Compositions and methods for treatment of metabolic and liver disorders

Abstract

To provide novel GIP / GLP1 dual agonist compounds that can be used to treat fatty liver diseases and other diseases and disorders without dose-limiting side effects.SOLUTION: The above problem is solved by the compound defined in claim 1 of the present application.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Reference to sequence listing This application is filed together with a sequence listing in electronic format. The sequence listing is provided as a file entitled SeqListing_VIKNG.017WO.xml, created on September 7, 2022, and is 60,684 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to the field of treatments for metabolic disorders and fatty liver disease. More specifically, the present disclosure relates to the field of small molecule drugs for the treatment of diseases such as non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). [Background technology]

[0003] Incretin peptides, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are metabolic hormones. Both GIP and GLP-1 are secreted within minutes of oral intake of nutrients, facilitating rapid disposal of orally ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct but related receptors. Incretin receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage through direct action on adipose tissue. In contrast, GLP-1 exerts glucoregulatory effects through slowing down gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss in both preclinical and clinical studies.

[0004] Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the most common cause of chronic liver disease. NAFLD can progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GIP / GLP-1 dual receptor agonists have been developed to treat NAFLD, nonalcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of 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 have found that tolerability at high doses was limited by gastrointestinal adverse events. Dose limitations associated with gastrointestinal adverse events can prevent dosing to a desired effective dose, impair patient compliance to treatment, and limit the effectiveness of treatment regimens. Thus, there is a need for novel GIP / GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and disorders without dose-limiting side effects. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO 87 / 05297, Johnston et al., published September 11, 1987 [Non-patent literature]

[0006] [Non-Patent Document 1] Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon", J. Biol. Chem. 2010 285: pp. 11039-11044 [Non-Patent Document 2] Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press [Non-Patent Document 3] Protective Groups in Organic Chemistry (edited by JFW McOmie, Plenum Press, 1973) [Non-Patent Document 4] PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999) [Non-Patent Document 5] R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 [Non-Patent Document 6] L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995. [Non-Patent Document 7] Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991) [Non-Patent Document 8] Rodd's Chemistry of Carbon Compounds, vols. 1-5 [Non-Patent Document 9] Supplementals (Elsevier Science Publishers, 1989) [Non-Patent Document 10] Organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991) [Non-Patent Document 11] March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001) [Non-Patent Document 12] Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) [Non-Patent Document 13] Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (ed. J. Howl, Humana Press, 2005); and Amino Acids, Peptides and Proteins in Organic Chemistry, vol. 3, Building Blocks, Catalysts and Coupling Chemistry, (ed. AB Hughs, Wiley-VCH, 2011) [Non-Patent Document 14] Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005) [Non-Patent Document 15] Modern Pharmaceutics, 4th ed., Chapters 9 and 10 (Banker & Rhodes, 2002) [Non-Patent Document 16] Lieberman et al., Pharmaceutical Dosage Forms; Tablets (1989) [Non-Patent Document 17] Ansel, Introduction to Pharmaceutical Dosage Forms 8th edition (2004) [Non-Patent Document 18] Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 pp. 238-311 [Non-Patent Document 19] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 pp. 287-332 [Non-Patent Document 20] March Advanced Organic Chemistry (Wiley) [Non-Patent Document 21] Care and Sundberg, Advanced Organic Chemistry [Non-Patent Document 22] T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th ed., John Wiley & Sons (2007) [Non-Patent Document 23] Boland et al., World J Gastroenterol, 2019, 25(33):4904-4920 [Non-Patent Document 24] Lau, J. et al., J. Med. Chem. 2015, 58, 7370-7380 Summary of the Invention [Means for solving the problem]

[0007] Formula I:

[0008] [ka]

[0009] or a pharma- ceutically acceptable salt thereof, wherein: Aib is 2-aminoisobutyric acid; J 1 , J 2 and J 3each instance of is independently an amino acid selected from Aib, a naturally occurring amino acid, and a non-naturally occurring amino acid; U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 - and; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 - and; J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 and J 11 each instance of 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 -C(=O)(OZ 1 ), -P(=O)(X)(Y), and 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein heteroaryl is selected from halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 is optionally replaced by; R 2 is -C(=O)(OZ2 ), -P(=O)(X)(Y), and 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein heteroaryl is selected from halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 is optionally replaced by; Each R 7 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 independently selected from the group consisting of alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryl and C 7~11 arylalkyl; Each R 5 are independently hydrogen or C 1~6 is alkyl; Each R 6 are independently hydrogen or C 1~6 is alkyl; Z 1 and Z 2 are hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C3~10 Cycloalkyl and C 6~10 aryl.

[0010] In some embodiments, the compound of formula (I) does not include:

[0011] [ka]

[0012] Some embodiments include a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0013] Some embodiments include a method of preventing, treating or ameliorating one or more fatty liver disorders in a subject, comprising administering to a subject in need thereof a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0014] Other embodiments include methods of preventing, treating or ameliorating one or more diseases or disorders in a subject comprising administering to a subject in need thereof a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, wherein the disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 illustrates the effect of compounds of the present disclosure on hepatic triglyceride (TG) levels. [Diagram 2] FIG. 1 illustrates the effect of compounds of the present disclosure on liver lipid levels. [Diagram 3] FIG. 1 illustrates the effect of compounds of the present disclosure on hepatic galectin-3 levels. [Figure 4]FIG. 1 illustrates the effect of compounds of the present disclosure on plasma triglyceride (TG) levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] 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. In the event that there are multiple definitions for terms herein, those in this section prevail unless otherwise stated.

[0017] "Solvate" refers to the compound formed by the interaction of a solvent with a compound described herein, or a salt thereof. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0018] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical product. In many cases, the compounds herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases formed from the following elements: sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium, and magnesium base salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published Sep. 11, 1987, which is incorporated herein by reference in its entirety.

[0019] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a From C b " or "C a~b" refers to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, "C1 to C4 alkyl" or "C 1~4 An "alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0020] The term "halogen" or "halo" as used herein means any one of the radioactive stable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0021] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition encompasses the occurrence of the term "alkyl" even when no numerical range is specified). The alkyl group can be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compound can be a "C 1~4 Alkyl" or a similar designation. By way of example only, "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0022] As used herein, "haloalkyl" refers to a straight or branched chain alkyl group having from 1 to 12 carbon atoms in the chain in which one or more hydrogens are replaced with halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that would be considered equivalent to any one of the foregoing examples in light of ordinary skill in the art and the teachings provided herein.

