-3, CCL-4, Fas, TIMP-1, or a Thl, Th2, and / or a Thl7 derived cytokine or proinflammatory chemokine.

11. A method of increasing levels of IL-10-producing regulatory T cells in a subject in need thereof, comprising administering to the subject i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:(IX), or(X-am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula 8 or 10 or a pharmaceutically acceptable salt and / or prodrug thereof:[ ormu a ]iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH); and Xdd is selected from:iv) a peptide having any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

12. The method of claim 11, wherein administering the compound to the subject increases expression of IL- 10 in the subject.

13. The method of claim 11 or claim 12, wherein administering the compound to the subject decreases the level of effector T-cells in the subject.

14. The method of any one of claims 11-13, wherein administering the compound to the subject decreases the level of Thl7 cells in the subject.

15. The method of any one of claims 11-13, wherein administering the compound to the subject decreases the level of Th2 cells in the subject.

16. The method of any one of claims 11-15, wherein administering the compound to the subject prevents and / or treats a chronic inflammatory lung disease or disorder in the subject.

17. The method of claim 16, wherein the chronic inflammatory lung disease or disorder is chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, bronchiectasis, cystic fibrosis, pulmonary alveolar microlithiasis, coal worker's pneumoconiosis, asbestosis, pneumoconiosis due to talc dust, silicosis, aluminosis of lung, bauxite fibrosis of lung, berylliosis, graphite fibrosis of lung, siderosis, stannosis, pneumoconiosis associated with tuberculosis, byssinosis, flax-dresser's disease, cannabinosis, bagassosis, bird fancier's lung, suberosis, malt worker’s lung, mushroom-worker's lung, maple-bark-stripper's lung, air-conditioner lung, humidifier lung, cheese-washer lung, coffeeworker lung, fishmeal- worker lung, furrier lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, fumes and vapors, pneumonitis due to solids and liquids, radiation pneumonitis, fibrosis of lung following radiation, chronic drug-induced interstitial lung disorders, pulmonary permeability edema, high-altitude pulmonary edema, eosinophilic asthma, Loffler’s pneumonia, tropical pulmonary eosinophilia, alveolar and parietoalveolar conditions, Hamman-Rich syndrome, abscess of lung with pneumonia, pyothorax, pleural plaque, pneumothorax, chylous effusion, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary insufficiency following surgery, chronic lung allograft dysfunction, chronic lung allograft dysfunction - bronchiolitis obliterans syndrome, lung ischemia reperfusion injury, primary graft dysfunction after lung transplantation, Mendelson's syndrome, pulmonary collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensatory emphysema, mediastinitis, congenital pneumonia due to viral agent, congenital pneumonia due to Chlamydia, congenital pneumonia due to Staphylococcus, congenital pneumonia due to Streptococcus group B, congenital pneumonia due to Escherichia coli, congenital pneumonia due to Pseudomonas, congenital pneumonia due to Haemophilus influenzae, congenital pneumonia due to Klebsiella pneumoniae, congenital pneumonia due to Mycoplasma,neonatal aspiration of meconium, interstitial emphysema originating in the perinatal period, pneumothorax originating in the perinatal period, pneumomediastinum originating in the perinatal period, pulmonary hemorrhage originating in the perinatal period, or Wilson-Mikity syndrome.

18. The method of claim 16 or 17, wherein the chronic inflammatory lung disease or disorder is emphysema, chronic bronchitis, or COPD.

19. The method of any one of claims 16-18, wherein the chronic inflammatory lung disease or disorder is COPD.

20. The method of any one of claims 11-15, wherein administering the compound to the subject prevents and / or treats scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

21. The method of any one of claims 11-15, wherein administering the compound to the subject prevents and / or treats scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

22. The method of any one of claims 11-21, wherein the subject has elevated levels of IL- la, IL-10, IL-2, IL-6, IL-8, TNF-α, MMP3, CCL-2, CCL-3, CCL-4, Fas, TIMP-1, or a Thl, Th2, and / or a Thl7 derived cytokine or proinflammatory chemokine.

