TW202444420A - Pharmaceutical compositions and methods for the treatment of metabolic and liver disorders - Google Patents

Abstract

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

Description

Pharmaceutical compositions and methods for treating metabolic and liver diseases

The present disclosure generally relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to a solid oral pharmaceutical composition for treating metabolic disorders and fatty liver disease.

Intestinal insulin peptides Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are metabolic hormones. GIP and GLP-1 are secreted within minutes of nutrient ingestion and promote rapid excretion of ingested nutrients. Both peptides have common effects on pancreatic β cells, acting through structurally different but related receptors. Activation of intestinal insulin receptors leads to glucose-dependent insulin secretion, induction of β cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage through direct effects on adipose tissue. In contrast, GLP-1 exerts glucoregulatory effects via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1 receptor activation has been associated with weight loss in both preclinical and clinical studies.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and the most common cause of chronic liver disease. NAFLD can progress to hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. GLP-1 agonists and GIP/GLP-1 dual receptor agonists have been developed for the treatment of NAFLD, non-alcoholic 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 GIP/GLP1 dual receptor agonist compounds found that tolerability at high doses was limited by gastrointestinal adverse events. Dose limitations associated with gastrointestinal adverse events may prevent the administration of the required effective dose, may impair patient compliance with treatment, and may limit the effectiveness of treatment regimens. Therefore, there is a need for GLP-1 agonists and GIP/GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and conditions.

Peptide compounds show some promise as GLP-1 agonists and GIP/GLP-1 dual agonists useful for treating metabolic disorders such as NAFLD. However, there are many difficulties in preparing oral compositions of peptides. Such oral compositions have varying bioavailability of the active agents. Therefore, suitable pharmaceutical compositions of such peptide-based dual agonist compounds are needed.

In one aspect of the present disclosure, a pharmaceutical composition is provided, 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.

In some embodiments of the first aspect, the compound is a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof: wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ may be independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y may each be independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ may be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryloxy and C _6-10 arylalkoxy; each R ⁵ may be independently hydrogen or C _1-6 alkyl; each R ⁶ may be independently hydrogen or C _1-6 alkyl; and Z ¹ and Z ² may each be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C 1-6 alkoxy, C _{1-6 C 1-6} alkoxy, C _3-10 cycloalkyl and C _6-10 aryl.

In some embodiments of the compounds of formula (I), at least one of Z ¹ and Z ² is not hydrogen.

In other embodiments of the first aspect, the compound is a compound having a structure of formula (II): or a pharmaceutically acceptable salt thereof, wherein: Aib is 2-aminoisobutyric acid; each of ^J1 , ^J2 and ^J3 is independently an amino acid selected from Aib, a naturally occurring amino acid and a non-natural amino acid; ^U1 is -(J4) _n1- ( ^J5 ) _n2- ( ^J6 ) _n3- ( ^J7 ) _n4- ; ^U2 is -( ^J8 ) _n5- ( ^J9 ) _n6- ( ^J10 ) _n7- ( ^J11 ) _n8- ; each of ^J4 , ^J5 , ^J6 , ^J7 , ^J8 , ^J9 , ^{J10 and J11} is independently a naturally occurring amino acid or a non-natural amino acid; each of n1, n2, n3, n4, n5, n6, n7 and n8 is independently 0 or 1, with the proviso that the sum of n1 + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4; R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted with 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl group containing ₁ to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R 7 independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _{1-6 alkyl, halogen C 1-6 alkoxy} , -OR 5 , C 3-10 cycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocyclic group; each R ⁷ is independently selected from the ^group consisting of: halogen, C 1-6 alkyl, halogen C 1-6 alkyl, halogen C 1-6 alkoxy, -OR ⁵ , C _{3-10 cycloalkyl, C 6-10 aryl} , a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocyclic group; wherein X and Y are each independently selected from the group consisting of -OR ₄ , NR ₅ R ⁶ , C _{1-6 alkyl and halogenated C 1-6 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl} ^, _halogenated C _1-6 alkyl, C _6-10 aryl and ^C _7-11 aralkyl; each ^R ₅ is independently _{hydrogen or C 1-6 alkyl; each R 6 is independently hydrogen or C 1-6 alkyl} ^{; and} _{Z 1} ^and _Z ² are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl.

In some embodiments, the compound is not: .

In some embodiments of the compound of formula (II), at least one of Z ¹ and Z ² is not hydrogen.

In yet other embodiments of the first aspect, the compound is a compound having a structure of formula (III): , or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -(CH ₂ CH ₂ ) _n P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ is independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y are each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryloxy and C _6-10 arylalkoxy; each R ⁵ is independently hydrogen or C _1-6 alkyl; each R ⁶ is independently hydrogen or C _1-6 alkyl; Z ¹ and Z ² are each independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, and n is 0 _{, 1 ,} 2, 3 or 4.

In some embodiments of the first aspect, the permeability enhancer is salcaprozate sodium (SNAC), sodium decanoate (C10), or a combination thereof.

In the second aspect of the present disclosure, a pharmaceutical composition is provided herein, comprising: sodium saprolidine; and a therapeutically effective amount of a compound having a structure of formula I or a pharmaceutically acceptable salt thereof: wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ is independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y are each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryl and C _6-10 aralkyl; each R ⁵ is independently hydrogen or C _1-6 alkyl; each R ⁶ is independently hydrogen or C _1-6 alkyl; and Z ¹ and Z ² are each independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, _3-10 cycloalkyl and C _6-10 aryl; and wherein the mass of saprolidone is greater than about 300 mg.

In some embodiments of the second aspect, at least one of ^Z1 and ^Z2 is not hydrogen.

In some embodiments of the present disclosure, the pharmaceutical composition is formulated for oral administration. In some of these embodiments, the pharmaceutical composition is coated with an enteric coating.

In a third aspect of the present disclosure, provided herein is a method for preventing, treating or improving one or more fatty liver diseases in an individual, comprising administering the pharmaceutical composition disclosed herein to an individual in need thereof.

In a fourth aspect of the present disclosure, provided herein is a method for preventing, treating or ameliorating one or more diseases or conditions in an individual, comprising administering the pharmaceutical composition disclosed herein to an individual in need thereof, wherein the disease or condition is liver fibrosis, kidney fibrosis, bile fibrosis, pancreatic fibrosis, nonalcoholic fatty hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis.

In a fifth aspect of the present disclosure, a method for preventing, treating or ameliorating a metabolic disorder or metabolic syndrome is provided herein. In some embodiments, the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity or Prader-Willi syndrome.

In the sixth aspect of the present disclosure, a method for preparing a pharmaceutical composition is provided herein. In some embodiments, the method comprises the following steps: (i) combining a permeability enhancer and magnesium stearate to form a first granule; (ii) combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidone to form a second granule; (iii) combining the first granules and the second granules to form a mixture; (iv) adding magnesium stearate to the mixture to form a third granule; (v) pressing the third granules into tablets.

In other embodiments, the method comprises the following steps: (i) combining sodium sapolidate (SNAC) and magnesium stearate to form a first granule; (ii) combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidone to form a second granule; (iii) combining the first granules and the second granules to form a mixture; (iv) adding magnesium stearate to the mixture to form a third granule; (v) pressing the third granules into tablets.

In other embodiments, the method comprises the following steps: (i) combining C10 and magnesium stearate to form a first granule; (ii) combining microcrystalline cellulose, a compound disclosed herein, and polyvinyl pyrrolidone to form a second granule; (iii) combining the first granules and the second granules to form a mixture; (iv) adding magnesium stearate to the mixture to form a third granule; (v) pressing the third granules into tablets.

In some embodiments, provided herein is a method for preparing a pharmaceutical composition, the method comprising the following steps: (i) combining microcrystalline cellulose and a compound disclosed herein in a first container; (ii) combining polyvinylpyrrolidone and water in a second container; (iii) adding the contents of the first container to the second container to form wet granules; (iv) drying the wet granules to form dry granules; (v) combining the dry granules with magnesium stearate; and (vi) pressing the resulting mixture of step (v) into granules.

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 63/490,512 filed on March 15, 2023, which is incorporated herein by reference in its entirety. Reference to Sequence Listing

This application is filed with a sequence listing in electronic format. The sequence listing is provided as a file named VIKNG.025PR.xml, created on March 14, 2023, and is 40,752 bytes in size. The information in the electronic sequence listing is incorporated herein by reference in its entirety.

In some embodiments, pharmaceutical compositions are provided for administration to an individual in need thereof. Various embodiments of such 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 amount of a compound described elsewhere herein or a pharmaceutically acceptable salt thereof. Some embodiments of the pharmaceutical compositions are administered for the prevention, treatment, or amelioration of one or more fatty liver diseases in an individual. Definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as 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. Unless otherwise stated, in the event that a term has multiple definitions in this document, the definition in this section shall prevail.

"Solvent complex" refers to a compound formed by the interaction of a solvent and a compound described herein or a salt thereof. Suitable solvent complexes are pharmaceutically acceptable solvent complexes, including hydrates.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound and is not biologically or otherwise unsuitable for use in medicine. In many cases, the compounds herein are capable of forming acid salts and/or base salts by virtue of the presence of amino 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, citric 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 bases 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; ammonium, potassium, sodium, calcium and magnesium salts are particularly preferred. 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 resins and the like, in particular, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art and are described in WO 87/05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

As used herein, "C _a to C _b " or "C _ab " wherein "a" and "b" are integers refers to the number of carbon atoms in the specified group. That is, the group may contain "a" to "b" (inclusive) carbon atoms. Thus, for example, "C ₁ to C ₄ alkyl" or "C _1-4 alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e., CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )-, and (CH ₃ ) ₃ C-.

As used herein, the term "halogen" or "halogen group" means any of the radioactive stable atoms in row 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

As used herein, "alkyl" refers to a fully saturated (i.e., containing no double or triple bonds) straight or branched hydrocarbon chain. An alkyl group may have 1 to 20 carbon atoms (whenever a numerical range such as "1 to 20" appears herein, it refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but the present definition also encompasses the presence of the term "alkyl" in which no numerical range is specified). An alkyl group may also be an intermediate size alkyl group having 1 to 9 carbon atoms. An alkyl group may also be a lower carbon number alkyl group having 1 to ₄ carbon atoms. The alkyl group of a compound may be designated as "C _1-4 alkyl" or a similar name. By way of example only, "C _1-4 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, isobutyl, di-butyl and tertiary butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.

As used herein, "haloalkyl" refers to a straight or branched chain alkyl group having 1 to 12 carbon atoms in the chain in which one or _more hydrogen atoms are replaced by a halogen. Examples of halogenalkyl groups include, but are not limited to, _-CF3 , _-CHF2 , _-CH2F , _{-CH2CF3 , -CH2CHF2 , -CH2CH2F} , _-CH2CH2Cl , _{-CH2CF2CF3 ,} and other groups that will be considered equivalent to any of the _foregoing examples in _view of one of ordinary skill in the art and the teachings provided herein.

As used herein, "alkoxy" refers to the formula -OR, wherein R is an alkyl group as defined above, such as "C _1-9 alkoxy", including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, di-butoxy and tert-butoxy and the like.

As used herein, "polyethylene glycol" refers to , wherein n is an integer greater than one and R is hydrogen or an alkyl group. The number of repeating units "n" can be specified by reference to the number of members. Thus, for example, "2- to 5-membered polyethylene glycol" means that n is an integer selected from two to five. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, di-butoxy, and tertiary butoxy.

As used herein, "heteroalkyl" refers to a straight or branched alkyl chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the main chain. A heteroalkyl group may have 1 to 20 carbon atoms, but the present definition also encompasses the presence of the term "heteroalkyl" without specifying a numerical range. A heteroalkyl group may also be a medium-sized heteroalkyl group having 1 to 9 carbon atoms. A heteroalkyl group may also be a low-carbon heteroalkyl group having 1 to 4 carbon atoms. In various embodiments, a heteroalkyl group may have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compound may be named "C _1-4 heteroalkyl" or a similar name. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C _1-4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and one or more additional heteroatoms in the backbone of the chain.

The term "aromatic" refers to a ring or ring system having a conjugated π electron system, and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, with the proviso that the entire ring system is aromatic.

As used herein, "aryl" refers to an aromatic ring or ring system containing carbon only in the main chain of the ring (i.e., two or more fused rings that share two adjacent carbon atoms). When aryl is a ring system, each ring in the system is aromatic. Aryl can have 6 to 18 carbon atoms, but the present definition also encompasses the presence of the term "aryl" without specifying a numerical range. In some embodiments, aryl has 6 to 10 carbon atoms. Aryl can be named "C _6-10 aryl", "C ₆ or C ₁₀ aryl" or similar names. Examples of aryl include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is aryl as defined above, such as "C _6-10 aryloxy" or "C _6-10 arylthio" and the like, including but not limited to phenoxy.

"Aralkyl" or "arylalkyl" refers to an aryl group as a substituent connected via an alkylene group, such as "C _7-14 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., C _1-4 alkylene group).

As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) containing one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in the main ring chain. When the heteroaryl is a ring system, each ring in the system is aromatic. The heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms, including carbon atoms and heteroatoms, that make up the main ring chain), but the present definition also encompasses the presence of the term "heteroaryl" without specifying a numerical range. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be named as "5- to 7-membered heteroaryl group", "5- to 10-membered heteroaryl group" or similar names. In various embodiments, the heteroaryl group contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl group 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, furanyl, thienyl, oxazolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazolyl, triazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothiophenyl.

"Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent through an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C _1-4 alkylene group).

As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the main chain of the ring system. When the carbocyclyl is a ring system, two or more rings can be joined together in a fused, bridged or spiro manner. The carbocyclyl can have any saturation, with the proviso that at least one ring in the ring system is not aromatic. Therefore, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. The carbocyclyl can have 3 to 20 carbon atoms, but the present definition also covers the existence of the term "carbocyclyl" without specifying a numerical range. The carbocyclyl can also be a medium-sized carbocyclyl with 3 to 10 carbon atoms. The carbocyclyl can also be a carbocyclyl with 3 to 6 carbon atoms. Carbocyclyl groups may be named " _{C3-6carbocyclyl} " or similar names. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl.

"(Carbocyclyl)alkyl" refers to a carbocyclyl group connected as a substituent via an alkylene group, such as "C _4-10 (carbocyclyl)alkyl" and the like, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower carbon number alkylene group.

As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

As used herein, "heterocyclic group" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the main ring chain. Heterocyclic groups can be joined together in a fused, bridged or spiro manner. Heterocyclic groups can have any degree of saturation, with the proviso that at least one ring in the ring system is not aromatic. Heteroatoms can be present in non-aromatic or aromatic rings in the ring system. Heterocyclic groups can have 3 to 20 ring members (i.e., the number of atoms constituting the main ring chain, including carbon atoms and heteroatoms), but the present definition also covers the presence of the term "heterocyclic group" without specifying a numerical range. The heterocyclic group may also be a medium-sized heterocyclic group having 3 to 10 ring members. The heterocyclic group may also be a heterocyclic group having 3 to 6 ring members. The heterocyclic group may be named "3- to 6-membered heterocyclic group" or a similar name.