[0023] As used herein, "alkoxy" refers to a group of the formula -OR where R is alkyl as defined above, including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. 1~9 Refers to "alkoxy."

[0024] As used herein, "polyethylene glycol" refers to a compound of the formula

[0025] [ka]

[0026] where n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by a number of members. Thus, for example, "2- to 5-membered polyethylene glycol" refers to n being an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0027] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the chain backbone, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. Heteroalkyl groups can have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" when no numerical range is specified. Heteroalkyl groups can be medium size heteroalkyls having 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having 1 to 4 carbon atoms. In various embodiments, heteroalkyls can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl groups of the compounds are defined as "C 1~4 A heteroalkyl group may be designated as "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" means that the heteroalkyl chain has 1 to 4 carbon atoms and, additionally, one or more heteroatoms in the backbone of the chain.

[0028] The term "aromatic" refers to a ring or ring system having a conjugated pi-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 which share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0029] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, every ring in the system is aromatic. An aryl group can have from 6 to 18 carbon atoms, although this definition also encompasses occurrences of the term "aryl" when no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is defined as "C 6~10 Aryl, C6 or C10 The aryl group may be designated as "aryl" or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0030] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, including, but not limited to, phenyloxy. 6~10 aryloxy" or "C 6~10 "Arylthio" etc.

[0031] "Aralkyl" or "arylalkyl" refers to an aryl group connected as a substituent through an alkylene group, such as, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl, "C 7~14 In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0032] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms in the ring backbone, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, every ring in the system is aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" when no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members, or 5 to 7 ring members. Heteroaryl groups can be designated as "5-membered to 7-membered heteroaryl," "5-membered to 10-membered heteroaryl," or similar designations. In various embodiments, heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0033] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0034] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. Carbocyclyl groups can have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" when no numerical range is specified. Carbocyclyl groups may be medium-sized carbocyclyls having 3 to 10 carbon atoms. Carbocyclyl groups can also be carbocyclyls having 3 to 6 carbon atoms. Carbocyclyl groups are defined as "C 3~6 Carbocyclyl may be designated as "carbocyclyl" or a similar designation. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclic [2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0035] "(Carbocyclyl)alkyl" refers to a carbocyclyl group connected as a substituent via an alkylene group, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. 4-10 (carbocyclyl)alkyl." In some cases, the alkylene group is a lower alkylene group.

[0036] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0037] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, where no ring in the ring system is aromatic. An example is cyclohexenyl.

[0038] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged, or spiro-connected fashion. Heterocyclyls can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in either the non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have from 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclyl" when no numerical range is specified. Heterocyclyl groups may be medium-sized heterocyclyls having from 3 to 10 ring members. Heterocyclyl groups can also be heterocyclyls having from 3 to 6 ring members. Heterocyclyl groups can be designated as "3- to 6-membered heterocyclyl" or similar designations.

[0039] In various embodiments, the heterocyclyl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to up to 3 O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2H-1,2-oxazinyl, trioxadiyl, 1H-1,2-oxazin ... nyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0040] "(Heterocyclyl)alkyl" is a heterocyclyl group connected as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0041] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl and acryl.

[0042] An "O-carboxy" group refers to a "-OC(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0043] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, C(=O) or C(=O) as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0044] A "cyano" group refers to a "-CN" group.

[0045] A "cyanato" group refers to a "-OCN" group.

[0046] An "isocyanato" group refers to a "-NCO" group.

[0047] A "thiocyanato" group refers to a "-SCN" group.

[0048] An "isothiocyanato" group refers to a "-NCS" group.

[0049] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0050] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0051] The "S-sulfonamide" group is "-SONR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0052] An “N-sulfonamide” group is defined as “-N(R A )SO2R B " group, where RA and R b each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0053] The "O-carbamyl" group is "-OC(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0054] The "N-carbamyl" group is defined as "-N(R A )OC(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0055] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0056] The "N-thiocarbamyl" group is defined as "-N(R A )OC(=S)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0057] A "C-amide" group is defined as "-C(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0058] An "N-amide" group is defined as "-N(R A )C(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0059] The "amino" group is "-NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0060] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0061] An "alkoxyalkyl" group is an alkoxy group connected via an alkylene group, e.g., "C 2~8 "Alkoxyalkyl" and the like.

[0062] As used herein, "natural amino acid side chain" refers to a side chain substituent of a naturally occurring amino acid. Naturally occurring amino acids have a substituent attached to the α-carbon and include the 20 common amino acids, listed with their one-letter abbreviations as follows: alanine (A); arginine (R); asparagine (N); aspartate (D); aspartate or asparagine (B); cysteine ​​(C); glutamate (E); glutamine (Q); glutamate or glutamine (Z); glycine (G); histidine (H); isoleucine (I); leucine (L); lysine (K); methionine (M); phenylalanine (F); proline (P); serine (S); threonine (T); tryptophan (W); tyrosine (Y); and valine (V). The term "unnatural amino acid" refers to an amino acid that has been synthesized, derivatized, and / or otherwise obtained using an artificial process.

[0063] As used herein, "unnatural amino acid side chain" refers to the side chain substituents of a non-naturally occurring amino acid. Unnatural amino acids include β-amino acids (β 3 and β2 ), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids and N-methyl amino acids. Illustrative unnatural amino acids are available from Sigma-Aldridge, listed under "Unnatural Amino Acids & Derivatives." See also Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in its entirety.

[0064] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group is independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 5- to 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5- to 10-membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,It is meant to be substituted with one or more substituents selected from C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo (=O). Whenever a group is described as "optionally substituted", that group may be substituted with the above-mentioned substituents.

[0065] In some embodiments, substituted groups are individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0066] It should be understood that certain group naming conventions can include either mono or di groups, depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, the substituent is understood to be a di group. For example, a substituent identified as an alkyl requiring two points of attachment includes di groups such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a di group, such as "alkylene" or "alkenylene".

