Pharmaceutical compositions and methods for the treatment of metabolic and liver disorders

Abstract

Disclosed herein are oral compositions of small molecule GLP-1 agonists and GIP / GLP-1 dual receptor agonists and uses thereof.

Description

VIKNG.036 WO PATENTPHARMACEUTICAL COMPOSITIONS AND METHODS FOR THE TREATMENT OF METABOLIC AND LIVER DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 696,306, filed September 18, 2024, which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled “VIKNG.036WO.xml” created on September 11, 2025, which is 41,108 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUNDField

[0003] The present disclosure relates generally to the fields of chemistry and medicine. More specifically, the present disclosure relates to solid oral pharmaceutical compositions for the treatment of metabolic disorders and fatty liver diseases. Description of the Related Art

[0004] Incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-l) are metabolic hormones. GIP and GLP-l are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet p-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of p-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue. In contrast, GLP-l exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-l also promotes satiety and sustained GLP-l -receptor activation is associated with weight loss in both preclimcal and clinical studies.

[0005] Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is the most common cause of chronic liver disease. NAFLD may progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GLP-1 agonists and GIP / GLP-1 dual receptor agonists have been developed for treating N AFLD, nonalcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of GLP-1 agonists and GIP / GLP-1 dual receptor agonists is associated with nausea, vomiting, and / or diarrhea. For example, clinical trials of a GIP / GLP1 dual receptor agonist compound found that tolerability at high doses was limited by gastrointestinal adverse events. The dose limitation associated with gastrointestinal adverse events may prevent dosing to the desired effective dose, may compromise patient compliance with treatment, and may limit the effectiveness of the treatment regimen. Therefore, a need exists for GLP-1 agonist and GIP / GLP1 dual agonist compounds that can be used to treat fatty liver diseases and other diseases and disorders.

[0006] Peptide compounds show some promise as GLP-1 agonists and GIP / GLP- 1 dual agonists that can be used to treat metabolic disorders such as NAFLD. However, there are many difficulties in preparing oral compositions of peptides. Such oral compositions have varying bi oavail abilities of the active agent. Accordingly, there is a need for suitable pharmaceutical compositions of such peptide-based dual agonist compounds.SUMMARY

[0007] In one aspect of the present disclosure, provided herein is a pharmaceutical composition comprising: a permeability enhancer; and a therapeutically effective amount of a compound, wherein the compound is a GLP-1 agonist or a GLP / GIP dual agonist, wherein the mass of the permeability enhancer is greater than 300 mg.

[0008] In some embodiments of the first aspect, the compound is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from the group consisting of ('( ();■{() / jJ. P( ()){X)(¥) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R7;R2is selected from the group consisting of -C(=O)(OZ2), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R7; each R7may be independently selected from the group consisting of halogen, Cue alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, Cue alkoxy, -OR5, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y may each be independently selected from the group consisting of -OR4, NR5R6, C1-6 alkyl and haloC1-6 alkyl; each R4may be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, Cs-io aryl, and C7-11 arylalkyl; each R5may be independently hydrogen or C1-6 alkyl; each R6may be independently hydrogen or C1-6 alkyl; andZ1and Z2may each be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl.

[0009] In some embodiments of the compound of Formula (I), at least one of Z1and Z2is not hydrogen.

[0010] In other embodiments of the first aspect, the compound is a compound having the structure of Formula (II):H-Y AibP P P S -NH2(SEQ ID NO: 4) (SEQ ID NO: 5)(II) or a pharmaceutically acceptable salt thereof, wherein:Aib is 2-aminoisobutyric acid; each instance of J1, J2, and J3is independently an amino acid selected from Aib, a naturally occurring ammo acid, and an unnatural ammo acid;U1IS -(J4)nl-(J5)n2-(J6)n3-(J7)n4-,U2is -(J8)n5-(J9)n6-(J1°)n7-(J11)n8-; each instance of J4, F, J6, J7, J8, J9, J10, and J11is independently a naturally occurring amino acid or an unnatural amino acid, each of nl, n2, n3, n4, n5, n6, n'7, and n8 is independently 0 or 1, provided that the sum nl + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4;R1is selected from the group consisting of ('( OhOZ’ j. -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1 -2 R7;R2is selected from the group consisting of ~-C(=O)(OZ2), P( O;-(X}(¥) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1 -2 R7;each R7is independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, Ct-6 alkoxy, -OR’, C3-10 cycloalkyl, C6-10 aryl, 5- 10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of -OR4, NR5R6, CI -6 alkyl and haloC1-6 alkyl; each R4is independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, CY-io aryl and C7-11 arylalkyl; each R5is independently hydrogen or C1-6 alkyl; each R1' is independently hydrogen orC1-6 alkyl; andZ1and Z2each are independently selected from the group consisting of hydrogen, Ct-6 alkyl, haloC1-6 alkyl, ( C6-10 aryl)-C1-6 alkyl, C3-10 cycloalkyl and Ce-io aryl

[0011] In some embodiments, the compound is not:H -Y (S AEibQ eID BNTOF:T6)S D Y S I Atb I. D K i A Q --N HT Y J;r-A F V Q W L I A 6 G P S (SSEGQAI13PNPOP: S7)-NH?

[0012] In some embodiments of the compound of Formula (II), at least one of Z!and Z2is not hydrogen.

[0013] In yet other embodiments of the first aspect, the compound is a compound having the structure of Formula (III):(III), or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of ~C(=O)(OZ1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with 1-2 R7;R2is selected from the group consisting of -C(=O)(OZ2), -(CH2CH2)nP(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with 1-2 R7; each R' is independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxyC, 1-6 alkoxy, -OR3, C3-10 cycloalkyl, Co-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of -OR4, NR5R°, C1-6 alkyl and haloC1-6 alkyl; each R4is independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, Cs-io aryl, and C7-11 arylalkyl, each R5is independently hydrogen or C1-6 alkyl; each R'Jis independently hydrogen or C1-6 alkyl;Z!and Z2each are independently selected from the group consisting of hydrogen, C1-6 alkyl, haloCt-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and n is 0, 1, 2, 3 or 4.

[0014] In some embodiments of the first aspect, the permeability enhancer is a pharmaceutically acceptable salt of a medium chain fatty acid comprising 6 to 12 carbon atoms, or a combination thereof. In some embodiments, the permeability enhancer is apharmaceutically acceptable salt of a fatty acid comprising six, seven, eight, nine, or ten carbon atoms. In some embodiments, the permeability enhancer is sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof In some embodiments, the permeability enhancer is sodium caprate (i.e., sodium decanoate), lithium decanoate, potassium decanoate, or a combination thereof. In some embodiments, the permeability enhancer may be any combination of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate salcoprozate sodium (SNAC) and sodium decanoate.

[0015] In some embodiments of the aspects of the present disclosure, the pharmaceutical composition is formulated for oral administration. In some such embodiments, the pharmaceutical composition is entencally coated.

[0016] In a second aspect of the present disclosure, provided herein is a method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject, comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof,

[0017] In a third aspect of the present disclosure, provided herein is a method of preventing, treating, or ameliorating one or disease or disorders in a subject, comprising administering a pharmaceutical composition disclosed herein to a subject in need thereof, wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

[0018] In a fourth aspect of the present disclosure, provided herein is a method of preventing, treating, or ameliorating a metabolic disorder or metabolic syndrome. In some embodiments, the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or prader-willi syndrome.

[0019] In a fifth aspect of the present disclosure, provided herein is a method of preparing a pharmaceutical composition. In some embodiments, the method comprises the steps of:(i) combining a permeability enhancer and magnesium stearate to form first granules;(ii) combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidinone to form second granules(Hi) combining the first granules and the second granules to form a mixture;(iv) adding magnesium stearate to the mixture to form third granules;(v) pressing the third granules into tablets.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0020] In some embodiments, pharmaceutical compositions are provided for administration to a subject in need thereof. Various embodiments of these pharmaceutical compositions include a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable diluent, and any combination of the foregoing. Some embodiments of the pharmaceutical compositions include a therapeutically effective dosage of a compound, or a pharmaceutically acceptable salt thereof, as described elsewhere herein. Some embodiments of the pharmaceutical compositions are administered for the prevention, treatment, or amelioration of one or more fatty liver diseases in the subject.Definitions

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0022] “Solvate” refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0023] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable offorming acid and / or base salts by virtue of the presence of ammo and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resms, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0024] As used herein, “Cato Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to Ca alkyl” or “Ci-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CHE-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH 3CH2CI hCl I3)- and ( ( = Iv ) C-

[0025] The term “halogen” or “halo,” as used herein, means any one of the radiostable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0026] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbonatoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as “Ci-4 alkyl” or similar designations. By way of example only, “Ci-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyL Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0027] As used herein, “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain, substituting one or more hydrogens with halogens. Examples of haloalkyl groups include, but are not limited to, -CFs, -CHFz, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2CI, -CH2CF2CF3 and other groups that in light of the ordinary’ skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.