In various embodiments, the heterocyclic group contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatoms. For example, in various embodiments, the heterocyclic group 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 heterocyclic groups, the heteroatoms are selected from one to three of O, N, or S, and in preferred five-membered monocyclic heterocyclic groups, the heteroatoms are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclic rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, oxazolinyl, dioxolane, imidazolinyl, imidazolidinyl, oxolinyl, oxathiophene, oxathiophene, oxathiophene, piperidinyl, piperonyl, dioxopiperidinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidone ... pyridinedione, 4-piperidone, pyrazolyl, pyrazolidinyl, 1,3-dioxacyclohexenyl, 1,3-dioxacyclohexanyl, 1,4-dioxacyclohexanyl, 1,4-dioxacyclohexanyl, 1,3-oxathiacyclohexanyl, 1,4-thiathiacyclohexanyl, 1,4-oxathiacyclohexanyl, 2 H -1,2-oxadiazole, trioxadiazole, hexahydro-1,3,5-trioxadiazole, 1,3-dioxolanyl, 1,3-dithiocyclopentenyl, 1,3-dithiocyclopentyl, isoxadiazole, isoxadiazole, isoxadiazole, oxadiazole, oxadiazole, oxadiazole In some embodiments, the present invention comprises a 1,2-dihydro-2-pyranyl group, a 1,3-dihydro-2-pyranyl group, a 1,4-dihydro-1,6-thia-2-yl group, a 1,4-dihydro-2-pyranyl group, a 1,3-dihydro-2-pyranyl group, a 1,4-dihydro-3-thia-2-yl group, a 1,4-dihydro-3-thia-2-yl group, a 1,4-dihydro-2-pyran ...

"(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryl.

"O-carboxy" refers to a "-OC(=O)R" group, wherein 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.

"C-carboxyl" refers to a "-C(=O)OR" radical, wherein 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. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

"Cyano" refers to the "-CN" group.

“Cyanato” refers to the “-OCN” group.

“Isocyanato” refers to the “-NCO” group.

“Thiocyanate” refers to the “-SCN” group.

“Isothiocyanato” refers to the “-NCS” group.

“Sulfinyl” refers to a “—S(═O)R” group, wherein R is selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, as defined herein.

"Sulfonyl" refers to a " _-SO2R " radical, wherein R is 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.

“S-sulfonamido” refers to a “—SO ₂ NR _A R _B ” radical, wherein _RA and _RB are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, as defined herein.

An "N-sulfonamido" group refers to a "-N( _RA ) _{SO2RB "} group, wherein _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.

“O-aminoformyl” refers to a “—OC(═O)NR _A R _B ” radical, wherein _RA and _RB are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, as defined herein.

“N-aminocarboxyl” refers to a “—N( _RA )OC(═O) _RB ” radical, wherein _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- to 10 _- membered heteroaryl and 5- to 10-membered heterocyclyl, as defined herein.

“O-thiaminecarboxyl” refers to a “—OC(═S)NR _A R _B ” radical, wherein _RA and _RB are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, as defined herein.

“N-thiaminocarboxyl” refers to a “—N( _RA )OC(═S) _RB ” radical, wherein _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.

“C-amido” refers to a “—C(═O)NR _A R _B ” radical, wherein _RA and _RB are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, as defined herein.

“N-amido” refers to a “—N( _RA )C(═O) _RB ” radical, wherein _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.

“Aminyl” refers to a “—NR _A R _B ” group, wherein _RA and _RB are each independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, C _6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, as defined herein.

"Aminoalkyl" refers to an amine group linked through an alkylene group.

"Alkoxyalkyl" refers to an alkoxy group linked through an alkylene group, such as "C _2-8 alkoxyalkyl" and the like.

As used herein, a substituted group is derived from an unsubstituted parent group wherein one or more hydrogen atoms already present are replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it means that the group is substituted with one or more substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₇ carbocyclyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy), C ₃ -C ₇ carbocyclyl-C ₁ -C ₆ alkyl (optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C 6 haloalkyl and C ₁ -C ₆ haloalkoxy), _{C 1} -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy groups), 5- to 10-membered heterocyclic groups (optionally substituted with a halogen group, C ₁ -C 6 alkyl, C ₁ -C ₆ alkoxy groups, C ₁ -C 6 halogenalkyl and C ₁ -C ₆ halogenalkoxy groups), 5- to 10-membered heterocyclic groups-C 1 -C ₆ alkyl (optionally substituted with a halogen group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy groups), aryl groups (optionally substituted with a halogen group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy groups), aryl(C ₁ -C 6)alkyl (optionally substituted with a halogen group, C ₁ -C ₆ C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy), 5- to 10-membered heteroaryl (optionally substituted with a halogen group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy), 5- to 10-membered heteroaryl (C ₁ -C ₆ ) alkyl (optionally substituted with a halogen group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ halogenalkyl and C ₁ -C ₆ halogenalkoxy), halogen, cyano, hydroxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy (C ₁ -C ₆ )alkyl (i.e., ether), aryloxy, hydrothio(hydroxy), halogen(C ₁ -C ₆ )alkyl (e.g., —CF ₃ ), halogen(C ₁ -C ₆ )alkoxy (e.g., —OCF ₃ ), C ₁ -C ₆ alkylthio, arylthio, amino, amino(C ₁ -C ₆ )alkyl, nitro, O-aminoformyl, N-aminoformyl, O-thiaminoformyl, N-thiaminoformyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, acyl, cyano, isocyanato, thiocyano, isothiocyano, sulfinyl, sulfonyl, and pendant (═O). Whenever a group is described as "optionally substituted," that group may be substituted with the above substituents.

In some embodiments, the substituted groups are substituted with one or more substituents individually and independently selected from C ₁ -C ₄ alkyl, amino, hydroxyl, and halogen.

It is understood that certain group naming conventions may include either a monoradical or a diradical, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, substituents that require two points of attachment that are identified as alkyl include diradicals, such as _-CH2- , _-CH2CH2- , _-CH2CH ( _CH3 ) _CH2- , and the like. Other group naming conventions explicitly indicate that the group is _a diradical, such as "alkylene" or "alkenylene."

When two R groups are referred to as forming a ring (e.g., a carbocyclic, heterocyclic, aryl, or heteroaryl ring) "together with the atoms to which they are attached," it is meant that the entire unit of atoms and the two R groups is the described ring. The ring is not otherwise limited by the definitions of each R group when used individually. For example, when the following substructures are present:

When ^R1 and ^R2 are defined as being selected from the group consisting of hydrogen and alkyl, or when ^R1 and ^R2 together with the nitrogen to which they are attached form a heterocyclic group, it means that ^R1 and ^R2 can be selected from hydrogen or alkyl, or the substructure has the following structure:

wherein Ring A is a heterocyclic ring containing the depicted nitrogen.

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 entire unit of atoms, intervening bonds, and the two R groups is the described ring. For example, when the following substructure is present:

And ^R1 and ^R2 are defined as being selected from the group consisting of hydrogen and alkyl, or ^R1 and ^R2 together with the atoms to which they are attached form an aryl group or a carbocyclic group, meaning that ^R1 and ^R2 can be selected from hydrogen or alkyl, or the substructure has the following structure:

wherein A is an aryl ring or a carbocyclic group containing the depicted double bond.

Unless otherwise indicated, whenever a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation. Substituents with A include substituents oriented so that A is attached at the left-most point of attachment of the molecule as well as instances where A is attached at the right-most point of attachment of the molecule.

The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

As used herein, "subject" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird (e.g., chicken), as well as any other vertebrate or invertebrate.

As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to alleviate one or more symptoms of a disease or condition to some extent or reduce the likelihood of its onset, and includes a cure for the disease or condition. "Cure" means eliminating the symptoms of the disease or condition; however, even after a cure is achieved, some long-term or permanent effects (such as extensive tissue damage) may exist.

As used herein, "treat" refers to the administration of a pharmaceutical composition for the purpose of prophylaxis and/or treatment. The term "prophylactic treatment" refers to treatment of an individual who does not yet display symptoms of a disease or condition, but is susceptible to or otherwise at risk for 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 the administration of a treatment to an individual who already has a disease or condition. Compounds

In some embodiments, the pharmaceutical composition includes a compound that is a non-macrocyclic functionalized peptide that acts as a GIP/GLP-1 dual receptor agonist. In other embodiments, the pharmaceutical composition includes a compound that is a non-macrocyclic functionalized peptide that acts as a GLP-1 receptor monoagonist.

When the compounds disclosed herein have at least one chiral center, they may exist in the form of individual mirror image isomers and non-mirror image isomers or in the form of mixtures of such isomers (including racemates). The separation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods known to practitioners in this technology. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. In addition, the 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 form. In addition, some compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvents are included within the scope of the compounds disclosed herein.

Those skilled in the art will recognize that some of the structures depicted herein may be resonant forms or tautomers of compounds that can be clearly represented by other chemical structures, even when represented kinetically; the skilled artisan recognizes that such a structure may represent only a very small portion of a sample of such a compound. Such compounds are considered to be within the scope of the depicted structures, but such resonant forms or tautomers are not presented herein. Compounds of Formula (I)

Various embodiments of these compounds include compounds having the structure of formula (I) described above or a pharmaceutically acceptable salt thereof. The structure of formula (I) encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

In some embodiments of compounds of formula (I):

R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted with 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo;

R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted with 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo;

Each R ⁷ may be independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic;

X and Y may be each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl;

Each R ⁴ may be independently selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryl and C _6-10 aralkyl;

Each R ⁵ may independently be hydrogen or C _1-6 alkyl;

Each R ⁶ may independently be hydrogen or C _1-6 alkyl; and

^Z1 and ^Z2 may each be independently selected from the group consisting of hydrogen, _C1-6 alkyl, halogen _C1-6 alkyl, halogen _C1-6 alkoxy, _C1-6 alkoxy, _C3-10 cycloalkyl and _C6-10 aryl.

In some embodiments, at least one of ^Z1 and ^Z2 is not hydrogen.

Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ia): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof; Z ¹ is selected from hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof; Z ¹ is selected from hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ can be independently selected from hydrogen, C _6-10 aryl and C _6-10 aralkyl.

In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof; Z ¹ is hydrogen and each R ⁴ can independently be hydrogen or C _6-10 aralkyl.

In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof; each R ⁴ is hydrogen.

In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof; Z ¹ is hydrogen and each R ⁴ is hydrogen.

Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ib): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof; Z ² is selected from hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof; Z ² is selected from hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ can be independently selected from hydrogen, C _6-10 aryl and C _6-10 aralkyl.

In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof; Z ² is hydrogen and each R ⁴ can independently be hydrogen or C _6-10 aralkyl.

In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof; each R ⁴ is hydrogen.

In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof; Z ² is hydrogen and each R ⁴ is hydrogen.

Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ic): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (Ic) or a pharmaceutically acceptable salt thereof; X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (Ic) or a pharmaceutically acceptable salt thereof; each R ⁴ can be independently selected from hydrogen, C _6-10 aryl and C _6-10 aralkyl.

In some embodiments of the compound of formula (Ic) or a pharmaceutically acceptable salt thereof; each R ⁴ is hydrogen.

Some embodiments include compounds having a structure selected from the group consisting of: and their pharmaceutically acceptable salts.

Some embodiments include compounds wherein "*" indicates a chiral carbon with an "S" configuration.

Some embodiments include compounds wherein "*" indicates a chiral carbon with an "R" configuration.

The compounds of formula (I ) described herein (e.g., compounds 1 to 12) can be prepared according to the method described in International Patent Publication No. WO 2022/159395, the disclosure of which is incorporated herein in its entirety.

Various embodiments of these compounds include compounds having the structure of formula (II) described herein or a pharmaceutically acceptable salt thereof. The structure of formula (II) encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof: or a pharmaceutically acceptable salt thereof. Formula (II) can also be written as: In formula (II) and the compounds described herein, "H-" represents the hydrogen on the N-terminal amine, and " _-NH2 " represents the amine group forming the C-terminal amide.

In some embodiments of the compound of formula (II): Aib is 2-aminoisobutyric acid; each instance of ^J1 , ^J2 and ^J3 is independently an amino acid selected from Aib, naturally occurring amino acids and unnatural amino acids.

In some embodiments of the compound of formula (II): ^U1 is -( ^J4 ) _n1- ( ^J5 ) _n2- ( ^J6 ) _n3- ( ^J7 ) _n4- ; ^U2 is -(J8)n5-( ^J9 ) _n6- ( ^J10 ) _n7- ( ^J11 ) _n8- ; each of ^J4 , ^J5 , ^J6 , _J7 , ^J8 , ^J9 , ^J10 and ^J11 is independently a naturally occurring amino acid or a non-natural amino acid; each of n1, n2, ⁿ³ , n4, n5, n6, n7 and n8 is independently 0 or ¹ , with the proviso that the sum of n1+n2+n3+n4+n5+n6+n7+n8 is 4; R ^{R 1} is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ is independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y are each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryl and C _7-11 aralkyl; each R ⁵ is independently hydrogen or C _1-6 alkyl; each R ⁶ is independently hydrogen or C _1-6 alkyl; and Z ¹ and Z ² are each independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, _{C 3-10} cycloalkyl and C _6-10 aryl.

In some embodiments, the compound is not: .

In some embodiments of the compound of formula (II), each instance of J ¹ , J ^{2 ,} and J ³ is independently an amino acid selected from Aib and naturally occurring amino acids.

In some embodiments of compounds of formula (II), each instance of J ¹ , J ² and J ³ is independently an amino acid selected from Aib, A, F, N, R and Q. In some embodiments, J ¹ is Aib or F. In some embodiments, J ¹ is F. In some embodiments, J ² is N or Q. In some embodiments, J ² is N. In some embodiments, J ³ is A or R. In some embodiments, J ³ is R.

In some embodiments of compounds of formula (II), each instance of J ⁴ , J ⁵ , J ⁶ and J ⁷ is independently an amino acid selected from A, I, K, R, Q, S, T and V. In some embodiments, J ⁴ is K or R. In some embodiments, J ⁴ is R. In some embodiments, J ⁵ is I, T or V. In some embodiments, J ⁵ is T or V. In some embodiments, J ⁶ is A or S. In some embodiments, J ⁶ is S. In some embodiments, J ⁷ is Q. In some embodiments, J ⁷ is K.

In some embodiments of compounds of formula (II), each instance of J ⁸ , J ⁹ , J ¹⁰ and J ¹¹ is independently an amino acid selected from A, I and Q. In some embodiments, J ⁸ is I or Q. In some embodiments, J ⁹ is A or Q. In some embodiments, J ¹⁰ is Q. In some embodiments, J ¹¹ is Q.

In some embodiments of compounds of formula (II), ^J1 is selected from Aib or F; ^J2 is selected from Q or N; ^J3 is selected from A or R; ^U1 is selected from -KVA-, -KIAQ- (SEQ ID NO: 8), -KTAQ- (SEQ ID NO: 9), -KTSQ- (SEQ ID NO: 10), -KVAQ- (SEQ ID NO: 11), -RIAQ- (SEQ ID NO: 12), -KIAK- (SEQ ID NO: 13), -KISQ- (SEQ ID NO: 14), or is absent; and ^U2 is selected from -Q-, -IAQQ- (SEQ ID NO: 15), -IAQK- (SEQ ID NO: 16), -VAQK- (SEQ ID NO: 17), or is absent.