23. A method of preventing or treating chronic obstructive pulmonary disease in a subject, comprising administering to the subject i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:(X-am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula (8) or (10) or a pharmaceutically acceptable salt and / or prodrug thereof:iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH); andXdd is selected from:iv) a peptide having any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

24. The method of claim 23, wherein administering the compound to the subject increases the level of regulatory T cells in the subject.

25. The method of claim 23 or 24, wherein administering the compound to the subject increases the level of IL-10-producing regulatory T cells in the subject.

26. The method of any one of claims 23-25, wherein administering the compound to the subject increases expression of IL- 10 in the subject.

27. The method of any one of claims 23-26, wherein administering the compound to the subject decreases the level of Thl7 cells in the subject.

28. The method of any one of claims 23-27, wherein administering the compound to the subject decreases the level of Th2 cells in the subject.

29. The method of any one of claims 23-28, wherein the subject has elevated levels of IL- la, IL-10, IL-2, IL-6, IL-8, TNF-α, MMP3, CCL-2, CCL-3, CCL-4, Fas, TIMP-1, or a Thl, Th2, and / or a Thl7 derived cytokine or proinflammatory chemokine.

30. A method of increasing IL- 10 expression in a subject in need thereof, comprising administering to the subject i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula (8) or (10) or a pharmaceutically acceptable salt and / or prodrug thereof:ormu a ] iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH); andXdd is selected from:iv) a peptide having any one amino acid sequence selected from: Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

31. The method of claim 30, wherein administering the compound increases IL- 10 expression in a subject by at least 30% relative to an untreated control.

32. The method of claim 30, wherein administering the compound increases IL- 10 expression in a subject by at least 50% relative to an untreated control.

33. The method of claim 30, wherein administering the compound increases IL- 10 expression in a subject by at least 70% relative to an untreated control.

34. The method of any one of claims 30-33, wherein administering the compound to the subject increases the level of regulatory T cells in the subject.

35. The method of claim 34, wherein administering the compound to the subject increases the level of IL-10-producing regulatory T cells in the subject.

36. The method of claim 34 or 35, wherein administering the compound to the subject decreases the level of effector T-cells in the subject.

37. The method of any one of claims 30-36, wherein administering the compound to the subject decreases the level of Thl7 cells in the subject.

38. The method of any one of claims 30-36, wherein administering the compound to the subject decreases the level of Th2 cells in the subject.

39. The method of any one of claims 30-38, wherein administering the compound to the subject prevents and / or treats a chronic inflammatory lung disease or disorder in the subject.

40. The method of claim 39, wherein the inflammatory disease or disorder is chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, bronchiectasis,cystic fibrosis, pulmonary alveolar microlithiasis, coalworker’s pneumoconiosis, asbestosis, pneumoconiosis due to talc dust, silicosis, aluminosis of lung, bauxite fibrosis of lung, berylliosis, graphite fibrosis of lung, siderosis, stannosis, pneumoconiosis associated with tuberculosis, byssinosis, flax-dresser’s disease, cannabinosis, bagassosis, bird fancier’s lung, suberosis, malt worker’s lung, mushroom- worker’s lung, maple-bark- stripper’s lung, airconditioner lung, humidifier lung, cheese-washer lung, coffee- worker lung, fishmeal- worker lung, furrier lung, sequiosis, allergic alveolitis, hypersensitivity pneumonitis, respiratory conditions due to inhalation of chemicals, gases, fumes and vapors, pneumonitis due to solids and liquids, radiation pneumonitis, fibrosis of lung following radiation, chronic drug-induced interstitial lung disorders, pulmonary permeability edema, high-altitude pulmonary edema, eosinophilic asthma, Loffler’s pneumonia, tropical pulmonary eosinophilia, alveolar and parietoalveolar conditions, Hamman-Rich syndrome, abscess of lung with pneumonia, pyothorax, pleural plaque, pneumothorax, chylous effusion, fibrothorax, hemothorax, hemopneumothorax, hydrothorax, chronic pulmonary insufficiency following surgery, chronic lung allograft dysfunction, chronic lung allograft dysfunction - bronchiolitis obliterans syndrome, lung ischemia reperfusion injury, primary graft dysfunction after lung transplantation, Mendelson’s syndrome, pulmonary collapse, atelectasis, interstitial emphysema, mediastinal emphysema, compensatory emphysema, mediastinitis, congenital pneumonia due to viral agent, congenital pneumonia due to Chlamydia, congenital pneumonia due to Staphylococcus, congenital pneumonia due to Streptococcus group B, congenital pneumonia due to Escherichia coli, congenital pneumonia due to Pseudomonas, congenital pneumonia due to Haemophilus influenzae, congenital pneumonia due to Klebsiella pneumoniae, congenital pneumonia due to Mycoplasma, neonatal aspiration of meconium, interstitial emphysema originating in the perinatal period, pneumothorax originating in the perinatal period, pneumomediastinum originating in the perinatal period, pulmonary hemorrhage originating in the perinatal period, or Wilson-Mikity syndrome.