[0028] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl as is defined above, such as “Civ alkoxy”, including but not limited to methoxy, ethoxy, n- propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

[0029] As used herein, “polyethylene glycol” refers to the formulawherein n is an integer greater than one and R is a hydrogen or alkyl. The number of repeat units “n” may be indicated by referring to a number of members. Thus, for example, “2- to 5- membered polyethylene glycol” refers to n being an integer selected from two to five. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0030] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may alsobe a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. In various embodiments, the heteroalkyl may have from I to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compounds may be designated as “CM heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “Ci-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0031] The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0032] As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as “Gvio aryl,” “Co or Cio aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0033] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as “ C6-10 aryloxy” or “Q-io arylthio” and the like, including but not. limited to phenyl oxy.

[0034] An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such “C7-14 aralkyl” and the like, including but. not limited to benzyl, 2- phenylethyl, 3 -phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).

[0035] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contam(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system isaromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations. In various embodiments, a heteroaryl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or I heteroatom. For example, in various embodiments, a heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0036] A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a Ci-4 alkylene group),

[0037] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6 carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0038] A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropyl butyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0039] As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0040] As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein 110 ring in the ring system is aromatic. An example is cyclohexenyl.

[0041] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations.

[0042] In various embodiments, a heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, a heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or twoheteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3- dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4- oxathianyl, 2Jf-l,2-oxazinyl, trioxanyl, hexahydro-1, 3, 5-triazinyl, 1,3-dioxolyl, 1,3- dioxolanyl, 1 ,3-dithiolyl, 1,3 -dithio lanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidmyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro- 1 ,4-thiazinyl, thiamorpholinyl, dihy drobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0043] A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0044] As used herein, “acyl” refers to -C(=O)R, wherein R is hydrogen, Ct-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0045] An “O-carboxy” group refers to a “~OC(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0046] A “C-carboxy” group refers to a “-C(=::O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(:::())OH).

[0047] A “cyano” group refers to a “-CN” group.

[0048] A “cyanate” group refers to an “-OCN” group.

[0049] An “isocyanate” group refers to a “-NCO” group.

[0050] .A “thiocyanate” group refers to a “-SCN” group.

[0051] An “isothiocyanate” group refers to an “ -NCS” group.

[0052] A “sulfinyl” group refers to an “-S(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Q-to aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0053] .A “sulfonyl” group refers to an “-SO2R” group in which R is selected from hydrogen. Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0054] An “S-sulfonamido” group refers to a “-SO2NRARB” group in winch RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0055] An “N-sulfonamido” group refers to a “-N(RA)SO2RB” group in which RA and Rb are each independently selected from hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0056] An “O-carbamyl” group refers to a “-OC(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, Ct-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0057] An “N-carbamyl” group refers to an “-N(RA)OC(=:O)RB” group in which RA and RB are each independently selected from hydrogenC, 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0058] An “O-thiocarbamyl” group refers to a “-OC(::::S)NRARB” group in which RA and RB are each independently selected from hydrogenC, 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0059] An “N-thiocarbamyl” group refers to an “-N(RA)OC(=S)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2- s alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0060] A “C-amido” group refers to a “-C(=O)NRARB” group in which RA and RB are each independently selected from hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0061] An “N-amido” group refers to a “-N(RA)C(=O)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0062] An “ammo” group refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Cfi-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0063] An “aminoalkyl” group refers to an amino group connected via an alkylene group.

[0064] An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.

[0065] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that the group is substituted with one or more subsitutents independently selected from Ci-Ce alkyl, Ci-Cs alkenyl, Ci-Ce alkynyl, Ci-Ce heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Cs haloalkoxy), C3- Cv-carbocyclyl-Ci-Cs-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci- Ce haloalkyl, and C1-C5 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Cs haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heterocyclyl-Ci-Ce-alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), aryl(Ci-Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Cs alkoxy, Ci-Cs haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), 5-10 membered heteroaryl(Ci -Ce)alkyl (optionally substituted with halo, Ci-Ce alkyl, Ci-Cs alkoxy, Ci-Ce haloalkyl, and Ci-Ce haloalkoxy), halo, cyano, hydroxy, Ci-Ce alkoxy, Ci-Ce alkoxy(Ci-C’6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci- C6)alkyl (e.g., -CF3,), halo(C1-C6)alkoxy (e.g., -OCF3,), C1-C6 alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0066] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C 1-C4 alkyl, amino, hydroxy, and halogen.

[0067] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of atta chment includes di-radicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0068] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) “together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:

[0069] and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R1and R2together with the nitrogen to which they are attached form a heterocyclyl, it is meant that Rland R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

[0070] where ring A is a heterocyclyl ring containing the depicted nitrogen.

[0071] Similarly, when two “adjacent” R groups are said to form a ring “together with the atoms to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:

[0072] and R1and R2are defined as selected from the group consisting of hydrogen and alkyl, or R’!and R2together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that R1and R2can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

[0073] where A is an aryl ring or a carbocyclyl containing the depicted double bond.

[0074] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AB- orincludes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is atta ched at the rightmost attachment point of the molecule.

[0075] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.

[0076] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0077] An “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated: however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0078] “Treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.Compounds

[0079] In some embodiments, the pharmaceutical compositions include compounds that are non-macrocyctic functionalized peptides that act as GIP / GLP-1 dual receptor agonists. In other embodiments, the pharmaceutical compositions include compounds that are non-macrocyclic functionalized peptides that act as GLP-1 receptor monoagonists.[00S0] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may formsolvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0081] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.Compounds of Formula (I)

[0082] Various embodiments of these compounds include compounds having the structure of Formula (I) as described above or pharmaceutically acceptable salts thereof. The structure of Formula (I) encompasses all stereoisomers and racemic mixtures, including the following structure and mixtures thereof:

[0083] In some embodiments of compounds of Formula (I):

[0084] Rlis selected from the group consisting of -C(=O)(OZ3), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1 -2 R?;

[0085] R2is selected from the group consisting of -C(=O)(OZ2), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R / ;

[0086] each R7may be independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxyC, 1-6 alkoxy, -OR5, C3-10 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0087] X and Y may each be independently selected from the group consisting of OR4, NR5Rb, C1-6 alkyl and haloC1-6 alkyl;

[0088] each R4may be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C6-10 aryl and C7-11 arylalkyl;

[0089] each R5may be independently hydrogen or Cue alkyl;

[0090] each R6may be independently hydrogen or C1-6 alkyl; and

[0091] Z{and Z2may each be independently selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and Ce-w aryl.

[0092] In some embodiments, at least one of Z1and Z2is not hydrogen.

[0093] Some embodiments of compounds of Formula I include compounds having the structure of Formula (I-a):or pharmaceutically acceptable salts thereof.

[0094] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; Z!is selected from hydrogen, Cue alkyl, haloC1-6 alkyl, C7- 11 arylalkyl. C3-10 cycloalkyl and C6-10 aryl; and X and Y each are -OR4.

[0095] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; Z!is selected from hydrogen,C1-6 alkyl, and haloC1-6 alkyl; and each R4may be independently selected from hydrogen, C6-10 aryl and Cs-io arylalkyl.

[0096] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; Z!is hydrogen and each R4may be independently hydrogen or C7-11 arylalkyd.

[0097] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; each R4is hydrogen.

[0098] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; Z1is hydrogen and each R4is hydrogen.

[0099] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-b):I-b or pharmaceutically acceptable salts thereof.

[0100] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; Z2is selected from hydrogen,C1-6 alkyl, haloC1-6 alkyl, C?- 11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and X and Y each are -OR4.

[0101] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; Z2is selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl; and each R4may be independently selected from hydrogen, C6-10 aryl and C7-11 arylalkyl.

[0102] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; Z2is hydrogen and each R4may be independently hydrogen or C7-11 arylalkyl.

[0103] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; each R4is hy drogen.

[0104] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; Zzis hydrogen and each R4is hydrogen.

[0105] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-c):or pharmaceutically acceptable salts thereof

[0106] In some embodiments of compounds of Formula (I-c) or their pharmaceutically acceptable salts; X and Y each are -OR4.

[0107] In some embodiments of compounds of Formula (I-c) or their pharmaceutically acceptable salts; each R4may be independently selected from hydrogen, Ce- 10 aryl and C7-11 arylalkyl.

[0108] In some embodiments of compounds of Formula (I-c) or their pharmaceutically acceptable salts; each R4is hydrogen.

[0109] Some embodiments include a compound having the structure selected from the group consisting of:and pharmaceutically acceptable salts thereof.

[0110] Some embodiments include a compound wherein indicates a chiral carbon with “S” configuration.