In some embodiments of the compound of formula (II), each instance of n1, 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.

In some embodiments of the compound of formula (II), at least one of Z ¹ and Z ² is not hydrogen.

Some embodiments of the compound of formula (II) include compounds having the structure of formula (II-a): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (II-a) or a pharmaceutically acceptable salt thereof, Z ¹ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _{1-6 alkoxy, C 1-6 alkoxy} , C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (II-a) or a pharmaceutically acceptable salt thereof, Z ¹ is hydrogen and each R ⁴ is independently hydrogen or C _7-11 aralkyl.

In some embodiments of the compound of formula (II-a) or a pharmaceutically acceptable salt thereof, each R ⁴ is hydrogen.

In some embodiments of the compound of formula (II-a) or a pharmaceutically acceptable salt thereof, Z ¹ is hydrogen and each R ⁴ is hydrogen.

Some embodiments of the compound of formula (II) include compounds having the structure of formula (II-b): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (II-b) or a pharmaceutically acceptable salt thereof, each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryl and C _7-11 aralkyl.

In some embodiments of the compound of formula (II-b) or a pharmaceutically acceptable salt thereof, each R ⁴ is hydrogen.

Some embodiments include compounds having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

The compounds of formula (II) disclosed herein can be synthesized by the methods described below or by modifications of such methods. The methods of modifying the methods include, among others, temperatures, solvents, reagents, etc. known to those skilled in the art. In general, during any process for preparing the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved with the aid of known protecting groups, such as those described in Protective Groups in Organic Chemistry (JFW McOmie, ed., Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999), which are hereby incorporated by reference in their entirety. The protecting groups may be removed at an appropriate subsequent stage using methods known in the art. Synthetic chemical transformations suitable for synthesizing suitable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations , VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons, 1995 (each of which is hereby incorporated by reference in its entirety). The pathways shown and described herein are merely illustrative and are not intended, nor are they to be construed, to limit the scope of the claims in any way. Those skilled in the art will be able to understand modifications of the disclosed syntheses based on the disclosure herein and may deduce alternative pathways; all such modifications and alternative pathways are within the scope of the claims.

In the following schemes, protecting groups used on oxygen atoms are chosen for compatibility with the necessary synthetic steps and for compatibility of the steps for introduction and removal of the protecting group with the overall synthetic scheme (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

If the compounds of the present invention contain one or more chiral centers, the compounds can be prepared or isolated in the form of pure stereoisomers, that is, in the form of individual mirror image isomers or d(l) stereoisomers, or in the form of stereoisomer enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included in the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated using, for example, chiral column chromatography, chiral analytical agents and the like.

The starting materials used in the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials can be purchased from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

Scheme 1 depicts a method for preparing a compound according to formula ( II ). The method may include constructing a peptide backbone using solid phase peptide synthesis techniques to provide a resin-bound peptide. The side chain of the central lysine containing the Dde group can then be expanded with a linker comprising two PEG ₂ amide linkers and an isoglutamine (or related analog) linker to provide an intermediate ( II-A ). The method includes a coupling reaction between the amine of the isoglutamine (or related analog) of the intermediate (II-A ) and the intermediate ( II-B ) to provide a resin-bound intermediate ( II-C ). In formula ( II-A ) to formula ( II-C ), R ¹ 'and R ² 'are protected forms of the R ¹ and R ² groups described herein. In one embodiment, the method involves subjecting the intermediate ( II-C ) to hydrolysis under acidic conditions to remove the resin and protecting groups, followed by purification to obtain the final product ( II ). The peptide backbone disclosed herein can be synthesized by solid phase peptide synthesis techniques described in Methods in Molecular Biology, 298, Peptide Synthesis and Applications , (J. Howl, ed., Humana Press, 2005); and Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3 , Building Blocks, Catalysts and Coupling Chemistry , (AB Hughs, ed., Wiley-VCH, 2011), which are hereby incorporated by reference in their entirety. Scheme 1 :

The above example schemes are provided to guide the reader and generally represent example methods for preparing the compounds covered herein. In addition, other methods for preparing the compounds described herein will be readily apparent to one of ordinary skill in the art in view of the following reaction schemes and examples. Unless otherwise indicated, all variables are defined above. Compounds of Formula (III)

Various embodiments of these compounds include compounds having the structure of formula (III) described herein or a pharmaceutically acceptable salt thereof. The structure of formula (III) encompasses all stereoisomers.

In some embodiments of the compound of formula (III): R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, wherein the heteroaryl group is optionally substituted with 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclo group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ may be independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y can each be independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ can be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryloxy and C _6-10 arylalkoxy; each R ⁵ can be independently hydrogen or C _1-6 alkyl; each R ⁶ can be independently hydrogen or C _1-6 alkyl; Z ¹ and Z ² can each be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, and n is 0 _{, 1 ,} 2, 3 or 4.

In some embodiments, at least one of ^Z1 and ^Z2 is not hydrogen.

Some embodiments of the compound of formula (III) include compounds having the structure of formula (III-a): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt thereof, Z ¹ is selected from hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt _thereof , Z ¹ is selected from hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ can be independently selected from hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy.

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt thereof; Z ¹ is hydrogen and each R ⁴ can independently be hydrogen or C _6-10 arylalkoxy.

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt thereof, each R ⁴ is hydrogen.

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt thereof, Z ¹ is hydrogen and each R ⁴ is hydrogen.

In some embodiments of the compound of formula (III-a) or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In yet other embodiments, n is 2. In yet other embodiments, n is 3. In some embodiments, n is 4.

Some embodiments of the compound of formula (III) include compounds having the structure of formula (III-b): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt thereof; Z ² is selected from hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt _thereof ; Z ² is selected from hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ can be independently selected from hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy.

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt thereof; Z ² is hydrogen and each R ⁴ can independently be hydrogen or C _6-10 arylalkoxy.

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt thereof; each R ⁴ is hydrogen.

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt thereof; Z ² is hydrogen and each R ⁴ is hydrogen.

In some embodiments of the compound of formula (III-b) or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In yet other embodiments, n is 2. In yet other embodiments, n is 3. In some embodiments, n is 4.

Some embodiments of the compound of formula (III) include compounds having the structure of formula (III-c): or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of formula (III-c) or a pharmaceutically acceptable salt thereof, X and Y are each -OR ⁴ .

In some embodiments of the compound of formula (III-c) or its pharmaceutically acceptable salt, each R ⁴ can be independently selected from hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. In some embodiments of the compound of formula (III-c) or its pharmaceutically acceptable salt, each R ⁴ is hydrogen.

In some embodiments of the compound of formula (III-c) or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In still other embodiments, n is 2. In still other embodiments, n is 3. In some embodiments, n is 4.

Some embodiments include compounds having a structure selected from the group consisting of: , and their pharmaceutically acceptable salts.

Some embodiments include compounds wherein "*" indicates a chiral carbon with an "S" configuration.

Some embodiments include compounds wherein "*" indicates a chiral carbon with an "R" configuration.

The compounds of formula (III) disclosed herein can be synthesized by the methods described below or by modifications of such methods. The methods of modifying the methods include, among others, temperatures, solvents, reagents, etc. known to those skilled in the art. In general, during any process for preparing the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved with the aid of known protecting groups, such as those described in Protective Groups in Organic Chemistry (JFW McOmie, ed., Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999), which are hereby incorporated by reference in their entirety. The protecting groups may be removed at an appropriate subsequent stage using methods known in the art. Synthetic chemical transformations suitable for synthesizing suitable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations , VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons, 1995 (each of which is hereby incorporated by reference in its entirety). The pathways shown and described herein are merely illustrative and are not intended, nor are they to be construed, to limit the scope of the claims in any way. Those skilled in the art will be able to understand modifications of the disclosed syntheses based on the disclosure herein and may deduce alternative pathways; all such modifications and alternative pathways are within the scope of the claims.

In the following schemes, protecting groups used on oxygen atoms are chosen for compatibility with the necessary synthetic steps and for compatibility of the steps for introduction and removal of the protecting group with the overall synthetic scheme (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

If the compounds of the present invention contain one or more chiral centers, the compounds can be prepared or isolated in the form of pure stereoisomers, that is, in the form of individual mirror image isomers or d(l) stereoisomers, or in the form of stereoisomer enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included in the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated using, for example, chiral column chromatography, chiral analytical agents and the like.

The starting materials used in the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials can be purchased from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

In one embodiment, the method disclosed herein may include using solid phase peptide synthesis technology to construct a 31-amino acid peptide backbone to provide an intermediate ( III-A ). The peptide backbone includes two PEG ₂ amide linkers. The method includes an amide coupling reaction between the amine of the terminal PEG ₂ amide of the intermediate ( III-A ) and a suitably substituted carboxylic acid ( III-B ) to provide a resin-bound intermediate ( III-C ). In one embodiment, the method involves subjecting the intermediate ( III-C ) to hydrolysis under acidic conditions, followed by purification to obtain the final product ( III ) ( Scheme 2 ). Scheme 2 :

The above example schemes are provided to guide the reader, and generally represent example methods for preparing the compounds covered herein. In addition, other methods for preparing the compounds described herein will be readily apparent to one of ordinary skill in the art in view of the following reaction schemes and examples. Unless otherwise indicated, all variables are defined above. Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises one or more permeability enhancers. In some embodiments, the pharmaceutical composition further comprises an excipient. In some embodiments, the pharmaceutical composition is suitable for oral administration.

Compounds that are usually not orally administered due to poor oral bioavailability can be formulated with permeability enhancers. Permeability enhancers can increase the absorption of active pharmaceutical ingredients 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 a weight percentage within the range defined by any two of the foregoing weight percentages. For example, in some embodiments, the permeability enhancer is present in the pharmaceutical composition at a weight percentage of about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 50% to about 75%, about 60% to about 75%, or about 70% to about 75%. In some embodiments, the permeability enhancer is sodium sapolisar (i.e., sodium 8-(2-hydroxybenzamido)octanoate or "SNAC"), sodium caproate (C10), or a combination thereof. In some embodiments, the permeability enhancer is SNAC. In other embodiments, the permeability enhancer is C10. In yet other embodiments, the permeability enhancer is a combination of SNAC and C10. In some embodiments, the permeability enhancer is lauryl-L-carnitine chloride (LCC). In some embodiments, the permeability enhancer is Labrasol®. Labrasol® contains PEG-8 monoesters and diesters of caprylic acid (C8) and capric acid (C10), and minor portions of monoglycerides, diglycerides, and triglycerides.

In some embodiments, the amount of a permeability enhancer in a pharmaceutical composition 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, 260 mg, 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 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 In some embodiments, the amount of the permeability enhancer in the pharmaceutical compositions described herein is about 1 mg to about 1000 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 400 mg to about 800 mg, about 400 mg to about 600 mg, or about 500 mg to about 750 mg. In some embodiments, the amount of permeability enhancer in the pharmaceutical compositions described herein is greater than 300 mg, greater than 350 mg, greater than 400 mg, 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.

In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) in the pharmaceutical composition is 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%, 3.5%, 4.6%, 5.8%, 6.9%, 7.1%, 8.1%, 9.2%, 10.4%, 11.3%, 12.5%, 13. %, 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 more, or a weight percentage within a range defined by any two of the foregoing values. In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is in the range of about 1.0% to about 5.0%, about 2.0% to about 4.0%, about 3.0% to about 4.0%, or about 3.5% to about 4.0%. In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is about 3.6% by weight.

In some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-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, 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 foregoing values. For example, in some embodiments, the amount of the compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) in the pharmaceutical composition is about 1 mg to about 30 mg, about 5 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg or about 20 mg to about 30 mg.

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 foregoing values. For example, in some embodiments, the amount of compound 4 in the pharmaceutical composition is about 1 mg to about 30 mg, about 5 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg, or about 20 mg to about 30 mg.

In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 5 mg to about 30 mg and the amount of SNAC is about 350 mg to about 1000 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 10 mg to about 30 mg and the amount of SNAC is about 400 mg to about 800 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 15 mg to about 25 mg and the amount of SNAC is about 450 mg to about 750 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 20 mg and the amount of SNAC is about 450 mg. In some embodiments, the amount of Compound 4 in the pharmaceutical composition is about 25 mg and the amount of SNAC is about 500 mg.

In some embodiments, the mass ratio of the permeability enhancer to the compound of formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-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, 19:2, 20:3, 21:4, 22:5, 23:6, 24:7, 25:8, 26:9, 27:10, 28:11, 29:12, 30:13, 31:14, 32:15 :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 the range defined by any two of the foregoing 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), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) in the pharmaceutical composition is about 1:1 to about 50:1, about 10:1 to about 25:1, about 15:1 to about 25:1 or about 20:1 to about 25:1.

In some embodiments, the pharmaceutical compositions described herein include one or more additional pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" as used herein includes but is not limited to solvents, dispersants, coatings, antimicrobial agents, adjuvants, isotonic agents, and absorption delaying agents and the like. In some embodiments, 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 carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; gelatin; talc; binders such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol, cellulose and cellulose derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl 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, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers and surfactants such as TWEENS; humectants such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives such as benzalkonium chloride chloride), PHMB, chlorobutanol, thimerosal, phenylmercuric and phenylmercuric nitrate; tonicity regulators such as sodium chloride, potassium chloride, mannitol and glycerol; vehicles such as polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose and hydroxyethylcellulose; and pyrogen-free water. In some embodiments, the pharmaceutically acceptable formulation is selected based on the route of administration and may include solid or liquid fillers, binders, diluents, hydrotropes, surfactants and encapsulating materials. For example, in the case of intravenous administration, the excipient may include gelatin; carbohydrates such as dextrose, mannitol and polydextrose; and antioxidants such as sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde, sulfoxylate, thiourea and EDTA. In some embodiments, pharmaceutically acceptable excipients include antimicrobial agents such as phenylmercuric nitrate, thimerosal, benzethonium chloride, benzothiocarbamide, phenol, cresol and chlorobutanol. Additional examples of suitable pharmaceutically acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Compositions, PDA J Pharm Sci 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 Sci and Tech 2011 , 65 287-332, each of which is incorporated herein by reference in its entirety.

In some embodiments, the pharmaceutical compositions described herein may include a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) and SNAC. In some of these embodiments, the pharmaceutical composition may further include microcrystalline cellulose, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof.

In some embodiments, the pharmaceutical composition described herein may include a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) and C10. In some of these embodiments, the pharmaceutical composition may further include microcrystalline cellulose, polyvinyl pyrrolidone (PVP), polyvinyl pyrrolidone-vinyl acetate copolymer (PVP-VA), magnesium stearate or a combination thereof.

In some embodiments, the pharmaceutical compositions described herein may include a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) and a combination of SNAC and C10. In some of these embodiments, the pharmaceutical composition may further include microcrystalline cellulose, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof.

