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

Abstract

Oral compositions of small molecule GLP-1 agonists and GIP / GLP-1 dual receptor agonists, as well as their use, are disclosed herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Application No. 63 / 490,512, filed on 15 March 2023, which is incorporated herein by reference in its entirety.

[0002] Reference to sequence listings This application is filed together with the sequence listing in electronic format. The sequence listing is provided as a file titled VIKNG.025PR.xml, created on March 14, 2023, with a size of 40,752 bytes. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0003] This disclosure generally relates to the fields of chemistry and pharmaceuticals. More specifically, this disclosure relates to solid oral pharmaceutical compositions for the treatment of metabolic disorders and fatty liver disease. [Background technology]

[0004] Incretin peptides, specifically glucose-dependent insulin-secreting polypeptides (GIP) and glucagon-like peptide-1 (GLP-1), are metabolic hormones. Both GIP and GLP-1 are secreted within minutes of oral nutrient intake, facilitating the rapid processing of orally ingested nutrients. Although structurally distinct, both peptides share common effects on islet β-cells acting via related receptors. Incretin receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP further promotes energy storage through its direct action on adipose tissue. In contrast, GLP-1 exerts glucose-regulating effects through slowing gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety, and sustained GLP-1 receptor activation has been associated with weight loss in both preclinical and clinical studies.

[0005] Non-alcoholic fatty liver disease (NAFLD) is a 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. GLP-1 agonists and GIP / GLP-1 dual receptor agonists have been developed to treat NAFLD, non-alcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of GLP-1 agonists and GIP / GLP-1 dual receptor agonists is associated with nausea, vomiting, and / or diarrhea. For example, clinical trials of GIP / GLP-1 dual receptor agonist compounds have found that tolerability at high doses is limited by gastrointestinal adverse events. Dose limitations associated with gastrointestinal adverse events may prevent administration to the desired effective dose, impair patient compliance with treatment, and limit the effectiveness of the treatment regimen. Therefore, there is a need for GLP-1 agonists and GIP / GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and disorders.

[0006] Peptide compounds show some potential as GLP-1 agonists and GIP / GLP-1 dual agonists that can be used to treat metabolic disorders such as NAFLD. However, there are many difficulties in preparing oral compositions of peptides. Such oral compositions have fluctuating bioavailability of the active agent. Therefore, there is a need for suitable pharmaceutical compositions of these peptide-based dual agonist compounds. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO 87 / 05297, Johnston et al., published September 11, 1987. [Patent Document 2] International Patent Publication Number WO2022 / 159395 [Non-patent literature]

[0008] [Non-Patent Document 1] Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238~311 [Non-Patent Document 2] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287~332 [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, Volumes 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) [Non-Patent Document 14] Amino Acids, Peptides and Proteins in Organic Chemistry, 3 volumes, Building Blocks, Catalysts and Coupling Chemistry, (edited by AB Hughs, Wiley-VCH, 2011) [Non-Patent Document 15] March Advanced Organic Chemistry (Wiley) [Non-Patent Document 16] Carey and Sundberg, Advanced Organic Chemistry [Non-Patent Document 17] T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 4th edition, John Wiley & Sons (2007) [Overview of the project] [Means for solving the problem]

[0009] In one aspect of the present disclosure, a pharmaceutical composition is provided that includes a permeability enhancer; and a therapeutically effective amount of a compound, where the compound is a GLP-1 agonist or a GLP / GIP dual agonist; and where the mass of the permeability enhancer is greater than 300 mg.

[0010] In some embodiments of the first aspect, the compound is a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

[0011]

Chemical formula

[0012] Where: R 1 is selected from the group consisting of -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two R 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, independently selected from one or two R 7 substituted optionally, and one or two heteroatoms selected from N, O and S, and consisting of 5- to 10-membered heteroaryl; R 2 [[ID=S43]]is selected from the group consisting of -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two R 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, independently selected from one or two R 7Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 They can be independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y are each -OR 4 , NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 It can be independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 It can be independently selected from the group consisting of arylalkoxys; Each R 5 These are independently hydrogen or C 1~6 It may be alkyl; Each R 6 These are independently hydrogen or C 1~6 It may be alkyl; Z 1 and Z 2 These are hydrogen and C, respectively. 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 It can be selected independently from the group consisting of aryls.

[0013] In some embodiments of the compound of formula (I), Z 1 and Z 2 At least one of them is not hydrogen.

[0014] In another embodiment of the first aspect, the compound is of formula (II):

[0015]

Chemical formula

[0016] a compound having the structure of, or a pharmaceutically acceptable salt thereof, wherein: Aib is 2-aminoisobutyric acid; J 1 、J 2 、and J 3 each instance of is independently an amino acid selected from Aib, naturally occurring amino acids, and non-natural amino acids; U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 -; 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, provided 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 selected from the group consisting of 5- to 10-member heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 1 to 2 Rs independently selected from 5- to 10-member heteroaryl and 5- to 10-member heterocyclyl 7 and optionally substituted by; R 2 is, -C(=O)(OZ 2 ), -P(=O)(X)(Y), and selected from the group consisting of 5- to 10-member heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 1 to 2 Rs independently selected from 5- to 10-member heteroaryl and 5- to 10-member heterocyclyl 7 and optionally substituted by; each R 7 is halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~10 aryl, independently selected from the group consisting of 5- to 10-member heteroaryl and 5- to 10-member heterocyclyl; each of X and Y is, -OR 4 , NR 5 R 6 , C 1~6 alkyl and haloC 1~6 alkyl and independently selected from the group consisting of; each R 4 is hydrogen, C 1~6 alkyl, haloC 1~6Alkyl, C 6~10 Aryl and C 7~11 Independently selected from the group consisting of arylalkyl; Each R 5 Is independently hydrogen or C 1~6 Alkyl; Each R 6 Is independently hydrogen or C 1~6 Alkyl; Z 1 And Z 2 Each is independently selected from the group consisting of hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Aryl.

[0017] In some embodiments, the compound is not:

[0018]

Chemical formula

[0019] In some embodiments of the compound of formula (II), Z 1 And Z 2 At least one of which is not hydrogen.

[0020] In still other embodiments of the first aspect, the compound is of formula (III):

[0021]

Chemical formula

[0022] A compound having the structure of, or a pharmaceutically acceptable salt thereof, wherein: R 1 Is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ),-(CH2CH2) n P(=O)(X)(Y), as well as halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y respectively are -OR 4 , NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 Independently selected from the group consisting of arylalkoxys; Each R 5 These are independently hydrogen or C 1~6 It is alkyl; Each R 6 These are independently hydrogen or C 1~6 It is alkyl; Z 1 and Z 2 Each is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Independently selected from the group consisting of aryls; n is 0, 1, 2, 3, or 4.

[0023] In some embodiments of the first aspect, the permeability enhancer is sodium salcaprozate (SNAC), sodium caprate (C10), or a combination thereof.

[0024] In a second aspect of this disclosure, a pharmaceutical composition comprising the following is provided herein: Sodium salcaprozate; and The therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof:

[0025] [ka]

[0026] (In the formula: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y respectively are -OR 4 , NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryl and C 6~10 Independently selected from the group consisting of arylalkyls; Each R 5 These are independently hydrogen or C 1~6 Alkyl Each R 6 These are independently hydrogen or C 1~6 It is alkyl; Z 1 and Z2 Each is independently selected from the group consisting of hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 aryl); Here, the mass of sarcaproth is greater than about 300 mg.

[0027] In some embodiments of the second aspect, Z 1 and Z 2 at least one of which is not hydrogen.

[0028] In some embodiments of the aspects of the present disclosure, the pharmaceutical composition is formulated for oral administration. In some such embodiments, the pharmaceutical composition is enteric-coated.

[0029] In a third aspect of the present disclosure, provided herein is a method of preventing, treating, or alleviating one or more fatty liver diseases in a subject, comprising administering to the subject the pharmaceutical composition disclosed herein, wherein the subject has a need therefor.

[0030] In a fourth aspect of the present disclosure, provided herein is a method of preventing, treating, or alleviating one or more diseases or disorders in a subject, comprising administering to the subject the pharmaceutical composition provided herein, wherein the subject has a need therefor, wherein the disease or disorder is liver fibrosis, kidney fibrosis, bile duct fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

[0031] A fifth aspect of this disclosure provides methods for preventing, treating, or alleviating metabolic disorders or metabolic syndromes. In some embodiments, the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes mellitus, hyperglycemic diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or Prader-Willi syndrome.

[0032] In a sixth aspect of this disclosure, a method for preparing a pharmaceutical composition is provided herein. In some embodiments, the method includes the following steps: (i) A step of forming first granules by combining a permeability enhancer and magnesium stearate; (ii) A step of forming a second granule by combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidinone. (iii) The step of forming a mixture by combining the first granules and the second granules; (iv) A step of forming a third granule by adding magnesium stearate to the mixture; (v) The process of pressurizing the third granule into a tablet.

[0033] In other embodiments, the method includes the following steps: (i) A step of forming first granules by combining sodium salcaprozate (SNAC) and magnesium stearate; (ii) A step of forming a second granule by combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidinone. (iii) The step of forming a mixture by combining the first granules and the second granules; (iv) A step of forming a third granule by adding magnesium stearate to the mixture; (v) The process of pressurizing the third granule into a tablet.