41. The method of claim 39 or 40, wherein the chronic inflammatory lung disease or disorder is emphysema, chronic bronchitis, or COPD.

42. The method of any one of claims 39-41, wherein the chronic inflammatory lung disease or disorder is COPD.

43. The method of any one of claims 30-38, wherein administering the compound to the subject prevents and / or treats scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

44. The method of any one of claims 30-38, wherein administering the compound to the subject prevents and / or treats scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, or peanut allergy in the subject.

45. The method of any one of claims 30-44, wherein the subject has elevated levels of IL- la, IL-10, IL-2, IL-6, IL-8, TNF-α, MMP3, CCL-2, CCL-3, CCL-4, Fas, TIMP-1, or a Thl, Th2, and / or a Thl7 derived cytokine or proinflammatory chemokine.

46. The method of any one of claims 1-45, wherein the compound is selected from the following:NH2Hyp Gly Gin Asp lie Leu Ala Gly Pro Lys(2S,4R)Hyp Gly Gin Leu Gly Leu Ala Gly Pro Tyr(2S,4R)IllHyp Gly Gin Leu Gly Leu Ala Gly Pro Glu (2S,4R)Hyp Gly Gin Leu Gly Leu Ala Gly Pro Nle(6-OH)(2S,4R)(4-Fluoro)Pro Gly Gin Leu Gly Leu Ala Gly Pro Lys(4R)or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 1-45, wherein the compound is selected from the following:pharmaceutically acceptable salt thereof.

48. The method of any one of claims 1-45, wherein the compound is represented by Formula (I):or a pharmaceutically acceptable salt and / or prodrug thereof, wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CH20Rb, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl; and R7, R8, and R9are each independently hydrogen or alkyl.

49. The method of claim 48, wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, arylalkyl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, oxo, hydroxyl, -0Rb, hydroxyalkyl, -CH20Rb, and halo;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl;R6is hydrogen or substituted or unsubstituted alkyl; and R7, R8, and R9are each independently hydrogen or alkyl.

50. The method of claim 48 or 49, wherein, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -CN, -NO2, =N-0H, -N3, -Ra, -0Ra, -SRa, -N(Ra)2, - N(Ra)3+, =NRa, -NHC(=O)RC, -C(=O)RC, -C(=0)N(Ra)2, -S(=O)2RC, -OS(=O)2ORa, - S(=O)2ORa, -S(=O)2N(Ra)2, -S(=O)RC, -OP(=O)(ORa)2, -(alkylene)-C(=O)Rc, -C(=S)RC, - C(=0)0Ra, -(alkylene)-C(=O)ORa, -C(=S)ORa, -C(=O)SRa, -C(=S)SRa, -(alkylene)- C(=0)N(Ra)2, -C(=S)N(Ra)2, and -C(-NRa)N(Ra)2;Ra, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocyclo alkyl) alkyl; andRc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

51. The method of any one of claims 48-50, wherein, where indicated, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl is unsubstituted or is substituted with one or more substituents selected from halo, haloalkyl, oxo, -Ra, -ORa, -N(Ra)2, -N(Ra)3+, -NHC(=O)RC, -C(=O)RC, - C(=0)N(Ra)2, -C(=0)0Ra, -(alkylene)-C(=O)ORa, and -(alkylene)-C(=O)N(Ra)2; andRa, independently for each occurrence, is hydrogen, or substituted or unsubstituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocyclo alkyl) alkyl; andRc, independently for each occurrence, is substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or (cycloalkyl)alkyl.