In some embodiments, the pharmaceutical compositions described herein may include microcrystalline cellulose in an amount within a range defined by 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, or any two of the foregoing percentages. For example, the pharmaceutical compositions described herein may comprise about 10% to 50% by weight, 10% to 40% by weight, 10% to 30% by weight, 15% to 30% by weight, 15% to 25% by weight, or 15% to 20% by weight of microcrystalline cellulose. In some embodiments, the pharmaceutical compositions described herein comprise about 19.4% microcrystalline cellulose by weight.

In some embodiments, the pharmaceutical compositions described herein may include polyvinylpyrrolidone in an amount within a range defined by 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 any two of the foregoing percentages. For example, the pharmaceutical compositions described herein may include about 1.0% to about 5.0% by weight, about 1.0% to about 4.0% by weight, about 1.0% to about 3.0% by weight, about 1.5% to about 3.0% by weight, about 1.5% to about 2.5% by weight, or about 1.5% to about 2.0% by weight of polyvinylpyrrolidone. In some embodiments, the pharmaceutical compositions described herein include about 1.9% polyvinylpyrrolidone by weight.

In some embodiments, the pharmaceutical compositions described herein may include magnesium stearate in an amount within a range defined by 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 any two of the foregoing percentages. For example, the pharmaceutical compositions described herein may include about 1.0% to about 5.0% by weight, about 1.0% to about 4.0% by weight, about 1.0% to about 3.0% by weight, about 1.5% to about 3.0% by weight, about 1.5% to about 2.5% by weight, or about 1.5% to about 2.0% by weight of magnesium stearate. In some embodiments, the pharmaceutical compositions described herein include about 2.3% magnesium stearate by weight.

In some embodiments, the pharmaceutical compositions described herein may include a disintegrant. In some embodiments, the pharmaceutical compositions may include 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 any two of the foregoing percentages. For example, the pharmaceutical compositions described herein may include about 1.0% to about 5.0% by weight, about 1.0% to about 4.0% by weight, about 1.0% to about 3.0% by weight, about 1.5% to about 3.0% by weight, about 1.5% to about 2.5% by weight, or about 1.5% to about 2.0% by weight of disintegrant. In some embodiments, the pharmaceutical compositions described herein include about 1.9% disintegrant by weight. In some embodiments, the disintegrant may be sodium cross-linked carboxymethylcellulose (e.g., primellose, AcDiSol). In some embodiments, the disintegrant may be sodium alginate. In some embodiments, the disintegrant may be cross-linked povidone. In some embodiments, the disintegrant may be sodium starch glycolate.

In some embodiments, the pharmaceutical compositions described herein may include about 1.0% to about 5.0% by weight of a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 50% to about 80% by weight of saprolidine sodium; about 10% to about 30% by weight of microcrystalline cellulose; about 1.0% to about 3.0% by weight of polyvinylpyrrolidone; and about 1.0% to about 3.0% by weight of magnesium stearate. In some of these embodiments, the pharmaceutical composition comprises: about 3.6% by weight of a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 72.7% by weight of saprolidine sodium; about 19.4% by weight of microcrystalline cellulose; about 1.9% by weight of polyvinylpyrrolidone; and about 2.3% by weight of magnesium stearate. In other embodiments of this invention, the pharmaceutical composition comprises: about 3.2% by weight of a compound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 71.1% by weight of sodium saprolidone; about 21.1% by weight of microcrystalline cellulose; about 2.1% by weight of polyvinylpyrrolidone; and about 2.6% by weight of magnesium stearate.

The pharmaceutical composition comprises a therapeutically effective dose or amount of a compound of formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c). The term "therapeutically effective dose" or "therapeutically effective amount" as used herein depends on the individual being treated and the disease condition, the severity of the disease, the mode and schedule of administration, and the judgment of the prescribing physician. In some embodiments, the therapeutically effective dose may be a daily dose of about 0.0125 mg/kg body weight to about 120 mg/kg body weight or more, about 0.025 mg/kg body weight or less to about 70 mg/kg body weight, about 0.05 mg/kg body weight to about 50 mg/kg body weight, or about 0.075 mg/kg body weight to about 10 mg/kg body weight. Thus, for administration to a 70 kg individual, the dose range would be about 0.88 mg/day to about 8000 mg/day, about 1.8 mg/day or less to about 7000 mg/day or more, about 3.6 mg/day to about 6000 mg/day, about 5.3 mg/day to about 5000 mg/day, or about 11 mg/day to about 3000 mg/day. In some embodiments, the therapeutically effective amount is 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, 0.14 mg/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, 100 mg/kg, 200 mg/kg, 500 mg/kg In some embodiments, the therapeutically effective amount is about 0.01 mg/kg to about 5 mg/kg. In some embodiments, the therapeutically effective amount is about 0.05 mg/kg to about 1 mg/kg. In some embodiments, the therapeutically effective amount is about 0.15 mg/kg to about 0.25 mg/kg.

The pharmaceutical composition can be administered using a route of administration including, but not limited to, enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intrapulmonary, vaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration is selected from the group consisting of enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered orally.

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

In some embodiments, the pharmaceutical composition is administered to a subject that is a mammal. In some such embodiments, the pharmaceutical composition is administered to a subject that is a human. Methods of Preparing Dosage Formulations

The pharmaceutical composition can be formulated into an oral dosage form. In some embodiments, the oral dosage form can be a tablet. In some of these embodiments, the tablet can be enteric-coated.

In some embodiments, a dry granulation method can be used to prepare tablets. In some embodiments, the method comprises the following steps: (i) combining a permeability enhancer and magnesium stearate to form a first granule; (ii) combining microcrystalline cellulose, a compound of formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (III), (III-a), (III-b) or (III-c) and polyvinylpyrrolidone to form a second granule; (iii) combining the first granule and the second granule to form a mixture; (iv) adding magnesium stearate to the mixture to form a third granule; and (v) pressing the third granule into a tablet. In some embodiments, the permeability enhancer is SNAC. In some embodiments, the compound is Compound 4.

In some embodiments, a wet granulation method can be used to prepare tablets. In some embodiments, the method comprises the following steps: (i) combining microcrystalline cellulose and a compound disclosed herein in a first container; (ii) combining polyvinylpyrrolidone and water in a second container; (iii) adding the contents of the first container to the second container to form wet granules; (iv) drying the wet granules to form dry granules; (v) combining the dry granules with magnesium stearate; and (vi) pressing the resulting mixture of step (v) into granules.

In some embodiments, tablets can be prepared by a spray drying dispersion method. For example, in some embodiments, the compounds disclosed herein can be combined with polymers including, but not limited to, hydroxypropylmethylcellulose acetate succinate M type (HPMCAS-M); hydroxypropylmethylcellulose acetate succinate L type (HPMCAS-L); polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA64); Eudragit® L100 or any combination thereof in a solvent to form a solution for spray drying. The solution is then dried with a heated nitrogen stream and collected using a cyclone separator. The spray dried material is then combined with microcrystalline cellulose, magnesium stearate, and additional fillers and disintegrants, and pressed into tablets.

In some embodiments, tablets can be prepared by a wet granulation process. In some embodiments, the compounds disclosed herein are combined with microcrystalline cellulose and hydroxypropyl cellulose. In some embodiments, the mixture of materials is wet granulated using purified water as the granulation liquid and then dried. Thereafter, the dry granules are ground and blended. A lubricant (e.g., magnesium stearate) can then be added to the blended mixture, and the resulting mixture is compressed into tablets. Treatment Methods

The pharmaceutical composition disclosed herein includes a compound that can effectively act as a GIP/GLP1 dual receptor agonist or its tautomer and/or its pharmaceutically acceptable salt. The pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and one or more pharmaceutically acceptable diluents.

Some embodiments provide a method for preventing, treating or ameliorating one or more fatty liver diseases in an individual. In some embodiments, the method comprises administering one or more of the pharmaceutical compositions disclosed herein to an individual in need thereof.

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

In some embodiments, the methods of administering one or more of the pharmaceutical compositions disclosed herein result in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom.

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

In some embodiments, the methods of administering one or more of the pharmaceutical compositions disclosed herein result in a reduction in the level of extracellular matrix protein in one or more tissues of the subject.

In some embodiments, the methods of administering one or more of the pharmaceutical compositions disclosed herein result in a decrease in collagen levels in one or more tissues of the subject.

In some embodiments, the methods of administering one or more of the pharmaceutical compositions disclosed herein result in a decrease in the level of type I, type Ia, or type III collagen in one or more tissues of the subject.

Some embodiments provide a method for preventing, treating or ameliorating one or more of liver fibrosis, kidney fibrosis, bile fibrosis, pancreatic fibrosis, nonalcoholic fatty hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis in an individual. In some embodiments, the method comprises administering one or more of the pharmaceutical compositions disclosed herein to an individual in need thereof.

Some embodiments provide a method for preventing, treating or ameliorating one or more of nonalcoholic fatty hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis or primary biliary cirrhosis in an individual. In some embodiments, the method comprises administering one or more of the pharmaceutical compositions disclosed herein to an individual in need thereof.

Some embodiments provide a method for preventing, treating or ameliorating one or more metabolic diseases or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more of the pharmaceutical compositions disclosed herein to an individual in need thereof.

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

Some embodiments include co-administration of pharmaceutical compositions and/or compounds described herein, or pharmaceutically acceptable salts thereof, with additional agents. "Co-administration" means that two or more agents can be present 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, combined administration is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered by the same route, such as orally. In another embodiment, the agents are administered by different routes, such as subcutaneously, orally, and intravenously.

To further illustrate the present disclosure, the following examples are included. Of course, the examples should not be construed as specifically limiting the present disclosure. Variations of these examples within the scope of the claims are within the skill of the art and are considered to be within the scope of the present disclosure as described and claimed herein. The reader should recognize that a skilled artisan who is familiar with the present disclosure and is skilled in the art does not need the detailed examples to be able to prepare and use the present disclosure. The following examples will further describe the present disclosure and are for illustrative purposes only and should not be construed as limiting. Example General Procedure

It will be apparent to the skilled artisan that methods for preparing promotors and functional groups relevant to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to use variants which are known per se to those of ordinary skill in the art but are not mentioned in more detail. The skilled artisan with reference to the literature and the present disclosure is well equipped to prepare any of the compounds.

It will be appreciated that the skilled artisan in organic chemistry techniques can readily perform the manipulations without further guidance, i.e., it is well within the scope and practice of the skilled artisan to perform such manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions (both electrophilic and nucleophilic), etherifications, esterifications and saponifications, and the like. Such manipulations are described in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in its entirety), and the like. Unless otherwise specified, all intermediates disclosed herein may be used without further purification.

Skilled technicians should readily appreciate that certain reactions are best performed when shielding or protecting other functional groups in the molecule, thereby avoiding any undesirable side reactions and/or increasing the reaction yield. Skilled technicians typically utilize protecting groups to achieve this increased yield or to avoid undesirable reactions. Such reactions are found in the literature and are also fully within the scope of skilled technicians. Examples of many such operations can be found in, for example, T. Greene and P. Wuts Protecting Groups in Organic Synthesis, the 4th edition, John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

The following example schemes are provided to guide the reader and represent preferred methods for preparing the compounds exemplified herein. These methods are not limiting, and it will be apparent that other approaches can be used to prepare these compounds. This method specifically includes solid phase-based chemical reactions, including combinatorial chemical reactions. Skilled technicians are fully prepared to prepare these compounds by those methods given in the literature and this disclosure. The compound numbers used in the synthetic schemes described below are only meant for those specific schemes and should not be interpreted as the same numbers in other parts of this application or confused with those numbers.

The trademarks used herein are examples only and reflect the illustrative material used in the present disclosure. A skilled artisan should recognize variations in expected batches, manufacturing processes, and the like. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but are merely illustrative of how a skilled artisan may choose to implement one or more of the embodiments of the present disclosure.

The following abbreviations have the specified meanings: λz = λz (apparent elimination rate constant) AUC = area under the plasma concentration versus time curve AUC _last = AUC from time 0 to the time of the last quantifiable concentration AUC _inf = AUC extrapolated from time 0 to infinity Aib = aminoisobutyric acid BLQ = below limit of quantification C _max = maximum observed concentration occurring at T _max CL/F = systemic clearance after extravascular administration CV% = coefficient of variation in percent DMF = dimethylformamide HPLC = high performance liquid chromatography LC-MS/MS = liquid chromatography-mass spectrometry LLOQ = lower limit of quantification N = number of samples with a value NMR = nuclear magnetic resonance PCC = chloropyridinium chromate PEG = polyethylene glycol PK = pharmacokinetics PO = oral administration PVP = Polyvinylpyrrolidone PVP-VA = Polyvinylpyrrolidone-vinyl acetate copolymer R ² = Regression correlation coefficient T _max = Time of C _max appearance t _1/2 = Half-life V _z /F = Volume of distribution after extravascular administration

The following example schemes are provided to guide the reader and generally represent example methods for preparing the compositions provided herein. In addition, in view of the following reaction schemes and examples, other methods for preparing the compositions described herein will be readily apparent to one of ordinary skill in the art. Unless otherwise indicated, all variables are defined above. Example 1 Synthesis of Intermediate 1 (INT 1)

Methyl 7-bromoheptanoate is reacted with triphenylphosphine to form the corresponding phosphonium bromide salt. The thoroughly dried salt is treated with one equivalent of NaHMDS to produce a dipole which reacts immediately with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol by a Wittig reaction. The resulting olefin is purified by silica gel chromatography to give a pale yellow oil. The olefin is hydrogenated and the bromoester can be wet triturated with methanol to give an off-white solid. The bromide displaces diphenylmethyl phosphite in a weak base to give the phosphonate which is purified by chromatography. Hydrolysis of the methyl ester in LiOH provides the desired INT-1 which can be precipitated from aqueous HCl at pH 2. The final product can be obtained in 10-100 g batches with HPLC purity >99% with satisfactory MS ( m/z 559.3) and NMR data. The key ³¹ P signal of the phosphonate of INT-1 appears at 33.3 ppm in DMSO -d ₆ . Example 2 Synthesis of peptide main chain

Each 39-amino acid peptide backbone was constructed using Fmoc solid phase peptide synthesis technology with diimide, HATU or HBTU activation for amide bond synthesis on Rink resin. Reagent selection varied based on the properties of the amino acid being linked. Lysine at lysine-16, lysine-19 or lysine-20 was protected with a Dde protecting group. After the entire backbone was completed, the aminoalkyl side chain of lysine-16, lysine-19 or lysine-20 was extended with two PEG ₂ amide linkers followed by an isoglutamine residue. Specifically, the Dde group on the lysine was cleaved. The deprotected amine group on the lysine was then coupled to a Boc-protected PEG ₂ group having the following structure:

After the Boc group is removed, the second PEG ₂ is added. Finally, after the Boc group of the second PEG ₂ is removed, the Fmoc-protected isoglutamic acid ester is coupled to the second PEG _2. The Fmoc group is then removed.

The entire main chain and side chains on lysine-16, lysine-19 or lysine-20 were synthesized before coupling with INT-1 . Therefore, the following intermediates were obtained before coupling with INT-1 .

The aminoalkyl side chain of lysine-16 was elongated as indicated above to prepare peptide 13BB .

