Compositions and methods for modulating G protein-coupled receptors

Abstract

Disclosed herein are compounds, salts thereof, and compositions that may be useful as agonists of G protein-coupled receptors, and methods for using the same. In some embodiments, the compounds, salts thereof, and compositions are agonists of G protein-coupled receptor 40 (GPR40), G protein-coupled receptor 119 (GPR119), or TGR5, and may be useful for treating, preventing, and suppressing diseases mediated by G protein-coupled receptor 40, GPR119, or TGR5.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 616892 (filed January 2, 2024) and U.S. Provisional Application No. 63 / 486649 (filed February 23, 2023), the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present disclosure relates to compositions and methods for modulating G protein-coupled receptors (GPCRs), and more particularly, to compositions and methods for modulating GPCRs by administering a therapeutically effective amount of an oral composition and a carrier. [Background technology]

[0003] Activation of multiple G protein-coupled receptors, such as GPR40, GPR119, GRP120, and GPR30, has been shown to have beneficial effects on glucose homeostasis, food intake, weight gain, and possibly β-cell maintenance. Free fatty acids (FFAs) appear to stimulate insulin secretion through direct pancreatic islet GPCR signaling and indirect stimulation of incretin secretion via receptor-mediated mechanisms. GPR40 and GPR119 are among several receptors that play important physiological roles in insulin release. Both GPR40 and GPR119 are now known to be expressed in pancreatic β-cells, and activation of these receptors stimulates insulin secretion in a glucose-dependent manner. GPR120 is a receptor for unsaturated fatty acids, such as α-linolenic acid. Its expression is observed in both intestinal L-cells and pancreatic islets. Stimulation of GPR120 has been shown to increase insulin levels and β-cell proliferation. GPR30 is a functional estrogen receptor and has been shown to be involved in glucose homeostasis and weight loss in rodent models of DIO. Compounds that can activate these receptors could be useful drugs for the treatment of type 2 diabetes and obesity, but previously identified ligands are generally low-affinity agonists, potentially limiting their therapeutic use.

[0004] Furthermore, the development of most synthetic small molecules has been accompanied by multiple safety concerns. Clearly, there is an unmet need for the development of safe and robust GPCR agonists. Summary of the Invention

[0005] One aspect of the present disclosure relates to one or more compounds in a composition. Some embodiments of the present disclosure relate to oral compositions. In some embodiments, the oral composition comprises, for example, a therapeutically effective amount of a compound (the compound is a G protein-coupled receptor agonist or a salt thereof) and one or more carriers or excipients, wherein the agonist is capable of treating, alleviating, modulating, or ameliorating a disease or condition mediated by a G protein-coupled receptor. Some embodiments of the present disclosure relate to one or more compounds. In some embodiments, the compound is an agonist of GPR40. In some embodiments, the oral composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical, or a pharmaceutical composition. In some embodiments, the oral composition is in any of the following dosage forms: softgel capsule, hard capsule, liquid, powder, and tablet. In some embodiments, the oral composition comprises 1.0% to 99% w / w of a plant extract. In some embodiments, the composition further comprises a preservative. In some embodiments, the composition further comprises a sweetener. In some embodiments, the composition further comprises a colorant. In some embodiments, the composition further comprises an additive. In some embodiments, the composition further comprises a flavoring. In some embodiments, the compound is a compound of Table 1, Table 2, or Table 3.

[0006] Some embodiments relate to methods for treating, preventing, alleviating, modulating, or ameliorating a disease or disorder associated with GPR40 in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a composition described herein. In some embodiments, the composition activates GPR40. In some embodiments, the composition is provided with food to induce GPR40 activation. In some embodiments, activation of GPR40 by administration of the composition is sufficient to regulate appetite and glucose metabolism in the subject.

[0007] Some embodiments relate to methods of treating, preventing, alleviating, reducing the risk of, modulating, or ameliorating obesity in a subject in need thereof, hi some embodiments, the methods comprise administering a therapeutically effective amount of a composition, including an oral composition described herein.

[0008] Some embodiments relate to methods for treating, preventing, alleviating, reducing the risk of, modulating, or ameliorating diabetes in a subject in need thereof. In some embodiments, the method comprises administering a therapeutically effective amount of a composition, including an oral composition described herein. In some embodiments, the diabetes is type 2 diabetes.

[0009] Some embodiments relate to methods of treating, preventing, alleviating, reducing the risk of, modulating, or ameliorating metabolic syndrome in a subject in need thereof, hi some embodiments, the methods comprise administering a therapeutically effective amount of a composition, including an oral composition described herein.

[0010] Some embodiments relate to methods of treating, preventing, alleviating, reducing the risk of, modulating, or ameliorating a lipid disorder in a subject in need thereof, hi some embodiments, the methods comprise administering a therapeutically effective amount of a composition, including an oral composition described herein.

[0011] Features and advantages of the compositions and methods described herein will become apparent from the following description read in conjunction with the accompanying drawings. These drawings illustrate certain aspects of the compositions and methods described herein and are not to be construed as limiting. In the drawings, like reference numbers or symbols generally refer to like elements unless the context dictates otherwise. The drawings are not necessarily drawn to scale. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 illustrates an example in vitro assay setup of the present disclosure. [Figure 2] FIG. 1 illustrates an example workflow of the present disclosure. [Figure 3] FIG. 1 shows an example assay of the present disclosure. [Figure 4] FIG. 1 shows a counter screen using CHO parent cells according to an example of the present disclosure. [Figure 5] 1 is a graph of assay results showing % activity in GPR40+ / - cells. [Figure 6] 1 is a graph of assay results comparing %hGPR40 activity and % off-target activity in CHO cells. [Figure 7] FIG. 1 shows pure compounds identified in the IP1 assay. [Figure 8] 1 is a graph showing the TGR5 control of DMSO and K-155 versus HTRF ratio. [Figure 9] 1 is a graph showing TGR5 pure compounds in cAMP screening. [Figure 10] 1 is a graph showing DMSO, K-003 and K-13 GPR40 control versus HTRF ratios. [Figure 11] 1 is a graph showing GPR40 pure compounds in IP1 screening. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure provides, inter alia, compounds, compositions, uses, and methods of providing or administering the compounds or compositions for treating, alleviating, modulating, or ameliorating a disease or disorder, or a symptom associated with a disease or disorder. In some embodiments, the disease or disorder or a symptom associated with a disease or disorder is associated with a G protein-coupled receptor (GPCR). In some embodiments, the composition comprises a therapeutically effective amount of a plant extract and one or more carriers or excipients. In some embodiments, a method of treating, preventing, alleviating, modulating, or ameliorating a disease or disorder associated with GPR40 in a subject comprises providing or administering one or more compounds or compositions described herein.

[0014] composition In some embodiments, a composition is provided comprising a compound that may be useful as an agonist of a G protein-coupled receptor. In some embodiments, the compound is a GPCR ligand. As used herein, the term "ligand" refers to a molecule (e.g., a test compound) that specifically binds to a polypeptide. In some embodiments, the compound is an agonist of a GPR. As used herein, the term "agonist" refers to an agent (e.g., a ligand, a test compound) that activates (e.g., stimulates) a GPCR by binding to it and induces a GPCR-mediated intracellular response. In some embodiments, the compound is a partial agonist of a GPR. As used herein, the term "partial agonist" refers to an agent (e.g., a ligand, a test compound) that activates (e.g., stimulates) a GPCR by binding to it and induces a GPCR-mediated intracellular response, but to a lesser extent or magnitude than a full agonist, e.g., having lower binding affinity and / or intracellular response-inducing activity. In some embodiments, the compound is an antagonist of a GPR. The term "antagonist" refers to an agent (e.g., a ligand, a test compound) that binds to a GPCR at approximately the same site as an agonist or partial agonist, preferably competitively, but does not activate the intracellular response initiated by an activated GPCR, thereby inhibiting the intracellular response induced by an agonist or partial agonist. Antagonists typically do not reduce the baseline intracellular response in the absence of an agonist or partial agonist. In some embodiments, the compound is an inverse agonist of the GPCR. The term "inverse agonist" refers to an agent (e.g., a ligand, a test compound) that binds to a GPCR and inhibits the baseline intracellular response initiated by an activated receptor below the normal basal level activity observed in the absence of an agonist or partial agonist. In some embodiments, the compound is an agonist of G protein-coupled receptor 40 (GPR40). In some embodiments, the compound is a selective GPR40 agonist. In some embodiments, the composition is an oral composition.

[0015] In some embodiments, the compound of the present disclosure is a compound represented by formula (I): [ka]

[0016] In some embodiments, R 1 and R 2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkyl, and optionally substituted -O-C1-C6-alkyl.

[0017] In some embodiments, X and Y are each independently an optionally substituted C-C 18 Alkyl, optionally substituted C-C 18 Alkenyl and optionally substituted -O-C-C 18 -alkyl. In some embodiments, Y is absent.

[0018] In some embodiments, the compounds of the present disclosure are represented by the compounds of formula (II): [ka]

[0019] In some embodiments, R 1 , R 2 and R 3 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted aryl, optionally substituted amino, optionally substituted C1-C6 alkyl, and optionally substituted —O—C1-C6-alkyl.

[0020] In some embodiments, X, Y, and Z are each independently an optionally substituted C-C18 Alkyl, optionally substituted C-C 18 Alkenyl, optionally substituted -O-C-C 18 In some embodiments, Y is selected from -alkyl, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, or optionally substituted ester. In some embodiments, Y is absent. In some embodiments, Z is absent.

[0021] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms. (When a numerical range such as "1 to 20" appears in this specification, it refers to each integer within that range. That is, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, ... up to 20 carbon atoms; even when no numerical range is specified, this definition applies when the term "alkyl" appears.) The alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or similar notation. For example, "C1-C4 alkyl" indicates that the alkyl chain has 1 to 4 carbon atoms, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0022] As used herein, "alkenyl" refers to an alkyl group, as defined above, which contains in its straight or branched hydrocarbon chain one or more double bonds. An alkenyl group can be unsubstituted or substituted.

[0023] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (e.g., including fused, bridged, or spiro ring systems, where two carbon rings share a chemical bond; e.g., one or more aryl rings and one or more aryl or non-aryl rings), where at least one ring has a fully delocalized pi-electron system. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C6 14 Aryl groups, C6-C 10 It may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0024] As used herein, the term "halogen" or "halo" refers to any of the radiostable atoms of Group 7 of the Periodic Table of the Elements, such as chloro (Cl), fluoro (F), bromo (Br), and iodo (I) groups.

[0025] When a group is described as "optionally substituted," the group can be unsubstituted or substituted with one or more specified substituents. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituents can be selected from one or more specified substituents. When no substituents are specified, the "optionally substituted" or "substituted" group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and the like. "amino" means that the amino group is optionally substituted with one or more groups individually and independently selected from the group consisting of aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino and disubstituted amino groups, and protected derivatives thereof.

[0026] In some embodiments, the compound of formula (I) or formula (II) is a compound that can be useful as an agonist of a G protein-coupled receptor. In some embodiments, the compound of formula (I) or formula (II) targets GPR40.

[0027] In some embodiments, the composition comprises one or more compounds set forth in Table 1. Table 1 lists compounds according to the present disclosure and may include isomers and stereoisomers of the listed compounds. For example, the compounds in Table 1 are Both the cis and trans isomers can be represented simultaneously by representing JPEG2026506941000004.jpg1551. Such representations may represent a mixture of both cis and trans isomers, or may represent either the cis or trans isomer individually.