[0034] In other embodiments, the method includes the following steps: (i) A step of forming first granules by combining C10 and magnesium stearate; (ii) A step of forming a second granule by combining microcrystalline cellulose, a compound disclosed herein, and polyvinylpyrrolidinone. (iii) The step of forming a mixture by combining the first granules and the second granules; (iv) A step of forming a third granule by adding magnesium stearate to the mixture; (v) The process of pressurizing the third granule into a tablet.

[0035] In some embodiments, a method for preparing a pharmaceutical composition is provided herein, the method comprising the following steps: (i) A step of combining microcrystalline cellulose and the compounds disclosed herein in a first tank; (ii) The process of combining polyvinylpyrrolidinone and water in a second tank; (iii) A step of forming wet granules by adding the contents of the first tank to the second tank; (iv) A step of forming dry granules by drying the wet granules; (v) the step of combining dried granules with magnesium stearate; and (vi) A step of pressurizing the mixture obtained as a result of step (v) into granules. [Brief explanation of the drawing]

[0036] [Figure 1] This graph illustrates the mean plasma concentration versus time profile following oral administration of various compounds to male beagle dogs. [Figure 2] This graph shows a comparison of AUC values ​​for dogs administered with varying amounts of salcaprozate sodium (SNAC) and formulations of compound 4. [Figure 3] This graph illustrates the mean plasma concentration versus time profile following oral administration of various compounds to male beagle dogs. [Figure 4]This graph illustrates the mean plasma concentration versus time profile following administration of various formulations of compound 4 to male cynomolgus monkeys. [Figure 5A] This graph illustrates the mean plasma concentration versus time profile following administration of compound 24 with various excipients to male Sprague Dawley rats. [Figure 5B] This graph illustrates the mean plasma concentration versus time profile following administration of compound 27 with various excipients to male Sprague Dawley rats. [Figure 5C] This graph illustrates the mean plasma concentration versus time profile following administration of compound 4 with various excipients to male Sprague Dawley rats. [Modes for carrying out the invention]

[0037] In some embodiments, the pharmaceutical composition is provided for administration to subjects requiring it. Various embodiments of these pharmaceutical compositions include a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable diluent, and any combination thereof. Some embodiments of the pharmaceutical composition include a therapeutically effective dose of a compound as otherwise described herein, or a pharmaceutically acceptable salt thereof. Some embodiments of the pharmaceutical composition are administered for the prevention, treatment, or relief of one or more fatty liver diseases in subjects.

[0038] definition Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated in their entirety by reference. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise specified.

[0039] A "solvate" refers to a compound formed by the interaction of a solvent with a compound or a salt thereof described herein. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0040] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a compound and is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds used herein can form acid and / or base salts in the presence of an amino group and / or a carboxyl group or similar group. Pharmaceutically acceptable acid addition salts can form inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include 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, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which salts can be derived include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum; ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many of these salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (which is incorporated herein by reference in its entirety).

[0041] As used herein, "a" and "b" are integers. a From Cb " or "C a~b " refers to the number of carbon atoms in the specified group. That is, the group can contain an inclusive "a" to "b" carbon atoms. Therefore, for example, "C1 to C4 alkyl" or "C 1~4 The "alkyl" group refers to all alkyl groups having one to four carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0042] As used herein, the term "halogen" or "halo" means any one of the radioactively stable atoms in the seventh column of the periodic table, for example, fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0043] 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). An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, numerical ranges such as “1 to 20” refer to each integer within a given range; for example, “1 to 20 carbon atoms” means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms and including them, although this definition also includes the use of the term “alkyl” where no numerical range is specified). An alkyl group may also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group of the compound is “C 1~4 It may be designated as "alkyl" or a similar name. For example, "C 1~4The term "alkyl" indicates that there are one to four carbon atoms in the alkyl chain; that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0044] As used herein, “haloalkyl” refers to a linear or branched alkyl group having one to twelve carbon atoms in the chain, in which one or more hydrogen atoms are substituted with halogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that are considered equivalent to any one of the above examples in light of the usual art and the teachings provided herein.

[0045] As used herein, “alkoxy” means an alkyl of the formula -OR, for example, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, etc. 1~9 It refers to "alkoxy".

[0046] As used herein, "polyethylene glycol" is defined as formula

[0047] [ka]

[0048] The term "n" refers to a repeating unit, where n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by referring to a number of members. For example, "2-membered to 5-membered polyethylene glycol" refers to n, which is 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.

[0049] As used herein, “heteroalkyl” refers to a linear or branched hydrocarbon chain containing one or more heteroatoms in its chain skeleton, i.e., an element other than carbon, including but not limited to nitrogen, oxygen, and sulfur. A heteroalkyl group may have 1 to 20 carbon atoms, but this definition also includes the occurrence of the term “heteroalkyl” when no numerical range is specified. A heteroalkyl group may be a medium-sized heteroalkyl group having 1 to 9 carbon atoms. A heteroalkyl group may also be a lower heteroalkyl group having 1 to 4 carbon atoms. In various embodiments, a heteroalkyl group may have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compound is “C 1~4 It may be designated as "heteroalkyl" or a similar name. A heteroalkyl group may contain one or more heteroatoms. For example, "C 1~4 "Heteroalkyl" indicates that the heteroalkyl chain contains one to four carbon atoms and, additionally, one or more heteroatoms in the backbone of the chain.

[0050] 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 polycyclic (i.e., rings sharing adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0051] As used herein, “aryl” refers to an aromatic ring or ring system containing only carbon atoms in its ring skeleton (i.e., two or more fused rings sharing two adjacent carbon atoms). If the aryl is a ring system, all rings in the system are aromatic. While an aryl group can have 6 to 18 carbon atoms, this definition also includes instances where the term “aryl” is used without specifying a numerical range. In some embodiments, an aryl group has 6 to 10 carbon atoms. 6~10 "Aryl", "C6 or C 10 It can be designated as "aryl" or by a similar name. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azlenyl, and anthracenyl.

[0052] As used herein, “aryloxy” and “arylthio” include RO- and RS-, where R is an aryl as defined above, for example, phenyloxy, but not limited to “C 6~10 "aryloxy" or "C 6~10 This refers to "arylthio," etc.

[0053] "Aralkyl" or "arylalkyl" refers to an aryl group linked via an alkylene group as a substituent, for example, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl, including "C 7~14 These include "aralkyl" and others. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0054] As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms in a ring skeleton, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. If the heteroaryl is a ring system, all rings in the system are aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also includes the occurrence of the term “heteroaryl” when no numerical range is specified. In some embodiments, a heteroaryl group has 5 to 10 ring members, or 5 to 7 ring members. A heteroaryl group may be designated as a “5- to 7-membered heteroaryl,” a “5- to 10-membered heteroaryl,” or similar names. In various embodiments, a heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl contains one to four nitrogen atoms, one to three nitrogen atoms, one to two nitrogen atoms, two nitrogen atoms and one sulfur or oxygen atom, one nitrogen atom and one sulfur or oxygen atom, or one 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.

[0055] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked via an alkylene group as a substituent. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 (Alkylene group)

[0056] As used herein, “carbocyclyl” means a non-aromatic cyclic ring or cyclic system containing only carbon atoms in its cyclic framework. If a carbocyclyl is a cyclic system, two or more rings may be joined together by condensation, bridging, or spiroconjugation. A carbocyclyl can have any degree of saturation, provided that at least one ring in the cyclic system is non-aromatic. Therefore, examples of carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. A carbocyclyl group may have 3 to 20 carbon atoms, but this definition also includes the use of the term “carbocyclyl” when no numerical range is specified. A carbocyclyl group may be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is a “C 3~6 It may be designated as "carbocykrill" or a similar name. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicyclic[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0057] "(Carbocyclyl)alkyl" includes, but is not limited to, carbocyclyl groups connected via alkylene groups as substituents, such as cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. 4-10 Examples include "(carbocykyl)alkyl" groups. In some cases, the alkylene group is a lower alkylene group.

[0058] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0059] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein the ring in the ring system is not aromatic. An example is cyclohexenyl.

[0060] As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in its ring skeleton. Heterocyclyls may be joined together by condensation, bridging, or spiroconjugation. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. Heteroatoms may be present in either the non-aromatic or aromatic rings in the ring system. A heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also includes the use of the term “heterocyclyl” when no numerical range is specified. A heterocyclyl group may be a medium-sized heterocyclyl having 3 to 10 ring members. A heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. A heterocyclyl group may be designated as a “3- to 6-membered heterocyclyl” or similar designation.