[0111] Some embodiments include a compound wherein indicates a chiral carbon with “R” configuration.

[0112] The compounds of Formula (I) described herein, e.g., Compounds 1-12, may be prepared according to methods described in International Patent Publication No. WO 2022 / 159395, the disclosure of which is incorporated herein in its entirety.Compounds Formula (II)

[0113] Various embodiments of these compounds include compounds having the structure of Formula (II) as described herein or pharmaceutically acceptable salts thereof. The structure of Formula (II) encompasses all stereoisomers and racemic mixtures, including the following structure and mixtures thereof:H-Y Aibor a pharmaceutically acceptable salt thereof. Formula (II) can also be written as:In Formula (II) and the compounds described herein, “H-” represents hydrogen on the N- terminal amine and “-NH2” represents an ammo forming a C-terminal amide.

[0114] In some embodiments of compounds of Formula (II):Aib is 2-aminoisobutyric acid; each instance of J1, J2, and J3is independently an amino acid selected from Aib, a naturally occurring amino acid, and an unnatural amino acid.

[0115] In some embodiments of compounds of Formula (II):each instance of J4, J5, J°, J7, J8, J9, J5u, and J11is independently a naturally occurring ammo acid or an unnatural amino acid; each of nl , n2, n3, n4, n5, n6, n7, and n8 is independently 0 or 1, provided that the sum nl + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4;R1is selected from the group consisting of -C(=O)(OZ1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1 -2 R?;R2is selected from the group consisting of -C(=O)(OZ2), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1-2 R7;each R7is independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, Cue alkoxy, -OR5, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of --OR4, NR5R6,Ci -6 alkyl and haloC1-6 alkyl; each R4is independently selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, C6-10 aryl and C7-11 arylalkyl; each R5is independently hydrogen or Cue alkyl; each R6is independently hydrogen or Cue alkyl; andZ1and Z2each are independently selected from the group consisting of hydrogen, Cue alkyl, haloCue alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl.

[0116] In some embodiments, the compound is not:

[0117] In some embodiments of compounds of Formula (II), each instance of J1, J2, and J3is independently an ammo acid selected from Aib and a naturally occurring amino acid.

[0118] In some embodiments of compounds of Formula (II), each instance of J1, J2, and J3is independently an ammo acid selected from Aib, A, F, N, R, and Q. In some embodiments, J!is Aib or F. In some embodiments, J1F. In some embodiments, J2is N or Q. In some embodiments, J2is N. In some embodiments, ,F is A or R. In some embodiments, JJis R.

[0119] In some embodiments of compounds of Formula (II), each instance of J4, J5, J6, and J7is independently an ammo acid selected from A, I, K, R, Q, S, T, and V. In some embodiments, J4is K or R. In some embodiments, J4is R. In some embodiments, J5is I, T, or V. In some embodiments, J'!is T or V. In some embodiments, J6is A or S. In some embodiments, J6is S. In some embodiments, J7is Q. In some embodiments, J7is K.

[0120] In some embodiments of compounds of Formula (II), each instance of Js, J9, J! 0, and J11is independently an amino acid selected from A, I, and Q. In some embodiments, J8is I or Q. In some embodiments, J9is A or Q. In some embodiments, J10is Q. In some embodiments, JHis Q.

[0121] In some embodiments of compounds of Formula (II), J1is selected from Aib or F; J2is selected from Q or N; J3is selected from A or R; U!is selected from -K-V-A-, -K-I-A-Q- (SEQ ID NO: 8), -K-T-A-Q- (SEQ ID NO: 9), -K-T-S-Q- (SEQ ID NO: 10), -K-V- A-Q- (SEQ ID NO: 11), -R-I-A-Q- (SEQ ID NO: 12), -K-I-A-K- (SEQ ID NO: 13), -K-I-S- Q- (SEQ ID NO: 14), or is absent; and U2is selected from -Q-, -I-A-Q-Q- (SEQ ID NO: 15), -I-A-Q-K- (SEQ ID NO: 16), -V-A-Q-K- (SEQ ID NO: 17) or is absent.

[0122] In some embodiments of compounds of Formula (II), each instance of nl, n2, n3, and n4 is zero. In some embodiments, each instance of n4, n6, n7, and n8 is zero. In some embodiments, each instance of n5, n6, n7, and n8 is zero.

[0123] In some embodiments of compounds of Formula (II), at least one of Z1and Zzis not. hydrogen.

[0124] Some embodiments of compounds of Formula (II) include compounds having the structure of Formula (Il-a):H-a or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments of compounds of Formula (Il-a) or their pharmaceutically acceptable salts, Z!is selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and X and ¥ each are - OR4

[0126] In some embodiments of compounds of Formula (Il-a) or their pharmaceutically acceptable salts, Z1is hydrogen and each R4independently is hydrogen or C7-11 arylalkyl.

[0127] In some embodiments of compounds of Formula (Il-a) or their pharmaceutically acceptable salts, each R4is hydrogen.

[0128] In some embodiments of compounds of Formula (Il-a) or their pharmaceutically acceptable salts, Z1is hydrogen and each R4is hydrogen.

[0129] Some embodiments of compounds of Formula (II) include compounds having the structure of Formula (Il-b):Il-b or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments of compounds of Formula (Il-b) or their pharmaceutically acceptable salts, each R4is independently selected from the group consisting of hydrogen, C6-10 aryl and C7-11 arylalkyi.

[0131] In some embodiments of compounds of Formula (Il-b) or their pharmaceutically acceptable salts, each R4is hydrogen.

[0132] Some embodiments include a compound having the structure selected from the group consisting of:1316H-Y Aib E G T F T S D Y S I Aib L D K V A Q A F V Q W L i R G G P S S G A P P P S -NHo (SEQ ID NO: 22) (SEQ ID NO: 26)or pharmaceutically acceptable salts thereof.

[0133] The compounds of Formula (11) disclosed herein may be synthesized according to methods described in International Patent Publication No. WO 2023 / 044290, the disclosure of which is incorporated herein in its entirety.Compounds of Formula (III)

[0134] Various embodiments of these compounds include compounds having the structure of Formula (III) as described herein or pharmaceutically acceptable salts thereof. The structure of Formula (III) encompasses all stereoisomers.

[0135] In some embodiments of compounds of Formula (III):R!is selected from the group consisting of --C(==O)(OZ!), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with I -2 R7;R2is selected from the group consisting of ~C(==O)(OZ2), P( ()){ .'<)(¥} and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with 1-2 R7; each R7may be independen tly selected from the group consisting of halogen, Ct-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxy, -OR5, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y may each be independently selected from the group consisting of -OR4, NR5R6, CI -e alkyl and haloC1-6 alkyl; each R4may be independently selected from the group consisting of hydrogen. Ci -6 alkyl, haloC1-6 alkyl, C6-10 aryl, and C7-11 arylalkyl; each R5may be independently hydrogen orC1-6 alkyl; each R6may be independently hydrogen or C1-6 alkyl;Z1and Z2may each be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, , C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl n is 0, 1 , 2, 3, or 4.

[0136] In some embodiments, at least one of Z1and Z2is not hydrogen,

[0137] Some embodiments of compounds of Formula (III) include compounds having the structure of Formula ( 111-a ):(Ill-a) or pharmaceutically acceptable salts thereof.

[0138] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts, Z1is selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7- 11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and X and Y each are ---OR4.

[0139] In some embodiments of compounds of Formula (III-a) or their pharmaceutically acceptable salts, Z1is selected from hydrogen, Ct-6 alkyl and haloC1-6 alkyl; and each R4may be independently selected from hydrogen, C6-10 aryl, and C7-11 arylalkyl.

[0140] In some embodiments of compounds of Formula (III-a) or their pharmaceutically acceptable salts; Z1is hydrogen and each R4may be independently hydrogen or C7-11 arylalkyl.

[0141] In some embodiments of compounds of Formula (III-a) or their pharmaceutically acceptable salts, each R4is hydrogen.

[0142] In some embodiments of compounds of Formula (III-a) or their pharmaceutically acceptable salts, Z1is hydrogen and each R4is hydrogen.

[0143] In some embodiments of compounds of Formula (III-a) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1, In yet other embodiments, n is 2. In still yet other embodiments, n is 3. In some embodiments, n is 4.

[0144] Some embodiments of compounds of Formula (III) include compounds having the structure of Formula (Ill-b):or pharmaceutically acceptable salts thereof.

[0145] In some embodiments of compounds of Formula (Ill-b) or their pharmaceutically acceptable salts; Z2is selected from hydrogen, Cue alkyl, haloCne alkyl, C7- u arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and X and Y each are -OR4.