52. The method of claim 50 or 51, wherein Ra, independently for each occurrence, is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; andRc, independently for each occurrence, is alkyl, aryl, arylalkyl, heterocyclyl, or heterocyclylalkyl.

53. The method of any one of claims 48-52, wherein the compound has the structure of formula (I-10L):

54. The method of any one of claims 48-52, wherein the compound has the structure of formula (I-10D):

55. The method of any one of claims 48-54, wherein R1is substituted or unsubstituted alkyl, arylalkyl, or heteroarylalkyl.

56. The method of any one of claims 48-55, wherein R1is selected from substituted orn is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

57. The method of any one of claims 48-56, wherein R1is selected from OH58. The method of any one of claims 48-57, wherein59. The method of any one of claims 48-57, wherein60. The method of any one of claims 48-59, wherein the compound has the structure of formula (I- IL)61. The method of any one of claims 48-59, wherein the compound has the structure of formula (LID)62. The method of any one of claims 48-61, wherein R2is H or substituted or unsubstituted alkyl, arylalkyl, or heteroarylalkyl.

63. The method of any one of claims 48-62, wherein R2is selected from hydrogen,Rais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

64. The method of any one of claims 48-63, wherein R2is selected from65. The method of any one of claims 48-64, wherein R2is hydrogen.

66. The method of any one of claims 48-65, wherein the compound has the structure of formula (I-2L):

67. The method of any one of claims 48-65, wherein the compound has the structure of formula (I-2D):

68. The method of any one of claims 48-67, wherein R3is substituted or unsubstituted alkyl or arylalkyl.

69. The method of any one of claims 48-68, wherein R3is selected from substituted orRais hydrogen or alkyl; and n is an integer from 1 to 10, preferably 1-5, more preferably 1-3.

70. The method of any one of claims 48-69, wherein R3is selected from NH2,71. The method of any one of claims 48-70, wherein72. The method of any one of claims 48-71, wherein the compound has the structure of formula (I-3L):

73. The method of any one of claims 48-71, wherein the compound has the structure of formula (I-3D):

74. The method of any one of claims 48-73, wherein p is 1 or 2; andR4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, - ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl.

75. The method of any one of claims 48-74, wherein p is 1 or 2; andR4, independently for each occurrence, is selected from -CH3, halo, hydroxyl, and hydroxyalkyl.

76. The method of claim 75, wherein R4is hydroxyl.

77. The method of claim 75, wherein R4is -CH3.

78. The method of any one of claims 74-77, wherein p is 1.

79. The method of any one of claims 48-78, wherein the compound has the structure of formula (I-4Lg):4Lg).

80. The method of any one of claims 48-79, wherein the compound has the structure of formula (I-4La):

81. The method of any one of claims 48-78, wherein the compound has the structure of formula (I-4Lb):

82. The method of any one of claims 48-75, 77, and 78, wherein the compound has the structure of formula (I-4Lc):4Lc).

83. The method of any one of claims 48-78, wherein the compound has the structure of formula (I-4Dg):4Dg).

84. The method of any one of claims 48-78, wherein the compound has the structure of formula (I-4Da):4Da).

85. The method of any one of claims 48-78, wherein the compound has the structure of formula (I-4Db):4Db).

86. The method of any one of claims 48-75, 77, and 78, wherein the compound has the structure of formula (I-4Dc):4Dc).

87. The method of any one of claims 48-73, wherein R4is oxo.

88. The method of claim 87, wherein the compound has the structure of formula (I-4Ld):4Ld).

89. The method of claim 87, wherein the compound has the structure of formula (I-4Le):4Le).

90. The method of claim 87, wherein the compound has the structure of formula (I-4Dd):

91. The method of claim 87, wherein the compound has the structure of formula (I-4De):4De).

92. The method of any one of claims 48-91, wherein R6is hydrogen or alkyl, wherein the alkyl is optionally substituted with one occurrence of -C(=O)NH2.