[0067] When two R groups are described as "together with the atoms to which they are attached" forming a ring (e.g., a carbocyclyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring), the collective unit of the atoms and the two R groups is meant to be the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, the following substructures exist:

[0068] [ka]

[0069] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R2 together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0070] [ka]

[0071] where Ring A is the nitrogen-containing heterocyclyl ring as shown.

[0072] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," the collective unit of the atoms, intervening bonds, and two R groups is meant to be the recited ring. For example, the following substructure exists:

[0073] [ka]

[0074] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0075] [ka]

[0076] where A is an aryl ring or a carbocyclyl containing the double bond as shown.

[0077] Whenever a substituent is depicted as a digroup (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or

[0078] [ka]

[0079] Substituents depicted as include those where A is oriented such that it is attached at the leftmost attachment point of the molecule, and those where A is attached at the rightmost attachment point of the molecule.

[0080] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

[0081] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants as commonly used in the art may be included. Considerations for the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0082] "Subject", as used herein, means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0083] An "effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent that is effective to alleviate to some extent one or more of the symptoms of a disease or condition or to reduce the likelihood of its occurrence, as well as to cure the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated; however, even after a cure is obtained, certain long-term or permanent effects may exist (such as extensive tissue damage).

[0084] "Treat", "treatment" or "treating" as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who no longer exhibits symptoms of the disease or condition, but who is susceptible 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 administering a treatment to a subject who is already suffering from a disease or condition.

[0085] compound In some embodiments, compounds are provided that are non-macrocyclic functionalized peptides and act as dual GIP / GLP-1 receptor agonists. Various embodiments of these compounds include compounds having the structure of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof. The structure of formula (I) can be any of the following structures and mixtures thereof:

[0086] [ka]

[0087] or a pharma- ceutically acceptable salt thereof, including all stereoisomers and racemic mixtures. Formula (I) may also be written as:

[0088] [ka]

[0089] In formula (I) and compounds described herein, "H-" represents the hydrogen on the N-terminal amine and "-NH2" represents the amino that forms the C-terminal amide.

[0090] In some embodiments of the compounds of formula (I): Aib is 2-aminoisobutyric acid; J 1 , J 2 and J 3 Each instance of is independently an amino acid selected from Aib, a naturally occurring amino acid, and a non-naturally occurring amino acid.

[0091] In some embodiments of the compounds of formula (I): U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 - and; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 - and; J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 and J 11each instance of 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 -C(=O)(OZ 1 ), -P(=O)(X)(Y), and 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein heteroaryl is selected from halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 is optionally replaced by; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, wherein heteroaryl is selected from halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 is optionally replaced by; Each R 7 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 independently selected from the group consisting of alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryl and C 7~11 arylalkyl; Each R 5 are independently hydrogen or C 1~6 is alkyl; Each R 6 are independently hydrogen or C 1~6 is alkyl; Z 1 and Z 2 are hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; With the proviso that the compound is not:

[0092] [ka]

[0093] In some embodiments of the compounds of Formula (I), J 1 , J 2 and J 3 Each instance of is independently an amino acid selected from Aib and a naturally occurring amino acid.

[0094] In some embodiments of the compounds of Formula (I), J 1 , J 2 and J 3Each instance of is independently an amino acid selected from Aib, A, F, N, R, and Q. 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.

[0095] In some embodiments of the compounds of Formula (I), J 4 , J 5 , J 6 and J 7 Each instance of is independently an amino acid selected from A, I, K, R, Q, S, T, and V. 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.

[0096] In some embodiments of the compounds of Formula (I), J 8 , J 9 , J 10 and J 11 Each instance of J is independently an amino acid selected from A, I, and Q. 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.

[0097] In some embodiments of the compounds of Formula (I), J 1 is selected from Aib or F; 2 is selected from Q or N; 3 is selected from A or R; U 1 is selected from -KVA-, -KIAQ- (SEQ ID NO: 5), -KTAQ- (SEQ ID NO: 6), -KTSQ- (SEQ ID NO: 7), -KVAQ- (SEQ ID NO: 8), -RIAQ- (SEQ ID NO: 9), -KIAK- (SEQ ID NO: 10), -KISQ- (SEQ ID NO: 11), or is absent; U 2 is selected from -Q-, -IAQQ- (SEQ ID NO: 12), -IAQK- (SEQ ID NO: 13), -VAQK- (SEQ ID NO: 14), or is absent.

[0098] In some embodiments of the compound of formula (I), 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.

[0099] In some embodiments of the compounds of Formula (I), Z 1 and Z 2 At least one of is not hydrogen.

[0100] Some embodiments of the compounds of formula (I) include those of formula (Ia):

[0101] [ka]

[0102] or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments of the compounds of formula (Ia) or pharma- ceutically acceptable salts thereof, Z 1 is hydrogen, C 1~6 Alkyl, haloC1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; X and Y are each selected from the group consisting of -OR 4 It is.

[0104] In some embodiments of the compounds of formula (Ia) or pharma- ceutically acceptable salts thereof, Z 1 is hydrogen, and each R 4 are independently hydrogen or C 7~11 It is arylalkyl.

[0105] In some embodiments of the compounds of Formula (Ia) or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0106] In some embodiments of the compounds of formula (Ia) or pharma- ceutically acceptable salts thereof, Z 1 is hydrogen, and each R 4 is hydrogen.

[0107] Some embodiments of the compounds of formula (I) include those of formula (Ib):

[0108] [ka]

[0109] or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments of the compound of Formula (Ib) or a pharma- ceutically acceptable salt thereof, each R 4 is hydrogen, C 6~10 Aryl and C 7~11 arylalkyl.

[0111] In some embodiments of the compound of Formula (Ib) or a pharma- ceutically acceptable salt thereof, each R 4 is hydrogen.

[0112] In some embodiments, the present invention includes the following:

[0113] [ka] [ka] [ka]

[0114] or a pharma- ceutically acceptable salt thereof.

[0115] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is achieved by application of various methods well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein, including any polymorphic forms. In addition, some of the compounds disclosed herein can form solvates (i.e., hydrates) with water or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0116] The skilled artisan will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that may be significantly, even kinetically, represented by other chemical structures; the skilled artisan will recognize that such structures may only represent a very small proportion of the samples of such compounds. Although such compounds are believed to be within the scope of the depicted structures, such resonance forms or tautomers are not represented herein.