[0146] In some embodiments of compounds of Formula (III-b) or their pharmaceutically acceptable salts; Z2is selected from hydrogen, C1-6 alkyl and haloC1-6 alkyl; and each R4may be independently selected from hydrogen, CY-io aryl, and C7-11 arylalkyl.

[0147] In some embodiments of compounds of Formula (III-b) or their pharmaceutically acceptable salts; Z2is hydrogen and each R4may be independently hydrogen or C6-10 aryl alkoxy.

[0148] In some embodiments of compounds of Formula (III-b) or their pharmaceutically acceptable salts; each R4is hydrogen.

[0149] In some embodiments of compounds of Formula (III-b) or their pharmaceutically acceptable salts; Z2is hydrogen and each R4is hydrogen.

[0150] In some embodiments of compounds of Formula (III-b) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In yet other embodiments, n is 2. In still yet other embodiments, n is 3. In some embodiments, n is 4.

[0151] Some embodiments of compounds of Formula (III) include compounds having the structure of Formula (III-c):or pharmaceutically acceptable salts thereof.

[0152] In some embodiments of compounds of Formula (III-c) or their pharmaceutically acceptable salts, X and Y each are -OR4.

[0153] In some embodiments of compounds of Formula (III-c) or their pharmaceutically acceptable salts, each R4may be independently selected from hydrogen, Q- 10 aryl and C7-11 arylalkyl. In some embodiments of compounds of Formula (III-c) or their pharmaceutically acceptable salts, each R4is hydrogen.

[0154] In some embodiments of compounds of Formula (III-c) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In yet other embodiments, n is 2. In still yet other embodiments, n is 3. In some embodiments, n is 4.

[0155] Some embodiments include a compound having the structure selected from the group consisting of:and pharmaceutically acceptable salts thereof.

[0156] Some embodiments include a compound wherein indicates a chiral carbon with “S’1configuration.10157] Some embodiments include a impound wherein indicates a chiral carbon with “R” configuration.

[0158] The compounds of Formula (III) disclosed herein may be synthesized according to methods described in International Patent Publication No. WO 2023 / 044290, the disclosure of which is incorporated herein in its entirety.Pharmaceutical Compositions

[0159] Some embodiments include pharmaceutical compositions comprising a compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceuticalcomposition comprises one or more permeability enhancer. In some embodiments, the pharmaceutical composition further comprises an excipient. In some embodiments, the pharmaceutical composition is suitable for use as an oral dosage form.

[0160] Compounds that normally cannot be administered orally due to poor oral bioavailability may be formulated with a permeability enhancer. Permeability enhancers may increase absorption of an active pharmaceutical ingredient by enhancing membrane permeation. In some embodiments, the permeability enhancer is present in the pharmaceutical composition at a weight percentage of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 85%, or more, or within a range defined by any two of the aforementioned weight percentages. For examples, in some embodiments, the permeability enhancer is present in the pharmaceutical composition a weight percentage of from about 30% to about 80%, from about 40% to about 80%, from about 50% to about 80%, from about 50% to about 75%, from about 60% to about 75%, or from about 70% to about 75% percent. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 12 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 9 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 10 carbon atoms. In some embodiments, the permeability enhancer may be a sodium, lithium, or potassium salt. In some embodiments, the permeability enhancer is sodium hexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof. In some embodiments, the permeability enhancer may further comprise salcaprozate sodium (SNAC) and / or sodium caprate.

[0161] In some embodiments, the amount of permeability enhancer in the pharmaceutical compositions described herein is about 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg,370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg,580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg,790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg. 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg,1000 mg, or more, or within a range defined by any two of the aforementioned values. For example, in some embodiments, the amount of permeability enhancer in the pharmaceutical compositions described herein is from about 1 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 nig to about 800 mg, from about 400 nig to about 800 mg, from about 400 nig to about 600 mg, or from about 500 mg to about 750 nig. In some embodiments, the amount of permeability’ enhancer in the pharmaceutical compositions described herein is greater than 300 mg, greater than 350 nig, greater than 400 nig, greater than 450 mg, greater than 500 mg, greater than 550 mg, greater than 600 mg, greater than 650 mg, greater than 700 mg, greater than 750 mg, greater than 800 mg greater than 850 mg, greater than 900 mg, greater than 950 mg, or greater than 1000 mg.

[0162] In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c), in the pharmaceutical composition has a weight percentage of about 0.5%, 0.6%, 0.7%, 0.8%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2,6%,2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%,4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%,7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, or higher, or within a range defined by any two of the aforementioned values. In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c) in the pharmaceutical composition is in the range of from about 1.0% to about 5.0%, from about 2.0% to about 4.0%, from about 3.0% to about 4.0%, or from about 3.5% to about 4.0% by weight. In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), ( 11 -a ), (Il-b), (III), (Ill-a), (IH-b), or (III-c) in the pharmaceutical composition is about 3.6% by weight.

[0163] In some embodiments, the amount of the compound of Formula (I), (I -a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c), in the pharmaceutical composition is about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg,18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg,29.5 mg, 30 nig, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 nig, 35 mg, 35.5 mg, 36 mg, 36.5 mg, 37 nig, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg,40.5 mg, 41 nig, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 nig, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, or more, or within a range defined by any two of the aforementioned values. For example, in some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c), in the pharmaceutical composition is from about 1 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about 30 mg, or from about 20 mg to about 30 mg.

[0164] In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 1 mg, 1 ,5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 34 mg, 34.5 mg, 35 mg, 35.5 mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, or more, or within a range defined by any two of the aforementioned values. For example, in some embodiments, the amount of Compound 4 in the pharmaceutical composition is from about 1 mg to about 30 mg, from about 5 mg to about 25 mg, from about 10 mg to about 20 mg, from about 10 mg to about 30 nig, or from about 20 mg to about 30 mg.

[0165] In some embodiments, the amount of Compound 4 in the pharmaceutical composition is from about 5 mg to about 30 mg and the amount of permeability enhancer is from about 350 mg to about 1000 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is from about 10 mg to about 30 mg and the amount of permeability enhancer is from about 400 mg to about 800 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is from about 15 mg to about 25 mg and the amount of permeability enhancer is from about 450 mg to about 750 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 20 mg to and the amount of permeability enhancer is about 450 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 25 mg to and the amount of permeability enhancer is about 500 mg. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 12 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 9 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 10 carbon atoms. In some embodiments, the permeability enhancer may be a sodium, lithium, or potassium salt. In some embodiments, the permeability enhancer is sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof In some embodiments, the permeability enhancer may further comprise salcaprozate sodium (SNAC) and / or sodium caprate.

[0166] In some embodiments, the mass ratio of the permeability enhancer to the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c) in the pharmaceutical composition is about 1:1, 2:1, 3:1, 5:1, 10: 1, 15: 1, 16: 1 , 17: 1 , 18: 1 , 19:1 , 20: 1, 20.5:1,, 21: 1, 21.5: 1, 22: 1, 22.5: 1, 23: 1, 23.5: 1, 24: 1, 24.5: 1, 25: 1, 26:1, 27:1, 28: 1, 29:1, 30: 1, 35:1, 40: 1, 45:1, 50: 1, or more, or within a range defined by any two of the aforementioned ratios. For example, in some embodiments, the mass ratio of the permeability enhancer to the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (II-b), (III), ( I II -a ), (III-b), or (III-c) in the pharmaceutical composition is from about 1 :1 to about 50:1, from about 10: 1 to about 25:1, from about 15: 1 to about 25:1, or from about 20:1 to about 25: 1.

[0167] In some embodiments, the pharmaceutical compositions described herein include one or more additional pharmaceutically-acceptable excipient(s). The term “pharmaceutically acceptable excipient,” as used herein, includes but is not limited to solvents, dispersants, coatings, antimicrobial bacterial agents, adjuvants, isotonic and absorption delaying agents and the like. In some embodiments, the pharmaceutically-acceptable excipients include sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as microcrystalline cellulose, sodium carboxyniethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; binders such as polyvinylpyrrolidinone (PVP) polyvinyl alcohols, polyethylene glycol, cellulose and derivatives of cellulose (such as methyl cellulose, ethyl cellulose, hydroxy propyl cellulose), polyvinyl alcohol; solid lubricants, such as stearic acid, silicon dioxide and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers and surfactants, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, and phenylmercuric nitrate; tonicity adjustors such as sodium chloride, potassium chloride, mannitol and glycerin; vehicles such as polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, and hydroxyethyl cellulose; and pyrogen-free water. In some embodiments, the pharmaceutically- acceptable excipient(s) are selected based on the route of administration and can include solid or liquid fillers, binders, diluents, hydrotropies, surface-active agents, and encapsulating substances. For example, in the case of intravenous administration, excipients may include gelatin; carbohydrates such as dextrose, mannitol, and dextran; and antioxidants such as sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. In some embodiments, the pharmaceutically-acceptable excipient(s) include antimicrobial agents such as phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol. Additional examples of suitable pharmaceutically-acceptable excipient(s) are described in Powell, et al.. Compendium ofExcipients for Parenteral Compositions, PDA J Pharm Set and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Set and Tech 2011, 65 287-332, each of which are incorporated herein by reference in their entirety.