93. The method of any one of claims 48-92, wherein R6is alkyl optionally substituted with one occurrence of -C(=O)NH2.

94. The method of any one of claims 48-93, wherein R6is -CH3.The method of any one of claims 48-93, wherein96. The method of any one of claims 48-95, wherein the compound has the structure of formula (I-6L):6L).

97. The method of any one of claims 48-95, wherein the compound has the structure of formula (I-6D):

98. The method of any one of claims 48-97, wherein R7is (Ci-Cio)alkyl.

99. The method of any one of claims 48-98, wherein R7is CH3100. The method of any one of claims 48-98, wherein101. The method of any one of claims 48-100, wherein the compound has the structure of formula (I-7L):

102. The method of any one of claims 48-100, wherein the compound has the structure of formula (I-7D):7D).

103. The method of any one of claims 48-102, wherein the compound has the structure of formula (I-11L):11L).

104. The method of any one of claims 48-102, wherein the compound has the structure of formula (I-11D):11D).

105. The method of any one of claims 48-104, wherein R8is -CH3 or -H.

106. The method of any one of claims 48-105, wherein R8is -H.

107. The method of any one of claims 48-106, wherein R9is -CH3 or -H.

108. The method of any one of claims 48-107, wherein R9is -H.

109. The method of claim 48, wherein the compound is selected from the following:acceptable salt thereof.

110. The method of claim 48, wherein the compound is selected from the following:acceptable salt thereof.

111. The method of claim 48, wherein the compound is selected from the following:acceptable salt thereof.

112. The method of claim 48, wherein the compound is selected from the following:D-Hyp Gly Gin Leu Gly Leu Ala Gly Pro Ala(2R,4S) , andD-Hyp Ala Gin Leu Gly Leu Ala Gly Pro Ala(2R’4S') , or a pharmaceutically acceptable salt thereof.

113. The method of claim 48, wherein the compound is selected from the following:pharmaceutically acceptable salt thereof.

114. The method of any one of claims 1-47, wherein the peptide has an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me).

115. The method of any one of claims 1-47, wherein the peptide has an amino acid sequence represented by HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly.

116. The method of any one of claims 1-47, wherein the peptide has an amino acid sequence represented by HyP-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro- Xcc; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-0H).

117. The method of any one of claims 1-47, wherein the peptide has an amino acid sequence represented by Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys; or a pharmaceutically acceptable salt and / or stereoisomer thereof; wherein Xdd is selected from:

118. The peptide of any one of claims 1-47, wherein at least one, at least two, at least three, at least four, at least five, at least six, or at least seven amino acid residues in the peptide are D-amino acid residues.

119. The method of any one of claims 1-47, wherein the compound is represented by Formula (V):or a pharmaceutically acceptable salt thereof; wherein:R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CPhOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl; andR9is hydrogen or alkyl.

120. The method of claim 107, wherein:R1and R2are each independently H or substituted or unsubstituted alkyl;R4for each occurrence is hydroxyl;P is 1;R6is alkyl optionally substituted with one occurrence of -C(=O)NH2; and R9is hydrogen.

121. The method of claim 120, wherein the compound is selected from the following:D-Hyp Gly Gin Leu Gly<2R 4S> , or a pharmaceutically acceptable salt thereof.

122. The method of claim 120, wherein the compound is selected from the following:pharmaceutically acceptable salt thereof.

123. The method of any one of claims 1-47, wherein the compound is represented by Formula (VI):or a pharmaceutically acceptable salt thereof; wherein:R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CH20Rb, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7is hydrogen or alkyl; andR9is hydrogen or alkyl.

124. The method of claim 123, wherein:R1and R2are each independently H or substituted or unsubstituted alkyl;R4for each occurrence is hydroxyl; p is 1;R6is alkyl optionally substituted with one occurrence of -C(=0)NH2; and R9is hydrogen.

125. The method of claim 123, wherein the compound is selected from the following:Hyp Gly Gin Leu Gly Leu D-Hyp Gly D-GIn D-Leu Gly D-Leu(2S.4R) ;anc[ (2R.4S) ,or apharmaceutically acceptable salt thereof.