[0117] Method of preparation The compounds disclosed herein can be synthesized by the methods described below or by modification of these methods. The manner of modifying the methodology includes, among others, temperature, solvent, reagents, etc., known to those skilled in the art. In general, during any of the processes for the preparation of 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 by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd Edition) Wiley, New York (1999), both of which are hereby incorporated by reference in their entirety. The protecting groups can be removed at a convenient subsequent stage using methods known from the art. Synthetic chemical transformations useful in synthesizing applicable 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, 19955, both of which are hereby incorporated by reference in their entirety. The routes shown and described herein are exemplary only and are in no way intended or to be construed as limiting the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and may undertake alternative routes based on the disclosures herein; all such modifications and alternative routes are within the scope of the claims.

[0118] In the schemes below, protecting groups for the oxygen atoms are selected for their compatibility with the synthetic steps required, and for compatibility of the installation and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0119] If the compounds of the present technology contain one or more chiral centers, these compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents that are well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0120] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others 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 Supplementals (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.

[0121] Scheme 1 illustrates one method of making a compound according to formula (I). The method can 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 linkers including two PEG2 amide linkers and an isoglutamic acid (or related analogue) linker to provide intermediate (II). The method includes a coupling reaction between the amine of the isoglutamic acid (or related analogue) of intermediate (II) and intermediate (III) to provide a resin-bound intermediate (IV). In formulae (II)-(IV), R 1 ' and R 2' is R as described herein 1 Groups and R 2 The intermediate (IV) is a protected version of the protecting group. In one embodiment, the method involves subjecting intermediate (IV) to hydrolysis under acidic conditions to remove the resin and the protecting group, followed by purification to obtain the final product (I). The peptide scaffolds disclosed herein can be synthesized by solid phase peptide synthesis techniques as described in Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (ed. J. Howl, Humana Press, 2005); and Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3, Building Blocks, Catalysts and Coupling Chemistry, (ed. AB Hughs, Wiley-VCH, 2011), both of which are hereby incorporated by reference in their entireties, or obvious modifications thereof.

[0122] [ka]

[0123] The above example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0124] Administration and Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising a therapeutically effective amount of at least one compound as described elsewhere herein, and a pharma- ceutically acceptable excipient.

[0125] The compound is administered in a therapeutically effective dosage.Although human dosage level has not yet been optimized for the compounds described herein, generally, the daily dosage can be about 0.0125mg / kg to about 120mg / kg or more of body weight, about 0.025mg / kg or less to about 70mg / kg of body weight, about 0.05mg / kg to about 50mg / kg of body weight, or about 0.075mg / kg to about 10mg / kg of body weight.Thus, for administration to a 70kg human, the dosage range is about 0.08mg per day to about 8000mg per day, about 1.8mg per day or less to about 7000mg per day or more, about 3.6mg per day to about 6000mg per day, about 5.3mg per day to about 5000mg per day, or about 11mg per day to about 3000mg per day. The amount of active compound administered will, of course, be dependent on the subject and the disease condition being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician.

[0126] Administration of the compounds disclosed herein or their pharma- ceutically acceptable salts may be via any of the accepted modes of administration for agents serving similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are the norm in treating the indications that are the subject of the preferred embodiments.

[0127] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating these conditions.Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated by reference in its entirety.Thus, some embodiments include pharmaceutical compositions that include: (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs and solvates) or its pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0128] In addition to the selected compounds useful as described above, some embodiments include compositions containing pharma- ceutically acceptable carriers. The term "pharma- ceutically acceptable carriers" or "pharma- ceutically acceptable excipients" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharma- ceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants as commonly used in the art may be included. Considerations for the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0129] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tweens; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0130] The choice of a pharma- ceutically acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0131] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. Such dosage forms are contemplated to be administered once, twice, three or more times per day, can be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given more than once during a course of treatment, although single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate an entire course of treatment, and such a decision is left to the skilled artisan of treatment rather than formulation.

[0132] The compositions useful as described above may be in any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, subcutaneous or other parenteral routes of administration. In some embodiments, the compositions may be in a form suitable for subcutaneous administration. The skilled artisan will recognize that oral and nasal compositions include compositions administered by inhalation and made using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surface active agents, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes ed., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0133] A variety of oral dosage forms may be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents, and may be compressed, tablet powder, enteric coated, sugar coated, film coated, or multiple compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0134] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma- ceutically compatible adjuvants such as inert diluents, e.g., calcium carbonate, sodium carbonate, mannitol and lactose; binders, e.g., starch, gelatin and sucrose; disintegrants, e.g., starch, alginic acid and croscarmellose; lubricants, e.g., stearic acid and talc. Glidants, e.g., silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Coloring agents, e.g., FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, e.g., aspartame, saccharin, menthol, peppermint and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents as disclosed above. The selection of carrier components depends on secondary considerations, such as taste, cost and storage stability, and is not critical and can be easily made by those skilled in the art.

[0135] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavorings and colorings disclosed above.

[0136] These compositions can also be coated by conventional methods, typically using pH or time dependent coatings, so that the compound of interest is released in the vicinity of the desired local application or at various times in the gastrointestinal tract to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coating, wax and shellac.

[0137] The compositions described herein can optionally include other pharmaceutical actives.

[0138] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal and nasal dosage forms.These compositions typically comprise soluble filler material, such as sucrose, sorbitol and mannitol; and binder, such as one or more of acacia, carboxymethylcellulose and hydroxypropylmethylcellulose.They can also comprise the glidant, lubricant, sweetener, colorant, antioxidant and flavoring agent disclosed above.

[0139] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered locally to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In cases where comfort cannot be maximized, the liquid should be formulated so that the liquid is tolerable to patients for topical ophthalmic use. In addition, ophthalmically acceptable liquids should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0140] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0141] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0142] Tonicity adjusters can be added where necessary or convenient, including, but not limited to, salts, especially sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0143] Various buffers and means for adjusting pH can be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations when necessary.

[0144] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0145] Another vehicle component that can be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents can be used as appropriate or in conjunction therewith.