The aminoalkyl side chain of the lysine-20 side chain was extended to prepare peptides 14BB , 15BB , 16BB , 17BB , 18BB , 19BB , 21BB , and 22BB .

The side chain of lysine-19 was extended to prepare peptide 20BB . Example 3 Synthesis of Compound 13

Peptide 13BB was coupled to INT-1 to give the resin-bound protected compound 13. Coupling to INT-1 was achieved by coupling INT-1 to the _NH2 group of the isoglutamine of lysine-16 in peptide 13BB using amide coupling conditions. Cleavage of the resin, protecting groups on the peptide chain, and benzyl esters was performed with TFA to provide compound 13, which was then purified by reverse phase HPLC. Purity was 95.0% by RP-HPLC. The peptide content was 96.0% and produced a satisfactory amino acid analysis. LCMS analysis showed a molecular weight of 4849.4 g/mol. Example 4 Synthesis of Compound 14

Compound 14 was prepared from peptide 14BB and INT-1 in a manner similar to the preparation of compound 13 . Example 5 Synthesis of Compound 15

Compound 15 was prepared from peptide 15BB and INT-1 in a manner similar to the preparation of compound 13 . Example 6 Synthesis of Compound 16

Compound 16 was prepared from peptide 16BB and INT-1 in a manner similar to the preparation of compound 13 . Example 7 Synthesis of Compound 17

Compound 17 was prepared from peptide 17BB and INT-1 in a manner similar to the preparation of compound 13 . Example 8 Synthesis of Compound 18

Compound 18 was prepared from peptide 18BB and INT-1 in a manner similar to the preparation of compound 13 . Example 9 Synthesis of Compound 19

Compound 19 was prepared from peptide 19BB and INT-1 in a manner similar to the preparation of compound 13 . Example 10 Synthesis of Compound 20

Compound 20 was prepared from peptide 20BB and INT-1 in a manner similar to the preparation of compound 13 . Example 11 Synthesis of Compound 21

Compound 21 was prepared from peptide 21BB and INT-1 in a manner similar to the preparation of compound 13 . Example 12 Synthesis of Compound 22

Compound 22 was prepared from peptide 22BB and INT-1 in a manner similar to the preparation of compound 13 . Example 13 Synthesis of Compound 23

Compound 23 was prepared in a manner similar to the preparation of compound 13 from a peptide backbone similar to that described herein and INT-1 . Example 14 Synthesis of Intermediate 2 (INT 2)

Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to generate a dipole which reacts immediately with the aldehyde from PCC oxidation of 10-bromo-1-decanol in a Wittig reaction. The resulting bromoalkene is hydrogenated and treated with diphenylmethyl phosphite in a weak base to form the phosphonate. Hydrolysis of the carboxylic acid methyl ester provides the desired INT 2 with a terminal carboxylic acid and diphenylmethyl phosphonate. Synthesis of Intermediate 2A (INT 2A)

Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to generate a dipole which reacts immediately with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol in a Wittig reaction. The resulting bromoalkene is hydrogenated and treated with diphenylmethyl phosphite in a weak base to form the phosphonate. Hydrolysis of the carboxylic acid methyl ester provides the desired INT 2A with a terminal carboxylic acid and diphenylmethyl phosphonate. Synthesis of Intermediate 3 (INT 3)

Coupling of octadecane dioic acid with benzyl alcohol using EDC·HCl and DMAP in THF afforded INT 3 as the monobenzyl ester. Synthesis of Intermediate 4 (INT 4)

Tributyl 4-hydroxybutyrate is subjected to Swern oxidation to give the aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form the imine. Addition of the lithium salt of diethyl phosphite in THF produces the α-aminophosphonate, which is subjected to hydrogenation to cleave the N-alkyl group and provide INT 4 with a free primary amine, a tertiary butyl ester, and a diethyl phosphonate. The optical purity of INT 4 is confirmed to be at least 96% by ¹ H-NMR via Mosher's amide analysis. Synthesis of Intermediate 5 (INT 5)

INT 2 was coupled with 1-tert-butyl ester of D-glutamine in the presence of HATU and triethylamine in DMF to provide INT 5 . Synthesis of Intermediate 5A (INT 5A)

INT 2A was coupled with 1-tert-butyl ester of D-glutamine in the presence of HATU and triethylamine in DMF to provide INT 5A . Synthesis of Intermediate 6 (INT 6)

INT 3 was coupled with INT 4 in DMF in the presence of HATU and triethylamine to prepare a new amide linkage. The ethyl phosphonate was cleaved with TMS-Br to produce the free phosphonic acid. Reesterification with a large excess of the benzyl ester of N,N'-diisopropylcarbamimidic acid provided the corresponding diphenylmethyl phosphonate. The tertiary butyl ester was cleaved with TFA to provide INT 6 . Synthesis of Intermediate 7 (INT 7)

INT 2 was coupled with INT 4 in the presence of HATU and triethylamine in DMF to provide a new amide linkage. Cleavage of the benzyl phosphonate and the ethyl phosphonate with TMS-Br produced two free phosphonic acids. Re-esterification with a large excess of the benzyl ester of N,N'-diisopropylaminoimidic acid provided the corresponding tetraphenylmethyl diphosphonate. Cleavage of the tertiary butyl ester with TFA gave INT 7 . Example 15 Synthesis of the common peptide backbone

The 31-amino acid peptide backbone was constructed using solid phase peptide synthesis techniques utilizing diimide, HATU or HBTU activation for amide bonded synthesis on Linker resin. Reagent selection varied based on the nature of the amino acid being attached. The R group of lysine-20 was extended with two PEG ₂ amide linkers. The entire backbone was synthesized on resin prior to coupling INT 5 , INT 5A , INT 6 or INT 7 to the amino terminus of the lysine-bound linker. Example 16 Synthesis of Compound 24

The peptide backbone was coupled with INT 5 to give the resin-bound protected compound 24. Cleavage of the protecting groups on the resin, peptide chain and benzyl ester of INT 5 with TFA provided compound 24 which was purified by HPLC. Example 17 Synthesis of Compound 25

The peptide backbone was coupled with INT 6 to give the resin-bound protected compound 25. Cleavage of the protecting groups on the resin, peptide chain and benzyl ester of INT 6 with TFA provided compound 25 which was purified by HPLC. Example 18 Synthesis of Compound 26

The peptide backbone was coupled with INT 7 to give the resin-bound protected compound 26. Cleavage of the protecting groups on the resin, peptide chain and benzyl ester of INT 7 with TFA provided compound 26 which was purified by HPLC. Example 19 Synthesis of Compound 27

The peptide backbone was coupled with INT 5A to give the resin-bound protected compound 27. Cleavage of the protecting groups on the resin, peptide chain and benzyl ester of INT 5A with TFA provided compound 27 which was purified by HPLC. Example 20 Pharmacokinetic study in dogs

The pharmacokinetic properties of selected compounds disclosed herein were assessed following administration of an oral dosage form (tablet) to male beagle dogs. Animals were acclimated to the study room for a minimum of 3 days prior to initial dosing. Dogs (N=3) received a single oral tablet dose containing the compound. Plasma samples were collected prior to dosing the dogs and at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours after dosing. The compositions provided to the dogs are shown in Table 1. Table 1 - Tablet Formulations for Canine Studies Components Mass(mg) Total percentage Compound 20 3.3 Sodium Sapolinate(SNAC) 300 50 Microcrystalline Cellulose 258 43.0 Polyvinylpyrrolidone K90 10 1.7 Magnesium stearate 12 2.0 Total 600 100%

Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis capabilities (linear trapezoidal rule for AUC calculations). Nominal dose values and sampling times were used for calculations. _Cmax and corresponding _Tmax values were determined by direct assessment of concentration versus time data. All AUC calculations were performed using the linear trapezoidal rule. Terminal rate constants (λz, λz) were determined when the data permitted. The value of λz was calculated by the slope of the regression line of natural log-transformed concentration versus time, where the data points were randomly distributed around a straight line, at least three data points after _Cmax were used in the regression, the correlation coefficient ( ^R2 ) of the regression was >0.90, and the time period (span) of the regression was determined to be at least 2.0 times greater than the calculated half-life itself.

In order to optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC _INF values were calculated as: AUC _last + (C _last / λz). Cl/F values were calculated as dose/AUC _INF and Vz/F values were calculated as dose/(AUC _INF * λz). If the percentage of extrapolated area of AUC _INF was >20%, AUC _INF , Vz/F and CL/F values were not reported. The terminal half-life (t _1/2 ) was calculated as: ln(2) / λz. If the span defining the λ z line was less than 2 times that of t _1/2 , the t _1/2 value was marked with an asterisk (*) and removed from the summary statistics. Administration of Compound 4, Compound Z and Compound 24 to beagle dogs provided the plasma concentration versus time curves shown in Figure 1. The data showed that the mean plasma concentrations of Compound 4 and Compound 24 were higher than the mean plasma concentrations of similar formulations of peptide Compound Z having the following structure and 300 mg SNAC: , and both Compound 4 and Compound 24 were detected in plasma 144 hours after administration. Example 21 Pharmacokinetic evaluation after oral administration

The pharmacokinetic properties of various peptide compounds disclosed herein were evaluated after administration of oral dosage forms (tablets) to male beagle dogs. The test compounds were formulated with varying amounts of sapolisar sodium (SNAC). Animals were acclimated to the study room for at least 3 days prior to initial dosing. Dogs (N=6) received oral tablet doses containing the test compounds. Plasma samples were collected on day 1 before dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 24 hours after dosing. On day 3, samples were collected only before dosing. On day 5, plasma samples were collected prior to dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours after dosing. The formulations and dosing groups provided to the dogs are shown in Table 2. Table 2 - Dosing Groups Used in Dog Studies Dosage group Number of animals Compound/ SNAC (mg) Dosage of compound ( mg/ tablet) 1 6 Compound Z / 300 mg 20 2 6 Compound 24 /200 mg 20 3 6 Compound 24 /300 mg 20 4 6 Compound 24 / 450 mg 20 5 6 Compound 27 /200 mg 20 6 6 Compound 27 /300 mg 20 7 6 Compound 27 / 450 mg 20 8 6 Compound 4 / 200 mg 20 9 6 Compound 4 / 300 mg 20 10 6 Compound 4 /450 mg 20

Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis capabilities (linear trapezoidal rule for AUC calculations). Nominal dose values and sampling times were used for calculations. _Cmax and corresponding _Tmax values were determined by direct assessment of concentration versus time data. All AUC calculations were performed using the linear trapezoidal rule. Terminal rate constants (λz, λz) were determined when the data permitted. The value of λz was calculated by the slope of the regression line of natural log-transformed concentration versus time, where the data points were randomly distributed around a straight line, at least three data points after _Cmax were used in the regression, the correlation coefficient ( ^R2 ) of the regression was >0.90, and the time period (span) of the regression was determined to be at least 2.0 times greater than the calculated half-life itself.

To optimize the reliability of the identified terminal phase (λz), data points used to define λz were manually selected. AUC _INF values were calculated as: AUC _last + (C _last / λz). Cl/F values were calculated as dose/AUC _INF and Vz/F values were calculated as dose/(AUC _INF * λz). AUC _INF , Vz/F, and CL/F values were not reported if the percentage of extrapolated area from AUC _INF was >20%. The terminal half-life (t _1/2 ) was calculated as: ln(2) / λz. If the span defining the λ z line was less than 2 times that of t _1/2 , the t _1/2 value was marked with an asterisk (*) and removed from the summary statistics.

Table 3 below discloses the average pharmacokinetic data obtained from each experiment with each of Cohorts 1 to 10. Various ratios of SNAC to peptide compound were tested. For Compound 24 (Cohorts 2 to 4), Compound 27 (Cohorts 5 to 7), and Compound 4 (Cohorts 8 to 10), exposure increased with increasing SNAC content over the tested range of 200 mg to 450 mg. Table 3 - Pharmacokinetic Data of Peptide Compound Dosing Study in Dogs Group Days _Tmax (h) C _max (ng/mL) AUC _last (h*ng/mL) AUC _INF (h*ng/mL) t _1/2 (h) 1 1 3.13 8.25 222 222 -- 5 0.917 29.5 779 1850 77.0 2 1 0.792 40.2 1080 1080 -- 5 29.1 83.9 2780 7110 66.6 3 1 2.00 315 8350 8350 -- 5 1.63 187 5550 12400 73.6 4 1 1.42 736 20600 20600 -- 5 1.13 408 11800 21700 56.8 5 1 1.46 22.4 775 775 -- 5 1.38 34.3 1230 3980 97.6 6 1 196 66.4 1880 1880 -- 5 2.17 270 8190 17600 69.3 7 1 1.83 804 21900 21900 -- 5 1.13 799 24300 51200 59.6 8 1 1.71 23.0 815 815 -- 5 1.21 41.7 1340 4420 88.6 9 1 1.13 50.1 1550 1550 -- 5 1.17 99.2 3080 8410 92.2 10 1 1.96 57.3 1800 1800 -- 5 0.667 245 6630 15200 86.7 Example 22 Pharmacokinetic evaluation after oral administration

The pharmacokinetic properties of various peptide compounds disclosed herein were evaluated after administration of oral dosage forms (tablets) to male beagle dogs. The test compounds were formulated with 450 mg of sapolisar sodium (SNAC). The animals were acclimated to the study room for at least 3 days prior to initial dosing. Dogs (N=6) received a single oral tablet dose containing the test compound. Plasma samples were collected on day 1 before dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 24 hours after dosing. On day 3, samples were collected only before dosing. On day 5, plasma samples were collected prior to dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours after dosing. The formulations and dosing groups provided to the dogs are shown in Table 4. Table 4 - Dosing Groups for Dog Studies Dosage group Number of animals Compound/ SNAC (mg) Dosage of compound ( mg/ tablet) 1 6 Compound 4 / 450 mg 20 2 6 Compound 15 / 450 mg 20 3 6 Compound 18 / 450 mg 20 4 6 Compound 23 / 450 mg 20

Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis capabilities (linear trapezoidal rule for AUC calculations). Nominal dose values and sampling times were used for calculations. _Cmax and corresponding _Tmax values were determined by direct assessment of concentration versus time data. All AUC calculations were performed using the linear trapezoidal rule. Terminal rate constants (λz, λz) were determined when the data permitted. The value of λz was calculated by the slope of the regression line of natural log-transformed concentration versus time, where the data points were randomly distributed around a straight line, at least three data points after _Cmax were used in the regression, the correlation coefficient ( ^R2 ) of the regression was >0.90, and the time period (span) of the regression was determined to be at least 2.0 times greater than the calculated half-life itself.

To optimize the reliability of the identified terminal phase (λz), data points used to define λz were manually selected. AUC _INF values were calculated as: AUC _last + (C _last / λz). Cl/F values were calculated as dose/AUC _INF and Vz/F values were calculated as dose/(AUC _INF * λz). AUC _INF , Vz/F, and CL/F values were not reported if the percentage of extrapolated area from AUC _INF was >20%. The terminal half-life (t _1/2 ) was calculated as: ln(2) / λz. If the span defining the λ z line was less than 2 times that of t _1/2 , the t _1/2 value was marked with an asterisk (*) and removed from the summary statistics.