[0061] In various embodiments, the heterocyclil contains one to four heteroatoms, one to three heteroatoms, one to two heteroatoms, or one heteroatom. For example, in various embodiments, the heterocyclil contains one to four nitrogen atoms, one to three nitrogen atoms, one to two nitrogen atoms, two nitrogen atoms and one sulfur or oxygen atom, one nitrogen atom and one sulfur or oxygen atom, or one sulfur or oxygen atom. In a preferred six-membered monocyclic heterocyclil, the heteroatoms are selected from one to a maximum of three O, N, or S atoms, and in a preferred five-membered monocyclic heterocyclil, the heteroatoms are selected from one or two heteroatoms selected from O, N, or S atoms. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanil, imidazolinyl, imidazolidinyl, morpholinil, oxylanil, oxepanil, thiepanil, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxynyl, 1,3-dioxanyl, 1,4-dioxynyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxathianyl Examples include yl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiadinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0062] "(heterocyclyl)alkyl" refers to a heterocyclyl group that is linked via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0063] As used herein, “acyl” refers to -C(=O)R, where R is hydrogen, C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 These include carbocyclyls, aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclyls. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylic.

[0064] The "O-carboxyl" group refers to the "-OC(=O)R" group, where R is hydrogen and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 The selection is made from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0065] The "C-carboxyl" group refers to the "-C(=O)OR" group, where R is hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 The compounds are selected from carbocyclyls, aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclyls. Non-limiting examples include carboxyls (i.e., -C(=O)OH).

[0066] The "cyano" group refers to the "-CN" group.

[0067] The "cyanato" group refers to the "-OCN" group.

[0068] The "isocyanate" group refers to the "-NCO" group.

[0069] The "thiocyanate" group refers to the "-SCN" group.

[0070] The "isothiocyanate" group refers to the "-NCS" group.

[0071] The "sulfinyl" group refers to the "-S(=O)R" group, where R is hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0072] The "sulfonyl" group refers to the "-SO2R" group, where R is hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0073] The "S-sulfonamide" group is "-SO2NR A R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0074] The "N-sulfonamide" group is "-N(R A )SO2R B " refers to the base, where RA and R b Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0075] The "O-carbamyl" group is "-OC(=O)NR" A R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0076] The "N-carbamyl" group is "-N(R A )OC(=O)R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0077] The "O-thiocarbamyl" group is "-OC(=S)NR" A R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0078] The "N-thiocarbamyl" group is "-N(R A )OC(=S)R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0079] The "C-amide" group is "-C(=O)NR A R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0080] The "N-amide" group is "-N(R A )C(=O)R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0081] The "amino" group is "-NR A R B " refers to the base, where R A and R B Each is independently of hydrogen, and C as defined herein. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~7 Carbocyclyl, C 6~10 The selection is made from aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines.

[0082] The "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0083] The "alkoxyalkyl" group is an alkoxy group connected via an alkylene group, for example, "C 2~8 This refers to terms such as "alkoxyalkyl."

[0084] As used herein, substituted groups are derived from unsubstituted parent groups in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise indicated, when a group is considered "substituted", the group is independently a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyrill (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyrill-C1-C6-alkyl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyrill-C1-C6-alkyl (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), (may be substituted with coxy), 5- to 10-membered heterocyclyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl-C1-C6-alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy) (may be substituted with lucoxy), aryl(C1-C6)alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-membered to 10-membered heteroaryl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-membered to 10-membered heteroaryl(C1-C6)alkyl (may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy (and may be substituted with C1-C6 haloalkoxys), 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,This means that the group is substituted with one or more substituents selected from C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanate, thiocyanate, isothiocyanate, sulfinyl, sulfonyl, and oxo (=O). Whenever it is stated that a group "may be substituted," that group may be substituted with the substituents listed above.

[0085] In some embodiments, the substituted groups are individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy, and halogen groups.

[0086] Certain nomenclature conventions should be understood to include either monogroups or digroups, depending on the context. For example, a substituent is understood to be a digroup if it requires two bonding sites to the rest of the molecule. Examples of substituents identified as alkyl groups requiring two bonding sites include digroups such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2-. Other nomenclature conventions clearly indicate that the group is a digroup such as "alkylene" or "alkenylene".

[0087] When it is stated that two R groups "together with the atom to which they are bonded" form a ring (e.g., a carbocykyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring), the collective unit of the atom and the two R groups is meant to be the listed ring. The ring, when considered individually, is not otherwise limited by the definition of each R group. For example, the following substructures exist:

[0088] [ka]

[0089] R 1 and R 2 However, it is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R2 However, if they form a heterocycline together with the nitrogen to which they are bound, R 1 and R 2 This means that it can be selected from hydrogen or alkyl, or alternatively, the substructure is structure:

[0090] [ka]

[0091] The formula has such that ring A is a nitrogen-containing heterocyclyl ring as shown in the figure.

[0092] Similarly, when it is stated that two "adjacent" R groups "together with the atom to which they are bonded" form a ring, the atom, the intervening bond, and the collective unit of the two R groups are meant to be the enumerated ring. For example, the following substructures exist:

[0093] [ka]

[0094] R 1 and R 2 However, it is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 However, when they form an aryl or carbocykrine with the atoms to which they are bonded, R 1 and R 2 This means that it can be selected from hydrogen or alkyl, or alternatively, the substructure is structure:

[0095] [ka]

[0096] The formula comprises a carboxyl compound containing an aryl ring or the double bond shown in the figure.

[0097] Whenever a substituent is illustrated as a di group (i.e., having two bonding points to the rest of the molecule), it should be understood that the substituent may be bonded in any orientation unless otherwise indicated. Therefore, for example, -AE- or

[0098] [ka]

[0099] The substituents shown include those where A is bonded at the leftmost bond point of the molecule, and those where A is bonded at the rightmost bond point of the molecule.

[0100] The term "mammal" is used in its ordinary biological sense. Therefore, it specifically includes, but is not limited to, primates including monkeys (chimpanzees, apes, and monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, as well as many other species.

[0101] When used herein, “Subject” means human or non-human mammals, such as dogs, cats, mice, rats, cows, sheep, pigs, goats, non-human primates, or birds, such as chickens, and any other vertebrates or invertebrates.

[0102] When used herein, “effective dose” or “therapeutic dose” refers to the amount of a therapeutic agent that is effective in alleviating to some extent one or more symptoms of a disease or condition, or in reducing the likelihood of their occurrence, and also in curing the disease or condition. “Cure” means that the symptoms of the disease or condition are eliminated; however, even after a cure has been achieved, certain long-term or permanent effects may exist (e.g., extensive tissue damage).

[0103] When used herein, “to treat,” “treatment,” or “to treat” refers to administering a pharmaceutical composition for preventive and / or therapeutic purposes. The term “preventive treatment” refers to treating a subject who no longer exhibits symptoms of a disease or condition but is susceptible to or otherwise at risk of a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering a treatment to a subject who already has a disease or condition.

[0104] compound In some embodiments, the pharmaceutical composition comprises a compound that is a non-macrocyclic functionalized peptide acting as a GIP / GLP-1 dual receptor agonist. In other embodiments, the pharmaceutical composition comprises a compound that is a non-macrocyclic functionalized peptide acting as a GLP-1 receptor monoagonist.

[0105] If the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, including racemates, or as mixtures of such isomers. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the category of compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms, including any polymorphs, are included in the category of compounds disclosed herein. In addition, some of the compounds disclosed herein can form solvates (i.e., hydrates) using water or common organic solvents. Unless otherwise indicated, such solvates are included in the category of compounds disclosed herein.

[0106] Skilled technicians will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be more clearly represented by other chemical structures, even kinetically; and those skilled in the art will recognize that such structures may represent only a very small sample of such compounds. While these compounds are considered to fall within the range of the illustrated structures, such resonance forms or tautomers are not represented herein.

[0107] Compound of formula (I) Various embodiments of these compounds include compounds having the structure of formula (I) as described above, or pharmaceutically acceptable salts thereof. The structure of formula (I) encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0108] [ka]

[0109] In some embodiments of the compound of formula (I): R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5, C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 They can be independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y are each -OR 4 , NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 It can be independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryl and C 6~10 It can be independently selected from the group consisting of arylalkyls; Each R 5 These are independently hydrogen or C 1~6 It may be alkyl; Each R 6 These are independently hydrogen or C 1~6 It may be alkyl; Z 1 and Z 2 These are hydrogen and C, respectively. 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 It can be selected independently from the group consisting of aryls.

[0110] In some embodiments, Z 1 and Z 2 At least one of them is not hydrogen.

[0111] Some embodiments of the compound of formula I include formula (Ia):

[0112] [ka]

[0113] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0114] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts; Z 1 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from the alphabet; X and Y are each -OR 4 That is the case.

[0115] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts; Z 1 Hydrogen, Halo C 1~6 Alkoxy and C 1~6 Selected from alkoxy; each R 4 is hydrogen, C 6~10 Aryl and C 6~10 It can be selected independently of arylalkyl groups.

[0116] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts; Z 1 is hydrogen, and each R 4 These are independently hydrogen or C 6~10 It may be an arylalkyl.

[0117] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts; each R 4 It is hydrogen.

[0118] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts; Z 1 is hydrogen, and each R 4 It is hydrogen.

[0119] Some embodiments of the compound of formula (I) include formula (Ib):

[0120] [ka]

[0121] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0122] In some embodiments of the compounds of formula (Ib) or their pharmaceutically acceptable salts; Z 2 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from the alphabet; X and Y are each -OR 4 That is the case.