[0146] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0147] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 pp. 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 pp. 287-332, both of which are incorporated herein by reference in their entireties. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0148] Compositions for intravenous administration can be provided to the caregiver in one or more solid forms that are reconstituted with an appropriate diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready to be administered parenterally. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein and another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0149] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated; selection of the appropriate dose is well within the knowledge of the skilled artisan.

[0150] The compounds and compositions described herein can be present in a pack or dispenser device, if desired, which contains one or more unit dosage forms containing the active ingredient. Such a pack or device can include, for example, metal or plastic foil, such as blister pack, or glass and rubber stopper in vial. The pack or dispenser device can be accompanied by instructions for administration. The compounds and compositions described herein can be formulated in a compatible pharmaceutical carrier, and can be prepared for the treatment of the indicated pathology, placed in a suitable container, and labeled.

[0151] The amount of the compound in the formulation can vary within the full range used by those skilled in the art.Typically, the formulation contains about 0.0199.99wt% of the compound of the present technology based on the total formulation on a weight percent (wt%) basis, and the remainder is one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 180wt%.Representative pharmaceutical formulations are described below.

[0152] Treatment Method The compounds disclosed herein or their tautomers and / or pharma- ceutically acceptable salts can effectively act as GIP / GLP1 dual receptor agonists. Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharma- ceutically acceptable excipient.

[0153] Some embodiments provide a method for preventing, treating or ameliorating one or more fatty liver diseases in a subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0154] Some embodiments provide a method for preventing, treating or ameliorating steatosis, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0155] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom, hi some embodiments, the method comprises administering one or more of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a host of pathologies, including those resulting from fibrosis or inflammation and specifically associated with myofibroblast differentiation. Exemplary pathologies include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic and genetic chronic diseases), renal fibrosis (e.g., due to chronic inflammation, infection or type II diabetes), pulmonary fibrosis (idiopathic or due to environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, drugs, etc.), interstitial fibrosis, systemic sclerosis (an autoimmune disease in which many organs become fibrotic), macular degeneration (a fibrotic disease of the eye), pancreatic fibrosis (e.g., due to alcohol abuse and chronic inflammatory diseases of the pancreas), splenic fibrosis ( sickle cell anemia, from other blood disorders), cardiac fibrosis (due to infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, nonalcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemia-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0157] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the method comprises administering one or more of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0158] In some embodiments, the method of administering one or more of the compounds disclosed herein causes the amount of collagen present in one or more tissues of the subject to be reduced.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein.

[0159] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a reduction in the amount of collagen type I, type Ia or type III present in one or more tissues of the subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein or their pharma- ceutically acceptable salts.

[0160] Some embodiments provide a method for preventing, treating or ameliorating one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis in a subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0161] Some embodiments provide a method for preventing, treating or ameliorating one or more of non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis or primary biliary cirrhosis in a subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0162] Some embodiments provide a method for preventing, treating or ameliorating one or more metabolic disorders or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering one or more of the pharma- ceutically acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0163] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the GIP receptor and the GLP-1 receptor.

[0164] Some embodiments include co-administration of the compounds, compositions and / or pharmaceutical compositions described herein with additional pharmaceutical agents. By "co-administration" it is meant that two or more pharmaceutical agents can be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the pharmaceutical agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the pharmaceutical agents in a single dosage form. In another embodiment, the pharmaceutical agents are administered sequentially. In one embodiment, the pharmaceutical agents are administered via the same route, e.g., orally. In another embodiment, the pharmaceutical agents are administered via different routes, e.g., one is administered subcutaneously, another is administered orally, and another is administered iv.

[0165] The following examples are included to further illustrate the embodiments disclosed herein. The examples should not be construed as specifically limiting the present disclosure, of course. Variations of these examples within the scope of the claims are within the knowledge of a person skilled in the art and are considered to fall within the scope of the present disclosure as described and claimed herein. The reader will recognize that a skilled artisan equipped with this disclosure and the skills in the art can prepare and use the present disclosure without using the exhaustive examples. The following examples further describe the present disclosure and are used for illustrative purposes only and should not be construed as limiting. EXAMPLES

[0166] General Procedure It is clear to the skilled artisan that the methods for preparing precursors and functional groups related to the compounds claimed herein are generally described in the literature.In these reactions, it is also possible to utilize variants that are themselves known to those skilled in the art, but are not described in more detail.Given the literature and this disclosure, the skilled artisan is fully equipped to prepare any of the compounds.

[0167] It will be recognized that those skilled in the art of organic chemistry can readily perform the manipulations without further instruction, i.e., it is well within the scope and practice of the skilled artisan to perform these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification, and saponification, etc. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry, which are incorporated herein by reference in their entirety. All intermediate compounds in this disclosure were used without further purification unless otherwise specified.

[0168] The skilled artisan will readily recognize that certain reactions are best performed when other functional groups are masked or protected in the molecule, thus avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, the skilled artisan will utilize protecting groups to achieve such increased yields or avoid undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Many examples of these manipulations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Edition, John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0169] The following example schemes are provided for the reader's guidance and represent preferred methods for making the compounds illustrated herein. It is clear that these methods are not limiting and other routes can be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. The skilled artisan is fully equipped to prepare these compounds by the methods as provided in the literature and in this disclosure. The compound numbering used in the synthetic schemes illustrated below is only meaningful for those specific schemes and should not be interpreted or confused with the same numbering in other sections of this application.

[0170] The trademarks used herein are only examples and reflect the exemplary materials used at the time of this disclosure. A skilled artisan will recognize that variations in lots, manufacturing processes, etc. are expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but merely illustrative of how a skilled artisan may select to perform one or more of the embodiments of the present disclosure.