Table 5 below discloses the average pharmacokinetic data obtained from each experiment with each of Cohorts 1 to 4. Good drug exposure was achieved for all tested compounds. Table 5 - Pharmacokinetic Data of Peptide Compound Dosing Study in Dogs Group Days C _max (ng/mL) AUC _last (h•ng/mL) _Tmax (h) 1 1 83.4 2840 0.75 5 103 4360 1.80 2 1 154 4680 0.950 5 200 11800 2.1 3 1 53.6 1280 1.17 5 53.3 1610 1.92 4 1 68.2 1990 1.38 5 131 6200 1.65 Example 23 Pharmacokinetic evaluation of compound 4 after oral administration

The pharmacokinetic properties of Compound 4 were evaluated after administration of an oral dosage form (20 mg Compound 4 per tablet) to male beagle dogs. The test compounds were formulated with varying amounts of sapolisar sodium (SNAC) or C10. Animals were acclimated to the study room for a minimum of 3 days prior to initial dosing. Dogs (N=5) received oral tablet doses containing the test compound. Plasma samples were collected on day 1 before dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 24 hours after dosing. On day 3, samples were collected only before dosing. On day 5, plasma samples were collected prior to dosing the dogs and then at 15 min, 30 min, 45 min and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours after dosing. The formulations and dosing groups provided to the dogs are shown in Table 6. Table 6 - Dosing Groups for Oral Administration of Compound 4 in Dogs Dosage group Number of animals Compound 4 (mg) SNAC (mg) C10 (mg) Enteric coating 1 5 20 0 0 no 2 5 20 0 75 no 3 5 20 0 75 yes 4 5 20 0 150 no 5 5 20 0 150 yes 6 5 20 0 300 no 7 5 20 0 300 yes 8 5 20 300 0 no 9 5 20 700 0 no 10 5 20 450 0 no 11 5 20 450 0 yes 12 5 20 450 75 no 13 5 20 450 75 yes 14 5 20 450 150 no 15 5 20 450 150 yes 16 5 20 450 300 no 17 5 20 450 300 yes

Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis capabilities (linear trapezoidal rule for AUC calculations). Nominal dose values and sampling times were used for calculations. _Cmax and corresponding _Tmax values were determined by direct assessment of concentration versus time data. All AUC calculations were performed using the linear trapezoidal rule. Terminal rate constants (λz, λz) were determined when the data permitted. The value of λz was calculated by the slope of the regression line of natural log-transformed concentration versus time, where the data points were randomly distributed around a straight line, at least three data points after _Cmax were used in the regression, the correlation coefficient ( ^R2 ) of the regression was >0.90, and the time period (span) of the regression was determined to be at least 2.0 times greater than the calculated half-life itself.

To optimize the reliability of the identified terminal phase (λz), data points used to define λz were manually selected. AUC _INF values were calculated as: AUC _last + (C _last / λz). Cl/F values were calculated as dose/AUC _INF and Vz/F values were calculated as dose/(AUC _INF * λz). AUC _INF , Vz/F, and CL/F values were not reported if the percentage of extrapolated area from AUC _INF was >20%. The terminal half-life (t _1/2 ) was calculated as: ln(2) / λz. If the span defining the λ z line was less than 2 times that of t _1/2 , the t _1/2 value was marked with an asterisk (*) and removed from the summary statistics.

Table 7 below discloses the average pharmacokinetic data obtained from each experiment with each of Groups 1 to 17 at the end of the study. Examination of Groups 8, 9, and 10 showed that increasing SNAC levels resulted in increased exposure of Compound 4, followed by decreased exposure. The data are also plotted in Figure 2, which shows the AUC _INF values for Day 1 and Day 5. For both days, the dose including 450 mg SNAC resulted in higher exposure than 300 mg SNAC or 700 mg SNAC. Groups 1 to 3 did not show measurable plasma levels of drug. Therefore, the appropriate mixture of Compound 4 and SNAC in the formulation is critical to achieving effective concentrations of the drug in the plasma. Table 7 - Pharmacokinetic Data of Dosing Studies of Peptide Compounds in Dogs Group Days _Tmax (h) C _max (ng/mL) AUC _last (h*ng/mL) AUC _INF (h*ng/mL) t _1/2 (h) 1 1 -- -- -- -- -- 5 -- -- -- -- -- 2 1 -- -- -- -- -- 5 -- -- -- -- -- 3 1 -- -- -- -- -- 5 -- -- -- -- -- 4 1 2.0 79.8 2398.6 3812 33.2 5 2.5 50.9 2131.0 2980 42.7 5 1 5.2 39.7 791.5 589 26.3 5 6.0 139.3 7351.8 8746 67.3 6 1 0.9 194.0 5284.2 8925 36.2 5 1.7 151.6 8671.8 9967 59.1 7 1 1.9 188.8 6111.6 10773 40.5 5 3.8 101.2 7233.9 8788 62.6 8 1 1.3 23.7 303.9 1409 42.0 5 1.1 35.3 1349.8 2575 58.9 9 1 1.5 102.7 2834.5 4895 38.3 5 1.8 80.6 5432.5 6841 66.9 10 1 0.7 81.9 2052.7 5042 70.2 5 1.2 181.8 8434.5 9753 56.3 11 1 -- -- -- -- -- 5 3.8 59.8 2814.5 4020 64.7 12 1 0.9 134.2 3249.1 8059 83.8 5 1.3 102.9 5247.3 6549 62.7 13 1 2.8 318.3 7352.4 12132 31.5 5 0.6 199.5 13365.2 15052 66.6 14 1 0.9 134 3389.5 6038 36.5 5 0.9 150.9 9048.2 10539 64.5 15 1 1.2 51.8 1239.5 2118 39.5 5 2.7 103.8 4724.8 5927 59.0 16 1 1.4 144.2 3710.9 7112 38.7 5 1.4 189.0 12130.1 13923 178.8 17 1 1.9 83.5 2265.6 3844 36.8 5 3.7 116.4 7681.2 8698 52.9 Example 24 Pharmacokinetic evaluation of compounds 4 , 15 , 18 and 23 after oral administration

The pharmacokinetic properties of Compounds 15, 18, and 23 were evaluated following administration of an oral dosage form (20 mg of Compound 15, 18, or 23 and 450 mg of sapoliparin sodium (SNAC) per tablet) to male beagle dogs. Animals were acclimated to the study room for a minimum of 3 days prior to initial dosing. Dogs (N=6) received an oral tablet dose containing the test compound. Plasma samples were collected on day 1 prior to dosing the dogs and then at 15 min, 30 min, 45 min, and 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours after dosing. On day 3, samples were collected only prior to dosing. On day 5, plasma samples were collected from dogs prior to dosing and then at 15 min, 30 min, 45 min, and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192, and 240 hours after dosing.

Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis capabilities (linear trapezoidal rule for AUC calculations). Nominal dose values and sampling times were used for calculations. _Cmax and corresponding _Tmax values were determined by direct assessment of concentration versus time data. All AUC calculations were performed using the linear trapezoidal rule. Terminal rate constants (λz, λz) were determined when the data permitted. The value of λz was calculated by the slope of the regression line of natural log-transformed concentration versus time, where the data points were randomly distributed around a straight line, at least three data points after _Cmax were used in the regression, the correlation coefficient ( ^R2 ) of the regression was >0.90, and the time period (span) of the regression was determined to be at least 2.0 times greater than the calculated half-life itself.

In order to optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC _INF values were calculated as: AUC _last + (C _last / λz). Cl/F values were calculated as dose/AUC _INF and Vz/F values were calculated as dose/(AUC _INF * λz). If the percentage of extrapolated area of AUC _INF was >20%, AUC _INF , Vz/F and CL/F values were not reported. The terminal half-life (t _1/2 ) was calculated as: ln(2) / λz. If the span defining the λ z line was less than 2 times that of t _1/2 , the t _1/2 value was marked with an asterisk (*) and removed from the summary statistics. Figure 3 shows the mean plasma concentration versus time curves for compounds 15, 18 and 23, and the curve for compound 4 is also included. The formulations of each of the compounds demonstrated adequate drug exposure at 72 hours. Example 25 Tablet Formulation Wet Granulation Method - Tablet A

A batch of tablets (Tablet A) with Compound 4 as the active ingredient was prepared by a wet granulation process. The amounts of the components are shown in Table 8 below in mg/tablet and total mg/17 g batch. Table 8 - Tablet Formulations for Dog Studies Components mg/ tablet mg/17 g Compound 4 25 625 Sodium Sapolinate(SNAC) 500 12500 Microcrystalline Cellulose 133.3 3332.5 Polyvinylpyrrolidone K90 13.3 332.5 Magnesium stearate 16.2 405 Total 687.8 17195

The ingredients were passed through a No. 35 mesh sieve. Compound 4 and SNAC were weighed out and blended in a mortar and pestle. Polyvinylpyrrolidone was weighed out separately and dissolved in water at 65 mg/mL in a total volume of 5.1 mL. The polyvinylpyrrolidone solution was wet granulated with the blend of Compound 4 and SNAC. The granules were dried in a fluid bed dryer at 30°C to 35°C to ensure that the moisture content did not exceed 4%. The resulting granules were passed through a No. 35 mesh sieve and then combined with microcrystalline cellulose and magnesium stearate and mixed in a rotator. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #1 - Tablet B

A batch of tablets (Tablet B) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of the components are shown below in Tables 9 and 10 per tablet and per 17 g batch. Table 9 - Compounding Table for Tablet B ( per tablet ) Components Part 1 ​ Part 2 ​ Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose 95 mg 38.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.83 mg -- 3.3 mg Table 10 - Tablet B Mixing Tablet ( 17 g each ) Components Part 1 Part 2 Outside the particles Compound 4 -- 0.625 g -- Sodium Sapolinate(SNAC) 12.5 g -- -- Microcrystalline Cellulose 2.375 g 0.958 g -- Polyvinylpyrrolidone K90 -- 0.333 g -- Magnesium stearate 0.321 g -- 0.083 g

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture.

In a separate stainless steel bowl, microcrystalline cellulose was weighed out and then diluted 2× with the final magnesium stearate/SNAC mixture to form a premix. The premix was then added to the rest of the final magnesium stearate/SNAC mixture and hand mixed for at least 60 seconds until visually uniform. The resulting mixture was then mixed in a v-blender at 25 rpm for 10 minutes. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh screen to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet C

A batch of tablets (Tablet C) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of the components are shown in Tables 11 and 12 below per tablet and per 17 g batch. Table 11 - Compounding Table for Tablet C ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.83 mg -- 3.3 mg Table 12 - Tablet C Mixing Tablet ( 17 g each ) Components Part 1 Part 2 Outside the particles Compound 4 -- 0.625 g -- Sodium Sapolinate(SNAC) 12.5 g -- -- Microcrystalline Cellulose -- 3.33 g -- Polyvinylpyrrolidone K90 -- 0.33 g -- Magnesium stearate 0.321 g -- 0.083 g

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet D

A batch of tablets (Tablet D) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 13 below per tablet. Table 13 - Compounding Table of Tablet D ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 250 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet E

A batch of tablets (Tablet E) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 14 below per tablet. Table 14 - Compounding Tablet E ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 750 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet F

A batch of tablets (Tablet F) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 15 below per tablet. Table 15 - Compounding Table of Tablet F ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- PVP-VA -- 90 mg Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, PVP-VA and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet G

A batch of tablets (Tablet G) with Compound 15 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 16 below per tablet. Table 16 - Compounding Table for Tablet G ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 15 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 15 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablets H

A batch of tablets (Tablet H) with Compound 18 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 17 below per tablet. Table 17 - Compounding Table for Tablet H ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 18 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 18 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet J

A batch of tablets (Tablet J) with Compound 23 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 18 below per tablet. Table 18 - Compounding Table of Tablet J ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 23 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 23 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet K

A batch of tablets (Tablet K) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of the components are shown in Table 19 below per tablet. Table 19 - Compounding Tablet K ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 120 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Primellose (Cross-linked Carboxymethyl Cellulose Sodium) 13.3 mg Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, primellose and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet L

A batch of tablets (Tablet L) with Compound 4 as the active ingredient was prepared by dry granulation process. The amounts of the components are shown in Table 20 below per tablet. Table 20 - Compounding Table for Tablet L ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 120 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablet M

A batch of tablets (Tablet M) with Compound 23 as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 21 below per tablet. Table 21 - Compounding Tablet M ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 23 -- 25 mg -- Sodium Sapolinate(SNAC) 500 mg -- -- Microcrystalline Cellulose -- 120 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.85 mg -- 3.34 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 23 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a v-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Dry Granulation Method #2 - Tablets N

A batch of tablets (Tablet N) with Compound 4 (20 mg) as the active ingredient was prepared by dry granulation process. The amounts of each component are shown in Table 22 below per tablet. Table 22 - Compounding Table of Tablet N ( per tablet ) Components Part 1 Part 2 Outside the particles Compound 4 -- 20 mg -- Sodium Sapolinate(SNAC) 450 mg -- -- Microcrystalline Cellulose -- 133.3 mg -- Polyvinylpyrrolidone K90 -- 13.3 mg -- Magnesium stearate 12.87 mg -- 3.33 mg

Magnesium stearate was weighed out and passed through a 355 μm sieve. In a stainless steel bowl, magnesium stearate was diluted 2× with SNAC. The remainder of the SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate/SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate/SNAC mixture. The resulting powder was pressed into large tablets, broken up in a mortar and pestle and passed through a 180 μm mesh sieve to form the first portion of granules.

The second part of the granulation was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4 and polyvinylpyrrolidone into a stainless steel bowl. The contents of the bowl were mixed manually for 3 minutes until visually homogeneous and then transferred to a v-blender and tumbled for 1 minute. The resulting powder was pressed into large tablets and disintegrated in a mortar and pestle to form the second part of the granulation.

The first portion of granules was added to a V-blender, followed by the second portion of granules and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness. Example 26 Formulation Study

The pharmacokinetics of different formulations of Compound 4 were studied in male cynomolgus macaques. Animals were acclimated to the study room for a minimum of 3 days prior to the initiation of dosing. In this study, monkeys were dosed with 1 tablet per day. Blood samples (0.5 mL) were obtained from monkeys on Day 1 (pre-dose only), Day 2 (pre-dose only), and Day 3 (pre-dose and 1, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 hours post-dose). Sample analysis was measured using LC-MS/MS methods based on multiple reaction monitoring (MRM) of fragment ions used for monkey pharmacokinetic studies. All samples from the study were stored at -80°C until they were ready for analysis in a single batch. Pharmacokinetic parameters were calculated using non-compartmental analysis by Phoenix® WinNonlin® software (version 8.3).