[0123] In some embodiments of the compounds of formula (Ib) or their pharmaceutically acceptable salts; Z 2 Hydrogen, Halo C 1~6 Alkoxy and C 1~6 Selected from alkoxy; each R 4 is hydrogen, C 6~10 Aryl and C 6~10 It can be selected independently of arylalkyl groups.

[0124] In some embodiments of the compounds of formula (Ib) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R4 These are independently hydrogen or C 6~10 It may be an arylalkyl.

[0125] In some embodiments of the compounds of formula (Ib) or their pharmaceutically acceptable salts; each R 4 It is hydrogen.

[0126] In some embodiments of the compounds of formula (Ib) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 It is hydrogen.

[0127] Some embodiments of the compound of formula (I) include formula (Ic):

[0128] [ka]

[0129] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0130] In some embodiments of the compounds of formula (Ic) or their pharmaceutically acceptable salts; X and Y are, respectively, -OR 4 That is the case.

[0131] In some embodiments of the compounds of formula (Ic) or their pharmaceutically acceptable salts; each R 4 is hydrogen, C 6~10 Aryl and C 6~10 It can be selected independently of arylalkyl groups.

[0132] In some embodiments of the compounds of formula (Ic) or their pharmaceutically acceptable salts; each R 4 It is hydrogen.

[0133] Some embodiments include,

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138] Examples include compounds having a structure selected from the group consisting of the and pharmaceutically acceptable salts thereof.

[0139] Some embodiments include: * Examples include compounds in which the carbon atom exhibits a chiral configuration with an "S" stereochemistry.

[0140] Some embodiments include: * Examples include compounds in which the carbon atom exhibits a chiral configuration with an "R" stereochemistry.

[0141] The compounds of formula (I) described herein, for example, compounds 1 to 12, can be prepared according to the method described in International Patent Publication No. WO2022 / 159395, which is incorporated herein in its entirety.

[0142] Compound formula (II) Various embodiments of these compounds include compounds having the structure of formula (II) as described herein, or pharmaceutically acceptable salts thereof. The structure of formula (II) includes all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0143] [ka]

[0144] or include its pharmaceutically acceptable salt. Formula (II) can also be written as follows:

[0145] [ka]

[0146] In the formulas (II) and compounds described herein, "H-" represents a hydrogen atom on the N-terminal amine, and "-NH2" represents an amino acid that forms the C-terminal amide.

[0147] In some embodiments of the compound of formula (II): Aib is 2-aminoisobutyric acid; J 1 , J 2 , and J 3 Each instance of is an amino acid independently selected from Aib, naturally occurring amino acids, and unnatural amino acids.

[0148] In some embodiments of the compound of formula (II): 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 either a naturally occurring amino acid or a non-natural amino acid; Each of n1, n2, n3, n4, n5, n6, n7, and n8 is independently either 0 or 1, provided 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 a group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O and S, wherein the heteroaryl is a halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 It is replaced by optional selection; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and a group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O and S, wherein the heteroaryl is a halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 It is replaced by optional selection; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y are each -OR 4 , NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryl and C 7~11 Independently selected from the group consisting of arylalkyls; Each R 5 These are independently hydrogen or C 1~6 It is alkyl; Each R 6 These are independently hydrogen or C 1~6 It is alkyl; Z 1 and Z 2 These are hydrogen and C, respectively. 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 It is independently selected from the group consisting of aryls.

[0149] In some embodiments, the compound is not:

[0150] [ka]

[0151] In some embodiments of the compound of formula (II), J 1 , J 2 , and J 3 Each instance of is an amino acid independently selected from Aib and naturally occurring amino acids.

[0152] In some embodiments of the compound of formula (II), J 1 , J 2 , and J 3Each instance is independently an amino acid selected from Aib, A, F, N, R, and Q. In some embodiments, J 1 is Aib or F. In some embodiments, J 1 F 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 It is R.

[0153] In some embodiments of the compound of formula (II), J 4 , J 5 , J 6 , and J 7 Each instance is independently an amino acid selected from A, I, K, R, Q, S, T, and V. In some embodiments, J 4 is K or R. In some embodiments, J 4 R 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 Q is Q. In some embodiments, J 7 is K.

[0154] In some embodiments of the compound of formula (II), J 8 , J 9 , J 10 , and J 11 Each instance is independently an amino acid selected from A, I, and Q. In some embodiments, J 8 is I or Q. In some embodiments, J 9 is A or Q. In some embodiments, J 10 Q is Q. In some embodiments, J 11 Q is Q.

[0155] In some embodiments of the compound of formula (II), 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 -KVA-, -KIAQ- (sequence number 8), -KTAQ- (sequence number 9), -KTSQ- (sequence number 10), -KVAQ- (sequence number 11), -RIAQ- (sequence number 12), -KIAK- (sequence number 13), -KISQ- (sequence number 14), or none; U 2 It is selected from -Q-, -IAQQ- (sequence number 15), -IAQK- (sequence number 16), -VAQK- (sequence number 17), or does not exist.

[0156] In some embodiments of the compound of formula (II), instances n1, n2, n3, and n4 are zero. In some embodiments, instances n4, n6, n7, and n8 are zero. In some embodiments, instances n5, n6, n7, and n8 are zero.

[0157] In some embodiments of the compound of formula (II), Z 1 and Z 2 At least one of them is not hydrogen.

[0158] Some embodiments of the compound of formula (II) include formula (II-a):

[0159] [ka]

[0160] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0161] In some embodiments of the compounds of formula (II-a) or their pharmaceutically acceptable salts, Z 1is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from the group consisting of aryls; X and Y are each -OR 4 That is the case.

[0162] In some embodiments of the compounds of formula (II-a) or their pharmaceutically acceptable salts, Z 1 is hydrogen, and each R 4 These are independently hydrogen or C 7~11 It is an arylalkyl.

[0163] In some embodiments of the compounds of formula (II-a) or their pharmaceutically acceptable salts, each R 4 It is hydrogen.

[0164] In some embodiments of the compounds of formula (II-a) or their pharmaceutically acceptable salts, Z 1 is hydrogen, and each R 4 It is hydrogen.

[0165] Some embodiments of the compound of formula (II) include formula (II-b):

[0166] [ka]

[0167] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0168] In some embodiments of the compounds of formula (II-b) or their pharmaceutically acceptable salts, each R 4 is hydrogen, C 6~10 Aryl and C 7~11 It is independently selected from the group consisting of arylalkyls.

[0169] In some embodiments of the compounds of formula (II-b) or their pharmaceutically acceptable salts, each R 4 It is hydrogen.

[0170] Some embodiments include,

[0171] [ka]

[0172] [ka]

[0173] [ka]

[0174] Examples include compounds having a structure selected from the group consisting of pharmaceutically acceptable salts thereof.

[0175] The compounds of formula (II) disclosed herein can be synthesized by the methods described below or by modifications thereof. Modifications to these methodologies include, among other things, temperatures, solvents, reagents, etc., known to those skilled in the art. Generally, during any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect a sensitive or reactive group on any of the molecules involved. This can be achieved by means of conventional protecting groups, e.g., Protective Groups in Organic Chemistry (edited by 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 incorporated herein by reference in their entirety. Protecting groups can be removed in a convenient subsequent step using methods known from the art. Useful synthetic chemical transformations for synthesizing applicable compounds are known in the art, for example, those described in R. Larock, *Comprehensive Organic Transformations*, VCH Publishers, 1989, or L. Paquette, ed., *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended or to be construed as limiting the scope of the claims in any way. Those skilled in the art will recognize modifications of the disclosed synthesis and may take alternative routes based on the disclosures herein; all such modifications and alternative routes are within the scope of the claims.

[0176] In the following scheme, oxygen atom protecting groups are selected for their compatibility with the required synthetic steps, as well as for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition), Wiley, New York (1999)).

[0177] If a compound in this technology contains one or more chiral centers, such 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 in the scope of this technology unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0178] 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 commercially available suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made 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 by obvious modifications thereof.

[0179] Scheme 1 illustrates one method for preparing a compound according to formula (II). The method may include a step of providing a resin-binding peptide by constructing a peptide skeleton using a solid-phase peptide synthesis technique. The side chain of a central lysine containing a Dde group can then be extended with a linker containing two PEG2 amide linkers and an isoglutamic acid (or related analog) linker to provide intermediate (II-A). The method may include a step of providing a resin-binding intermediate (II-C) by a coupling reaction between intermediate (II-A) and the isoglutamic acid (or related analog) amine of intermediate (II-B). In formulas (II-A) to (II-C), R 1 'and R2 ' is R as described herein 1 Base and R 2 This is a protected version of the group. In one embodiment, the method involves removing the resin and protecting group by hydrolysis of the intermediate (II-C) under acidic conditions, followed by purification to obtain the final product (I). The peptide skeletons disclosed herein can be synthesized by solid-phase peptide synthesis techniques described in Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (edited by J. Howl, Humana Press, 2005); and Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3, Building Blocks, Catalysts and Coupling Chemistry, (edited by AB Hughs, Wiley-VCH, 2011), or by obvious modifications thereof, both of which are incorporated herein by reference in their entirety.

[0180] [ka]

[0181] The above example schemes are provided for the reader's reference and collectively represent exemplary methods for preparing the compounds contained herein. Furthermore, 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 variable compounds are as defined above.