[0028] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51

[0029] In some embodiments, compositions are provided that include compounds that may be useful as GPR119 agonists. As used herein, the term "GPR119 agonist" refers to a compound that binds to the GPR119 receptor and acts as an agonist. GPR119 is a G protein-coupled receptor that is primarily expressed in pancreatic beta cells and enteroendocrine cells in the gastrointestinal tract (including L cells, which are responsible for incretin hormone secretion). As used herein, the term "selective GPR119 agonist" refers to a GPR119 agonist that has selectivity for the GPR119 receptor over one or more related receptors, such as the corticotropin-releasing factor-1 (CRF-1) receptor. GPR119 is a G protein-coupled receptor (GPR119; e.g., human GPR119, GenBank® Accession No. AAP72125 and its alleles, e.g., mouse GPR119, GenBank® Accession No. AY288423 and its alleles). Stimulation of GPR119 by an agonist results in an increase in intracellular cAMP levels, consistent with GPR119 being coupled to Gs. In the patent literature, GPR119 is also referred to as RUP3 (e.g., WO 00 / 31258). GPR119 is also referred to as the glucose-dependent insulin secretory receptor (GDIR). In some embodiments, the compound is a PYY secretagogue. By "PYY secretagogue" is meant an agent (e.g., a ligand, a test compound) that promotes (e.g., stimulates) the secretion of PYY in a cell (e.g., an enteroendocrine cell) or that, upon administration to an individual (e.g., a vertebrate or mammal), increases total PYY levels, e.g., total PYY levels in blood or plasma. In certain embodiments, a PYY secretagogue is a compound suitable for increasing total PYY levels in an individual, e.g., total PYY levels in blood or plasma. In some embodiments, the compound is capable of modulation by PYY. As used herein, the term "PYY-regulated condition" refers to a condition in which a PYY receptor is capable of regulating a G protein-coupled receptor. 1-36 or a fragment thereof. In certain embodiments, the term "condition modulated by PYY" refers to a condition modulated by PYY3-36 In certain embodiments, the term "PYY-modulated condition" refers to a condition that is modulated by an agonist of the NPY Y2 receptor (Y2R). In certain embodiments, "PYY-modulated condition" refers to a condition that is modulated by stimulation of the Y2R. In certain embodiments, "PYY-modulated condition" refers to a condition that is modulated by stimulation of the Y2R. 3-36 The term "condition regulated by PYY3-36" refers to a condition regulated by an agonist of Y2R. In certain embodiments, the term "condition regulated by PYY3-36" refers to a condition regulated by stimulation of Y2R. In some embodiments, the compound may comprise a PYY-related activity. As used herein, the term "PYY-related activity" refers to an activity that regulates PYY levels or an activity associated with PYY. In certain embodiments, the term "PYY-related activity" refers to an activity that increases PYY levels or an activity associated with PYY. In some embodiments, the composition is an oral composition. In some embodiments, the composition comprises a compound set forth in Table 2. Table 2 lists compounds according to the present disclosure and may include isomers and stereoisomers of the listed compounds. For example, the compounds in Table 2 are Both cis and trans isomers can be simultaneously represented by JPEG2026506941000056.jpg1551. Such notations may represent a mixture of both cis and trans isomers, or may represent either the cis or trans isomer individually.

[0030] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20

[0031] In some embodiments, compositions containing one or more compounds that may be useful as TGR5 agonists are provided. TGR5, also known as G protein-coupled bile acid receptor 1 (GPBAR1) and "Takeda G protein-coupled receptor 5," is a G protein-coupled receptor believed to be involved in glucose metabolism through activation by bile acids. In some embodiments, the one or more compounds are TGR5 ligands. "TGR5 ligand" refers to a composition (e.g., a compound, amino acid, peptide, polypeptide, antibody, nucleic acid, polynucleotide) that selectively binds to TGR5. A TGR5 ligand may also be a "natural TGR5 agonist." The term "natural TGR5 agonist" refers to a physiological ligand of TGR5 that binds to and activates TGR5. This term encompasses TGR5 ligands such as bile acids (e.g., CA, LCA, DCA, CDCA, and UDCA) and bile acid derivatives naturally synthesized in the host organism. In some embodiments, the composition is an oral composition.

[0032] In some embodiments, the compounds of the present disclosure are represented by compounds of formula (III): [ka]

[0033] In some embodiments, the compound of Formula (III) is a pharmaceutically acceptable salt described herein.

[0034] In some embodiments of the compound of Formula (III), R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, hydroxyl, keto, halogen, optionally substituted amino, optionally substituted C-amido, optionally substituted ester, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C8 heterocyclylalkyl. In some embodiments, R 1 is hydroxyl. In some embodiments, R 2 is hydroxyl or keto. In some embodiments, R 3 is hydroxyl or keto. In some embodiments, R 4 is hydrogen, keto, or optionally substituted C1-C6 alkyl. In some embodiments, R 5 is hydroxyl, optionally substituted C1-C6 alkyl and optionally substituted C3-C8 heterocyclyl.

[0035] In some embodiments of the compound of Formula (III), X is a bond, -CH2-, -CH2CH2-, or -NH-. In some embodiments, X is absent. In some embodiments, X is a bond or -CH2-.

[0036] In some embodiments, the compound of formula (III) is selected from the following: [ka] [ka]

[0037] In some embodiments, compounds of formula (III) are shown in Table 3. In some embodiments, the composition comprises a compound listed in Table 3. Table 3 lists compounds according to the present disclosure and may include isomers and stereoisomers of the listed compounds. For example, compounds in Table 3 are Both cis and trans isomers can be simultaneously represented by JPEG2026506941000080.jpg1551. Such notations may represent a mixture of both cis and trans isomers, or may represent either the cis or trans isomer individually.

[0038] Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] [Table 3-24] [Table 3-25] [Table 3-26] [Table 3-27] [Table 3-28] [Table 3-29]

[0039] In some embodiments, the composition comprises one or more compounds listed in Table 4.

[0040] [Table 4-1] [Table 4-2] [Table 4-3] Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9

[0041] In some aspects, the present disclosure provides a composition comprising a plant extract and a carrier. In some embodiments, the composition is an oral composition. As used herein, "extract" refers to a composition containing a desired compound of interest separated from other substances present in the naturally-derived source from which the oral composition is obtained. In some embodiments, the plant extract comprises one or more compounds in Tables 1, 2, 3, and 4. Plant extracts can be obtained from any plant tissue, including whole plants; plant parts, such as developing organs / structures (e.g., leaves, stems, tubers), roots, flowers and floral organs / structures (e.g., bracts, calyxes, petals, stamens, pistils, anthers, and ovules), seeds (including embryos, endosperm, and seed coats), fruits (mature ovaries); plant tissues (e.g., vascular tissue, ground tissue, etc.); or cells (e.g., guard cells, egg cells, etc.), as well as their progeny, cultures, or cell lines. In some embodiments, the extract is generally recognized as safe for human consumption. Thus, in certain embodiments, the extract is of edible origin. In this respect, the extract is an edible extract. The extract can be prepared by freezing, crushing, macerating, pulverizing, and / or fermenting the target material, subjecting it to solvent extraction, and separating insoluble materials from soluble materials. In this respect, the "extract" of the present disclosure may be, but is not limited to, a crude product, a fraction, a subfraction, a separation product, an isolate, a concentrate, or a purified product.

[0042] In some embodiments, the plant extract may be a crude extract. As used herein, "crude" refers to a compound or molecule present in the original composition that has not been completely separated from other components of the composition. In embodiments involving fractionation or subfractionation, molecules in a crude extract may undergo partial separation to provide a less crude extract that contains other substances. In contrast, the term "isolated" means that a compound or molecule has been substantially enriched or purified relative to the complex cellular environment in which it naturally occurs, e.g., a crude extract. When an isolated molecule is enriched or purified, the absolute level of purity is not particularly important, and one of skill in the art can easily determine an appropriate level of purity depending on the intended use of the substance. In some cases, the isolated molecule may form part of a composition (e.g., a cruder or cruder extract containing numerous other substances) and may, for example, contain other components. In other cases, the isolated molecule may be purified to essential homogeneity, as determined, for example, by spectroscopy, NMR, or chromatography (e.g., LC-MS).

[0043] The substantially pure compounds described herein can be combined with a carrier and provided in any form suitable for ingestion or administration by a subject. As used herein, "substantially pure" refers to a state in which one or more desired active compounds are highly isolated and / or concentrated, with minimal undesired impurities. In some embodiments, the compound or extract is added as an exogenous component or additive to an ingestion product. Suitable ingestion forms include, but are not limited to, dietary supplements, food ingredients, food additives, medical foods, nutraceuticals, or pharmaceutical compositions. In some embodiments, the compound or extract is provided in either liquid or powder form. In some embodiments, the compound is derived from a plant and may be concentrated in a plant source without necessarily extracting the compound completely or partially from the plant.

[0044] Suitable solvents for preparing extracts include, for example, n-pentane, hexane, butane, chloroform, dichloromethane, diethyl ether, acetonitrile, water, butanol, isopropanol, ethanol, methanol, glacial acetic acid, acetone, norflurane (HFA134a), ethyl acetate, dimethyl sulfoxide, heptafluoropropane (HFA227), and subcritical or supercritical fluids such as liquid carbon dioxide and water, or combinations of these in any proportion. When using such solvents, the resulting extract typically contains nonspecific, lipid-soluble substances, which can be removed by various processes, such as "winterization," which involves cooling to a certain temperature (usually -20°C) followed by filtration or centrifugation to remove waxy contaminants; extraction with subcritical or supercritical carbon dioxide or a nonpolar solvent (e.g., hexane); or distillation.

[0045] In some embodiments, the oral composition comprises an extract from one or more plants. In some embodiments, the oral composition comprises an extract from two or more plants. In some embodiments, the oral composition comprises an extract from three or more plants.

[0046] In some embodiments, the extracts described herein include juices, infusions, and fermentation residues. The fermented plant-derived extracts or processed fractions thereof are utilized in ingestible compositions, such as health-promoting compositions or tonics for humans and animals.

[0047] In some embodiments, the oral compositions comprise salt forms of the compounds described herein. Salts of the compounds of the present disclosure are compounds that possess the desired pharmacological activity of the parent compound and include (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid); or organic acids (such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoic acid, ... or (2) salts formed when an acidic proton present in the parent compound is replaced by an acid addition salt formed with an acid such as benzenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (3) salts formed when an acidic proton present in the parent compound is replaced by an acid addition salt formed with an acid such as benzenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.

[0048] In some embodiments, the oral composition comprises a pharmaceutically acceptable salt form of the compound described herein. As used herein, the term "pharmaceutically acceptable salt" is broadly defined and refers to, without limitation, a salt of a compound that has the ordinary and customary meaning for those skilled in the art (without being limited to a special or customized meaning), does not cause significant irritation to the organism to which it is administered, and does not impair the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid (such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid (such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid, etc.). Pharmaceutical salts can also be obtained by reacting a compound with a base to form an ammonium salt, an alkali metal salt (such as a lithium, sodium, or potassium salt), an alkaline earth metal salt (such as a calcium, magnesium, or aluminum salt), a salt with an organic base (such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, etc.), a salt with an amino acid such as arginine or lysine, or an inorganic base (such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, or sodium hydroxide, etc.).

[0049] In any compound described herein, if it contains one or more chiral centers, each center may independently be in the R or S configuration, or a mixture thereof, unless the absolute stereochemistry is explicitly indicated. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or a stereoisomeric mixture, and include all diastereoisomeric and enantiomeric forms. Furthermore, in any compound described herein, if it contains one or more double bonds that result in geometric isomers that can be defined as E or Z, each double bond may independently be E or Z, or a mixture thereof. Stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. Similarly, it is understood that all tautomeric forms of any compound described herein are encompassed.

[0050] The compounds described herein may be labeled by isotopic or other means, including, but not limited to, the use of chromophores or fluorescent groups, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, such as increased half-life in the body or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, when a hydrogen atom is explicitly disclosed in a compound structure or understood to be present in the compound, at any position in the compound where a hydrogen atom may be present, the hydrogen may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (duthalium), or hydrogen-3 (tritium). Therefore, reference to a compound herein encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0051] The compounds described herein may be labeled by isotopic or other means, including, but not limited to, the use of chromophores or fluorescent groups, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, such as increased half-life in the body or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, when a hydrogen atom is explicitly disclosed in a compound structure or understood to be present in the compound, at any position in the compound where a hydrogen atom may be present, the hydrogen may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (duthalium), or hydrogen-3 (tritium). Therefore, reference to a compound herein encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0052] The oral compositions, formulations, and methods described herein include the use of crystalline forms, amorphous phases, and / or pharmaceutically acceptable salts, solvates, hydrates, and conformers of the compounds of some embodiments, as well as metabolites and active metabolites of the compounds with similar activity. Conformers refer to structures that are conformational isomers. Conformers are molecules that have the same structural formula but differ in the conformation of atoms around a rotatable bond (conformers). In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during crystallization with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Furthermore, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. Other forms in which the compounds of some embodiments may be provided include amorphous, milled and nanoparticulate forms.