Monkeys were administered tablet A, tablet B, or tablet C as described in the previous examples, or an oral solution of compound 4 (blend 1) comprising 25 mg of compound 4 and 500 mg of SNAC. Table 23 - Formulation studies of compound 4 Group Preparation Compound 4 (mg) SNAC (mg) 1 Mixture 1 25 500 2 Tablet A 25 500 3 Tablet B 25 500 4 Tablet C 25 500

The mean plasma concentration of Compound 4 versus time data after repeated oral administration in male cynomolgus monkeys are shown in Figure 4. Tablet Formulation C resulted in the highest mean exposure of Compound 4 of tablet formulations A, B, and C. All tablet formulations resulted in higher mean exposure of Compound 4 compared to Blend 1. Example 27 Additional Formulation Studies

The pharmacokinetics of different formulations of various peptide compounds were studied in male cynomolgus macaques. Animals were acclimated to the study room for a minimum of 3 days prior to the initiation of dosing. In this study, monkeys were dosed with 1 tablet per day. Blood samples (0.5 mL) were obtained from monkeys on days 1, 2, and 3 (before dosing and 1, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 hours after dosing). Sample analysis was measured using LC-MS/MS methods based on multiple reaction monitoring (MRM) of fragment ions used for monkey pharmacokinetic studies. All samples from the study were stored at -80°C until they were ready for analysis in a single batch. Pharmacokinetic parameters were calculated using non-compartmental analysis by Phoenix® WinNonlin® software (version 8.3).

Monkeys were administered tablet formulation C described in the previous example, which included 25 mg of compound 4 and 500 mg of SNAC. Compounds 15, 18, and 23 were administered as formulations G, H, and J, respectively. The mean plasma concentration versus time data and AUC data for compound 4, compound 15, compound 18, and compound 23 are provided in Table 24. Formulation C provided adequate drug exposure for all four compounds. Table 24 - Pharmacokinetic Data of Various Compounds Formulated as Tablet C Compound Preparation Compound (mg) SNAC (mg) C _max (ng/mL) AUC _inf h•ng/mL Compound 4 Tablet C 25 500 4090 399000 Compound 15 Tablet G 25 500 4050 411000 Compound 18 Tablet H 25 500 2140 209000 Compound 23 Tablet J 25 500 5980 690000 Example 28 Pharmacokinetic study using permeability enhancers

The study in this example was designed to evaluate the pharmacokinetics of the compounds of the present application when administered intraduodenally (ID) with the addition of PBS containing absorption enhancers (SNAC, C10, lauryl-L-carnitine chloride and Labrasol). Male Sprague Dawley rats were socially housed in individual ventilated caging (IVG) with three rats per cage for acclimatization lasting 3 to 7 days with alpha dri litter, free access to water, free access to 2016 Teklad chow and environmental enrichment. The room temperature was 72 +/- 2°F with a relative humidity of 30% to 70% and a 12-hour light cycle. Animals were housed individually just prior to the start of the study with free access to food and water for the duration of the study. Rats were dosed with the specified compound at a dose level of 5 mg/kg on study day 1. Blood samples (0.5 mL) were obtained from rats prior to dosing and at 0.25, 0.6, 1, 2, 4, 8, 12, 24, 36 and 48 hours after dosing. Compound 24 and SNAC, C10, lauryl-L-carnitine chloride and Labrasol were administered to groups 1 to 4, respectively; Compound 27 and SNAC, C10, lauryl-L-carnitine chloride and Labrasol were administered to groups 5 to 8, respectively; Compound 4 and SNAC, C10, lauryl-L-carnitine chloride (LCC) and Labrasol were administered to groups 9 to 12, respectively. There were three rats in each test group.

Sample analysis was measured by LC-MS/MS method based on multiple reaction monitoring (MRM) of fragment ions for rat pharmacokinetics studies. All samples from the study were stored at -80°C until ready for analysis.

Phosphate Buffered Saline (PBS): Prepare solutions at pH 7.4 (calcium-free, magnesium-free). For Labrasol, prepare an 80 mg/mL stock solution on the day of dosing by weighing 800 mg Labrasol into a vial, adding 9.2 ml PBS, and vortexing.

C10: Prepare a 200 mM solution of C10 in PBS. Warm the solution to 37°C in a water bath before use until the solution becomes clear. Cool the solution back to room temperature before adding any test compounds.

SNAC: Prepare a 200 mM solution in PBS. Prepare the solution on the day of dosing.

Lauroyl Carnitine Chloride (LCC): 100 mM solution of LCC in PBS (15 ml). Prepare LCC solution in advance and freeze in 5 mL aliquots. Compound Dosing Solution

Labrasol® and Test Compound: Doses are prepared at a concentration of 1 mg/mL compound (6 mL total). Add 3 mL of PBS to an appropriately sized glass container. Then add 6 mg of compound (corrected for purity) to 3 mL of PBS and vortex. Add 3 mL of Labrasol® stock solution to the above compound solution and vortex. Dose the animal 5 mL/kg of formulation.

C10 and Test Compounds: Prepare a 1 mg/mL test compound solution by warming 3 mL of C10 stock solution to 37°C until the solution is clear. Return the solution to room temperature before adding the test compound. In an appropriately sized glass container, add 3 mL of PBS followed by 6 mg of test compound (corrected for purity). Subsequently, add 3 mL of room temperature C10 stock solution to the test compound solution and vortex.

SNAC and Test Compounds: Prepare a 1 mg/mL test compound solution by adding 3 mL of PBS to an appropriately sized glass container followed by the addition of 6 mg of test compound (corrected for purity). Subsequently, add 3 mL of room temperature SNAC stock solution to the test compound solution and vortex.

LCC and Test Compounds: Prepare a 1 mg/mL test compound solution by adding 3 mL of PBS to an appropriately sized glass container followed by the addition of 6 mg of test compound (corrected for purity). Subsequently, add 3 mL of room temperature LCC stock solution to the test compound solution and vortex.

The plasma concentrations of each compound and each excipient are shown in Figures 5A to 5C. The plasma concentration of compound 24 after administration of various excipients showed that the initial concentration of C10 was the highest, while no trace was shown for compound 24 and SNAC when the plasma content of compound 24 was below the limit of quantification (Figure 5A). Similar phenomena were observed in the case of compound 27 and C10 (Figure 5B) and compound 4 and SNAC (Figure 5C). However, for the combination of compound 4 and SNAC, the plasma content of compound 4 was higher than the limit of quantification. Example 29 Additional Tablet Formulation Spray Drying Dispersion Method - Tablet O

A batch of tablets (Tablet O) having a compound disclosed herein as an active ingredient was prepared by a spray drying dispersion method. The compound disclosed herein was combined with the following in a solvent: (a) hydroxypropylmethylcellulose acetate succinate M form (HPMCAS-M); (b) hydroxypropylmethylcellulose acetate succinate L form (HPMCAS-L); (c) polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA64); or (d) Eudragit ® L100 to form a solution for spray drying. The solution was then dried by a heated nitrogen stream and collected using a cyclone separator. The spray dried material is then combined with microcrystalline cellulose, magnesium stearate and additional fillers and disintegrants and compressed into tablets. Wet Granulation Method #2 - Tablets P

A batch of tablets (Tablets P) having a compound disclosed herein as an active ingredient was prepared by a wet granulation process. The compound disclosed herein was combined with microcrystalline cellulose and hydroxypropyl cellulose. The mixture of materials was wet granulated using purified water as the granulation liquid. The wet granules were dried in a fluidized bed dryer. Thereafter, the dried granules were ground and blended for 10 minutes. Magnesium stearate was sieved and added to the blended mixture and blended for another 5 minutes. Thereafter, the mixture was compressed into tablets.

Although some embodiments have been described and illustrated, those skilled in the art may make changes, equivalent substitutions and other types of changes to the compounds or salts thereof, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures of the present invention described herein after reading the foregoing description. Each aspect and embodiment described above may also include or incorporate such changes or aspects disclosed in any or all other aspects and embodiments.

The present technology is also not limited to the specific aspects described herein, which are intended to be separate illustrations of individual aspects of the present technology. It will be apparent to those skilled in the art that many modifications and variations may be made to the present technology without departing from the spirit and scope of the present technology. In addition to those methods listed herein, functionally equivalent methods within the scope of the present technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the accompanying patent applications. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds, or biological systems, which may of course vary. It should also be understood that the terms used herein are for the purpose of describing specific aspects only and are not intended to be limiting. Therefore, it is intended that this specification be regarded as only indicating the breadth, scope and spirit of the present invention technology indicated by the scope of the attached application, the definitions therein and any equivalents thereof.

The embodiments illustratively described herein may be properly implemented in the absence of any one or more elements, any one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and non-restrictively. In addition, the terms and expressions employed herein have been used as terms of description rather than limitation, and when using such terms and expressions, it is not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications may be made within the scope of the claimed technology. In addition, the phrase "consisting essentially of..." should be understood to include those elements specifically enumerated and those additional elements that do not significantly affect the basic and novel characteristics of the claimed technology. The phrase "consisting of..." excludes any elements not specified.

In addition, when 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 more narrow species and subgeneric groups within the general disclosure also forms part of the present invention. This includes a general description of the present invention, with limitations or negative limitations removing any subject matter from that category, regardless of whether the deleted material is specifically described herein.

All publications, patent applications, issued patents, and other documents (e.g., journals, papers, and/or textbooks) mentioned in this specification are incorporated herein 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 contained in texts incorporated by reference are excluded if they conflict with definitions in this disclosure.

Other embodiments are described in the following claims, along with the full scope of equivalents to which this claim is entitled.

While the present disclosure has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure.

All references, issued patents, and patent applications cited in the text of this specification are incorporated herein by reference in their entirety for all purposes.

Although the present disclosure has been described with reference to embodiments and examples, it should be understood that many and various modifications can be made without departing from the spirit of the present disclosure. Therefore, the present disclosure is limited only by the scope of the following patent applications.

Figure 1 is a graph depicting mean plasma concentration versus time following oral doses of various compounds administered to male beagle dogs.

FIG. 2 is a graph showing comparison of AUC values of dosing groups of dogs administered with formulations of Compound 4 and different amounts of sapolisar sodium (SNAC).

Figure 3 is a graph depicting mean plasma concentration versus time following oral doses of various compounds administered to male beagle dogs.

Figure 4 is a graph depicting mean plasma concentration versus time curves following administration of various formulations of Compound 4 to male cynomolgus monkeys.

Figure 5A is a graph depicting mean plasma concentration versus time following administration of Compound 24 in various formulations to male Sprague Dawley rats.

Figure 5B is a graph depicting mean plasma concentration versus time curves following administration of Compound 27 in various formulations to male Sprague Dawley rats.

Figure 5C is a graph depicting mean plasma concentration versus time curves following administration of Compound 4 in various formulations to male Sprague-Dawley rats.

TW202444420A_113109451_SEQL.xml

Claims (135)