[0168] In some embodiments, the pharmaceutical compositions described herein may comprise the compound of Formula (I), (I-a), (I-b), (1-c), (II), ( 11 -a ), (Il-b), (III), ( 111 -a ), (Ill-b), or (III-c) and a permeability enhancer. In some such embodiments, the pharmaceutical compositions may further comprise microcrystalline cellulose, polyvinylpyrrolidinone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 12 carbon atoms. In some embodiments, the permeability' enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 9 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain faty acids comprising 6 to 10 carbon atoms. In some embodiments, the permeability enhancer may be a sodium, lithium, or potassium salt. In some embodiments, the permeability enhancer is sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof. In some embodiments, the permeability enhancer may further comprise salcaprozate sodium (SNAC) and / or sodium caprate.

[0169] In some embodiments, the pharmaceutical compositions described herein may comprise microcrystalline cellulose in an amount of about 5%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or more by weight, or within a range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may comprise about from 10% to 50%, 10% to 40%, 10% to 30%, 15% to 30%, 15% to 25%, or 15% to 20% by weight microcrystal line cellulose. In some embodiments, the pharmaceutical compositions described herein comprised about 19.4% microcrystaHine cellulose by weight.

[0170] In some embodiments, the pharmaceutical compositions described herein may comprise polyvinylpyrrolidinone in an amount of about 0.5%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2.%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.5%, or 5.0% by weight, or within a range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may comprise from about 1.0% to about 5.0%, from about 1.0% to about 4.0%, from about 1.0% to about 3.0%, from about 1.5% to about 3.0%, from about 1.5% to about 2.5%, or from about 1.5% to about 2.0% by weight polyvinylpyrrolidinone. In some embodiments, the pharmaceutical compositions described herein comprised about 1.9% polyvinylpyrrolidinone by weight.

[0171] In some embodiments, the pharmaceutical compositions described herein may comprise magnesium stearate man amount of about 0.5%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2.%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.5%, or 5.0% by weight, or within a range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may comprise from about 1.0% to about 5.0%, from about 1.0% to about 4,0%, from about 1 .0% to about 3.0%, from about 1 ,5% to about 3.0%, from about 1.5% to about 2.5%, or from about 1.5% to about 2.0% by weight magnesium stearate. In some embodiments, the pharmaceutical compositions described herein comprised about 2,3% magnesium stearate by weight.

[0172] In some embodiments, the pharmaceutical compositions described herein may comprise a disintegrant. In some embodiments, the pharmaceutical composition may comprise a disintegrant in an amount of 0.5%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2.%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.5%, or 5.0% by weight, or within a range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may comprise from about 1.0% to about 5.0%, from about 1.0% to about 4.0%, from about 1.0% to about 3.0%, from about 1.5% to about 3.0%, from about 1.5% to about 2.5%, or from about 1.5% to about 2.0% by weight disintegrant. In some embodiments, the pharmaceutical compositions described herein comprised about 1.9% disintegrant by weight. In some embodiments, the disintegrant may becroscarmellose sodium (e.g., primellose, AcDiSol)). In some embodiments, the disintegrant may be sodium alginate. In some embodiments, the disintegrant may be crospovidone. In some embodiments, the disintegrant may be sodium starch glycolate.

[0173] In some embodiments, the pharmaceutical compositions described herein may comprise from about 1.0 to about 5.0% by weight of the of compound of Formula (I), (I- a), (I-b), (I-c), (II), ( Il-a), (U-b), (III), (Ill-a), (Ill-b), or (III-c); from about 50% to about 80% by weight salcaprozate sodium; from about 10% to about 30% by weight microcrystal line cellulose; from about 1.0% to about 3.0% by weight polyvinylpyrrolidinone; and from about 1.0% to about 3.0% by weight magnesium stearate. In some such embodiments, pharmaceutical composition comprises: about 3.6% by weight of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (Ill-b), or (III-c); about 72.7% by weight salcaprozate sodium; about 19.4% by weight microcrystalline cellulose; about 1.9% by weight polyvinylpyrrolidinone; and about 2.3% by weight magnesium stearate. In other such embodiments, pharmaceutical composition comprises: about 3.2% by weight of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (II~b), (III), (IIT-a), (ITI-b), or (III-c); about 71 ,1% by weight salcaprozate sodium; about 21. 1 % by weight microcrystalline cellulose; about 2.1% by weight polyvinylpyrrolidinone; and about 2.6% by weight magnesium stearate.

[0174] The pharmaceutical compositions include a therapeutically effective dosage or amount of a compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (Il-b), (III), (Ill-a), (III- b), or (III-c). The term “therapeutically effective dosage” or “therapeutically effective amount,” as used herein, is dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. In some embodiments, the therapeutically effective dosage may be a daily dosage from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg, from about 0.05 mg / kg to about 50 mg / kg of body weight, or from about 0.075 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg per day or less to about 7000 mg per day or more, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg to about 3000 mg per day. In some embodiments, the therapeutically effective dosage is from about 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.12 mg / kg, 0.14mg / kg, 0.15 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.19 mg / kg, 0.20 mg / kg, 0.21 mg / kg, 0.22 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.26 mg / kg, 0.28 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, lOOv, 200 mg / kg, 500 mg / kg, or ranges including and / or spanning the aforementioned values. In some embodiments, the therapeutically effective dosage is from about 0.01 mg / kg to about 5 mg / kg. In some embodiments, the therapeutically effective dosage is from about 0.05 mg / kg to about 1 mg / kg. In some embodiments, the therapeutically effective dosage is from about 0.15 mg / kg to about 0.25 mg / kg.

[0175] The pharmaceutical compositions can be administered with a route of administration including, but not limited to, enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intrapulmonary, vaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration selected from the group consisting of enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal. In some embodiments, the pharmaceutical compositions are administered subcutaneously. In some embodiments, the pharmaceutical compositions are administered intravenously. In some embodiments, the pharmaceutical compositions are administered orally.

[0176] The pharmaceutical compositions can be provided in a dosage form. In some embodiments, the dosage form is a solid. The solid dosage forms include tablets, capsules, granules and bulk powders. In some embodiments, the solid dosage form is a tablet.

[0177] In some embodiments, the pharmaceutical compositions are administered to a subject that is a mammal. In some such embodiments, the pharmaceutical compositions are administered to a subject that is a human.Methods of Preparing Dosage Forms

[0178] The pharmaceutical compositions may be formulated into an oral dosage form. In some embodiments, the oral dosage form may be a tablet. In some such embodiments, the tablet may be enterically coated.

[0179] In some embodiments, tablets may be prepared using a dry granulation method. In some embodiments, the method comprises the steps of (i) combining the permeability enhancer and magnesium stearate to form first granules; (ii) combining microcrystallme cellulose, the compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), ( 11 - b ),(III), (Ill-a), (III-b), or (III-c), and polyvinylpyrrolidinone to form second granules; (in) combining the first granules and the second granules to form a mixture; (iv) adding magnesium stearate to the mixture to form third granules; and (v) pressing the third granules into tablets. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 12 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty acids comprising 6 to 9 carbon atoms. In some embodiments, the permeability enhancer may be one or more pharmaceutically acceptable salts of medium chain fatty’ acids comprising 6 to 10 carbon atoms. In some embodiments, the permeability enhancer may be a sodium, lithium, or potassium salt. In some embodiments, the permeability enhancer is sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof. In some embodiments, the permeability' enhancer may further comprise salcaprozate sodium (SNAC) and / or sodium caprate. In some embodiments, the compound is Compound 4.

[0180] In some embodiments, tablets may be prepared by a spray-dried dispersion method. For example, in some embodiments, the compound disclosed herein may be combined with a polymer including but not limited to hydroxypropylmethylcellulose acetate succinate type M (HPMCAS-M); hydroxypropylmethylcellulose acetate succinate type L (HPMCAS- L); (polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA64); Eudragit ® LI 00, or any combination thereof, in a solvent to form a solution for spray drying. The solutions are then dried with a heated nitrogen stream and collected using a cyclone. The spray dried matter is then combined with microcry stall ine cellulose, magnesium stearate, permeability enhancers and / or additional fillers and disintegrants, and pressed into tablets.Methods of Treatment

[0181] The pharmaceutical compositions disclosed herein include compounds or their tautomers and / or pharmaceutically acceptable salts thereof that can effectively act as GIP / GLPl dual receptor agonists. The pharmaceutical compositions further comprise one ormore pharmaceutically acceptable carriers and one or more pharmaceutically acceptable diluents.