[0182] Compound of formula (III) Various embodiments of these compounds include compounds having the structure of formula (III) as described herein, or pharmaceutically acceptable salts thereof. The structure of formula (III) encompasses all stereoisomers.

[0183] [ka]

[0184] In some embodiments of the compound of formula (III): R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 They can be independently selected from the group consisting of aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines; X and Y are each -OR 4, NR 5 R 6 , C 1~6 Alkyl and Halo C 1~6 It can be independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 It can be independently selected from the group consisting of arylalkoxys; Each R 5 These are, independently, hydrogen or C 1~6 It may be alkyl; Each R 6 These are independently hydrogen or C 1~6 It may be alkyl; Z 1 and Z 2 These are hydrogen and C, respectively. 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 It can be independently selected from the group consisting of aryls, n is 0, 1, 2, 3, or 4.

[0185] In some embodiments, Z 1 and Z 2 At least one of them is not hydrogen.

[0186] Some embodiments of the compound of formula (III) are shown in formula (III-a):

[0187] [ka]

[0188] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0189] In some embodiments of the compounds of formula (Ia) or their pharmaceutically acceptable salts, Z1 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from the alphabet; X and Y are each -OR 4 That is the case.

[0190] In some embodiments of the compounds of formula (III-a) or their pharmaceutically acceptable salts, Z 1 Hydrogen, Halo C 1~6 Alkoxy and C 1~6 Selected from alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 It can be selected independently of arylalkoxys.

[0191] In some embodiments of the compounds of formula (III-a) or their pharmaceutically acceptable salts; Z 1 is hydrogen, and each R 4 These are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0192] In some embodiments of the compounds of formula (III-a) or their pharmaceutically acceptable salts, each R 4 It is hydrogen.

[0193] In some embodiments of the compounds of formula (III-a) or their pharmaceutically acceptable salts, Z 1 is hydrogen, and each R 4 It is hydrogen.

[0194] In some embodiments of the compound of formula (III-a) or its pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In yet another embodiment, n is 2. In yet another embodiment, n is 3. In some embodiments, n is 4.

[0195] Some embodiments of the compound of formula (III) include formula (III-b):

[0196] [ka]

[0197] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0198] In some embodiments of the compounds of formula (III-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, C 1~6 Alkyl, Halo C 1~6 Alkyl, Halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from the alphabet; X and Y are each -OR 4 That is the case.

[0199] In some embodiments of the compounds of formula (III-b) or their pharmaceutically acceptable salts; Z 2 Hydrogen, Halo C 1~6 Alkoxy and C 1~6 Selected from alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 It can be selected independently of arylalkoxys.

[0200] In some embodiments of the compounds of formula (III-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 These are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0201] In some embodiments of the compounds of formula (III-b) or their pharmaceutically acceptable salts; each R 4 It is hydrogen.

[0202] In some embodiments of the compounds of formula (III-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 It is hydrogen.

[0203] In some embodiments of the compound of formula (III-b) or its pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In yet another embodiment, n is 2. In yet another embodiment, n is 3. In some embodiments, n is 4.

[0204] Some embodiments of the compound of formula (III) include formula (III-c):

[0205] [ka]

[0206] Examples include compounds having the structure shown, or pharmaceutically acceptable salts thereof.

[0207] In some embodiments of the compounds of formula (III-c) or their pharmaceutically acceptable salts, X and Y are, respectively, -OR 4 That is the case.

[0208] In some embodiments of the compounds of formula (III-c) or their pharmaceutically acceptable salts, each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 They can be independently selected from arylalkoxys. In some embodiments of the compounds of formula (III-c) or their pharmaceutically acceptable salts, each R 4 It is hydrogen.

[0209] In some embodiments of the compounds of formula (III-c) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In yet another embodiment, n is 2. In yet another embodiment, n is 3. In some embodiments, n is 4.

[0210] Some embodiments include,

[0211] [ka]

[0212] [ka]

[0213] Examples include compounds having a structure selected from the group consisting of the and pharmaceutically acceptable salts thereof.

[0214] Some embodiments include: * Examples include compounds in which the carbon atom exhibits a chiral configuration with an "S" stereochemistry.

[0215] Some embodiments include: * Examples include compounds in which the carbon atom exhibits a chiral configuration with an "R" stereochemistry.

[0216] The compounds of formula (III) disclosed herein can be synthesized by the methods described below or by modifications thereof. Modifications to these methodologies include, among other things, temperatures, solvents, reagents, etc., known to those skilled in the art. Generally, during any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect a sensitive or reactive group on any of the molecules involved. This can be achieved by means of conventional protecting groups, e.g., those described in Protective Groups in Organic Chemistry (edited by JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protective Groups in Organic Synthesis (3rd edition), Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. Protecting groups can be removed in a convenient subsequent step using methods known from the art. Useful synthetic chemical transformations for synthesizing applicable compounds are known in the art, for example, those described in R. Larock, *Comprehensive Organic Transformations*, VCH Publishers, 1989, or L. Paquette, ed., *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended or to be construed as limiting the scope of the claims in any way. Those skilled in the art will recognize modifications of the disclosed synthesis and may take alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0217] In the following scheme, protecting groups for oxygen atoms are selected based on their compatibility with the required synthetic steps, as well as their compatibility with the overall synthetic scheme and the introduction and deprotection steps (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition), Wiley, New York (1999)).

[0218] If a compound in this technology contains one or more chiral centers, such 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 in the scope of this technology unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0219] 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 commercially available suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other preparations can be made 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 by obvious modifications thereof.

[0220] In one embodiment, the method disclosed herein may include providing an intermediate (III-A) by constructing a 31-amino acid peptide skeleton using a solid-phase peptide synthesis technique. The peptide skeleton comprises two PEG2 amide linkers. The method includes providing a resin-bound intermediate (III-C) by an amide coupling reaction between the amine of the terminal PEG2 amide of intermediate (III-A) and a suitably substituted carboxylic acid (III-B). In one embodiment, the method involves hydrolyzing intermediate (III-C) under acidic conditions, followed by purification, to obtain the final product (III). (Scheme 2).

[0221] [ka]

[0222] The above example schemes are provided for the reader's reference and represent a collective example of methods for preparing the compounds contained herein. Furthermore, 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 variable substances are as defined above.

[0223] Pharmaceutical composition Some embodiments include pharmaceutical compositions comprising compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c), or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises one or more permeability enhancers. In some embodiments, the pharmaceutical composition further comprises excipients. In some embodiments, the pharmaceutical composition is suitable for use as an oral dosage form.

[0224] Compounds that cannot be properly administered orally due to insufficient oral bioavailability can be formulated using permeability enhancers. Permeability enhancers can increase the absorption of the pharmaceutically active ingredient by enhancing membrane permeability. In some embodiments, the permeability enhancer is present in the pharmaceutical composition at a mass percentage of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 85%, or more, or within the range defined by any two of the aforementioned mass percentages. For example, in some embodiments, the permeability enhancer is present in the pharmaceutical composition at a mass percentage of about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 50% to about 75%, about 60% to about 75%, or about 70% to about 75%. In some embodiments, the permeability enhancer is sodium salcaprozate (i.e., sodium 8-(2-hydroxybenzamide)octanoate or "SNAC"), sodium caproate (C10), or a combination thereof. In some embodiments, the permeability enhancer is SNAC. In other embodiments, the permeability enhancer is C10. In other embodiments, the permeability enhancer is a combination of SNAC and C10. In some embodiments, the permeability enhancer is lauroyl-L-carnitine chloride (LCC). In some embodiments, the permeability enhancer is Labrasol®. Labrasol® contains PEG-8 mono and diesters of caprylic acid (C8) and capric acid (C10) along with smaller fractions of mono, di, and triglycerides.

[0225] In some embodiments, the amount of permeability enhancer in the pharmaceutical compositions described herein is approximately 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 2 20mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 36 0mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500m g, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg , 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, The range is defined as 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg or more, or any two of the aforementioned values. For example, in some embodiments, the amount of permeability enhancer in the pharmaceutical composition described herein is about 1 mg to about 1000 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 400 mg to about 800 mg, about 400 mg to about 600 mg, or about 500 mg to about 750 mg. In some embodiments, the amount of the permeability enhancer in the pharmaceutical composition described herein is greater than 300 mg, greater than 350 mg, greater than 400 mg, greater than 450 mg, greater than 500 mg, greater than 550 mg, greater than 600 mg, greater than 650 mg, greater than 700 mg, greater than 750 mg, greater than 800 mg, greater than 850 mg, greater than 900 mg, greater than 950 mg, or greater than 1000 mg.

[0226] In some embodiments, the amounts of compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition are approximately 0.5%, 0.6%, 0.7%, 0.8%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, and 2. It has a mass percentage of 0.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, or more, or within the range defined by any two of the aforementioned values. In some embodiments, the amount of compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is in the range of about 1.0% to about 5.0% by mass, about 2.0% to about 4.0% by mass, about 3.0% to about 4.0% by mass, or about 3.5% to about 4.0% by mass. In some embodiments, the amount of compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is about 3.6% by mass.