[0053] Similarly, the compounds described herein, e.g., compounds of some embodiments, include the compounds in any form described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous forms, solvated forms, enantiomeric forms, tautomeric forms, etc.).

[0054] In some aspects, the present disclosure provides a composition comprising a compound described herein and a carrier. In some embodiments, the compound is a substantially pure compound. In some embodiments, the composition is an oral composition. As used herein, the term "carrier" refers to a material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one organ or part of the body to another, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulating material. Each carrier must be compatible with the other ingredients of the formulation and not harmful to the subject. Examples of materials that can function as carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives (sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, and the like); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) fats and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) glycols such as propylene glycol. (11) polyols such as glycerin, sorbitol, mannitol, polyethylene glycol, etc.; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers 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) pH buffers; (21) polyesters, polycarbonates, and / or polyanhydrides; (22) lipids and / or phospholipids; and (23) other non-toxic, compatible substances used in conventional formulations.

[0055] In some embodiments, the oral composition may further comprise a preservative. In some embodiments, the preservative may be about 0.01%, 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0% w / w, or ranges inclusive and / or spanning the above values. In some embodiments, the preservative is selected from the group consisting of, but not limited to, sodium benzoate, methylparaben, propylparaben, sodium nitrite, sulfur dioxide, sodium sorbate, and potassium sorbate. Other suitable preservatives include, but are not limited to, edetate salts (also known as salts of ethylenediaminetetraacetic acid, or EDTA, eg, disodium EDTA).

[0056] In some embodiments, the oral composition may further comprise a sweetener. In some embodiments, the sweetener may be about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges inclusive and / or intervening therein. In some embodiments, the sweetener may comprise a natural sweetener. In some embodiments, the sweetener may comprise an artificial sweetener. Non-limiting examples of sweeteners include sucrose, dextrose, maltose, dextrin, dry invert sugar, fructose, high fructose corn syrup, levulose, galactose, corn syrup solids, tagatose, polyols (e.g., sorbitol, mannitol, xylitol, lactitol, erythritol, maltitol), hydrogenated starch hydrolysates, isomalt, trehalose, and mixtures thereof.

[0057] In some embodiments, the oral composition may further comprise a flavoring agent. In some embodiments, the flavoring agent may be present at about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges inclusive and / or intervening therein. In some embodiments, the flavoring agent may comprise a natural or artificial flavor. In certain embodiments, the flavoring agent may comprise an essential oil derived from a plant or fruit, such as peppermint oil, spearmint oil, other mint oils, clove oil, cinnamon oil, wintergreen oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, allspice oil, sage oil, mace oil, or almond oil. In another particular embodiment, the flavoring agent comprises a plant extract or fruit essence such as apple, banana, watermelon, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, and mixtures thereof. In yet another particular embodiment, the flavoring agent comprises a citrus flavor such as lemon, lime, orange, tangerine, grapefruit, citron, or kumquat extract, essence, or oil.

[0058] In some embodiments, the oral composition may further comprise a colorant, which may be about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges inclusive and / or spanning the foregoing values.

[0059] In some embodiments, the oral composition may further comprise at least one additive. In some embodiments, the additive may be about 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.50%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25%, 4.5%, 4.75%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0% w / w, or ranges inclusive and / or spanning the foregoing values. In some embodiments, the at least one additive may be an emulsifier. In some embodiments, the additive may include one or more vitamins. In some embodiments, the additive may include one or more minerals. In some embodiments, the additive may include a stabilizer.

[0060] In some embodiments, the oral composition consists essentially of a G protein-coupled receptor agonist. In some embodiments, the G protein-coupled receptor agonist is an agonist of GPR30. In some embodiments, the G protein-coupled receptor agonist is an agonist of GPR40. In some embodiments, the G protein-coupled receptor agonist is an agonist of GPR119. In some embodiments, the G protein-coupled receptor agonist is an agonist of GPR120. The G protein-coupled receptor agonist is an agonist of TGR5. In some embodiments, the G protein-coupled receptor agonist comprises one or more compounds selected from Tables 1, 2, and 3. In some embodiments, the one or more compounds are selected from Formula (I) or Formula (II). In some embodiments, the oral composition consists essentially of a G protein-coupled receptor agonist that is not bound to lignocellulosic material. In some embodiments, the oral composition consists essentially of a G protein-coupled receptor antagonist. In some embodiments, the G protein-coupled receptor antagonist comprises one or more compounds selected from Tables 1, 2, and 3. In some embodiments, the oral composition consists essentially of a G protein-coupled receptor antagonist that is not bound to lignocellulosic material. Lignocellulosic material refers to a composite material primarily composed of lignin, cellulose, and hemicellulose, which are natural polymers present in plant cell walls. Lignocellulosic material is characterized by its rigid structure, high strength, and resistance to degradation. This material is commonly obtained from wood, grasses, and inedible parts of plants. In some embodiments, the composition does not include lignin, cellulose, and / or pectin. In some embodiments, the composition does not include extracts from natural sources.

[0061] formulation The composition comprising the plant extract or compound or its salt of the present disclosure can be combined with a carrier and provided in any form suitable for subject ingestion or administration.In this respect, the plant extract or compound is added to the ingestion product as an exogenous component or additive.Suitable ingestion forms include, but are not limited to, dietary supplements, food ingredients, food additives, medical foods, nutritionally functional foods, or pharmaceutical compositions.In some embodiments, the plant extract or compound is provided in either liquid or powder form.

[0062] A food ingredient or additive is an edible substance (including substances intended for use in producing, processing, wrapping, treating, preparing, treating, packaging, transporting, or storing food) intended to be a component of or otherwise affect the properties of food, directly or indirectly. Food products, particularly functional foods, are foods that have been enriched or concentrated to contain additional complementary nutrients and / or beneficial ingredients during processing. Food products according to the present disclosure may be in the form of, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, health bars, bread, cakes, cereals, candy, confectionery, soups, milk, yogurt, or fermented dairy products, cheese, fruit and vegetable-based beverages, fermented beverages, shakes, flavored waters, teas, oils, or other suitable foods. In some embodiments, a food product may be a whole food product in which the concentration of a compound has been concentrated to a level that is effective due to specific postharvest processing and food manufacturing processing methods.

[0063] A dietary supplement is a product that contains the compounds or extracts of the present disclosure and is taken orally to supplement the diet. A nutraceutical is a product derived from food that provides additional health benefits in addition to the basic nutritional value contained in food. A pharmaceutical composition is defined as a component of a drug product intended to provide pharmacological action or other direct effect in the diagnosis, treatment, mitigation, cure, or prevention of disease, or to affect the structure or function of the human or other animal body. Dietary supplements, nutraceuticals, and pharmaceutical compositions can be found in many capsules, tablets, coated tablets, pills, capsules, pellets, gummies, granules, softgels, gel capsules, liquids, powders, emulsions, suspensions, elixirs, syrups, and any other suitable forms for use.

[0064] The pharmaceutical compositions disclosed herein can be prepared by known methods, such as conventional mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, encapsulating, entrapping or tabletting processes. Furthermore, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical compositions disclosed herein can be provided as salts with pharmaceutically compatible counterions.

[0065] Multiple methods of administering compounds, salts, and / or compositions exist in the art, including, but not limited to, oral, rectal, pulmonary, transdermal, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intraosseous, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, the compounds described herein, including those described herein, or pharmaceutically acceptable salts thereof, can be administered orally.

[0066] The compounds, salts and / or compositions can also be administered locally rather than systemically, for example, by injecting or implanting the compounds directly into the affected area (often as a depot or sustained-release formulation).Furthermore, the compounds can be administered in targeted drug delivery systems, for example, by being contained in liposomes coated with tissue-specific antibodies.The liposomes are targeted to and selectively taken up by organs.For example, to target respiratory diseases or conditions, intranasal or pulmonary delivery may be desired.

[0067] The oral compositions may, if desired, be presented in the form of a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for administration to humans or animals. Such notice may, for example, be the label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the compounds and / or salts described herein in a compatible pharmaceutical excipient may also be prepared, placed in a suitable container, and labeled for the treatment of a given condition.

[0068] The composition comprising the plant extract or compound of the present disclosure can be combined with a carrier and provided in any form suitable for ingestion or administration by a subject.In this respect, the plant extract or compound is added to an ingestion product as an exogenous component or additive.Suitable ingestion forms include, but are not limited to, dietary supplements, food ingredients, food additives, medical foods, nutritionally functional foods, or pharmaceutical compositions.In some embodiments, the plant extract or compound is provided in either liquid or powder form.

[0069] As used herein, the term "food ingredient" or "food additive" includes an edible substance intended to be a component of or otherwise affect the characteristics of a food product, directly or indirectly, including substances intended for use in producing, processing, wrapping, treating, preparing, treating, packaging, transporting, or storing food. Food products, particularly functional foods, are foods that have been fortified or enriched with additional complementary nutrients and / or beneficial ingredients during processing. Food products according to the present disclosure may be in the form of, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, health bars, bread, cakes, cereals, candy, confectionery, soups, milk, yogurt or fermented dairy products, cheese, fruit and vegetable-based beverages, fermented beverages, shakes, flavored waters, teas, oils, or other suitable food products. In some embodiments, the food product may be a whole food product in which the concentration of the compound has been concentrated to an effective level through specific postharvest processing and food manufacturing processing methods. In some embodiments, the food product comprises one or more compounds described herein and a dietary fiber source. In some embodiments, the food product comprises one or more compounds described herein. In some embodiments, the food product is a food bar. In some embodiments, the food bar comprises from about 0.01% to about 20% (w / w) of one or more compounds described herein. In some embodiments, the food bar comprises from about 0.1% to about 10% (w / w) of one or more compounds described herein. In some embodiments, the food product is a crisp. In some embodiments, the food crisp comprises from about 0.01% to about 20% (w / w) of one or more compounds described herein. In some embodiments, the food crisp comprises from about 0.1% to about 10% (w / w) of one or more compounds described herein.

[0070] The compounds, compositions, and extracts of the present disclosure can be prepared as nutritional formulations, such as foods (including medicinal or functional foods). A "medical or functional food" is defined as one that is consumed as part of a normal diet but that has demonstrated physiological benefits and / or reduced risk of diseases or conditions, such as chronic diseases, beyond its basic nutritional function. By way of example, medicinal and functional foods may contain one or more of the following ingredients: compounds described herein, compositions described herein, extracts described herein, vitamins, minerals, herbs, botanicals, amino acids, dietary substances intended to supplement the diet by increasing total dietary intake, concentrates, metabolites, ingredients, extracts, or any combination thereof. Dietary supplements can also be incorporated into foods, such as functional foods, designed to promote health or prevent diseases or disorders. When administered as a pharmaceutical formulation, the compositions can be administered to patients in several ways, either prophylactically or therapeutically. In some embodiments, the compositions described herein are administered alone or in combination with other additives or pharmaceuticals, and can be combined with a physiologically acceptable carrier. The effective amount and method of administration, as well as the purpose of a particular formulation, may vary based on the individual subject, the stage of the disease or condition, and other factors apparent to those skilled in the art. In the case of pharmaceutical and nutraceutical formulations, the concentration of the subject composition may be monitored (e.g., plasma concentration may be monitored) during the course of treatment to ensure that the desired level is maintained.

[0071] In some embodiments, food products contain carbohydrates. A variety of carbohydrates, including various sugars and starches, are used in food products. Carbohydrates, including complex carbohydrates (such as whole grains and vegetables) and simple carbohydrates (such as sugar and refined grains), are important sources of energy for the body. Some common carbohydrates used in food products include starch, sugar, fructose, maltodextrin, dextrose, corn syrup, oligosaccharides, cellulose, complex carbohydrates, and inulin, which may be added to processed foods as a prebiotic fiber. According to the present disclosure, the concentration of carbohydrates may vary depending on the intended use of the product. In some embodiments, carbohydrates may comprise from about 1% to about 95% by weight of the food product. In some embodiments, carbohydrates may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain carbohydrates at about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or ranges therebetween and / or spanning said values, with the low and high values ​​each independently selected.