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. The pharmaceutical composition of claim 1, wherein the compound is a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof: wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ may be independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y may each be independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ may be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryloxy and C _6-10 arylalkoxy; each R ⁵ may be independently hydrogen or C _1-6 alkyl; each R ⁶ may be independently hydrogen or C _1-6 alkyl; and Z ¹ and Z ² may each be independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C 1-6 alkoxy, C _{1-6 C 1-6} alkoxy, C _3-10 cycloalkyl and C _6-10 aryl. The pharmaceutical composition of claim 2, wherein at least one of ^Z1 and ^Z2 is not hydrogen. The pharmaceutical composition of claim 2 or 3, wherein the compound is a compound having the structure of formula (Ia): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 4, wherein Z ¹ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of claim 4 or 5, wherein Z ¹ is selected from the group consisting of hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 4 to 6, wherein Z ¹ is hydrogen and each R ⁴ is independently hydrogen or C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 4 to 7, wherein each R ⁴ is hydrogen. The pharmaceutical composition of any one of claims 4 to 8, wherein Z ¹ is hydrogen and each R ⁴ is hydrogen. The pharmaceutical composition of claim 2, wherein the compound is a compound having a structure of formula (Ib): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 10, wherein Z ² is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of claim 10 or 11, wherein Z ² is selected from the group consisting of hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of claim 10 or 11, wherein Z ² is hydrogen and each R ⁴ is hydrogen or C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 10 to 13, wherein each R ⁴ is hydrogen. The pharmaceutical composition of any one of claims 10 to 14, wherein Z ² is hydrogen and each R ⁴ is hydrogen. The pharmaceutical composition of claim 2, wherein the compound is a compound having the structure of formula (Ic): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 16, wherein X and Y are each -OR ⁴ . The pharmaceutical composition of claim 16 or 17, wherein each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 16 to 18, wherein each R ⁴ is hydrogen. The pharmaceutical composition of claim 2 or 3, wherein the compound is a compound having a structure selected from the group consisting of: and their pharmaceutically acceptable salts. The pharmaceutical composition of claim 20, wherein the compound is a compound having the following structure: or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of any one of claims 2 to 21, wherein "*" indicates a chiral carbon with an "S" configuration. The pharmaceutical composition of any one of claims 2 to 21, wherein "*" indicates a chiral carbon with an "R" configuration. The pharmaceutical composition of claim 1, wherein the compound is a compound having a structure of formula (II), or a pharmaceutically acceptable salt thereof, wherein: Aib is 2-aminoisobutyric acid; each of ^J1 , ^J2 and ^J3 is independently an amino acid selected from Aib, a naturally occurring amino acid and a non-natural amino acid; ^U1 is -(J4) _n1- ( ^J5 ) _n2- ( ^J6 ) _n3- ( ^J7 ) _n4- ; ^U2 is -( ^J8 ) _n5- ( ^J9 ) _n6- ( ^J10 ) _n7- ( ^J11 ) _n8- ; each of ^J4 , ^J5 , ^J6 , ^J7 , ^J8 , ^J9 , ^{J10 and J11} is independently a naturally occurring amino acid or a non-natural amino acid; each of n1, n2, n3, n4, n5, n6, n7 and n8 is independently 0 or 1, with the proviso that the sum of n1 + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4; R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted with 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl group containing ₁ to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R 7 independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _{1-6 alkyl, halogen C 1-6 alkoxy} , -OR 5 , C 3-10 cycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocyclic group; each R ⁷ is independently selected from the ^group consisting of: halogen, C 1-6 alkyl, halogen C 1-6 alkyl, halogen C 1-6 alkoxy, -OR ⁵ , C _{3-10 cycloalkyl, C 6-10 aryl} , a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocyclic group; wherein X and Y are each independently selected from the group consisting of -OR ₄ , NR ₅ R ⁶ , C _{1-6 alkyl and halogenated C 1-6 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl} ^, _halogenated C _1-6 alkyl, C _6-10 aryl and ^C _7-11 aralkyl; each ^R ₅ is independently _{hydrogen or C 1-6 alkyl; each R 6 is independently hydrogen or C 1-6 alkyl} ^{; and} _{Z 1} ^and _Z ² are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl. The pharmaceutical composition of claim 24, wherein the compound is not: . The pharmaceutical composition of claim 24 or 25, wherein each instance of ^J1 , ^J2 and ^J3 is independently an amino acid selected from Aib and naturally occurring amino acids. The pharmaceutical composition of any one of claims 24 to 26, wherein each instance of ^J1 , ^J2 and ^J3 is independently an amino acid selected from the group consisting of Aib, A, F, N, R and Q. The pharmaceutical composition of any one of claims 24 to 27, wherein ^J1 is Aib or F. The pharmaceutical composition of any one of claims 24 to 28, wherein ^J1 is F. The pharmaceutical composition of any one of claims 24 to 29, wherein ^J2 is N or Q. The pharmaceutical composition of any one of claims 24 to 30, wherein ^J2 is N. The pharmaceutical composition of any one of claims 24 to 31, wherein ^J3 is A or R. The pharmaceutical composition of any one of claims 24 to 32, wherein ^J3 is R. The pharmaceutical composition of any one of claims 24 to 33, wherein each instance of ^J4 , ^J5 , ^J6 and ^J7 is independently an amino acid selected from the group consisting of A, I, K, R, Q, S, T and V. The pharmaceutical composition of any one of claims 24 to 34, wherein ^J4 is K or R. The pharmaceutical composition of any one of claims 24 to 35, wherein ^J4 is R. The pharmaceutical composition of any one of claims 24 to 36, wherein ^J5 is I, T or V. The pharmaceutical composition of any one of claims 24 to 37, wherein ^J5 is T or V. The pharmaceutical composition of any one of claims 24 to 38, wherein ^J6 is A or S. The pharmaceutical composition of any one of claims 24 to 39, wherein ^J6 is S. The pharmaceutical composition of any one of claims 24 to 40, wherein ^J7 is Q or K. The pharmaceutical composition of any one of claims 24 to 41, wherein each instance of ^J8 , ^J9 , ^J10 and ^J11 is independently an amino acid selected from A, I and Q. The pharmaceutical composition of any one of claims 24 to 42, wherein J ⁸ is I or Q. The pharmaceutical composition of any one of claims 24 to 43, wherein J ⁹ is A or Q. The pharmaceutical composition of any one of claims 24 to 44, wherein J ¹⁰ is Q. The pharmaceutical composition of any one of claims 24 to 45, wherein J ¹¹ is Q. The pharmaceutical composition of any one of claims 24 to 27, wherein ^J1 is selected from Aib or F; ^J2 is selected from Q or N; ^J3 is selected from A or R; ^U1 is selected from -KVA-, -KIAQ- (SEQ ID NO: 8), -KTAQ- (SEQ ID NO: 9), -KTSQ- (SEQ ID NO: 10), -KVAQ- (SEQ ID NO: 11), -RIAQ- (SEQ ID NO: 12), KIAK- (SEQ ID NO: 13), -KISQ- (SEQ ID NO: 14), or is absent; and ^U2 is selected from -Q-, -IAQQ- (SEQ ID NO: 15), -IAQK- (SEQ ID NO: 16), -VAQK (SEQ ID NO: 17), or is absent. A pharmaceutical composition as claimed in any one of claims 24 to 47, wherein each instance of n1, n2, n3 and n4 is zero. A pharmaceutical composition as claimed in any one of claims 24 to 47, wherein each instance of n4, n6, n7 and n8 is zero. A pharmaceutical composition as claimed in any one of claims 24 to 47, wherein each instance of n5, n6, n7 and n8 is zero. The pharmaceutical composition of any one of claims 24 to 50, wherein at least one of ^Z1 and ^Z2 is not hydrogen. The pharmaceutical composition of any one of claims 24 to 51, wherein the compound is a compound having the structure of formula (II-a): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 52, wherein Z ¹ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of claim 51, wherein Z ¹ is hydrogen and each R ⁴ is independently hydrogen or C _7-11 aralkyl. The pharmaceutical composition of claim 53 or 54, wherein each R ⁴ is hydrogen. The pharmaceutical composition of claim 51, wherein Z ¹ is hydrogen and each R ⁴ is hydrogen. The pharmaceutical composition of any one of claims 23 to 51, wherein the compound is a compound having the structure of formula (II-b): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 57, wherein each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryl and C _7-11 aralkyl. The pharmaceutical composition of claim 58, wherein each R ⁴ is hydrogen. The pharmaceutical composition of claim 24 or 25, wherein the compound is a compound having a structure selected from the group consisting of: and their pharmaceutically acceptable salts. The pharmaceutical composition of claim 1, wherein the compound is a compound having a structure of formula (III), , or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -(CH ₂ CH ₂ ) _n P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ is independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 membered aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y are each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryloxy and C _6-10 arylalkoxy; each R ⁵ is independently hydrogen or C _1-6 alkyl; each R ⁶ is independently hydrogen or C _1-6 alkyl; Z ¹ and Z ² are each independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, and n is 0 _{, 1 ,} 2, 3 or 4. The pharmaceutical composition of claim 61, wherein at least one of ^Z1 and ^Z2 is not hydrogen. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having the structure of formula (III-a): , or its pharmaceutically acceptable salts. The pharmaceutical composition of claim 63, wherein Z ¹ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of claim 63 or 64, wherein Z ¹ is selected from the group consisting of hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 63 to 65, wherein Z ¹ is hydrogen and each R ⁴ is independently hydrogen or C _6-10 arylalkoxy. A pharmaceutical composition as claimed in any one of claims 63 to 66, wherein each R ⁴ is hydrogen. A pharmaceutical composition as claimed in any one of claims 63 to 67, wherein Z ¹ is hydrogen and each R ⁴ is hydrogen. A pharmaceutical composition as claimed in any one of claims 63 to 68, wherein n is 1. A pharmaceutical composition as claimed in any one of claims 63 to 68, wherein n is 2. The pharmaceutical composition of claim 59, wherein the compound is a compound having the structure of formula (III-b): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 71, wherein Z ² is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of claim 71 or 72, wherein Z ² is selected from the group consisting of hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of any one of claims 71 to 73, wherein Z ² is hydrogen and each R ⁴ is hydrogen or C _6-10 arylalkoxy. A pharmaceutical composition as claimed in any one of claims 71 to 74, wherein each R ⁴ is hydrogen. A pharmaceutical composition as claimed in any one of claims 71 to 75, wherein Z ² is hydrogen and each R ⁴ is hydrogen. A pharmaceutical composition as claimed in any one of claims 71 to 76, wherein n is 1. A pharmaceutical composition as claimed in any one of claims 71 to 76, wherein n is 2. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having the structure of formula (III-c): , or its pharmaceutically acceptable salts. The pharmaceutical composition of claim 79, wherein X and Y are each -OR ⁴ . The pharmaceutical composition of claim 80, wherein each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryloxy and C _6-10 arylalkoxy. The pharmaceutical composition of claim 80 or 81, wherein each R ⁴ is hydrogen. A pharmaceutical composition as claimed in any one of claims 79 to 82, wherein n is 1. A pharmaceutical composition as claimed in any one of claims 79 to 82, wherein n is 2. The pharmaceutical composition of claim 61 or 62, wherein the compound is a compound having a structure selected from the group consisting of: , and their pharmaceutically acceptable salts. The pharmaceutical composition of any one of claims 61 to 85, wherein "*" indicates a chiral carbon with an "S" configuration. The pharmaceutical composition of any one of claims 61 to 85, wherein "*" indicates a chiral carbon with an "R" configuration. The pharmaceutical composition of any one of claims 1 to 87, wherein the mass of the permeability enhancer is about 350 mg to about 1000 mg. The pharmaceutical composition of any one of claims 1 to 87, wherein the mass of the permeability enhancer is about 400 mg to about 800 mg. The pharmaceutical composition of any one of claims 1 to 87, wherein the mass of the permeability enhancer is about 500 mg to about 750 mg. The pharmaceutical composition of any one of claims 1 to 87, wherein the mass of the permeability enhancer is about 500 mg; or wherein the mass of the permeability enhancer is 450 mg. The pharmaceutical composition of any one of claims 1 to 91, wherein the permeability enhancer accounts for about 40% to about 90% by weight of the composition. The pharmaceutical composition of any one of claims 1 to 91, wherein the permeability enhancer accounts for about 50% to about 80% by weight of the composition. The pharmaceutical composition of any one of claims 1 to 91, wherein the one or more permeability enhancers account for about 70% to about 80% by weight of the composition. The pharmaceutical composition of any one of claims 1 to 91, wherein the permeability enhancer accounts for about 73% by weight of the composition. The pharmaceutical composition of any one of claims 1 to 95, wherein the permeability enhancer is salcaprozate sodium (SNAC), sodium decanoate (C10), or a combination thereof. The pharmaceutical composition of any one of claims 1 to 95, wherein the permeability enhancer is sapolisar sodium. The pharmaceutical composition of any one of claims 1 to 95, wherein the permeability enhancer is sodium caprate. The pharmaceutical composition of any one of claims 1 to 95, wherein the one or more permeability enhancers are a combination of sodium sapolisar and sodium caprate. The pharmaceutical composition of any one of claims 1 to 99, comprising about 1 mg to about 50 mg of the compound. The pharmaceutical composition of any one of claims 1 to 99, comprising about 5 mg to about 40 mg of the compound. The pharmaceutical composition of any one of claims 1 to 99, comprising about 10 mg to about 30 mg of the compound. The pharmaceutical composition of any one of claims 1 to 99, comprising about 20 mg to about 30 mg of the compound. The pharmaceutical composition of any one of claims 1 to 99, comprising about 25 mg of the compound. The pharmaceutical composition of any one of claims 1 to 104, further comprising a disintegrant. The pharmaceutical composition of claim 105, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium. A pharmaceutical composition comprising: sodium saprolidine; and a therapeutically effective amount of a compound having a structure of formula I or a pharmaceutically acceptable salt thereof: wherein: R ¹ is selected from the group consisting of: -C(=O)(OZ ¹ ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the group consisting of: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, a 5- to 10-membered heteroaryl group and a 5- to 10-membered heterocyclic group; R ² is selected from the group consisting of: -C(=O)(OZ ² ), -P(=O)(X)(Y) and a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1 to 2 R ⁷ independently selected from the following: halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, -OR ⁵ , C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclo; each R ⁷ is independently selected from the group consisting of halogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic group; X and Y are each independently selected from the group consisting of: -OR ⁴ , NR ⁵ R ⁶ , C _1-6 alkyl and halogen C _1-6 alkyl; each R ⁴ is independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _6-10 aryl and C _6-10 aralkyl; each R ⁵ is independently hydrogen or C _1-6 alkyl; each R ⁶ is independently hydrogen or C _1-6 alkyl; and Z ¹ and Z ² are each independently selected from the group consisting of: hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, _3-10 cycloalkyl and C _6-10 aryl; and wherein the mass of saprolidone is greater than about 300 mg. The pharmaceutical composition of any one of claims 1 to 107, wherein at least one of ^Z1 and ^Z2 is not hydrogen. A pharmaceutical composition as claimed in any one of claims 1 to 107, wherein the composition further comprises one or more excipients. The pharmaceutical composition of claim 109, wherein the one or more excipients are selected from the group consisting of microcrystalline cellulose, magnesium stearate and polyvinylpyrrolidone. The pharmaceutical composition of any one of claims 1 to 110, wherein the compound has the structure of formula (Ia): or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of any one of claims 1 to 111, wherein Z ¹ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkoxy, C _3-10 cycloalkyl and C _6-10 aryl; and X and Y are each -OR ⁴ . The pharmaceutical composition of any one of claims 1 to 112, wherein Z ¹ is selected from the group consisting of hydrogen, halogen C _1-6 alkoxy and C _1-6 alkoxy; and each R ⁴ is independently selected from the group consisting of hydrogen, C _6-10 aryl and C _6-10 aralkyl. The pharmaceutical composition of any one of claims 1 to 113, wherein Z ¹ is hydrogen and each R ⁴ is independently hydrogen or C _6-10 aralkyl. The pharmaceutical composition of any one of claims 1 to 114, wherein each R ⁴ is hydrogen. The pharmaceutical composition of any one of claims 1 to 115, wherein the compound is: or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of any one of claims 1 to 116, wherein the composition is formulated for oral administration. A pharmaceutical composition as claimed in any one of claims 1 to 117, wherein the pharmaceutical composition comprises: About 1.0 wt% to about 5.0 wt% of the compound; About 50 wt% to about 80 wt% of sodium sapolidate; About 10 wt% to about 30 wt% of microcrystalline cellulose; About 1.0 wt% to about 3.0 wt% of polyvinylpyrrolidone; and About 1.0 wt% to about 3.0 wt% of magnesium stearate. A pharmaceutical composition as claimed in any one of claims 1 to 118, wherein the pharmaceutical composition comprises: About 3.6% by weight of the compound; About 72.7% by weight of sodium sapolisar; About 19.4% by weight of microcrystalline cellulose; About 1.9% by weight of polyvinylpyrrolidone; and About 2.3% by weight of magnesium stearate. The pharmaceutical composition of any one of claims 1 to 119, wherein the pharmaceutical composition is coated with an enteric coating. A method for preventing, treating or ameliorating one or more metabolic diseases or metabolic syndromes in an individual, comprising administering the pharmaceutical composition of any one of claims 1 to 120 to the individual in need thereof. The method of claim 119, wherein the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or Prader-Willi syndrome. The method of claim 119 or 120, wherein the metabolic disorder or metabolic syndrome is obesity or hypothalamic obesity. A method for preventing, treating or ameliorating one or more fatty liver diseases in an individual, comprising administering the pharmaceutical composition of any one of claims 1 to 120 to an individual in need thereof. The method of claim 122, wherein the fatty liver disease is selected from the group consisting of steatosis, nonalcoholic steatohepatitis, and nonalcoholic fatty liver disease. The method of claim 122 or 125, wherein the administration of the pharmaceutical composition results in the prevention, treatment or amelioration of fibrosis, a fibrotic condition or a fibrotic symptom. The method of any one of claims 122 to 126, wherein the administration of the pharmaceutical composition results in a reduction in the level of extracellular matrix protein in one or more tissues of the individual. The method of any one of claims 122 to 127, wherein the administration of the pharmaceutical composition results in a reduction in collagen content in one or more tissues of the subject. The method of claim 128, wherein the administration of the pharmaceutical composition results in a reduction in the level of type I, type Ia, or type III collagen in one or more tissues of the subject. A method for preventing, treating or ameliorating one or more diseases or conditions in an individual, comprising administering to an individual in need thereof a pharmaceutical composition of any one of claims 1 to 118, wherein the disease or condition is liver fibrosis, kidney fibrosis, bile fibrosis, pancreatic fibrosis, nonalcoholic steatosis hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis. The method of claim 130, wherein the disease or condition is nonalcoholic steatosis hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis. The method of any one of claims 121 to 131, wherein the route of administration is oral. A method for preparing a pharmaceutical composition, the method comprising the following steps: (i) combining sodium sapolisate and magnesium stearate to form a first granule; (ii) combining microcrystalline cellulose, compound 4 and polyvinylpyrrolidone to form a second granule; (iii) combining the first granules and the second granules to form a mixture; (iv) adding magnesium stearate to the mixture to form a third granule; (v) pressing the third granules into tablets. A method for preparing a pharmaceutical composition, the method comprising the following steps: (i) combining microcrystalline cellulose and a compound disclosed herein in a first container; (ii) combining polyvinylpyrrolidone and water in a second container; (iii) adding the contents of the first container to the second container to form wet granules; (iv) drying the wet granules to form dry granules; (v) combining the dry granules with magnesium stearate; and (vi) pressing the resulting mixture of step (v) into granules. A pharmaceutical composition prepared by the method of claim 133 or 134.