[0227] In some embodiments, the amounts of compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition are approximately 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg. g, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg , 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg, 30.5mg, 31mg , 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5mg, 38mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg or more, or within the range defined by any two of the aforementioned values. For example, in some embodiments, the amount of compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is approximately 1 mg to approximately 30 mg, approximately 5 mg to approximately 25 mg, approximately 10 mg to approximately 20 mg, approximately 10 mg to approximately 30 mg, or approximately 20 mg to approximately 30 mg.

[0228] In some embodiments, the amount of compound 4 in the pharmaceutical composition is approximately 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg, 18.5mg, 19mg, 19.5mg, 2 0mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5m g, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg, 30.5mg, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 3 3.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5mg, 38mg, 38.5mg, 39mg, 39.5mg, 40m g, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50 mg, or more, or within the range defined by any two of the aforementioned values. For example, in some embodiments, the amount of compound 4 in the pharmaceutical composition is about 1 mg to about 30 mg, about 5 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 30 mg, or about 20 mg to about 30 mg.

[0229] In some embodiments, the amount of compound 4 in the pharmaceutical composition is about 5 mg to about 30 mg, and the amount of SNAC is about 350 mg to about 1000 mg. In some embodiments, the amount of compound 4 in the pharmaceutical composition is about 10 mg to about 30 mg, and the amount of SNAC is about 400 mg to about 800 mg. In some embodiments, the amount of compound 4 in the pharmaceutical composition is about 15 mg to about 25 mg, and the amount of SNAC is about 450 mg to about 750 mg. In some embodiments, the amount of compound 4 in the pharmaceutical composition is about 20 mg, and the amount of SNAC is about 450 mg. In some embodiments, the amount of compound 4 in the pharmaceutical composition is about 25 mg, and the amount of SNAC is about 500 mg.

[0230] In some embodiments, the mass ratio of the permeability enhancer pair of compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is approximately 1:1, 2:1, 3:1, 5:1, 10:1, 15:1, 16:1, 17:1, 18:1, 19 :1, 20:1, 20.5:1, 21:1, 21.5:1, 22:1, 22.5:1, 23:1, 23.5:1, 24:1, 24.5:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 35:1, 40:1, 45:1, 50:1, or more, or within the range defined by any two of the aforementioned ratios. For example, in some embodiments, the mass ratio of the permeability enhancer pair compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) in the pharmaceutical composition is about 1:1 to about 50:1, about 10:1 to about 25:1, about 15:1 to about 25:1, or about 20:1 to about 25:1.

[0231] In some embodiments, the pharmaceutical compositions described herein include one or more additional pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipients,” as used herein, includes, but is not limited to, solvents, dispersants, coatings, antimicrobial agents, adjuvants, isotonic agents, and absorption retarders. In some embodiments, pharmaceutically acceptable excipients include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; binders, e.g., polyvinylpyrrolidinone (PVP), polyvinyl alcohol, polyethylene glycol, cellulose, and cellulose derivatives (methylcellulose, ethylcellulose, hydroxypropylcellulose, etc.), polyvinyl alcohol; solid lubricants, e.g., stearic acid, silicon dioxide, and magnesium stearate; calcium sulfate; vegetable oils, e.g., peanut oil. Examples include cottonseed oil, sesame oil, olive oil, and corn oil; polyols, e.g., propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers and surfactants, e.g., Tween; humectants, e.g., sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives, e.g., benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercury, and phenylmercury nitrate; tonicity modifiers, e.g., sodium chloride, potassium chloride, mannitol, and glycerin; vehicles, e.g., polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, and hydroxyethylcellulose; and pyrogen-free water. In some embodiments, pharmaceutically acceptable excipients are selected based on the route of administration and may include solid or liquid fillers, binders, diluents, hydrotropes, surfactants, and encapsulating substances.For example, in the case of intravenous administration, excipients may include gelatin; carbohydrates, such as dextrose, mannitol, and dextran; and antioxidants, such as sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. In some embodiments, pharmaceutically acceptable excipients may include antimicrobial agents, such as phenylmercury nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol. Examples of appropriate pharmaceutically acceptable additional excipients are described in Powell et al., Compendium of Excipients for Parenteral Compositions, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, each of which is incorporated herein by reference in their entirety.

[0232] In some embodiments, the pharmaceutical compositions described herein may include compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) and SNACs. In some such embodiments, the pharmaceutical compositions may further include microcrystalline cellulose, polyvinylpyrrolidinone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof.

[0233] In some embodiments, the pharmaceutical compositions described herein may include compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c) and C10. In some such embodiments, the pharmaceutical compositions may further include microcrystalline cellulose, polyvinylpyrrolidinone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof.

[0234] In some embodiments, the pharmaceutical compositions described herein may include compounds of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c), as well as combinations of SNAC and C10. In some such embodiments, the pharmaceutical compositions may further include microcrystalline cellulose, polyvinylpyrrolidinone (PVP), polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA), magnesium stearate, or a combination thereof.

[0235] In some embodiments, the pharmaceutical compositions described herein may contain microcrystalline cellulose in amounts of about 5% by mass, 10% by mass, 15%, 16% by mass, 17% by mass, 18% by mass, 19% by mass, 20% by mass, 21% by mass, 22% by mass, 23% by mass, 24% by mass, 25% by mass, 26% by mass, 27% by mass, 28% by mass, 29% by mass, 30% by mass, 31% by mass, 32% by mass, 33% by mass, 34% by mass, 35% by mass, 36% by mass, 37% by mass, 38% by mass, 39% by mass, 40% by mass, 41% by mass, 42% by mass, 43% by mass, 44% by mass, 45% by mass, 46% by mass, 47% by mass, 48% by mass, 49% by mass, 50% by mass, or more, or within the range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may contain about 10% to 50% by mass, 10% to 40% by mass, 10% to 30% by mass, 15% to 30% by mass, 15% to 25% by mass, or 15% to 20% by mass of microcrystalline cellulose. In some embodiments, the pharmaceutical compositions described herein contained about 19.4% by mass of microcrystalline cellulose.

[0236] In some embodiments, the pharmaceutical compositions described herein may contain polyvinylpyrrolidinone in amounts of about 0.5% by mass, 1.0% by mass, 1.1% by mass, 1.2% by mass, 1.3% by mass, 1.4% by mass, 1.5% by mass, 1.6% by mass, 1.7% by mass, 1.8% by mass, 1.9% by mass, 2.0% by mass, 2.1% by mass, 2.2% by mass, 2.3% by mass, 2.4% by mass, 2.5% by mass, 2.6% by mass, 2.7% by mass, 2.8% by mass, 2.9% by mass, 3.0% by mass, 3.1% by mass, 3.2% by mass, 3.3% by mass, 3.4% by mass, 3.5% by mass, 3.6% by mass, 3.7% by mass, 3.8% by mass, 3.9% by mass, 4.0% by mass, 4.5% by mass, or 5.0% by mass, or within the range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may contain polyvinylpyrrolidinone in amounts of about 1.0% to about 5.0% by mass, about 1.0% to about 4.0% by mass, about 1.0% to about 3.0% by mass, about 1.5% to about 3.0% by mass, about 1.5% to about 2.5% by mass, or about 1.5% to about 2.0% by mass. In some embodiments, the pharmaceutical compositions described herein contained about 1.9% by mass of polyvinylpyrrolidinone.

[0237] In some embodiments, the pharmaceutical compositions described herein may contain magnesium stearate in amounts of about 0.5% by mass, 1.0% by mass, 1.1% by mass, 1.2% by mass, 1.3% by mass, 1.4% by mass, 1.5% by mass, 1.6% by mass, 1.7% by mass, 1.8% by mass, 1.9% by mass, 2.0% by mass, 2.1% by mass, 2.2% by mass, 2.3% by mass, 2.4% by mass, 2.5% by mass, 2.6% by mass, 2.7% by mass, 2.8% by mass, 2.9% by mass, 3.0% by mass, 3.1% by mass, 3.2% by mass, 3.3% by mass, 3.4% by mass, 3.5% by mass, 3.6% by mass, 3.7% by mass, 3.8% by mass, 3.9% by mass, 4.0% by mass, 4.5% by mass, or 5.0% by mass, or within the range defined by any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may contain magnesium stearate in amounts of about 1.0% to about 5.0% by mass, about 1.0% to about 4.0% by mass, about 1.0% to about 3.0% by mass, about 1.5% to about 3.0% by mass, about 1.5% to about 2.5% by mass, or about 1.5% to about 2.0% by mass. In some embodiments, the pharmaceutical compositions described herein contained about 2.3% by mass of magnesium stearate.