[0072] In some embodiments, food products may contain sugars. Sugars such as high-fructose corn syrup, sucrose, glucose syrup, dextrose, and other sweeteners are often added to processed foods to make them more palatable. Additionally, sugar alcohols or maltodextrins may be added to food products to reduce the calorie content and / or improve the nutritional profile of the product. In some embodiments, food products may contain one or more sugars that are slowly or incompletely digested by humans (and may not be completely digested). These sugars may include isomaltose, panose, and branched oligomers with a degree of polymerization of 4 or higher. Additional non-limiting examples of sugars include sucrose, HFCS, fructose, brown sugar (which may be partially or fully refined), powdered sugar (also known as confectioner's sugar), high-fructose corn syrup, honey, molasses, maple syrup, agave nectar, coconut sugar, date sugar, fruit juice concentrate, maltodextrin, dextrose, glucose syrup, maple syrup, molasses, lactose, and the like. According to the present disclosure, the concentration of sugars may vary depending on the intended use of the product. In some embodiments, sugars may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the sugar(s) component may comprise from about 2% to about 10% by weight of the composition. In some embodiments, sugars may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain sugars at about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any range between and / or across any of the above values, with the low and high values ​​each independently selected.

[0073] In some embodiments, the food product comprises a dietary fiber source. In some embodiments, the food product comprises about 5% to about 30% (w / w) fiber. In some embodiments, the food product comprises at least 10% fiber. In some embodiments, the food product comprises at least 15% fiber. In some embodiments, the food product comprises at least 20% fiber. In some embodiments, the food product comprises at least 30% fiber. In some embodiments, the fiber may be selected from psyllium husk, inulin, beta-glucan, acacia fiber, pectin, wheat dextrin, cellulose, fructooligosaccharides, guar gum, fruit fiber, or a combination thereof. In some embodiments, the fiber is water-soluble dietary fiber.

[0074] In some embodiments, food products may contain protein. Protein may be present in various concentrations depending on the product. Protein sources may include soy protein, soy flour, soy protein isolate, whey protein isolate, casein, gelatin, legume protein isolate, soy protein concentrate, egg albumin or egg white, wheat protein concentrate, legume protein concentrate, and mixtures thereof. In some embodiments, meat products such as beef jerky, sausage, or meatballs may contain protein as a primary ingredient. Protein may be present at a concentration of about 10% to about 25% of the total ingredients. Dairy products such as cheese, yogurt, and milk may be primarily comprised of proteins such as casein or whey. Protein may be present at a concentration of about 3% to about 15% of the total ingredients. Plant-based products such as tofu, tempeh, or seitan may be primarily comprised of proteins derived from soybeans, peas, legumes, or wheat. Protein may be present at a concentration of about 10% to about 25% of the total ingredients. In energy and protein bars, proteins such as whey or soy, or any protein according to the present disclosure, may be added as a protein source. Proteins may be present at a concentration of about 10% to about 25% of the total ingredients. According to the present disclosure, the protein concentration may vary depending on the intended use of the product. In some embodiments, the protein may comprise about 1% to about 95% by weight of the food product. In some embodiments, the protein may comprise about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% protein, or ranges between and / or spanning the above values, with the low and high values ​​each independently selected.

[0075] In some embodiments, the food product may include starch. In some embodiments, the food product may further include a starch component in an amount sufficient to provide about 5% to 45%, or about 10% to 30%, or about 15% to 25% of the food product. The starch component may include purely added flour or other granules, as well as starch fractions provided by other ingredients, such as oat bran or soy protein. In some embodiments, the starch may be any starch or flour component conventionally used in ready-to-eat cereals. Examples of suitable starch grains include flour from staple grains such as wheat, rice, corn (maize), oats, barley, and rye, or starch fractions separated from flour (e.g., corn starch, wheat starch, rice starch), as well as various processed starches, such as pregelatinized and / or modified starches.

[0076] In some embodiments, food products may contain wheat flour. According to the present disclosure, multiple types of wheat flour can be used. For example, common types of wheat flour used in food products include all-purpose wheat flour (which, like many other wheat flours, contains protein content), whole wheat flour, bread flour, cake flour, pastry flour, self-rising flour, and gluten-free flour. According to the present disclosure, the concentration of wheat flour can vary depending on the intended use of the product. For example, in baked goods such as breads, cakes, and cookies, wheat flour is the primary ingredient and may be present at a concentration of 50% to 100% of the total dry ingredients. In soups and sauces, wheat flour is often used as a thickening agent and may be present at a concentration of 1% to 5% of the total ingredients. Batters and Coatings: In fried foods such as fried chicken and fish, wheat flour is often used as part of the batter or coating and may be present at a concentration of 20% to 50% of the total dry ingredients. In snack foods such as crackers and chips, wheat flour may be present at a concentration of 30% to 70% of the total ingredients. In some embodiments, wheat flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, wheat flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain wheat flour at any of about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any range between and / or across any of the foregoing values, with the low and high values ​​each independently selected.

[0077] In some embodiments, food products may include lipids. In some embodiments, food products may include oils. In some embodiments, food products may include one or more lipids or oils. According to the present disclosure, multiple types of lipids can be used. For example, common types of lipids include butter, margarine, vegetable oil, shortening, and lard. According to the present disclosure, the concentration of lipids can vary depending on the intended use of the product. In baked goods such as cakes, cookies, and pastries, lipids such as butter, shortening, or oil are often used to provide moisture, flavor, and texture. In some embodiments, lipids may be present at a concentration of about 10% to about 30% of the total ingredients. In some embodiments, lipids such as olive oil or mayonnaise are often used in sauces and dressings to provide flavor and texture. In some embodiments, lipids may be present at a concentration of about 10% to about 30% of the total ingredients. In fried foods such as chicken or French fries, lipids such as vegetable oil or lard are used for frying and may be present at a concentration of about 30% to about 60% of the total ingredients. In snack foods such as chips and crackers, lipids such as vegetable oils or palm oil are often used to provide flavor and texture. In some embodiments, lipids may be present at a concentration of about 10% to about 30% of the total ingredients. In some embodiments, lipids may comprise about 1% to about 95% by weight of the food product. In some embodiments, lipids may comprise about 1% to about 95% by weight of the food product. In some embodiments, lipids may comprise about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% lipid, or ranges therebetween and / or spanning the above values, with the low and high values ​​each independently selected.

[0078] In some embodiments, the food product may contain one or more additional ingredients. If desired, the food products of the present disclosure may further contain various substances designed to enhance their aesthetic or nutritional properties. These supplemental materials may include vitamin and / or mineral fortification, colorants, flavorings, sweeteners, and mixtures thereof. The exact ingredient concentrations may vary. However, generally, these substances may each comprise between about 0.01% and about 5%, or between about 0.1% and 2%, by dry weight of the food product. A particularly useful substance may include table salt. In some embodiments, salt comprises between about 0.1% and 5%, or between about 0.5% and 4.0%, of the food product.

[0079] In some embodiments, the food product is plant-derived. In some embodiments, the food product is derived from hemp hulls. In some embodiments, the food product is a solid food. In some embodiments, the food product is a semi-solid food. In some embodiments, the food product is a puffed product, a bakery product, a pressed cake, a cooked product, a food bar, a cereal, a crisp, or a spread.

[0080] A dietary supplement is a product that contains a compound or extract of the present disclosure and is taken orally to supplement the diet. A nutraceutical is a product derived from food and provides additional health benefits beyond the basic nutritional value of the food. A pharmaceutical composition is defined as any component of a pharmaceutical product intended to diagnose, cure, mitigate, treat, or prevent disease, or to affect the structure or function of the human or other animal body. Dietary supplements, nutraceuticals, and pharmaceutical compositions can be found in many forms, such as capsules, tablets, coated tablets, pills, capsules, pellets, granules, softgels, gel capsules, liquids, powders, emulsions, suspensions, elixirs, syrups, and any other form suitable for use. In some embodiments, the compositions described herein are provided as dietary supplements. In some embodiments, the dietary supplements are provided in the form of capsules, tablets, powders, or liquids. In some embodiments, the compositions described herein are provided as dietary supplements. In some embodiments, the dietary supplements are provided in the form of capsules, tablets, powders, or liquids. In some embodiments, the compositions described herein are provided as pharmaceutical products. In some embodiments, the pharmaceutical products are provided in the form of capsules, tablets, powders, or liquids.

[0081] The compounds, salts, and / or pharmaceutical compositions may be provided to the administering physician or other medical professional in the form of a kit. A kit is a package containing a container containing the compound in a suitable pharmaceutical composition and instructions for administering the pharmaceutical composition to a subject. The kit may optionally include one or more additional therapeutic agents. The kit may include individual doses of the compound or pharmaceutical composition for sequential or sequential administration. The kit may optionally include one or more diagnostic tools and instructions for use. The kit may include a suitable delivery device, such as a syringe, and instructions for administering the compound and any other therapeutic agents. The kit may optionally include instructions for storage, reconstitution (if applicable), and administration of any or all of the included therapeutic agents. The kit may include multiple containers reflecting the number of times to be administered to a subject.

[0082] Methods and Uses Aspects of the present disclosure relate to providing or administering a compound or composition of the present disclosure to a subject in need thereof. In some embodiments, the compound or composition may be provided or administered for the treatment, prevention, alleviation, or amelioration of a disease or condition. In some embodiments, the disease or condition is associated with a G protein-coupled receptor. In some embodiments, the compounds of the present disclosure are potent agonists of G protein-coupled receptors. The compounds and salts thereof may be effective in treating diseases in which the disease or condition can be treated by modulating GPCRs. In some embodiments, the compositions described herein may be effective in treating diseases modulated by GPR40 ligands, which are generally agonists. In some embodiments, the compositions described herein may be effective in treating diseases modulated by GPR119 ligands. In some embodiments, the compositions described herein may be effective in treating diseases modulated by TGR5 ligands.

[0083] One or more of these diseases can be treated by administering a therapeutically effective amount of a compound or composition of the present disclosure, or a salt thereof, to a subject in need thereof. The compound or composition of the present disclosure can also be used to manufacture a medicament useful for treating one or more of the following diseases: (1) non-insulin-dependent diabetes mellitus (type 2 diabetes); (2) hyperglycemia; (3) insulin resistance; (4) metabolic syndrome; (5) obesity; (6) hypercholesterolemia; (7) hypertriglyceridemia (elevated triglyceride-rich lipoproteins); (8) mixed or diabetic dyslipidemia; (9) low HDL cholesterol; (10) high LDL cholesterol; (11) hyperapo B lipoproteinemia; and (12) atherosclerosis. As used herein, the term "subject" refers to an animal, preferably a mammal. In some embodiments, the subject is a veterinary animal, companion animal, livestock, laboratory animal, or zoo animal. In other embodiments, the subject is a human.

[0084] As used herein, the terms "treating," "treatment," "treat," and the like refer to affecting a subject, tissue, or cell to obtain a desired pharmacological and / or physiological effect. The effect may be prophylactic, such as completely or partially preventing or reducing the severity of a disease or associated symptoms, and / or therapeutic, such as partially or completely curing a disease.

[0085] An "effective amount" refers to an amount sufficient to provide an amount of drug to achieve an effect when administered to a patient. Thus, an "effective amount" can also be a "therapeutically effective amount." A "therapeutically effective amount" refers to an amount sufficient to provide an amount of drug to treat a disease or a symptom of the disease when administered to a subject.

[0086] The terms "administration of a compound" or "administering a compound" should be understood to mean providing a compound of the present disclosure or a prodrug of a compound of the present disclosure to a human or other mammal in need of treatment.

[0087] The term "patient" should be understood to mean a human or other mammal in need of treatment.