[0171] The following abbreviations have the indicated meanings: Aib = aminoisobutyric acid Bn=benzyl Boc = tert-butoxycarbonyl Bu = butyl Dde = 2-acetyldimedone DMF = Dimethylformamide EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl Fmoc = fluorenylmethoxycarbonyl HATU = Hexafluorophosphate azabenzotriazole tetramethyluranium HBTU = hexafluorophosphate benzotriazole tetramethyluranium HMDS = hexamethyldisilazane HPLC = High Performance Liquid Chromatography Me = methyl NaHMDS = sodium hexamethyldisilazide NMR=nuclear magnetic resonance PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl

[0172] The following example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0173] Example 1 Synthesis of Intermediate 1 (INT 1) Methyl 7-bromoheptanoate was reacted with triphenylphosphine to form the corresponding phosphonium bromide salt. Treatment of the thoroughly dried salt with one equivalent of NaHMDS produced the ylide, which was immediately reacted in a Wittig reaction with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol. The resulting alkene was purified by silica gel chromatography to give a pale yellow oil. Hydrogenation of the alkene and trituration of the bromo ester with methanol afforded an off-white solid. Displacement of the bromide with dibenzyl phosphite in weak base afforded the phosphonate ester, which was purified by chromatography. Hydrolysis of the methyl ester in LiOH provided the desired INT-1, which could be precipitated from aqueous HCl at pH 2. The final product could be obtained in 10-100 gram batches in >99% purity by HPLC with satisfactory MS (m / z 559.3) and NMR data. Key findings for the phosphonate ester of INT-1 31 The P signal appears at 33.3 ppm in DMSO-d6.

[0174] [ka]

[0175] Example 2 Synthesis of the peptide backbone Each 39-amino acid peptide scaffold was constructed using Fmoc solid phase peptide synthesis techniques using diimide, HATU or HBTU activation for amide linkage synthesis on Rink resin. Reagent selection varied based on the identity of the amino acid being connected. The lysines at lysine-16, lysine-19 or lysine-20 were protected with a Dde protecting group. After completion of the complete scaffold, the aminoalkyl side chains of lysine-16, lysine-19 or lysine-20 were extended with two PEG2 amide linkers followed by an isoglutamic acid residue. Specifically, the Dde group on the lysine was cleaved. The deprotected amino group on the lysine was then converted to the following structure:

[0176] [ka]

[0177] The PEGyl group was coupled to a Boc-protected PEG2 group bearing the formula:

[0178] After removing the Boc group, the second PEG2 was added. Finally, after removing the Boc group of the second PEG2, an Fmoc-protected isoglutamate was coupled to the second PEG2. The Fmoc group was then removed.

[0179] The entire backbone and side chains on lysine-16, lysine-19 or lysine-20 were synthesized before coupling to INT-1. Thus, the following intermediates were obtained prior to INT-1 coupling:

[0180] Peptides 14BB and 15BB were prepared by extending the aminoalkyl side chain of lysine-16 as noted above.

[0181] [ka]

[0182] Peptides 16BB, 17BB, 18BB, 19BB, 20BB, and 21BB were prepared by extending the aminoalkyl side chain of lysine-20.

[0183] [ka] [ka] [ka]

[0184] Peptide 22BB was prepared by extending the side chain of lysine-19.

[0185] [ka]

[0186] Example 3 Synthesis of compound 15 Peptide 15BB was coupled to INT-1 to give resin-bound protected compound 15. Amide coupling conditions were used to achieve coupling to INT-1, where INT-1 was coupled to the NH2 group of isoglutamic acid of lysine-16 in peptide 15BB. Cleavage of the resin, protecting groups on the peptide chain, and benzyl ester was performed with TFA to give compound 15, which was then purified via reversed-phase HPLC. The purity was 95.0% by RP-HPLC. The peptide content was 96.0% with satisfactory amino acid analysis. LCMS analysis showed a molecular weight of 4849.4 g / mol.

[0187] [ka]

[0188] Example 4 Synthesis of compound 14 In a manner similar to the preparation of compound 15, compound 14 was prepared from peptides 14BB and INT-1.

[0189] [ka]

[0190] Example 5 Synthesis of compound 16 In a manner similar to the preparation of compound 15, compound 16 was prepared from peptides 16BB and INT-1.

[0191] [ka]

[0192] Example 6 Synthesis of compound 17 In a manner similar to the preparation of compound 15, compound 17 was prepared from peptides 17BB and INT-1.

[0193] [ka]

[0194] Example 7 Synthesis of compound 18 In a manner similar to the preparation of compound 15, compound 18 was prepared from peptide 18BB and INT-1.

[0195] [ka]

[0196] Example 8 Synthesis of compound 19 In a manner similar to the preparation of compound 15, compound 19 was prepared from peptides 19BB and INT-1.

[0197] [ka]

[0198] Example 9 Synthesis of compound 20 In a manner similar to the preparation of compound 15, compound 20 was prepared from peptides 20BB and INT-1.

[0199] [ka]

[0200] Example 10 Synthesis of compound 21 In a manner similar to the preparation of compound 15, compound 21 was prepared from peptide 21BB and INT-1.

[0201] [ka]

[0202] Example 11 Synthesis of compound 22 In a manner similar to the preparation of compound 15, compound 22 was prepared from peptide 22BB and INT-1.

[0203] [ka]

[0204] Example 12 Synthesis of compound 23 In a manner similar to the preparation of compound 15, compound 23 was prepared from peptide 23BB and INT-1.

[0205] [ka]

[0206] Example 13 Synthesis of compound 24 In a manner similar to the preparation of compound 15, compound 24 was prepared from peptide 24BB and INT-1.

[0207] [ka]

[0208] Example 14 Synthesis of compound 25 In a manner similar to the preparation of compound 15, compound 25 was prepared from a peptide scaffold similar to that described herein and INT-1.

[0209] [ka]

[0210] Example 15 In vitro GLP-1 and GIP binding activity using HSA modulation Binding data for compounds 15-25 were obtained for two human recombinant G protein-coupled receptors, GLP-1 and GIP, using the TagLite® binding assay and Epics Therapeutics cell line. The inhibitory agonist activity of the test compounds is shown in Table 1. The binding assay was repeated in the presence of 2% human serum albumin (HSA). The ratios of compound-receptor binding with 2% HSA to compound-receptor binding without HSA are listed in Table 1. Compounds 16, 21 and 22 have HSA ratios for the GLP-1 receptor of 7.1, 7.6 and 7.8, respectively. Compounds 15, 18 and 23 have HSA ratios for the GIP receptor of 7.3, 4.3 and 6.4, respectively. The lower HSA ratios indicate greater binding affinity to the receptor than to albumin when compared to compounds with higher HSA ratios.