[0238] In some embodiments, the pharmaceutical compositions described herein may contain a disintegrant. In some embodiments, the pharmaceutical composition may contain a disintegrant in an amount within the range defined by 0.5% by mass, 1.0% by mass, 1.1% by mass, 1.2% by mass, 1.3% by mass, 1.4% by mass, 1.5% by mass, 1.6% by mass, 1.7% by mass, 1.8% by mass, 1.9% by mass, 2.0% by mass, 2.1% by mass, 2.2% by mass, 2.3% by mass, 2.4% by mass, 2.5% by mass, 2.6% by mass, 2.7% by mass, 2.8% by mass, 2.9% by mass, 3.0% by mass, 3.1% by mass, 3.2% by mass, 3.3% by mass, 3.4% by mass, 3.5% by mass, 3.6% by mass, 3.7% by mass, 3.8% by mass, 3.9% by mass, 4.0% by mass, 4.5% by mass, or 5.0% by mass, or any two of the aforementioned percentages. For example, the pharmaceutical compositions described herein may contain a disintegrant in amounts of about 1.0% to about 5.0% by mass, about 1.0% to about 4.0% by mass, about 1.0% to about 3.0% by mass, about 1.5% to about 3.0% by mass, about 1.5% to about 2.5% by mass, or about 1.5% to about 2.0% by mass. In some embodiments, the pharmaceutical compositions described herein contained about 1.9% by mass of a disintegrant. In some embodiments, the disintegrant may be croscarmellose sodium (e.g., Primellose, AcDiSol). In some embodiments, the disintegrant may be sodium alginate. In some embodiments, the disintegrant may be crospovidone. In some embodiments, the disintegrant may be sodium starch glycolate.

[0239] In some embodiments, the pharmaceutical compositions described herein may contain about 1.0% to about 5.0% by mass of a compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 50% to about 80% by mass of sodium salcaprozate; about 10% to about 30% by mass of microcrystalline cellulose; about 1.0% to about 3.0% by mass of polyvinylpyrrolidinone; and about 1.0% to about 3.0% by mass of magnesium stearate. In some of these embodiments, the pharmaceutical composition comprises: about 3.6% by mass of a compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 72.7% by mass of sodium salcaprozate; about 19.4% by mass of microcrystalline cellulose; about 1.9% by mass of polyvinylpyrrolidinone; and about 2.3% by mass of magnesium stearate. In other such embodiments, the pharmaceutical composition comprises: about 3.2% by mass of a compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c); about 71.1% by mass of sodium salcaprozate; about 21.1% by mass of microcrystalline cellulose; about 2.1% by mass of polyvinylpyrrolidinone; and about 2.6% by mass of magnesium stearate.

[0240] The pharmaceutical composition comprises a therapeutically effective dose or amount of a compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c). The terms “therapeutic dose” or “therapeutic amount,” as used herein, depend on the subject and disease state being treated, the severity of the distress, the method and schedule of administration, and the judgment of the prescribing physician. In some embodiments, the therapeutic dose may be a daily dose of about 0.0125 mg / kg to about 120 mg / kg or more of body weight, about 0.025 mg / kg or less to about 70 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.075 mg / kg to about 10 mg / kg of body weight. Therefore, for administration to a 70kg person, the dosage range is approximately 0.88mg to 8000mg per day, approximately 1.8mg or less per day to approximately 7000mg or more per day, approximately 3.6mg to 6000mg per day, approximately 5.3mg to 5000mg per day, or approximately 11mg to 3000mg per day. In some embodiments, the therapeutically effective dose is approximately 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.12 mg / kg, 0.14 mg / kg, 0.15 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.19 mg / kg, 0.20 mg / kg, 0.21 mg / kg, 0.22 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.26 mg / kg, 0.28 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, 500 mg / kg, or a range including and / or spanning the aforementioned values. In some embodiments, the therapeutically effective dose is approximately 0.01 mg / kg to approximately 5 mg / kg. In some embodiments, the therapeutically effective dose is approximately 0.05 mg / kg to approximately 1 mg / kg. In some embodiments, the therapeutically effective dose is approximately 0.15 mg / kg to approximately 0.25 mg / kg.

[0241] The pharmaceutical composition may be administered by routes of administration including, but are not limited to, enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intrapulmonary, vaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration is selected from the group consisting of enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered orally.

[0242] The pharmaceutical composition can be provided in dosage form. In some embodiments, the dosage form is solid. Examples of solid dosage forms include tablets, capsules, granules, and bulk powders. In some embodiments, the solid dosage form is a tablet.

[0243] In some embodiments, the pharmaceutical composition is administered to a mammalian subject. In some such embodiments, the pharmaceutical composition is administered to a human subject.

[0244] Method for preparing dosage forms The pharmaceutical composition can be formulated into an oral dosage form. In some embodiments, the oral dosage form may be a tablet. In some such embodiments, the tablet may be enterically coated.

[0245] In some embodiments, tablets can be prepared using a dry granulation method. In some embodiments, the method includes the following steps: (i) forming a first granule by combining a permeability enhancer and magnesium stearate; (ii) forming a second granule by combining microcrystalline cellulose, a compound of formula (I), (Ia), (Ib), (Ic), (II), (II-a), (II-b), (III), (III-a), (III-b), or (III-c), and polyvinylpyrrolidinone; (iii) forming a mixture by combining the first and second granules; (iv) forming a third granule by adding magnesium stearate to the mixture; and (v) pressurizing the third granule into a tablet. In some embodiments, the permeability enhancer is SNAC. In some embodiments, the compound is compound 4.

[0246] In some embodiments, tablets can be prepared using a wet granulation method. In some embodiments, the method comprises the steps of: (i) combining microcrystalline cellulose and a compound disclosed herein in a first tank; (ii) combining polyvinylpyrrolidinone and water in a second tank; (iii) adding the contents of the first tank to the second tank to form wet granules; (iv) drying the wet granules to form dry granules; (v) combining the dry granules with magnesium stearate; and (vi) pressurizing the mixture obtained as a result of step (v) into granules.

[0247] In some embodiments, tablets can be prepared by a spray-drying dispersion method. For example, in some embodiments, the compounds disclosed herein, but not limited to, hydroxypropyl methylcellulose acetate succinate type M (HPMCAS-M); hydroxypropyl methylcellulose acetate succinate type L (HPMCAS-L); polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA64); Eudragit® L100, or any combination thereof, can be combined in a solvent with polymers to form a solution for spray drying. The solution is then dried with a stream of heated nitrogen and recovered using a cyclone. The spray-dried material is then combined with microcrystalline cellulose, magnesium stearate, and additional fillers and disintegrants and pressurized into tablets.

[0248] In some embodiments, tablets can be prepared by a wet granulation method. In some embodiments, the compounds disclosed herein are combined with microcrystalline cellulose and hydroxypropyl cellulose. In some embodiments, a mixture of materials is wet-granulated using purified water as the granulation liquid and then dried. The dried granules are then milled and blended. A lubricant (e.g., magnesium stearate) is then added to the blend mixture, and the resulting mixture can be compressed into tablets.

[0249] Treatment method The pharmaceutical compositions disclosed herein comprise compounds or tautomers thereof and / or pharmaceutically acceptable salts thereof that can effectively act as GIP / GLP1 dual receptor agonists. The pharmaceutical compositions further comprise one or more pharmaceutically acceptable carriers and one or more pharmaceutically acceptable diluents.

[0250] Some embodiments provide methods for preventing, treating, or alleviating one or more fatty liver diseases in a subject. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need.

[0251] Some embodiments provide methods for preventing, treating, or alleviating steatosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need.

[0252] In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in the prevention, treatment, or relief of fibrosis, fibrotic conditions, or fibrotic symptoms.

[0253] In some embodiments, the pharmaceutical compositions described herein can be used to treat hosts with conditions including those resulting from fibrosis or inflammation and specifically associated with myofibroblast differentiation. Exemplary conditions include progressive hepatic fibrosis (alcoholic, viral, autoimmune, metabolic, and hereditary chronic diseases), renal fibrosis (e.g., resulting from chronic inflammation, infection, or type II diabetes), pulmonary fibrosis (idiopathic, or resulting from environmental intrusion including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, drugs, etc.), interstitial fibrosis, systemic scleroderma (an autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (e.g., resulting from alcohol abuse and chronic inflammatory disease of the pancreas), and splenic fibrosis. Examples include sickle cell anemia (due to other blood disorders), cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endocardial myocardial fibrosis, retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, non-alcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection of transplanted organs, ischemia-reperfusion injury-related fibrosis, fibrosis due to injection, cirrhosis, diffuse parenchymal pulmonary disease, post-vasectomy pain syndrome, and rheumatoid arthritis or disorders.

[0254] In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in a reduction of the amount of extracellular matrix proteins present in one or more tissues of the subject.

[0255] In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in a reduction of the amount of collagen present in one or more tissues of the subject.

[0256] In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in a reduction of the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

[0257] Some embodiments provide methods for preventing, treating, or alleviating one or more of the following conditions in a subject: hepatic fibrosis, renal fibrosis, cholangiofibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need.

[0258] Some embodiments provide methods for preventing, treating, or alleviating one or more of the following conditions in a subject: non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need.

[0259] Some embodiments provide methods for preventing, treating, or alleviating one or more metabolic disorders or metabolic syndromes. In some embodiments, the diseases or disorders are atherosclerosis, diabetes mellitus, hyperglycemic diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or Prader-Willi syndrome. In some embodiments, the method includes administering one or more of the pharmaceutical compositions disclosed herein to a subject in need.

[0260] In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in activation of glucose-dependent insulin-secreting polypeptide (GIP) receptors. In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in activation of glucagon-like peptide-1 (GLP-1) receptors. In some embodiments, a method of administering one or more of the pharmaceutical compositions disclosed herein results in activation of both GIP and GLP-1 receptors.