[0088] In some embodiments, methods and uses are provided for treating, preventing, alleviating, modulating, or ameliorating a disease or condition associated with GPR30 by providing or administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates blood glucose levels in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves glucose tolerance in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves insulin sensitivity in the subject. In some embodiments, providing one or more compounds or compositions to a subject modulates the release of an incretin in the subject. In some embodiments, the released incretin is glucagon-like peptide-1 (GLP-1). In some embodiments, the incretin is a hormone that enhances insulin secretion in response to food intake. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in response to food intake by the subject. In some embodiments, providing one or more compounds or compositions to a subject improves energy homeostasis in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates appetite in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats type 2 diabetes in the subject. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2. In some embodiments, the compound is a compound of Formula (I) or Formula (II).

[0089] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating a disease or condition associated with GPR40 in a subject in need thereof include providing or administering one or more compounds or compositions described herein. In some embodiments, providing one or more compounds or compositions to a subject modulates insulin secretion in the subject. In some embodiments, providing one or more compounds or compositions to a subject modulates glucose metabolism in the subject. In some embodiments, providing one or more compounds or compositions to a subject achieves glucose homeostasis in the subject. In some embodiments, providing one or more compounds or compositions to a subject modulates the release of an incretin in the subject. In some embodiments, the released incretin is glucagon-like peptide-1 (GLP-1). In some embodiments, the incretin is a hormone that enhances insulin secretion in response to food intake. In some embodiments, providing one or more compounds or compositions to a subject promotes insulin secretion in response to food intake in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves energy homeostasis in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates appetite in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats type 2 diabetes in the subject. In some embodiments, providing one or more compounds or compositions to a subject promotes lipid metabolism in the subject. In some embodiments, providing one or more compounds or compositions to a subject promotes or suppresses inflammation in the subject. In some embodiments, one or more compounds are compounds of Table 1, 2, or 3. In some embodiments, the compound is a compound of Formula (I) or Formula (II).In some embodiments, the compound is compound 180, 366, or 426.

[0090] In some embodiments, methods and uses are provided for treating, preventing, alleviating, modulating, or ameliorating a disease or condition associated with GPR119 by providing or administering a therapeutically effective amount of a compound or composition herein to a subject in need thereof. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates blood glucose levels in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves glucose tolerance in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves insulin sensitivity in the subject. In some embodiments, providing one or more compounds or compositions to a subject modulates the release of an incretin in the subject. In some embodiments, the released incretin is glucagon-like peptide-1 (GLP-1). In some embodiments, the incretin is a hormone that enhances insulin secretion in response to food intake. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in response to food intake by the subject. In some embodiments, providing one or more compounds or compositions to a subject improves energy homeostasis in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates appetite in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats type 2 diabetes in the subject. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2. In some embodiments, the compound is a compound of Formula (I) or Formula (II).

[0091] In some embodiments, methods and uses are provided for treating, preventing, alleviating, modulating, or ameliorating a disease or condition associated with GPR120 by providing or administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates blood glucose levels in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves glucose tolerance in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves insulin sensitivity in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates the release of an incretin in the subject. In some embodiments, the released incretin is glucagon-like peptide-1 (GLP-1). In some embodiments, the incretin is a hormone that enhances insulin secretion in response to food intake. In some embodiments, providing one or more compounds or compositions to a subject stimulates insulin secretion in response to food intake by the subject. In some embodiments, providing one or more compounds or compositions to a subject improves energy homeostasis in the subject. In some embodiments, providing one or more compounds or compositions to a subject regulates appetite in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats type 2 diabetes in the subject. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2. In some embodiments, the compound is a compound of Formula (I) or Formula (II).

[0092] In some embodiments, the methods and uses for regulating insulin in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2.

[0093] In some embodiments, the methods and uses for producing favorable glucose homeostasis in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2.

[0094] In some embodiments, the methods and uses for inducing beta cell preservation in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, or 3. In some embodiments, the compound is a compound of Table 2.

[0095] In some embodiments, methods and uses are provided for treating, preventing, alleviating, modulating, or ameliorating a disease or condition associated with TGR5 by providing or administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. In some embodiments, providing one or more compounds or compositions to a subject activates bile acids in the subject. In some embodiments, providing one or more compounds or compositions to a subject improves insulin sensitivity in the subject. In some embodiments, providing one or more compounds or compositions to a subject modulates the release of an incretin in the subject. In some embodiments, the released incretin is glucagon-like peptide-1 (GLP-1). In some embodiments, the incretin is a hormone that enhances insulin secretion in response to food intake. In some embodiments, providing one or more compounds or compositions to a subject promotes insulin secretion in response to food intake in the subject. In some embodiments, providing one or more compounds or compositions to a subject induces thermogenesis in the subject. In some embodiments, providing one or more compounds or compositions to a subject increases the conversion of thyroxine (T4) to the more active triiodothyronine (T3) in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats, reduces, prevents, or ameliorates a metabolic disorder in the subject. In some embodiments, providing one or more compounds or compositions to a subject treats, prevents, reduces, or ameliorates inflammation in the subject. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the compound is a compound in Table 1, 2, 3, or 4. In some embodiments, the compound is a compound in Table 3. In some embodiments, the compound is selected from Formula (I) or Formula (II).

[0096] In some embodiments, the methods and uses for modulating TGR5 comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, or 4. In some embodiments, the compound is a compound in Table 3 or 4. In some embodiments, the modulation of TGR5 comprises modulation of one or more signal transduction pathways. In some embodiments, the one or more signal transduction pathways are selected from the group consisting of nuclear factor κB (NF-κB), AKT, and extracellular signal-regulated kinase (ERK).

[0097] In some embodiments, the method and use for treating cancer in a subject in need thereof comprises administering a therapeutically effective amount of the compound or composition described herein.As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant or benign tumor found in mammals, including leukemia, carcinoma, and sarcoma.Exemplary cancers include acute myeloid leukemia ("AML"), chronic myeloid leukemia ("CML"), brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovarian, sarcoma, and prostate cancer. Additional examples include cervical cancer, gastric cancer, head and neck cancer, uterine cancer, mesothelioma, metastatic bone cancer, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, primary brain tumors, cancer, malignant pancreatic islet insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, and neoplasms of the endocrine and exocrine pancreas. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, the cancer can be selected from, but is not limited to, colon cancer, gastric cancer, liver cancer, ovarian cancer, or breast cancer.

[0098] In some embodiments, the method and use for treating hypertension in a subject in need thereof comprises administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the hypertension may be arterial hypertension. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof.

[0099] In some embodiments, the methods and uses for treating fibrinolysis in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein, in some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0100] In some embodiments, the methods and uses for treating vascular endothelial dysfunction in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0101] In some embodiments, the method and use for treating polycystic ovary syndrome in a subject in need thereof comprises administering a therapeutically effective amount of a compound or composition described herein. As used herein, the term "polycystic ovary syndrome" or "PCOS" refers to an endocrine disorder characterized by menstrual abnormalities and its associated diseases. Clinical symptoms of PCOS include, but are not limited to, hormonal imbalance, hyperandrogenemia, amenorrhea, acanthosis nigricans, acne, obesity, hirsutism, hair loss, and female infertility. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, the compound is a compound in Table 3.

[0102] In some embodiments, methods and uses for treating cardiovascular disease in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. As used herein, "cardiovascular disease" refers to a disease related to the heart, blood vessels, or both. Cardiovascular disease includes, but is not limited to, coronary artery disease, cardiomyopathy, hypertensive heart disease, heart failure, heart rhythm disorders, inflammatory heart disease, peripheral artery disease, cerebrovascular disease, and inflammatory heart disease. In some embodiments, methods and uses for treating coronary artery disease in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, methods and uses for treating arteriosclerosis in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, methods and uses for treating myocardial infarction in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0103] In some embodiments, the methods and uses for treating atherothrombosis in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0104] In some embodiments, the method and use for treating fatty liver disease in a subject in need thereof comprises administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0105] In some embodiments, methods and uses for treating hyperglycemia in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, methods and uses for treating insulin resistance in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, methods and uses for treating hyperinsulinemia in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof.

[0106] In some embodiments, methods and uses for treating dyslipidemia in a subject in need thereof include administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof. In some embodiments, methods and uses for treating hypertriglyceridemia in a subject in need thereof include administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound in Table 1, 2, 3, 4, or a combination thereof.

[0107] In some embodiments, the methods and uses for reducing blood pressure in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0108] In some embodiments, the methods and uses for treating reduced glycated hemoglobin (HBA1c) in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0109] In some embodiments, the methods and uses for reducing liver weight in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0110] In some embodiments, the methods and uses for reducing kidney weight in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0111] In some embodiments, the methods and uses for treating liver disease in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0112] In some embodiments, the methods and uses for regulating energy homeostasis in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0113] In some embodiments, the methods and uses for regulating glucose metabolism in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0114] In some embodiments, the methods and uses for modulating an inflammatory response in a subject in need thereof comprise administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0115] In some embodiments, the method and use for liver regulation in a subject in need thereof comprises administering a therapeutically effective amount of a compound or composition described herein. In some embodiments, the compound is a compound of Table 1, 2, 3, 4, or a combination thereof.

[0116] In some embodiments, methods and uses for treating, preventing, reducing, modulating, or ameliorating obesity in a subject comprise administering a therapeutically effective amount of a compound or composition described herein. As used herein, the term "obesity" refers to a condition in which excess body fat is present. An operational definition of obesity is the body mass index (BMI (kg / m)), which is weight divided by height squared. 2 "Obesity" is defined as a body mass index (BMI) of 30 kg / m in an otherwise healthy subject. 2 or a BMI of 27 kg / m or greater in subjects with at least one comorbidity 2 An "obese subject" is an otherwise healthy subject with a body mass index (BMI) of 30 kg / m 2 or a BMI of 27 kg / m or greater in subjects with at least one comorbidity 2 An overweight subject is a subject at risk of obesity. An "at risk of obesity" is an otherwise healthy subject with a BMI of 25 kg / m^2 or greater and 30 kg / m^2 or greater. 2 or a BMI of 25 kg / m in subjects with at least one comorbidity 2 More than 27kg / m 2 Refers to subjects less than

[0117] Increased risk associated with obesity occurs at lower body mass index (BMI) in Asians. In Asian countries, including Japan, "obesity" is defined as a BMI of 25 kg / m2 or greater in subjects with at least one obesity-induced or obesity-related comorbidity that requires or is improved by weight loss. 2 In Asian countries, including Japan, an "obese subject" is defined as a person who has at least one obesity-induced or obesity-related comorbidity that requires or is improved by weight loss, and whose BMI is 25 kg / m or less. 2 In the Asia-Pacific region, "subjects at risk of obesity" refers to subjects with a BMI of 23 kg / m or more. 2 Super 25kg / m 2 Refers to subjects less than

[0118] As used herein, the term "obesity" is intended to encompass all of the above definitions of obesity.

[0119] Obesity-induced or obesity-related comorbidities include, but are not limited to, diabetes, non-insulin-dependent diabetes mellitus type 2, obesity-associated diabetes, impaired glucose tolerance, impaired fasting glucose, insulin resistance syndrome, dyslipidemia, hypertension, obesity-associated hypertension, hyperuricemia, gout, coronary artery disease, myocardial infarction, angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disorders, osteoarthritis, back pain, menstrual disorders, infertility, etc. In particular, comorbidities include hypertension, hyperlipidemia, dyslipidemia, impaired glucose tolerance, cardiovascular disease, sleep apnea syndrome, and other obesity-related conditions.

[0120] Treatment of obesity and obesity-related disorders refers to administering a compound of the present invention to reduce or maintain the weight of an obese subject. One outcome of treatment can be reducing the weight of an obese subject compared to their weight immediately before administration of a compound of the present invention. Another outcome of treatment can be preventing regain of weight previously lost as a result of diet, exercise, or drug therapy. Another outcome of treatment can be reducing the incidence and / or severity of obesity-related disorders. Treatment can suitably result in a reduction in food or calorie intake (including a reduction in total food intake or a reduction in the intake of specific dietary components, such as carbohydrates or fats), and / or an inhibition of nutrient absorption, and / or an inhibition of metabolic rate decline, and weight loss in a subject in need thereof. Treatment can also result in a change in metabolic rate, such as an increase in metabolic rate, instead of or in lieu of an inhibition of metabolic rate decline, and / or minimize the metabolic resistance that typically results from weight loss.