[0182] Some embodiments provide a method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need thereof.

[0183] Some embodiments provide a method preventing, treating, or ameliorating steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need thereof.

[0184] In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the prevention, treatment, or amelioration, of a fibrosis, fibrotic condition, or fibrotic symptoms.

[0185] In some embodiments, the pharmaceutical compositions described herein can be used to treat a host of conditions arising from fibrosis or inflammation, and specifically including those associated with myofibroblast differentiation. Example conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary' chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type II diabetes), lung fibrosis (idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders), cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, non-alcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemic reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0186] In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the reduction in the amount of extracellular matrix proteins present in one or more tissues of said subject.

[0187] In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the reduction in the amount of collagen present in one or more tissues of said subject.

[0188] In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the reduction in the amount of Type I, Type la, or Type III collagen present in one or more tissues of said subject.

[0189] Some embodiments provide a method of preventing, treating, or ameliorating one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis in a subject. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need thereof.

[0190] Some embodiments provide a method of preventing, treating, or ameliorating one or more of nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis in a subject. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need thereof.

[0191] Some embodiments provide a method of preventing, treating, or ameliorating one or more metabolic disorders or metabolic syndromes. In some embodiments, said disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or prader-willi syndrome. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need thereof.

[0192] In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the activation of a glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the activation of aglucagon-like peptide- 1 (GLP-1) receptor. In some embodiments, the method of administering one or more of the pharmaceutical compositions disclosed herein results in the activation of the GIP receptor and the GLP-1 receptor.

[0193] Some embodiments include co-administering a pharmaceutical composition and / or a compound, or pharmaceutically acceptable salt thereof, described herein, with an additional medicament. By “co-administration,” it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered subcutaneously, another being administered orally and another being administered i.v.

[0194] To further illustrate this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview' of one skilled in the art and are considered to fall within the scope of the disclosure as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples. The following examples will further describe the present disclosure, and are used for the purposes of illustration only, and should not be considered as limiting.EXAMPLES

[0195] The following abbreviations have the indicated meanings: LC-MS / MS:::liquid chromatography tandem mass spectrometry

[0196] The following examples are provided for the guidance of the reader, and collectively represent an example method for making the compositions provided herein. Furthermore, other methods for preparing compositions described herein wall be readilyapparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0197] Trademarks used herein are examples only and reflect illustrative materials used at the time of the disclosure. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure.EXAMPLE 1Preparation of Tablet Formulations

[0198] A batch of tablets (Tablets A-E) with Compound 4 as the active ingredient were prepared by a dry granulation process. The amounts of each component are found in Table 1 below, shown per tablet.Table 1 - Compounding Table for Tablets A-E (per tablet)

[0199] The magnesium stearate was weighed out and passed through a 355 pm sieve. In a stainless-steel bowl, the magnesium stearate was combined with the permeability enhancer and was blended for five minutes or until a homogenous mixture was obtained. The resulting mixture was loaded into a Vector TFC Micro Roller Compactor and granulated at approximately 300 psi and a roll speed of 1.32 rpm. The granulated material was then ground with a mortar and pestle into coarse grannies and sieved through a 30-mesh hand screen to form the first fraction granules.

[0200] The microcrystalline cellulose, Compound 4, and polyvmylpyrrolidmone K90 was combined and blended for 30 minutes or until a homogenous mixture was obtained. The resulting mixture was then pressed into slugs by loading approximately 600 mg of this mixture into a tablet using a 12.7 mm round tool. The resulting tablets were then ground witha mortar and pestle into coarse granules and sieved through a 30-mesh hand screen to form the second fraction granules.

[0201] The first fraction granules were added to a Turbula mixer followed by the second fraction granules and extragranular magnesium stearate and mixed for 5 minutes or until a homogenous mixture is obtained. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. The permeability enhancers used in each particular tablet batch is found in Table 2.Table 2 - Permeability EnhancersEXAMPLE 2Pharmacokinetic Study Permeability

[0202] The pharmacokinetics of different formulations of Compound 4 and permeability enhancer are studied in male cynomolgus monkeys. The animals are acclimated to the study room for a minimum of 3 days prior to initiation of dosing. Monkeys are assigned to dosage groups (Tablet A, Tablet B, Tablet C, etc. through Tablet Q) and are orallyadministered doses of 1 tablet per day in the study. Blood samples (0.5 mL) were taken from the monkeys at Day 1, Day 2, and Day 3 (pre-dose and 1, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 hours after administration). Plasma wall be obtained within 30 minutes after blood collection by centrifugation at 3500 g and at 4°C for 5 minutes. At least 200 pL plasma will be collected and transferred into a 2 mL Eppendorf LoBmd tube, which will be stored upright temporarily in dry ice. Sample analysis is measured with a liquid chromatography tandem mass spectrometry (LC-MS / MS) method based on multiple reaction monitoring (MRM) of fragment ions for the monkey pharmacokinetic study. All samples from the study are stored at -80 °C until ready to be analyzed as a single batch. Pharmacokinetic parameters are calculated with Phoenix® WmNonlin® software (version 8.3) using non-compartmental analyses.

[0203] While some embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0204] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope andspirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0205] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0206] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present technology. This includes the generic description of the present technology with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0207] All publications, patent applications, issued patents, and other documents (for example, journals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0208] Although the disclosure has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the disclosure. Accordingly, the disclosure is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition, comprising: a permeability enhancer; and a therapeutically effective amount of a compound, wherein the compound is a GLP-1 agonist or a GLP / G1P dual agonist; wherein the mass of the permeability enhancer is greater than 300 mg; and wherein the permeability enhancer is selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof.

2. The pharmaceutical composition of claim 1, wherein the compound is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R!is selected from the group consisting of ~C(=O)(OZ1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R'';R2is selected from the group consisting of -C(=O)(OZ2), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1 -2 R7,each R7may be independently selected from the group consisting of halogen, Ct-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxy, -OR3, C3-10 cycloalkyl, (¥-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y may each be independently selected from the group consisting of -OR4, NR5R6, C1-6 alkyl and haloC1-6 alkyl; each R4may be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C6-10 aryl and C7-11 arylalkyl; each R5may be independently hydrogen orC1-6 alkyl; each R6may be independently hydrogen or C1-6 alkyl; andZ1and Z2may each be independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl.

3. The pharmaceutical composition of claim 2, wherein at least one of Z1and Z2is not hydrogen.

4. The pharmaceutical composition of claim 2 or 3, wherein the compound is a compound having the structure of Formula (I-a):or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 4, wherein Z1is selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl; C3-10 cycloalkyl and Ce-w aryl; and X and ¥ each are -OR4.

6. The pharmaceutical composition of claim 4 or 5, wherein Z1is selected from the group consisting of hydrogen, haloC1-6 alkyl and alkyl;C a1n-6d each R4independently is selected from the group consisting of hydrogen, C6-10 aryl and C7-11 arylalkyl.

7. The pharmaceutical composition of any one of claims 4 to 6, wherein Z’!is hydrogen and each R4independently is hydrogen or C7-11 arylalkyd.

8. The pharmaceutical composition of any one of claims 4 to 7, wherein each R4is hydrogen.

9. The pharmaceutical composition of any one of claims 4 to 8, wherein Z’!is hydrogen and each R4is hydrogen.

10. The pharmaceutical composition of claim 2, wherein the compound is a compound having the structure of Formula (I-b):or a pharmaceutically acceptable salt thereof.1 1 . The pharmaceutical composition of claim 10, wherein Z2is selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7.11 arylalkyl; Cs- 10 cycloalkyl and Ce-io aryl; and X and Y each are ---OR4.

12. The pharmaceutical composition of claim 10 or 11, wherein Z2is selected from the group consisting of hydrogen, haloC1-6 alkyl and C1-6 alkyl; and each R4independently is selected from the group consisting of hydrogen, C6-10 aryl and C7-11 ary lalkyl.

13. The pharmaceutical composition of claim 10 or 11, wherein Z2is hydrogen and each R4is hydrogen or C7-11 arylalkyl.

14. The pharmaceutical composition of any one of claims 10 to 13, wherein each R4is hydrogen.

15. The pharmaceutical composition of any of claims 10 to 14, wherein Z2is hydrogen and each R4is hydrogen.

16. The pharmaceutical composition of claim 2, wherein the compound is a compound having the structure of Formula (I-c):or a pharmaceutically acceptable salt thereof.17, The pharmaceutical composition of claim 16, wherein X and Y each are -OR4.18, The pharmaceutical composition of claim 16 or 17, wherein each R4is independently selected from the group consisting of hydrogen, C6-10 aryl and C7-11 arylalkyl.19, The pharmaceutical composition of any one of claims 16 to 18, wherein each R4is hydrogen.20, The pharmaceutical composition of claim 2 or 3, wherein the compound is a compound having the structure selected from the group consisting of:and pharmaceutically acceptable salts thereof.