126. The method of any one of claims 1-47, wherein the compound is represented by Formula (VII):or a pharmaceutically acceptable salt thereof; wherein:R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CPhOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7is hydrogen or alkyl; andR9is hydrogen or alkyl.

127. The method of any one of claims 1-47, wherein the peptide has any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly; or a pharmaceutically acceptable salt thereof.

128. The method of any one of claims 1-47, wherein the compound is represented by Formula (IX):or a pharmaceutically acceptable salt thereof;wherein:R1and R2are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CH2ORb, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring.

129. The method of any one of claims 1-47, wherein the compound is represented by Formula (X-am):am); or a pharmaceutically acceptable salt thereof; wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, -ORb, -CH2<DRb, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring.

130. The method of any one of claims 1-47, wherein the compound is represented byFormula 8:[Formula 8]; or a pharmaceutically acceptable salt thereof.

131. The method of any one of claims 1-47, wherein the compound is represented byFormula 10:[Formula 10]; or a pharmaceutically acceptable salt thereof.

132. The method of any one of claims 1-131, wherein the subject is a mammal.

133. The method of any one of claims 1-131, wherein the subject is a human.

134. A method of preventing or treating a disease selected from scleroderma, fibrosis, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, eczema, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a therapeutically effective amount of: i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:(X-am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula (8) or (10) or a pharmaceutically acceptable salt and / or prodrug thereof:ormu a iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH); andXdd is selected from:iv) a peptide, or a pharmaceutically acceptable salt thereof, having any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

135. A method of preventing or treating a disease selected from scleroderma, fatty liver disease, chronic kidney disease, ANCA vasculitis, urticaria, allergic rhinitis, chronic rhinosinusitis, and peanut allergy in a subject, comprising administering to the subject a therapeutically effective amount of: i) a compound represented by Formula (I), (V), (VI), (VII), (IX) or (X-am) or a pharmaceutically acceptable salt and / or prodrug thereof:(V),(X-am), wherein:R1, R2, and R3are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl;R4, independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, -ORb, -CthOR13, halo, hydroxyl, and hydroxyalkyl;Rbis substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; p is 0, 1, or 2;R6is hydrogen or substituted or unsubstituted alkyl;R7, R8, and R9are each independently hydrogen or alkyl;J is OH or -NRxRy; andRxand Ryare each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or Rxand Rytaken together with the intervening nitrogen atom form a ring, ii) a compound represented by Formula (8) or (10) or a pharmaceutically acceptable salt and / or prodrug thereof:iii) a peptide having an amino acid sequence represented by HyP-Gly-Gln-Xaa-Gly-Leu- Ala-Gly-Pro-Lys, HyP-Gly-Gln-Asp-Xbb-Leu-Ala-Gly-Pro-Lys, HyP-Gly-Gln-Leu-Gly- Leu-Ala-Gly-Pro-Xcc or Xdd-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys, or a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein:Xaa is selected from Glu, Asn, Gin, His, Lys, Ser, Thr, Ala, Vai, He, Leu, Phe, Tyr, Trp, homo-Ser, Asp(Me), and Asn(Me);Xbb is selected from Vai, He, Leu, Ala, Phe, Tyr, Trp, Ser, Thr, and (N-Me)Gly;Xcc is selected from Tyr, Leu, Glu, Gin, Ala, and Nle(6-OH); andXdd is selected from:iv) a peptide, or a pharmaceutically acceptable salt thereof, having any one amino acid sequence selected from:Ala-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Pro-Lys;Hyp-Gly-Gln-Leu-Gly-Leu-Ala-Gly-Ala-Lys;HyP-Gly-Gln-Leu-Gly-Leu-Ala;HyP-Gly-Gln-Glu-Gly-Leu-Gly;HyP-Gly-Gln-Leu-Gly-Leu;D-HyP(2R, 4S)-Gly-D-Gln-D-Leu-Gly-D-Leu;HyP-Gly-Gln-Leu-Gly, HyP-Gly-Gln-D-Leu-Gly; andD-HyP(2R, 4S)-Gly-Gln-Leu-Gly.

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