[0121] Prevention of obesity and obesity-related disorders refers to administering a compound of the present invention to reduce or maintain the body weight of a subject at risk of obesity. One outcome of prevention can be reducing the body weight of a subject at risk of obesity compared to their body weight immediately before administration of a compound of the present invention. Another outcome of prevention can be preventing the regain of weight previously lost as a result of diet, exercise, or drug therapy. Another effect of prevention can be preventing the onset of obesity by treating a subject at risk of obesity before the onset of obesity. Another outcome of prevention can be reducing the incidence and / or severity of obesity-related disorders by treating a subject at risk of obesity before the onset of obesity. Furthermore, when treatment is initiated in a subject who is already obese, the treatment can prevent the onset, progression, or severity of obesity-related disorders, such as atherosclerosis, type 2 diabetes, polycystic ovarian disease, cardiovascular disease, osteoarthritis, skin diseases, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.

[0122] The obesity-related disorder in this specification is related to obesity, caused by obesity, or results from obesity.Examples of obesity-related disorders include binge eating disorder and bulimia nervosa, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer and colon cancer, osteoarthritis, obstructive sleep apnea syndrome, cholelithiasis, gallstones, heart disease, cardiac rhythm abnormalities and arrhythmia, myocardial infarction, congestive heart failure, coronary artery disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, GH-deficient subjects, normal variant short stature, Turner syndrome, and other conditions that show reduced metabolic activity or reduced ratio of resting energy expenditure to total lean body mass, such as children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome (also known as syndrome X), insulin resistance syndrome, sexual and reproductive dysfunction (such as infertility, male hypogonadism and female hirsutism), gastrointestinal motility disorders (such as obesity-related gastroesophageal reflux disease), respiratory disorders (such as obesity-hypoventilation syndrome (Pickwickian syndrome)), cardiovascular disorders, inflammation (such as systemic inflammation of the vascular system), arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout and kidney cancer.The compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

[0123] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating metabolic syndrome in a subject comprise administering a therapeutically effective amount of a compound or composition described herein. "Metabolic syndrome" (also referred to as syndrome X) is defined in the National Institutes of Health's "Third Report of the National Cholesterol Education Program Task Force on the Detection, Evaluation, and Treatment of High Cholesterol in Adults (Adult Treatment Panel III, or ATP III)" (NIH Publication No. 01-3670, E.S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp. 356-359). Briefly, metabolic syndrome is defined as the presence of three or more of the following disorders: abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high blood pressure, and high fasting plasma glucose. These criteria are defined in ATP-III. Treating metabolic syndrome refers to administering a combination of the present invention to a subject with metabolic syndrome. Prevention of metabolic syndrome refers to the administration of the combinations of the present invention to a subject having two of the disorders that define metabolic syndrome. A subject having two of the disorders that define metabolic syndrome is one who has developed two of the disorders that define metabolic syndrome but has not yet developed three or more of the disorders that define metabolic syndrome.

[0124] In some embodiments, the methods and uses for treating, preventing, reducing, modulating, or ameliorating hypercholesterolemia in a subject comprise administering a therapeutically effective amount of a compound or composition described herein.

[0125] In some embodiments, methods and uses for treating, preventing, alleviating, modulating, or ameliorating type 2 diabetes in a subject comprise administering a therapeutically effective amount of a compound or composition described herein. As used herein, the term "diabetes" includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type 1 diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as type 2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (i.e., non-insulin-dependent diabetes), often develops despite normal or even elevated insulin levels and is thought to be due to the inability of tissues to respond appropriately to insulin. A majority of type 2 diabetes patients are also obese. The compositions of the present invention may be useful for treating both type 1 and type 2 diabetes. The term "obesity-related diabetes" refers to diabetes caused or resulting from obesity.

[0126] Diabetes is characterized by a fasting plasma glucose level of 126 mg / dl or greater. A diabetic subject has a fasting plasma glucose level of 126 mg / dl or greater. A prediabetic subject is one who has prediabetes. Prediabetes is characterized by an impaired fasting plasma glucose (FPG) level of 110 mg / dl or greater but less than 126 mg / dl, or impaired glucose tolerance, or insulin resistance. A prediabetic subject is a subject who has impaired fasting glucose (fasting plasma glucose (FPG) level of 110 mg / dl or greater but less than 126 mg / dl), or impaired glucose tolerance (2-hour plasma glucose level of ≥ 140 mg / dl but < 200 mg / dl), or insulin resistance, and is at increased risk of developing diabetes.

[0127] Treatment of diabetes refers to administering a compound or combination of the present invention to treat a diabetic subject. One outcome of treatment can be reducing glucose levels in a subject with high glucose levels. Another outcome of treatment can be reducing insulin levels in a subject with high insulin levels. Another outcome of treatment can be reducing plasma triglycerides in a subject with high triglyceride plasma levels. Another outcome of treatment can be reducing LDL cholesterol in a subject with high LDL cholesterol levels. Another outcome of treatment can be increasing HDL cholesterol in a subject with low HDL cholesterol levels. Another outcome of treatment can be increasing insulin sensitivity. Another outcome of treatment can be enhancing glucose tolerance in a subject with impaired glucose tolerance. Yet another outcome of treatment can be reducing insulin resistance in a subject with insulin resistance or high insulin levels. Prevention of diabetes, particularly diabetes associated with obesity, refers to administering a compound or combination of the present invention to prevent the onset of diabetes in a subject in need thereof. A subject in need of diabetes prevention is an overweight or obese pre-diabetic subject.

[0128] The term "diabetes-related disorder" should be understood to mean a disorder associated with, caused by, or resulting from diabetes. Examples of diabetes-related disorders include retinopathy, nephropathy, and neuropathy.

[0129] In some embodiments, the compounds or compositions of the present disclosure may also be useful for improving or restoring 3-cell function, and therefore may be useful for treating type 1 diabetes or delaying or preventing type 2 diabetes from progressing to the point where it requires insulin therapy. In some embodiments, the present disclosure also encompasses compounds (including pharmaceutically acceptable salts thereof) or compositions described herein that are useful for treating insulin resistance, type 2 diabetes, hyperglycemia, and dyslipidemia associated with type 2 diabetes and insulin resistance. In some embodiments, methods and uses are provided for lowering glucose and lipids in diabetic patients and non-diabetic patients with impaired glucose tolerance and / or prediabetes. In some embodiments, the compounds or compositions of the present disclosure may improve the hyperinsulinemia that often occurs in diabetic or prediabetic patients by regulating the fluctuations in serum glucose levels that often occur in these patients. In some embodiments, the compounds and compositions of the present disclosure may also be effective in treating or alleviating insulin resistance. In some embodiments, the compounds and compositions of the present disclosure may also be effective in treating or preventing gestational diabetes.

[0130] In some embodiments, methods and uses for treating, preventing, reducing, regulating, or ameliorating arteriosclerosis in a subject include administering a therapeutically effective amount of a compound or composition described herein. As used herein, the term "arteriosclerosis" encompasses vascular diseases and conditions recognized and understood by physicians in the relevant medical field. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease, and peripheral vascular disease are all clinical manifestations of arteriosclerosis and are therefore encompassed by the terms "arteriosclerosis" and "arteriosclerotic disease." A combination comprising a therapeutically effective amount of a GPR40 agonist in combination with a therapeutically effective amount of an antihypertensive agent can be administered to prevent or reduce the risk of coronary heart disease events, cerebrovascular events, or intermittent claudication, or the occurrence or recurrence of such events if a risk of recurrence exists. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., heart attack), and coronary revascularization. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also called cerebrovascular accident) and transient ischemic attack. Intermittent claudication is a clinical manifestation of peripheral vascular disease. As used herein, the term "atherosclerotic disease events" is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. A person who has previously experienced one or more non-fatal atherosclerotic disease events is intended to be a person who has the possibility of recurrence of such events. The term "atherosclerosis-related disorder" should be understood to mean a disorder that is related to, caused by, or resulting from atherosclerosis.

[0131] In some embodiments, methods and uses for treating, preventing, alleviating, regulating, or ameliorating hypertension in a subject comprise administering a therapeutically effective amount of a compound or composition described herein. As used herein, the term "hypertension" includes essential or primary hypertension, which may be of unknown or have multiple causes, such as both cardiac and vascular changes, and secondary hypertension, which has a known cause. Causes of secondary hypertension include, but are not limited to, obesity, kidney disease, hormonal disorders, and the use of certain medications (oral contraceptives, corticosteroids, cyclosporine, etc.). The term "hypertension" encompasses hypertension, in which both systolic and diastolic blood pressure levels are elevated (≥140 mmHg / ≥90 mmHg), as well as isolated systolic hypertension, in which only systolic blood pressure is elevated above 140 mmHg and diastolic blood pressure is below 90 mmHg. Normal blood pressure may be defined as a systolic blood pressure of less than 120 mmHg and a diastolic blood pressure of less than 80 mmHg. A hypertensive subject is one who has high blood pressure. A prehypertensive subject is a subject whose blood pressure is in the range of 120 mmHg / 80 mmHg to 139 mmHg / 89 mmHg. One outcome of treatment is to lower the blood pressure of a subject with hypertension. Treatment of hypertension refers to administering the compounds and combinations of the present invention to a hypertensive subject to treat hypertension. Treatment of hypertension-related disorders refers to administering the compounds or combinations of the present invention to treat hypertension-related disorders. Prevention of hypertension or hypertension-related disorders refers to administering the combinations of the present invention to a prehypertensive subject to prevent the onset of hypertension or hypertension-related disorders. Hypertension-related disorders herein are associated with, caused by, or result from hypertension. Examples of hypertension-related disorders include, but are not limited to, heart disease, heart failure, myocardial infarction, renal failure, and stroke.

[0132] In some embodiments, methods and uses for treating or preventing a lipid disorder in a subject include providing a therapeutically effective amount of a compound or composition described herein. In some embodiments, methods and uses for treating or preventing dyslipidemia in a subject include providing a therapeutically effective amount of a compound or composition described herein. Dyslipidemia and lipid disorders are disorders of lipid metabolism and include a variety of conditions characterized by abnormal concentrations of one or more lipids (i.e., cholesterol and triglycerides), and / or apolipoproteins (i.e., apolipoproteins A, B, C, and E), and / or lipoproteins (i.e., macromolecular complexes formed by lipids and apolipoproteins that allow lipids to circulate in the blood, such as LDL, VLDL, and IDL). Hyperlipidemia is associated with abnormally high levels of lipids, LDL and VLDL cholesterol, and / or triglycerides. Treating dyslipidemia refers to administering a combination of the present invention to a dyslipidemic subject. Preventing dyslipidemia refers to administering a combination of the present invention to a pre-dyslipidemic subject. Pre-dyslipidemia subjects are subjects who have higher than normal lipid levels but are not yet dyslipidemia.The term " dyslipidemia-related disorder " and " lipid disorder-related disorder " should be understood to mean the disorder that is related to dyslipidemia or lipid disorder, is caused by dyslipidemia or lipid disorder, or is the result of dyslipidemia or lipid disorder.Examples of dyslipidemia-related disorder and lipid disorder-related disorder include but are not limited to hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL) level, high plasma low-density lipoprotein (LDL) level, atherosclerosis and its sequelae, coronary or carotid artery disease, myocardial infarction and stroke.

[0133] Administration and Dose Range Any suitable route of administration can be used to provide a therapeutically effective dose of the compounds of the present invention to a mammal, particularly a human. For example, oral, rectal, transdermal, parenteral, ophthalmic, pulmonary, and nasal routes may be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The compounds of the present disclosure are preferably administered orally.

[0134] However, it should be understood that the specific dose level and frequency of administration for a particular patient will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, body weight, general condition, sex, diet, method and timing of administration, rate of excretion, drug combination, severity of the particular condition, and the patient being treated, and may vary.