21. The pharmaceutical composition of claim 20, wherein the compound is a compound having the structure:or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of any one of claims 2 to 21, wherein indicates a chiral carbon with “S” configuration.

23. The pharmaceutical composition of any one of claims 2 to 21 , wherein “*” indicates a chiral carbon with “R” configuration.

24. The pharmaceutical composition of claim 1, wherein the compound is a compound having the structure of Formula (II),or a pharmaceutically acceptable salt thereof, wherein:Aib is 2-aminoisobutyric acid;each instance of J1, J2, and J3is independently an amino acid selected from Aib, a naturally occurring ammo acid, and an unnatural ammo acid;each instance of J4, J3, J6, J7, J8, J9, J10, and J” is independently a naturally occurring amino acid or an unnatural amino acid; each of nl, n2, n3, n4, n5, n6, n7, and 118 is independently 0 or 1, provided that the sum nl + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4;R!is selected from the group consisting of -C(=O)(OZ1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1-2 R7;R2is selected from the group consisting of -C(=O)(OZ2), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, the heteroaryl optionally substituted with 1-2 Rz; each R?is independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloC1-6 alkoxy, Ct-6 alkoxy, -OR5, C3-10 cycloalkyl, Ce-io aryl, 5- 10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of -OR4, NR3R6, Ci -6 alkyl and haloC1-6 alkyl; each R4is independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, Cs-io aryl and C7-11 arylalkyl; each R3is independently hydrogen or C1-6 alkyl; each R° is independently hydrogen or C1-6 alkyl, andZ1and Z2each are independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and Cs-io aryl.

25. The pharmaceutical composition of claim 24, wherein the compound is not:

26. The pharmaceutical composition of claim 24 or 25, wherein each instance of J1, J2, and J3is independently an amino acid selected from Aib and a naturally occurring amino acid.

27. The pharmaceutical composition of any one of claims 24 to 26, wherein each instance of J1, J2, and J3is independently an amino acid selected from Aib, A, F, N, R, and Q.

28. The pharmaceutical composition of any one of claims 24 to 27, wherein J!is Aib or F.

29. The pharmaceutical composition of any one of claims 24 to 28, wherein J1is F.

30. The pharmaceutical composition of any one of claims 24 to 29, wherein J2is N orQ.

31. The pharmaceutical composition of any one of claims 24 to 30, wherein J2is N.

32. The pharmaceutical composition of any one of claims 24 to 31, wherein F is A orR.

33. The pharmaceutical composition of any one of claims 24 to 32, wherein J3is R34. The pharmaceutical composition of any one of claims 24 to 33, wherein each instance of J4, F, J6, and J7is independently an amino acid selected from A, I, K, R, Q, S, T, and V.

35. The pharmaceutical composition of any one of claims 24 to 34, wherein F is K or R.

36. The pharmaceutical composition of any one of claims 24 to 35, wherein J4is R.

37. The pharmaceutical composition of any one of claims 24 to 36, wherein J5is I, T, or V.

38. The pharmaceutical composition of any one of claims 24 to 37, wherein J5is T orV.

39. The pharmaceutical composition of any one of claims 24 to 38, wherein J6is A orS.

40. The pharmaceutical composition of any one of claims 24 to 39, wherein J'’ is S.

41. The pharmaceutical composition of any one of claims 24 to 40, wherein J7is Q or K.

42. The pharmaceutical composition of any one of claims 24 to 41, wherein each instance of J8, J9, J5u, and Juis independently an amino acid selected from A, I, and Q.

43. The pharmaceutical composition of any one of claims 24 to 42, wherein J8is I or Q44. The pharmaceutical composition of any one of claims 24 to 43, wherein J9is A or Q45. The pharmaceutical composition of any one of claims 24 to 44, wherein J10is Q.

46. The pharmaceutical composition of any one of claims 24 to 45, wherein J11is Q.

47. The pharmaceutical composition of any one of claims 24 to 27, whereinJ1is selected from Aib or F;J2is selected from Q or N;J3is selected from A or R;U1is selected from -K-V-A-, -K-I-A-Q- (SEQ ID NO: 8), -K-T-A-Q- (SEQ ID NO: 9), -K-T-S-Q- (SEQ ID NO: 10), -K-V-A-Q- (SEQ ID NO: 1 1), -R-I-A-Q- (SEQ ID NO: 12), K-I-A-K- (SEQ ID NO: 13), -K-I-S-Q- (SEQ ID NO: 14), or is absent; andU2is selected from -Q-, -I-A-Q-Q- (SEQ ID NO: 15), -I-A-Q-K- (SEQ ID NO: 16), -V-A-Q-K (SEQ ID NO: 17), or is absent.

48. The pharmaceutical composition of any one of claims 24 to 47, wherein each instance of nl, n2, n3, and n4 is zero.

49. The pharmaceutical composition of any one of claims 24 to 47, wherein each instance of n4, n6, n7, and n8 is zero.

50. The pharmaceutical composition of any one of claims 24 to 47, wherein each instance of n5, n6, n7, and n8 is zero.

51. The pharmaceutical composition of any one of claims 24 to 50, wherein at least one of Z1and Z2is not hydrogen.

52. The pharmaceutical composition of any one of claims 24 to 51, wherein the compound is a compound having the struc ture of Formula (Il-a):or a pharmaceutically acceptable salt thereof.

53. The pharmaceutical composition of claim 52, wherein Zlis selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and Ce-io aryl; and X and Y each are -OR4.

54. The pharmaceutical composition of claim 51 , wherein Z1is hydrogen and each R4independently is hydrogen or C7-11 arylalkyl.

55. The pharmaceutical composition of claim 53 or 54, wherein each R4is hydrogen.

56. The pharmaceutical composition of claim 51, wherein Z1is hydrogen and each R4is hydrogen.

57. The pharmaceutical composition of any one of claims 23 to 51, wherein the compound is a compound having the struc ture of Formula (Il-b):or a pharmaceutically acceptable salt thereof.

58. The pharmaceutical composition of claim 57, wherein each R4is independently selected from the group consisting of hydrogen, C6-10 aryl and C7-11 arylalkyl.

59. The pharmaceutical composition of claim 58, wherein each R4is hydrogen.

60. The pharmaceutical composition of claim 24 or 25, wherein the compound is a compound having the structure selected from the group consisting of:(SEQ ID NO: 22) (SEQ ID NO: 26) and pharmaceutically acceptable salts thereof.

61. The pharmaceutical composition of claim 1, wherein the compound is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof(III), or a pharmaceutically acceptable salt thereof, wherein:R!is selected from the group consisting of -C(:::O)(OZ!), -P(===O)(X)(Y) and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with I -2 R7;R2is selected from the group consisting of -C(=O)(OZ2), --(CTl2Cl-l2)nP(=;:O)(X)(Y) and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S optionally substituted with 1-2 R7; each R7is independently selected from the group consisting of halogen, C1-6 alkyl, lialoCne alkyl, haloCne alkoxy, Cue alkoxy, Cb-io cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of -OR4, NR5R6, Ci -s alkyl and haloC1-6 alkyl; each R4is independently selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, C6-10 aryl, and C7-11 arylalkyl;; each R5is independently hydrogen or Cue alkyl; each R6is independently hydrogen or Cue alkyl;Z1and Z2each are independently selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and n is 0, 1, 2, 3 or 4,62. The pharmaceutical composition of claim 61, wherein at least one of Z1and Z2is not hydrogen.

63. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having the structure of Formula (Ill-a):or a pharmaceutically acceptable salt thereof.

64. The pharmaceutical composition of claim 63, wherein Zlis selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and Ce-io aryl; and X and Y each are -OR'165. The pharmaceutical composition of claims 63 or 64, wherein Z!is selected from the group consisting of hydrogen, haloC1-6 alkyl and C1-6 alkyl; and each R4independently is selected from the group consisting of hydrogen, Q-io aryl, and C7-11 arylalkyl.

66. The pharmaceutical composition of any one of claims 63 to 65, wherein Z1is hydrogen and each R4independently is hydrogen or C7-11 arylalkyl.

67. The pharmaceutical composition of any one of claims 63 to 66, wherein each R4is hydrogen.

68. The pharmaceutical composition of any one of claims 63 to 67, wherein Z‘ is hydrogen and each R' is hydrogen.

69. The pharmaceutical composition of any one of claims 63 to 68, wherein n is 1.

70. The pharmaceutical composition of any one of claims 63 to 68, wherein n is 2.

71. The pharmaceutical composition of claim 59, wherein the compound is a having the structure of Formula (III -b):or a pharmaceutically acceptable salt thereof.

72. The pharmaceutical composition of claim 71, wherein Z2is selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, C7-11 arylalkyl, Cs-w cycloalkyl and Ce-io aryl; and X and ¥ each are -OR4.