[0211] [Table 1]

[0212] Example 16 Biological effects of compounds in mice NASH was induced in mice by feeding them the Gubra Amylin NASH (GAN) diet as described in Boland et al., World J Gastroenterol, 2019, 25(33):4904-4920. One week prior to administration of the first dose of compound, mice were weighed and randomized, and their food intake was measured. Mice were randomly assigned to dosing groups, with 12 mice per group. The assigned dose groups were: tirzepatide (10 nmol / kg); Compound 14 (10 nmol / kg), Compound 15 (10 nmol / kg), Compound 16 (10 nmol / kg), Compound 17 (10 nmol / kg), Compound 18 (10 nmol / kg), Compound 19 (10 nmol / kg), Compound 20 (10 nmol / kg), Compound 21 (10 nmol / kg), Compound 22 (10 nmol / kg), Compound 23 (10 nmol / kg), and Compound 24 (10 nmol / kg). One group was mock treated with vehicle only as a control.

[0213] After 2 weeks, animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured, terminal necropsies of each liver were performed, relative liver mass was determined as a percentage of body weight, and total liver biochemistry was assayed, including total liver triglycerides, plasma insulin, and total liver cholesterol, as well as histological evaluation of galectin-3 and alpha-smooth muscle actin.

[0214] Liver triglyceride (TG) levels are shown in Figure 1. The data show that administration of the compounds resulted in lower relative and total liver triglycerides when compared to vehicle alone ( *indicates p<0.05 relative to vehicle). In addition, all of the compounds resulted in at least comparable, and in many compounds, lower relative and total liver triglycerides when compared to administration of tirzepatide (compounds 16, 20, 23 and 24 were statistically significantly better than tirzepatide; # indicates p<0.05, ## indicates p<0.01, and ### indicates p<0.0001 relative to tirzepatide). Liver lipid levels are shown in FIG. 2. The data show that administration of the compounds resulted in lower total liver lipids when compared to administration of tirzepatide or vehicle alone. Compounds 16, 17, 20, 21, 22, 23 and 24 had statistically significantly lower total liver lipids than tirzepatide. Liver galectin-3 levels as determined by histological quantitative assessment are shown in FIG. 3. The data show that administration of the compounds resulted in comparable or lower total liver galectin-3 when compared to administration of tirzepatide. Compounds 17, 19 and 22 had statistically significantly lower total liver galectin-3 than tirzepatide. Plasma triglyceride levels are shown in FIG. 4. All compounds produced lower plasma triglyceride levels than vehicle ( * indicates p<0.5, ** (Indicates p<0.01). In addition, most of the compounds produced lower plasma triglyceride levels than tirzepatide. Overall, the data show a surprising improvement in efficacy measures when compared to tirzepatide.

[0215] (Example 17) Pharmacokinetics of compounds in monkeys Male cynomolgus monkeys were administered subcutaneous (SC) dosing of compounds in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline solution. The assigned dose groups were: tirzepatide (TRZ) (0.2 mg / kg), compound 15 (0.2 mg / kg), compound 16 (0.2 mg / kg), compound 17 (0.2 mg / kg), compound 18 (0.2 mg / kg), compound 19 (0.2 mg / kg), compound 20 (0.2 mg / kg), compound 21 (0.2 mg / kg), compound 22 (0.2 mg / kg), compound 23 (0.2 mg / kg), and compound 24 (0.2 mg / kg). Samples were obtained 1, 4, 8, 12, 24, 48, 72, 96, 120, 168, 192, 240 and 336 hours after administration of a single dose.

[0216] Half-life, T max , C max and t AUC The average values ​​for are shown in Table 2. Surprisingly, the data show that administration of the compounds resulted in significantly higher persistence in the bloodstream when compared to administration of tirzepatide. The average half-lives of compounds 17, 19, 20, 21, 22, 23 and 24 are at least 50% longer than tirzepatide, and the average half-lives of compounds 20, 22 and 23 are more than twice as long as tirzepatide.

[0217] [Table 2]

[0218] Furthermore, in previous studies, a direct correlation between in vivo half-life and albumin binding affinity was observed; compounds with longer half-life exhibited higher albumin binding affinity. (Lau, J. et al., J. Med. Chem. 2015, 58, 7370-7380). As described above, the experiment in Example 14 showed that the HSA ratio of compound 23 for the GLP-1 receptor was one of the lowest of all compounds tested, and the second lowest for the GIP receptor of all compounds tested. These results indicate that the binding affinity of compound 23 for both the GLP-1 receptor and the GIP receptor is greater than for albumin, relative to the other compounds tested. In contrast, pharmacokinetic experiments determined that the half-life of compound 23 was the longest (6.64 days) of all compounds tested. The long half-life of compound 23 relative to the other compounds was unexpected in light of previous studies. The smaller HSA ratio for compound 23 indicates that compound 23 is expected to have a lower albumin binding affinity and a shorter half-life relative to the other compounds tested. The long half-life for compound 23 is the opposite of the expected results.

[0219] A comparison of the mean half-life values ​​and HSA ratios for the GLP-1 and GIP receptors is shown in Table 3.

[0220] [Table 3]

[0221] Although some embodiments have been illustrated and described, a person of ordinary skill in the art, after reading the foregoing specification, may effect changes, equivalent substitutions, and other types of modifications to the compounds or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof of the present technology as described herein. Each aspect and embodiment described above may include or incorporate therewith variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0222] The present technology should not be limited in terms of the particular embodiments described herein, which are intended as single illustrations of individual embodiments of the technology. Many modifications and variations of the present technology can be made without departing from the spirit and scope thereof, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds, or biological systems, which may of course vary. Moreover, it should be understood that the terminology used herein is for the purpose of describing only particular embodiments, and is not intended to be limiting. Thus, it is intended that the specification be considered as illustrative only, with the breadth, scope, and spirit of the present technology being indicated only by the appended claims, definitions therein, and any equivalents thereof.

[0223] The embodiments illustratively described herein may be suitably practiced without any element(s), limitation(s) not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc. shall be read broadly and without limitation. In addition, the terms and expressions used herein are used as descriptive terms and not as limitations, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. In addition, the phrase "consisting essentially of" is understood to include the elements as specifically recited, as well as additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0224] In addition, where a feature or aspect of the disclosure is described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described in terms of any individual member of the Markush group or subgroup of members thereof. Each of the narrower species and subgeneric groupings that fall within the generic disclosure also form part of the technology. This includes the generic description of the technology with any provisos or negative limitations that remove any subject matter from the genus, regardless of whether the omitted material is specifically recited herein.