[0135] The compounds of the present invention can be used in pharmaceutical compositions comprising (a) the compounds or their pharmaceutically acceptable salts, and (b) a pharmaceutically acceptable carrier. The compounds of the present invention can be used in pharmaceutical compositions containing one or more other active pharmaceutical ingredients. The compounds of the present invention can also be used in pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are the only active ingredient.

[0136] The term "composition" in pharmaceutical composition is intended to encompass a product containing an active ingredient and an inactive ingredient constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or the dissociation of one or more ingredients, or any other type of reaction or interaction of one or more ingredients. Thus, the pharmaceutical composition of the present invention encompasses any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. [Example]

[0137] The following non-limiting examples are provided to further illustrate the present disclosure.

[0138] Example 1 In vitro validation and screening data were performed on GPR40 extracts and purified compounds.

[0139] Without wishing to be bound by theory, GPR40 agonism is thought to produce beneficial metabolic outcomes through its actions in the pancreas and intestine. Partial agonists (approximately 50% receptor stimulation) do not induce GLP-1 secretion but act on the pancreas to enhance glucose-dependent insulin secretion, resulting in beneficial glycemic outcomes. Full agonists (approximately 100% receptor stimulation) not only act on the pancreas but also induce GLP-1 secretion. In contrast, TGR5 agonism potently induces GLP-1 secretion, but small-molecule therapeutics are difficult to develop, making a safe bioactive approach desirable. Regarding GPR119, its activation enhances the effects of other substances that induce GLP-1 secretion, but its effect when used alone is thought to be relatively weak.

[0140] In vitro assays were performed as described in Figure 1. cAMP and IP1 (HTRF) were used in the assays. No interference was observed in the assays from the plant extracts of the tested samples. In preliminary tests using pilot plates, no positive signal was detected in the absence of cells. A β-arrestin assay was also set up, but this signaling pathway was ultimately determined to have little relevance to the desired pharmacological effect. The process of these experiments is detailed in Figure 2, and the specific HTRF IP1 assay procedure is shown in Figure 3. In all assays, the positive control was a full GPR40 agonist (K-003 / AM-5262; CAS number 1222088-90-5), and an additional reference assay was performed for a partial GPR40 agonist (K-103 / TAK-875; CAS number 1000413-72-8). Each sample was tested in triplicate.

[0141] The most active compounds were selected for further testing in counterscreening plates. Criteria for plate control were an assay window >2-fold and Z' >0.5. The lack of overexpressed receptors in the positive control identified a problem, and two plant extracts known to have significant "off-target" effects were added. The signal reduction caused by the extracts in this part of the experiment was less pronounced. The results of this stage of testing are shown in Figure 4. Two pure compounds, 180 and 366, were identified as strong hits. These two hits were well-optimized partial agonists, exceeding the 50% threshold for typical partial agonists. These results are shown in Figure 5. A summary of the results is provided in Table 5.

[0142] [Table 5]

[0143] Example 2 The hGPR40 IP1 counterscreen assay was performed on plant extracts and pure compounds. Plate controls had assay windows >2-fold and Z' >0.5, and K-003 showed no signal in the parental CHO cell line. All samples with activity >50% were run in the counterscreen. The results are shown in Figure 6. Pure compounds 180 and 366 (boxed in Figure 7) were hits obtained in the IP1 assay. Considering assay noise, they do not appear to exhibit significant off-target activity. The majority of plant extracts with high (>50%) hGPR40 activity also exhibited off-target activity. 78% (66 of 85 extracts performed) had >20% off-target activity. Only four extracts had >50% hGPR40 activity and ≤20% interference. Pure compounds 180 and 366 did not exhibit significant signal interference, as shown in Table 6.

[0144] [Table 6]

[0145] Interference values ​​for plant extracts were generally reproducible over two days.

[0146] Example 3 An in vitro assay was performed to screen TGR5 pure compounds. The percent activation was calculated by normalizing the HTRF signal of the samples, with 100% HTRF signal corresponding to 100 nM K-155 (average of 14 technical replicates) and 0% HTRF signal corresponding to DMSO (average of 14 technical replicates). The TGR5 control versus HTRF ratios of DMSO and K-155 are shown in Figure 8. The cutoff was set at >50% activity, yielding 7 / 80 hits. All compounds were counterscreened in TGR5-deficient cells. The activity is shown in Table 7.

[0147] [Table 7]

[0148] The compounds were screened to form a positive control. Figure 9 shows the results of TGR5 pure compounds in cAMP screening. Compounds 711, 725 and 727 had the highest maximum activity rate and μM potency.

[0149] Example 4 This study focused on the evaluation of pure GPR40 compounds in a dose-response study, based on the two initial hits discovered in Example 1. GPR40 compounds were considered for further consideration if they met either the following criteria: >50% hGPR40 activity in the previous IP1 assay, or ≥20% GPR40 activity in one of three technical replicates. The results of the control screen are shown in Figure 10, and K-003 EC 50 (Complete)=0.5nM, K-13 EC 50The results were as follows: (partial) = 3.4 nM, assay window = 2.5, Z' = 0.48. GPR40 pure compounds 180 and 366 were tested in a dose-response assay and compared to other hits. The results are shown in Figure 11. Screening confirmed that compound 180 had a high maximal activity rate and a potency of approximately 1 μM, and compound 366 had a high maximal activity rate and a potency of approximately 5 μM. Compound 19 also had a low maximal activity rate but demonstrated the onset of the dose-response.

[0150] Accordingly, some of the aspects described herein relate to the following numbered alternatives:

[0151] 1. An oral composition comprising a therapeutically effective amount of one or more compounds or salts thereof and one or more carriers or excipients, wherein said compounds are agonists of a G protein-coupled receptor, and said agonists are capable of treating, alleviating, modulating, or ameliorating a disease or condition mediated by said G protein-coupled receptor.

[0152] 2. The compound is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 and R 2 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-C alkyl, and optionally substituted —O—C-C alkyl; X and Y are each independently selected from optionally substituted C-C alkyl; 18 Alkyl, optionally substituted C-C 18 Alkenyl and optionally substituted -O-C-C 18 The oral composition of alternative 1, wherein the alkyl is selected from -alkyl.

[0153] 3. The compound of formula (I) [ka] The oral composition of alternative 2, selected from:

[0154] 4. The oral composition of any one of alternatives 1 to 3, wherein said compound is an agonist of GPR40.

[0155] 5. The oral composition of any one of alternatives 1-4, wherein said compound is an agonist of GPR119.

[0156] 6. The oral composition of any one of alternatives 1-5, wherein the compound is an agonist of TGR5.

[0157] 7. The oral composition of any one of alternatives 1 to 6, formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutritionally functional food, or a pharmaceutical composition.

[0158] 8. The oral composition of any one of alternatives 1 to 7, configured in any one of the following dosage forms: softgel capsule, hard capsule, gummy, functional drink, functional food, liquid, powder, and tablet.

[0159] 9. The oral composition of any one of alternatives 1-8, comprising 1.0%-99% w / w of the plant extract.

[0160] 10. The oral composition of any one of alternatives 1-9, further comprising a preservative.

[0161] 11. The oral composition of any one of alternatives 1-10, further comprising a sweetener.

[0162] 12. The oral composition of any one of alternatives 1-11, further comprising a colorant.

[0163] 13. The oral composition of alternatives 1-12, further comprising an excipient.

[0164] 14. The oral composition of any one of alternatives 1-13, further comprising a flavoring.

[0165] 15. The oral composition of any one of alternatives 1-14, wherein said compound is a compound of Table 1, Table 2, Table 3, and Table 4.

[0166] 16. A method for treating, preventing, alleviating, modulating, or ameliorating a disease or disorder associated with GPR40, GPR119, or TGR5 in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an oral composition described in any one of about 1 to 15.

[0167] 17. The method of alternative 16, wherein said composition activates GPR40.

[0168] 18. A method according to approximately 16 or 17, wherein the composition is provided with food to induce activation of GPR40.

[0169] 19. The method of any one of paragraphs 16 to 18, wherein activation of GPR40 regulates appetite and glucose metabolism in said subject.

[0170] 20. A method for treating, preventing, reducing, modulating, or ameliorating obesity in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an oral composition described in any one of alternatives 1-15.

[0171] 21. The method of alternative 24, wherein administering said composition to said subject results in sustained weight control.

[0172] 22. The method of alternative 20 or 21, wherein administering the composition to the subject results in fat loss.

[0173] 23. The method of any one of alternatives 20-22, wherein administering the composition to the subject results in normalization of glucose levels.

[0174] 24. The method of any one of alternatives 20-23, wherein the subject is prediabetic.

[0175] 25. The method of any one of alternatives 20-24, wherein administering the composition results in an improved metabolic rate.

[0176] 26. The method of any one of alternatives 20-26, wherein administering the composition to the subject results in an improvement in the subject's waist-to-hip ratio.

[0177] 27. The method of any one of alternatives 20-26, wherein administering said composition to said subject results in improved insulin sensitivity in said subject.

[0178] 28. The method of any one of alternatives 20-27, wherein administering the composition to the subject improves one or more biomarkers associated with inflammation and obesity.

[0179] 29. The method of any one of alternatives 20-28, wherein administering the composition results in a reduction in body fat mass.

[0180] 30. The method of any one of alternatives 20-29, wherein the reduction in body fat mass is at least 5% to about 15% from a baseline measurement and is measured in kilograms (kg) or pounds (lb).

[0181] 31. The method of any one of alternatives 20-29, further comprising maintaining fat loss within ±3% to ±10% of the achieved body fat mass loss.

[0182] 32. A method for treating, preventing, reducing, modulating, or ameliorating diabetes in a subject in need thereof, comprising providing a therapeutically effective amount of a composition comprising an oral composition described in any one of alternatives 1-15.

[0183] 33. The method of alternative 32, wherein said diabetes is type 2 diabetes.

[0184] 34. The method of alternative 32 or 33, wherein providing the composition to the subject results in normalization of glucose levels and subsequently a fat loss effect.

[0185] 35. The method of any one of alternatives 32-34, wherein normal blood glucose regulation is achieved in said subject, followed by a fat loss effect.

[0186] 36. The method of any one of alternatives 32-35, wherein providing the composition results in an improved metabolic rate.

[0187] 37. The method of any one of alternatives 32-36, wherein providing the composition to a subject results in an improvement in the subject's waist-to-hip ratio.

[0188] 38. The method of any one of alternatives 32-37, wherein providing said composition to said subject results in improved insulin sensitivity in said subject.

[0189] 39. The method of any one of alternatives 32-38, wherein providing said composition to said subject improves one or more biomarkers associated with inflammation and obesity.

[0190] 40. The method of any one of alternatives 32-39, wherein providing said composition results in improved insulin secretion and appetite regulation.

[0191] 41. A method for treating, preventing, alleviating, modulating or ameliorating metabolic syndrome in a subject in need thereof, comprising providing a therapeutically effective amount of a composition comprising an oral composition described in any one of alternatives 1-15.

[0192] 42. The method of alternative 41, wherein the metabolic syndrome is selected from obesity, insulin resistance, hyperlipidemia, cardiovascular disease, fatty liver, cholesterol, oxidative stress, and hypertension.

[0193] 43. The method of alternatives 41 or 42, wherein providing said composition reduces weight or reduces weight gain in said subject.

[0194] 44. The method of any one of alternatives 41-43, wherein providing the composition enhances inulin secretion in the subject.

[0195] 45. The method of any one of alternatives 41-44, wherein providing the composition enhances glucose metabolism.

[0196] 46. ​​A method for treating, preventing, alleviating, modulating or ameliorating a lipid disorder in a subject in need thereof, comprising providing a therapeutically effective amount of a composition comprising an oral composition described in any one of alternatives 1-15.

[0197] 47. The method of alternative 46, wherein providing said composition enhances insulin secretion and improves fatty acid metabolism.

[0198] 48. The method of alternative 46 or 47, wherein providing the composition improves dyslipidemia in the subject.

[0199] 49. The method of any one of alternatives 46-48, wherein providing the composition improves NAFLD in the subject.