73. The pharmaceutical composition of claim 71 or 72, wherein Z2is selected from the group consisting of hydrogen, haloCne alkyl and C1-6 alkyl; and each R4independently is selected from the group consisting of hydrogen, C6-10 aryl and C7-11 arylalkyl.

74. The pharmaceutical composition of any one of claims 71 to 73, wherein Z2is hydrogen and each R4is hydrogen or C7-11 arylalkyl.

75. The pharmaceutical composition of any one of claims 71 to 74, wherein each R4is hydrogen.

76. The pharmaceutical composition of any one of claims 71 to 75, wherein Zzis hydrogen and each R4is hydrogen.

77. The pharmaceutical composition of any one of claims 71 to 76, wherein n is 1 .

78. The pharmaceutical composition of any one of claims 71 to 76, wherein n is 2.

79. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having the structure of Formula (III-c):(III-c), or a pharmaceutically acceptable salt thereof.

80. The pharmaceutical composition of claim 79, wherein X and Y each are -OR4.

81. The pharmaceutical composition of claim 80, wherein each R4independently is selected from the group consisting of hydrogen, Cs-io aryl and C7-11 arylalkyl.

82. The pharmaceutical composition of claim 80 or 81, wherein each R1is hydrogen,83. The pharmaceutical composition of any one of claims 79 to 82, wherein n is 1,84. The pharmaceutical composition of any one of claims 79 to 82, wherein n is 2.

85. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having the structure selected from the group consisting of:and pharmaceutically acceptable salts thereof.

86. The pharmaceutical composition of any one of claims 61 to 85, wherein indicates a chiral carbon with “S” configuration.

87. The pharmaceutical composition of any one of claims 61 to 85, wherein indicates a chiral carbon with “R” configuration.

88. The pharmaceutical composition of any one of Claims 1 to 87, wherein the mass of the permeability enhancer is from about 350 mg to about 1000 mg.

89. The pharmaceutical composition of any one of Claims 1 to 87, wherein the mass of the permeability enhancer is from about 400 mg to about 800 mg.

90. The pharmaceutical composition of any one of Claims 1 to 87, wherein the mass of the permeability enhancer is from about 400 mg to about 600 mg.

91. The pharmaceutical composition of any one of Claims 1 to 87, wherein the mass of the permeability enhancer is 450 mg.

92. The pharmaceutical composition of any one of Claims 1 to 91, wherein the permeability enhancer comprises from about 40% to about 90% by weight of the composition.

93. The pharmaceutical composition of any one of Claims 1 to 91, wherein the permeability enhancer comprises from about 50% to about 80% by weight of the composition.

94. The pharmaceutical composition of any one of Claims 1 to 91, wherein the one or more permeability enhancer comprises from about 70% to about 80% by weight of the composition.

95. The pharmaceutical composition of any one of Claims 1 to 91, wherein the permeability enhancer comprises about 73% of the composition.

96. The pharmaceutical composition of any one of Claims 1 to 95, comprising from about 1 mg to about 50 mg of the compound.

97. The pharmaceutical composition of any one of Claims 1 to 95, comprising from about 5 mg to about 40 mg of the compound.

98. The pharmaceutical composition of any one of Claims 1 to 95, comprising from about 10 mg to about 30 mg of the compound.

99. The pharmaceutical composition of any one of Claims 1 to 95, comprising from about 20 mg to about 30 mg of the compound.

100. The pharmaceutical composition of any one of Claims 1 to 95, comprising from about 25 mg of the compound.

101. The pharmaceutical composition of any one of Claims 1 to 100, further comprising a disintegrant.

102. The pharmaceutical composition of Claim 101, wherein the disintegrant is croscarmellose sodium.

103. A pharmaceutical composition, comprising: a permeability enhancer selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, or a combination thereof; and a therapeutically effective amount of a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:wherein:R!is selected from the group consisting of -C(=O)(OZ3), -P(=O)(X)(Y) and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with I -2 R7;R2is selected from the group consisting of -C(=O)(OZ2), P( ()){ .'<)(¥} and a 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S optionally substituted with 1-2 R7; each R7is independently selected from the group consisting of halogen, C1-6 alkyl, haloC1-6 alkyl, haloCne alkoxy, Cue alkoxy, -OR3, C3-10 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;X and Y each are independently selected from the group consisting of -OR4, NR5R6, Cue alkyl and haloCue alkyl; each R4is independently selected from the group consisting of hydrogen, Cue alkyl, haloC1-6 alkyl, Co-10 aryl and C7-11 arylalkyl;each R5is independently hydrogen or C1-6 alkyl each R6is independently hydrogen or C1-6 alkyl; andZ1and Z2each are independently selected from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl, C7-11 arylalkyl, C3-10 cycloalkyl and C6-10 aryl; and wherein the mass of the permeability enhancer is greater than about 300 mg.

104. The pharmaceutical composition of any one of Claims 1 to 103, wherein at least one of Z!and Z2is not hydrogen.

105. The pharmaceutical composition of any one of Claims 1 to 104, wherein the composition further comprises one or more excipient.

106. The pharmaceutical composition of Claim 105, wherein the one or more excipient is selected from the group consisting of microcrystalline cellulose, magnesium stearate, and polyvinylpyrrolidone.

107. The pharmaceutical composition of any one of Claims 1 to 106, wherein the composition is formulated for oral administration.

108. The pharmaceutical composition of any one of Claims 1 to 107, wherein the pharmaceutical composition comprises: from about 1.0 to about 5.0% by weight of the compound; from about 50% to about 80% by weight of a permeability enhancer selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, potassium decanoate, and combinations thereof; from about 10% to about 30% by weight inicrocrystalline cellulose, from about 1.0% to about 3.0% by weight polyvinylpyrrolidinone; and from about 1 .0% to about 3.0% by weight magnesium stearate.

109. The pharmaceutical composition of any one of Claims 1 to 108, wherein the pharmaceutical composition comprises: about 3.6% by weight of the compound; about 72.7% by weight of a permeability enhancer selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithiumdecanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate; about 19.4% by weight microcrystallme cellulose; about 1.9% by weight polyvinylpyrrolidinone; and about 2.3% by weight magnesium stearate.

110. The pharmaceutical composition of any one of Claims 1 to 109, wherein the pharmaceutical composition is enter! cally coated.

111. A method of preventing, treating, or ameliorating one or more metabolic disorders or metabolic syndromes in a subject, comprising administering a pharmaceutical composition of any one of Claims 1 tol 10, to a subject in need thereof.

112. The method of Claim 111, wherein the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes meilitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or prader-willi syndrome.

113. The method of Claim 110 orl 11, wherein the metabolic disorder or metabolic syndrome is obesity or hypothalamic obesity,114. A method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject, comprising administering a pharmaceutical composition of any one of Claims 1 to 110, to a subject in need thereof1 15. The method of Claim 114, wherein said wherein said fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

116. The method of Claim 11 Ito 115, wherein said administration of said pharmaceutical composition results in the prevention, treatment, or amelioration, of a fibrosis, fibrotic condition, or fibrotic symptoms.1 17. The method of any one of Claims 111 to 116, wherein said administration of said pharmaceutical composition results in the reduction in the amount of extracellular matrix proteins present in one or more tissues of said subject.

118. The method of any of Claims 111 to 117, wherein said administration of said pharmaceutical composition results in the reduction in the amount of collagen present in one or more tissues of said subject.

119. The method of Claim 118, wherein said administration of said pharmaceutical composition results in the reduction in the amount of Type I, Type la, or Type III collagen present in one or more tissues of said subject.

120. A method of preventing, treating, or ameliorating one or disease or disorders in a subject, comprising administering a pharmaceutical composition of any one of Claims 1 to 110 to a subject in need thereof, wherein said disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

121. The method of Claim 120, wherein said disease or disorder is nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis.

122. The method of any one of Claims 111 to 121, wherein the route of administration is oral.

123. A method of preparing a pharmaceutical composition, the method comprising the steps of:(i) combining the permeability enhancer and magnesium stearate to form first granules;(li) combining microcrystalline cellulose, Compound 4, and polyvinylpyrrolidinone to form second granules(di) combining the first granules and the second granules to form a mixture,(iv) adding magnesium stearate to the mixture to form third granules;(v) pressing the third granules into tablets; wherein the permeability enhancer is selected from the group consisting of sodium hexanoate, sodium heptanoate, sodium octanoate; sodium nonanoate, lithium hexanoate, lithium heptanoate, lithium octanoate; lithium nonanoate, lithium decanoate, potassium hexanoate, potassium heptanoate, potassium octanoate; potassium nonanoate, and combinations thereof..

124. The pharmaceutical composition prepared by the method of Claim 123.

Images