[0225] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are hereby incorporated by reference to the same extent 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 the texts incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0226] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0227] While the present disclosure has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the present disclosure.

[0228] All references, issued patents and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0229] Although the present disclosure has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the disclosure. Accordingly, the present disclosure is limited only by the following claims.

Claims

1. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof. [In the formula, Aib is 2-aminoisobutyric acid; J 1 , J 2 and J 3 each instance of is independently an amino acid selected from Aib, a naturally occurring amino acid, and a non-naturally occurring amino acid; U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 - and; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 - and; J 1 , J 2 , and J 3 is independently an amino acid selected from Aib, A, F, N, R, and Q; 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; J 8 , J 9 , J 10 and J 11 is independently an amino acid selected from A, I, and Q; 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 -C(=O)(OZ 1 ) and -P(=O)(X)(Y); R 2 is -C(=O)(OZ 2 ) and -P(=O)(X)(Y); X and Y are each -OR 4 , C 1～6 Alkyl and haloC 1～6 independently selected from the group consisting of alkyl; Each R 4 is hydrogen, C 1～6 Alkyl, haloC 1～6 Alkyl, C 6～10 Aryl and C 7～11 arylalkyl; Z 1 and Z 2 are hydrogen, C 1～6 Alkyl, haloC 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 Aryl and C 7～11 arylalkyl; (However, the compound 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 Not only that, 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof. (But not really).

2. J 1 , J 2 , and J 3 2. The compound of claim 1, wherein each instance of is independently an amino acid selected from Aib and a naturally occurring amino acid.

3. J 1 The compound according to claim 1 or 2, wherein is Aib or F.

4. J 1 The compound according to any one of claims 1 to 3, wherein is F.

5. J 2 is N or Q.

6. J 2 6. The compound according to claim 1, wherein

7. J 3 is A or R.

8. J 3 is R.

9. J 4 is K or R.

10. J 4 is R.

11. J 5 is I, T, or V.

12. J 5 is T or V.

13. J 6 is A or S.

14. J 6 is S.

15. J 7 is Q or K.

16. J 8 16. The compound according to any one of claims 1 to 15, wherein is I or Q.

17. J 9 is A or Q.

18. J 10 is Q.

19. J 11 is Q.

20. J 1 is selected from Aib or F; J 2 is selected from Q or N; J 3 is selected from A or R; U 1 is selected from -KVA-, -KIAQ-, -KTAQ-, -KTSQ-, -KVAQ-, -RIAQ-, KIAK-, -KISQ-, or absent; U 2 is selected from -Q-, -IAQQ-, -IAQK-, -VAQK-, or is absent; 3. A compound according to claim 1 or 2.

21. 21. The compound of any one of claims 1 to 20, wherein each instance of n1, n2, n3 and n4 is zero.

22. 21. The compound of any one of claims 1 to 20, wherein each instance of n4, n6, n7 and n8 is zero.

23. 21. The compound of any one of claims 1 to 20, wherein each instance of n5, n6, n7 and n8 is zero.

24. Z 1 and Z 2 24. The compound according to any one of claims 1 to 23, wherein at least one of is not hydrogen.

25. Formula Ia: 【Chemistry 6】 25. The compound of any one of claims 1 to 24, having the structure:

26. Z 1 But hydrogen, C 1～6 Alkyl, haloC 1～6 Alkyl, C 3～10 Cycloalkyl and C 6～10 aryl; X and Y are each selected from the group consisting of -OR 4 26. The compound of claim 25,

27. Z 1 is hydrogen, and each R 4 are independently hydrogen or C 7～11 27. The compound of claim 26 which is arylalkyl.

28. Each R 4 28. The compound of claim 26 or 27, wherein is hydrogen.

29. Z 1 is hydrogen, and each R 4 27. The compound of claim 26, wherein is hydrogen.

30. Formula Ib: 【Chemistry 7】 25. The compound of any one of claims 1 to 24, having the structure:

31. Each R 4 But hydrogen, C 6～10 Aryl and C 7～11 31. The compound of claim 30, wherein said compound is independently selected from the group consisting of arylalkyl.

32. Each R 4 32. The compound of claim 31 , wherein is hydrogen.

33. 33. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 32 and a pharma- ceutically acceptable excipient.

34. 33. A pharmaceutical composition for preventing, treating or ameliorating one or more fatty liver diseases in a subject comprising a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof.

35. 35. The pharmaceutical composition of claim 34, wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

36. 36. The pharmaceutical composition of claim 34 or 35, wherein administration of the compound results in the prevention, treatment or amelioration of fibrosis, a fibrotic condition or a fibrotic symptom.

37. 37. The pharmaceutical composition of any one of claims 34 to 36, wherein administration of the compound results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject.

38. 38. The pharmaceutical composition of any one of claims 34 to 37, wherein administration of the compound results in a reduction in the amount of collagen present in one or more tissues of the subject.

39. 39. The pharmaceutical composition of claim 38, wherein administration of the compound results in a reduction in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

40. 36. The pharmaceutical composition of claim 35, wherein the compound activates the glucose-dependent insulinotropic polypeptide (GIP) receptor.

41. 36. The pharmaceutical composition of claim 35, wherein the compound activates the glucagon-like peptide-1 (GLP-1) receptor.

42. 36. The pharmaceutical composition of claim 35, wherein the compound activates the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor.

43. 33. A pharmaceutical composition for preventing, treating or ameliorating one or more diseases or disorders in a subject comprising a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein the disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

44. 44. The pharmaceutical composition of claim 43, wherein the disease or disorder is non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis or primary biliary cirrhosis.

45. 33. A pharmaceutical composition for preventing, treating or ameliorating one or more metabolic disorders or metabolic syndromes in a subject comprising a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome.

46. 46. ​​The pharmaceutical composition of any one of claims 34 to 45, wherein the subject is a mammal.

47. 47. The pharmaceutical composition of any one of claims 34 to 46, wherein the subject is a human.

48. 48. The pharmaceutical composition of any one of claims 34 to 47, wherein the route of administration is selected from the group consisting of enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal.

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