[0200] 50. A compound selected from Table 1, Table 2, Table 3 and Table 4.

[0201] 51. The compound according to alternative 50, which is substantially pure.

[0202] 52. The compound according to alternatives 50 or 51, which is 90% pure by weight excluding solvent molecules.

[0203] 53. Use of a composition for treating, alleviating, preventing, ameliorating or modulating a disease or condition associated with GPR40, the composition comprising: [ka] [ka] or a combination thereof.

[0204] 54. Use of a composition for treating, alleviating, preventing, ameliorating or modulating a disease or condition associated with TGR5, the composition comprising: [ka] [ka] [ka] or a combination thereof.

[0205] The foregoing description sets forth the best mode contemplated for carrying out the invention, and the manner and steps of making and using it, in full, clear, concise, and exact terms to enable those skilled in the art to make and use the same. However, the invention is susceptible to modifications and other arrangements different from those described above that are substantially equivalent. Therefore, the invention is not limited to the particular embodiments disclosed. Rather, the invention encompasses all modifications and alternative arrangements included within the spirit and scope of the invention as generally expressed by the following claims. While the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered exemplary or illustrative and not restrictive.

[0206] All documents cited herein are incorporated by reference in their entirety. In the event that a publication, patent, or patent application incorporated by reference conflicts with the disclosure contained herein, it is intended that the disclosure of this specification shall supersede and / or prevail over the conflicting content.

[0207] Unless otherwise defined, all terms (including technical and scientific terms) should be given their ordinary and customary meaning to those skilled in the art and should not be limited to any special or customized meaning unless expressly defined herein. The use of a particular term in describing a particular feature or aspect of the present disclosure should not be interpreted as the term being redefined herein to include the specific characteristics of the feature or aspect of the present disclosure to which the term pertains. Terms and phrases used in this specification and particularly in the appended claims, and variations thereof, should be interpreted as open-ended rather than limiting, unless expressly stated otherwise.As examples of the foregoing, the term "including" should be interpreted as "including without limitation" or "including but not limited to," etc., and as used herein, the term "comprising" should not be interpreted as "including," "containing," or "characterized by." the term "having" should be interpreted as "having at least" and the term "includes" should be interpreted as "including but not limited to"; the word "example" is used to indicate exemplary embodiments of the subject matter and is not intended to indicate an exhaustive or limiting list; the adjectives "known," "normal," "standard," and similar terms should not be interpreted as limiting the subject matter to a particular point in time or to that available at that time, but should be interpreted as embracing known, conventional, or standard technology that may be available or known at any time now or in the future; the use of the terms "preferably," "preferred," "desired," "desirable," and words of similar meaning should not be interpreted to imply that a particular feature is critical, essential, or even essential to the structure or function of the invention, but is merely intended to highlight alternative or additional features, whether or not utilized in a particular embodiment of the invention. Similarly, a group of items joined by "and" does not require all items to be present in the group and should be construed as "and / or" unless expressly stated otherwise. Similarly, a group of items joined by "or" does not require mutual exclusion and should be construed as "and / or" unless expressly stated otherwise.

[0208] When a range of values ​​is given, it is understood that the upper and lower limits, and each value between the upper and lower limits of the range, are encompassed within the embodiment.

[0209] For the use of almost all plural and / or singular terms herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate to the context and / or application. For purposes of clarity, various singular / plural combinations may be expressly set forth herein for clarity's sake. The indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Reference signs in the claims are not to be construed as limiting the scope.

[0210] Furthermore, when a specific number is intended to introduce a claim recitation, that intention will be explicitly stated in the claim; those skilled in the art will understand that, absent such a statement, no such intention exists. For example, to aid in understanding, the following appended claims may include the use of introductory phrases such as "at least one" and "one or more." However, the use of such phrases should not be construed herein as meaning that a claim recitation introduced by the indefinite article "a" or "an" is limited to embodiments containing only one of that recitation, even if the same claim also contains introductory phrases such as "one or more" or "at least one" (typically, "a" and / or "an" should be interpreted as "at least one" or "one or more"); the same applies to the use of definite articles when introducing claim recitations. Furthermore, even when a specific quantity is explicitly stated in an introduced claim recitation, those skilled in the art will understand that such recitation should typically be interpreted as the recited quantity or more (e.g., the mere recitation of "two recited items" typically means "at least two" or "two or more" recited items, unless otherwise modified). Furthermore, when phrases similar to "at least one of A, B, and C, etc." are used, they are intended to be interpreted according to conventions understood by those skilled in the art (e.g., "a system having at least one of A, B, and C" includes systems having, but not limited to, A only, B only, C only, A and B, A and C, B and C, and / or A, B, and C). When phrases similar to "at least one of A, B, or C" are used, they are also generally intended to be interpreted according to conventions understood by those skilled in the art (e.g., "a system having at least one of A, B, or C" includes systems having, but not limited to, A only, B only, C only, A and B, A and C, B and C, and / or A, B, and C).Furthermore, those skilled in the art will understand that almost all disjunctive words and / or phrases presenting two or more alternatives in the specification, claims, or drawings contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A," "B," or "both A and B."

[0211] It should be understood that numerical values ​​used herein, such as amounts of ingredients, reaction conditions, and the like, are modified in all instances by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any application claiming priority hereto, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0212] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Accordingly, the scope of the present invention should not be limited to the specific embodiments and examples described herein, but should be construed to embrace all modifications and alternatives consistent with the true scope and spirit of the invention.

Claims

1. a therapeutically effective amount of one or more compounds or salts thereof; one or more carriers or excipients; An oral composition comprising: the one or more compounds are agonists of a G protein-coupled receptor; The agonist is capable of treating, alleviating, modulating, or ameliorating a disease or condition mediated by said G protein-coupled receptor. Oral compositions.

2. The one or more compounds are compounds represented by the following formula (I) or salts thereof: 【Chemistry 1】 In the formula, R １ and R ２ are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C １ -C ６ Alkyl and optionally substituted —O—C １ -C ６ - alkyl, X and Y are each independently an optionally substituted C １ -C １８ Alkyl, optionally substituted C １ -C １８ Alkenyl and optionally substituted —O—C １ -C １８ - selected from alkyl, 10. The oral composition of claim 1.

3. wherein one or more compounds of formula (I) 【Chemistry 2】 Selected from: The oral composition of claim 2.

4. The one or more compounds are compounds represented by the following formula (III) or salts thereof: 【Transformation 3】 (III) In the formula, R １ , R ２ , R ３ , R ４ and R ５ are each independently hydrogen, deuterium, hydroxyl, keto, halogen, optionally substituted amino, optionally substituted C-amido, optionally substituted ester, optionally substituted C １ ~C ６ Alkyl, optionally substituted C １ ~C ６ Alkoxy, optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C ８ Heterocyclyl and optionally substituted C ３ ~C ８ heterocyclylalkyl; X is a bond, -CH ２ -, -CH ２ CH ２ - and -NH-; The oral composition of claim 1.

5. 5. The oral composition of claim 4, wherein the compound of formula (III) is selected from the following: 【Chemistry 4-1】 【Chemistry 4-2】

6. 2. The oral composition of claim 1, wherein the one or more compounds are selected from the group consisting of: 【Transformation 5】

7. The oral composition of claim 2, wherein the compound is an agonist of GPR40.

8. The oral composition of claim 2, wherein the compound is an agonist of GPR119.

9. The oral composition of claim 4, wherein the compound is an agonist of TGR5.

10. 3. The oral composition of claim 2, formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutritionally functional food, or a pharmaceutical composition.

11. 3. The oral composition of claim 2, which is in any one of the following dosage forms: soft gel capsule, hard capsule, gummy, functional drink, functional food, liquid, powder, and tablet.

12. 10. The oral composition of claim 1, comprising 1.0% to 99% w / w of the plant extract.

13. The oral composition of claim 2 further comprising a preservative.

14. The oral composition of claim 2 further comprising a sweetener.

15. The oral composition of claim 2 further comprising a colorant.

16. The oral composition of claim 2 further comprising an additive.

17. The oral composition of claim 2 further comprising a flavoring agent.

18. 2. The oral composition of claim 1, wherein the compound is a compound of Table 1, Table 2, Table 3, or Table 4.

19. 19. The oral composition of claim 18, wherein the compound is a compound of Table 4.

20. 1. A method for treating, preventing, alleviating, modulating, or ameliorating a disease or disorder associated with GPR40, GPR119, or TGR5 in a subject in need thereof, comprising:

20. The method of claim 1, further comprising administering a therapeutically effective amount of a composition comprising the oral composition of any one of claims 1 to 19. method.

21. 21. The method of claim 20, wherein the composition activates GPR40.

22. 21. The method of claim 20, wherein the composition is provided with food to induce activation of GPR40.

23. 21. The method of claim 20, wherein activation of GPR40 regulates appetite and glucose metabolism in the subject.

24. 1. A method for treating, preventing, reducing, modulating, or ameliorating obesity in a subject in need thereof, comprising:

20. The method of claim 1, further comprising administering a therapeutically effective amount of a composition comprising the oral composition of any one of claims 1 to 19. method.

25. 25. The method of claim 24, wherein administering the composition to the subject results in sustained weight control.

26. 25. The method of claim 24, wherein administering the composition to the subject results in fat loss.

27. 25. The method of claim 24, wherein administering the composition to the subject results in normalization of glucose levels.

28. 25. The method of claim 24, wherein the subject is pre-diabetic.

29. 25. The method of claim 24, wherein administering the composition results in an improved metabolic rate.

30. 25. The method of claim 24, wherein administering the composition to the subject results in improved insulin sensitivity in the subject.

31. 25. The method of claim 24, wherein administering the composition to the subject improves one or more biomarkers associated with inflammation and obesity.

32. 25. The method of claim 24, wherein administering the composition results in a reduction in body fat mass.

33. 33. The method of claim 32, wherein the reduction in body fat mass is at least 5% to about 15% from a baseline measurement, measured in kilograms (kg) or pounds (lb).

34. 34. The method of claim 33, further comprising maintaining fat loss within ±3% to ±10% of the achieved body fat mass loss.

35. 1. A method of treating, preventing, reducing, modulating, or ameliorating diabetes in a subject in need thereof, comprising: providing a therapeutically effective amount of a composition comprising the oral composition of any one of claims 1 to 19. method.

36. 36. The method of claim 35, wherein the diabetes is type 2 diabetes.

37. 36. The method of claim 35, wherein providing the composition to the subject results in normalization of glucose levels and subsequent fat loss effects.

38. 36. The method of claim 35, wherein normal blood glucose control is achieved in the subject, followed by a fat loss effect.

39. 36. The method of claim 35, wherein providing the composition results in an improved metabolic rate.

40. 36. The method of claim 35, wherein providing the composition to the subject results in improved insulin sensitivity in the subject.

41. 36. The method of claim 35, wherein providing the composition results in improved insulin secretion and appetite regulation.

42. 1. A method of treating, preventing, reducing, modulating, or ameliorating metabolic syndrome in a subject in need thereof, comprising: providing a therapeutically effective amount of a composition comprising the oral composition of any one of claims 1 to 18. method.

43. 43. The method of claim 42, wherein the metabolic syndrome is selected from obesity, insulin resistance, hyperlipidemia, cardiovascular disease, fatty liver, cholesterol, oxidative stress, and hypertension.

44. 43. The method of claim 42, wherein providing the composition reduces weight or reduces weight gain in the subject.

45. 43. The method of claim 42, wherein providing the composition enhances inulin secretion in the subject.

46. 43. The method of claim 42, wherein providing the composition enhances glucose metabolism.

47. 1. A method for treating, preventing, reducing, modulating, or ameliorating dyslipidemia in a subject in need thereof, comprising: providing a therapeutically effective amount of a composition comprising the oral composition of any one of claims 1 to 19. method.

48. 48. The method of claim 47, wherein providing said composition enhances insulin secretion and improves fatty acid metabolism.

49. 48. The method of claim 47, wherein providing the composition improves dyslipidemia in the subject.

50. 48. The method of claim 47, wherein providing the composition improves NAFLD in the subject.

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