[0261] Some embodiments involve the co-administration of a pharmaceutical composition and / or compound or a pharmaceutically acceptable salt thereof described herein, along with an additional pharmaceutical. “Co-administration” means that two or more drugs may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the drugs are administered simultaneously. In one such embodiment, the administration in combination is achieved by combining the drugs in single dosage forms. In another embodiment, the drugs are administered sequentially. In one embodiment, the drugs are administered via the same route, for example, orally. In another embodiment, the drugs are administered via different routes, for example, one subcutaneously, another orally, and another intravenously.

[0262] To further illustrate this disclosure, the following embodiments are provided. These embodiments should, of course, not be construed as specifically limiting the disclosure. Variations of these embodiments within the scope of the claims are within the knowledge of those skilled in the art and are considered to fall within the scope of the disclosure as described and claimed herein. Readers will recognize that a skilled technician with the skills in the art can prepare and use the disclosure without using the exhaustive embodiments. The following embodiments further describe the disclosure and are used for illustrative purposes only and should not be construed as limiting it. [Examples]

[0263] General procedure It is evident to a skilled technician that 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 known to those skilled in the art but not described in more detail. A skilled technician given the literature and this disclosure is well capable of preparing any of these compounds.

[0264] It is recognized that skilled technicians in the art of organic chemistry can easily perform these operations without further instruction; that is, these operations are well within the scope and practice of a skilled technician. These include the reduction, oxidation, acylation, aromatic substitution, electrophilic and nucleophilic properties, etherification, esterification, and saponification of carbonyl compounds to their corresponding alcohols. These operations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, and 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.

[0265] A skilled technician will readily recognize that certain reactions are best carried out when other functional groups are masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the reaction yield. Often, skilled technicians achieve such yield increases or avoid unwanted reactions by utilizing protecting groups. These reactions are found in the literature and are well within the realm of a skilled technician. Many examples of these operations 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 in its entirety by reference.

[0266] The following example schemes are provided for the reader's reference and represent preferred methods for preparing the compounds illustrated herein. These methods are not limiting, and it is evident that other routes may be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Skilled technicians are fully capable of preparing these compounds by methods such as those given in the literature and in this disclosure. The compound numbering used in the synthesis schemes illustrated below is meaningful only for those specific schemes and should not be interpreted or confused with the same numbering in other sections of this application.

[0267] The trademarks used herein are illustrative and reflect the exemplary materials used at the time of this disclosure. A skilled technician will be aware that variations in lot, manufacturing process, etc., are to be expected. Therefore, the examples and the trademarks used therein are not limiting and are not intended to be limiting, but are merely illustrative of how a skilled technician may choose to carry out one or more embodiments of the disclosure.

[0268] The following abbreviations have the meanings indicated: λz = lambda (apparent discharge rate constant) AUC = Area under the plasma concentration-time curve AUC last = AUC from time 0 to time of final quantifiable concentration AUC inf = AUC extrapolated from time 0 to infinity Aib = aminoisobutyric acid BLQ = Below the limit of quantification C max =T max The maximum observable concentration that occurs in this case CL / F = Systemic clearance following extravascular administration CV% = Percentage coefficient of variation DMF = Dimethylformamide HPLC = High-Performance Liquid Chromatography LC-MS / MS = Liquid Chromatography Tandem Mass Spectroscopy LLOQ = Lower limit of quantification N = Number of samples with numerical values NMR=nuclear magnetic resonance PCC = Pyridinium Chlorochromate PEG = polyethylene glycol Ph = Phenyl PK = Pharmacokinetics PO = Oral administration PVP = Polyvinylpyrrolidinone PVP-VA = Polyvinylpyrrolidinone-vinyl acetate copolymer R 2 = Regression correlation coefficient T max =C max The time when it occurred t 1 / 2 = Half-life V z / F = Volume of distribution following extravascular administration

[0269] The following example schemes are provided for the reader's reference and collectively represent exemplary methods for preparing the compositions provided herein. Furthermore, other methods for preparing the compositions 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.

[0270] (Example 1) Synthesis of Intermediate 1 (INT 1) Methyl 7-bromoheptanoate was reacted with triphenylphosphine to form the corresponding phosphonium bromide salt. The thoroughly dried salt was treated with 1 equivalent of NaHMDS to produce an 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 obtain a pale yellow oil. Hydrogenation of the alkene and trituration of the bromoester with methanol yielded an off-white solid. The bromide was replaced with dibenzyl phosphite in a weak base to obtain the phosphonic acid ester, which was purified by chromatography. Hydrolysis of the methyl ester in LiOH provided the desired INT-1, which could be precipitated from an aqueous HCl solution at pH 2. The final product could be obtained in 10-100 gram batches with >99% purity by HPLC, along with satisfactory MS (m / z 559.3) and NMR data. Key information regarding the phosphonic acid ester of INT-1. 31 The P signal appears at 33.3 ppm in DMSO-d6.

[0271] [ka]

[0272] (Example 2) Peptide skeleton synthesis Each 39-amino acid peptide skeleton was constructed using the Fmoc solid-phase peptide synthesis technique with diimide, HATU, or HBTU activation for amide linkage synthesis on Rink resin. Reagent selection varied based on the identity of the linked amino acids. Lysine was protected with a Dde protecting group at lysine-16, lysine-19, or lysine-20. Upon completion of the complete skeleton, the aminoalkyl side chain of lysine-16, lysine-19, or lysine-20 was extended with two PEG2 amide linkers followed by an isoglutamic acid residue. Specifically, the Dde group on lysine was cleaved. The deprotected amino group on lysine was then coupled to a Boc-protected PEG2 group having the following structure:

[0273] [ka]

[0274] After removing the BOC group, a second PEG2 was added. Finally, after removing the BOC group from the second PEG2, Fmoc-protected isoglutamate was coupled to the second PEG2. The Fmoc group was then removed.

[0275] The entire skeleton and side chain on lysine-16, lysine-19, or lysine-20 were synthesized and then coupled to INT-1. Therefore, the following intermediates were obtained before the INT-1 coupling.

[0276] Peptide 13BB was prepared by extending the aminoalkyl side chain of lysine-16 as noted above.

[0277] [ka]

[0278] Peptides 14BB, 15BB, 16BB, 17BB, 18BB, 19BB, 21BB, and 22BB were prepared by extending the aminoalkyl side chain of the lysine-20 side chain.

[0279] [ka]

[0280] [ka]

[0281] [ka]

[0282] Peptide 20BB was prepared by extending the side chain of lysine-19.

[0283] [ka]

[0284] (Example 3) Synthesis of compound 13 Protecting compound 13 for the resin bond was obtained by coupling peptide 13BB to INT-1. Coupling to INT-1 was achieved using amide coupling conditions, by coupling INT-1 to the NH2 group of the isoglutamic acid at lysine-16 in peptide 13BB. The resin, protecting group on the peptide chain, and benzyl ester were cleaved with TFA to provide the compound, which was then purified by reverse-phase HPLC. The purity was 95.0% by RP-HPLC. The peptide content was 96.0%, giving satisfactory amino acid analysis results. LC-MS analysis showed a molecular weight of 4849.4 g / mol.

[0285] [ka]

[0286] (Example 4) Synthesis of compound 14 Compound 14 was prepared from peptide 14BB and INT-1 using a method similar to that used for preparing compound 13.

[0287] [ka]

[0288] (Example 5) Synthesis of Compound 15 Compound 15 was prepared from peptide 15BB and INT-1 using a method similar to that used for preparing compound 13.

[0289] [ka]

[0290] (Example 6) Synthesis of compound 16 Compound 16 was prepared from peptide 16BB and INT-1 using a method similar to that used for preparing compound 13.

[0291] [ka]

[0292] (Example 7) Synthesis of Compound 17 Compound 17 was prepared from peptide 17BB and INT-1 using a method similar to that used for preparing compound 13.

[0293] [ka]

[0294] (Example 8) Synthesis of compound 18 Compound 18 was prepared from peptide 18BB and INT-1 using a method similar to that used for preparing compound 13.

[0295] [ka]

[0296] (Example 9) Synthesis of compound 19 Compound 19 was prepared from peptide 19BB and INT-1 using a method similar to that used for preparing compound 13.

[0297] [ka]

[0298] (Example 10) Synthesis of compound 20 Compound 20 was prepared from peptide 20BB and INT-1 using a method similar to that used for preparing compound 13.

[0299] [ka]

[0300] (Example 11) Synthesis of Compound 21 Compound 21 was prepared from peptide 21BB and INT-1 using a method similar to that used for preparing compound 13.

[0301] [ka]

[0302] (Example 12) Synthesis of compound 22 Compound 22 was prepared from peptide 22BB and INT-1 using a method similar to that used for preparing compound 13.

[0303] [ka]

[0304] (Example 13) Synthesis of compound 23 Compound 23 was prepared using a method similar to that used for the preparation of compound 13, from a peptide skeleton and INT-1 similar to those described herein.

[0305] [ka]

[0306] (Example 14) Synthesis of Intermediate 2 (INT 2) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. This salt is treated with 1 equivalent of NaHMDS to produce an ylide, which is immediately reacted in a Wittig reaction with the aldehyde from the PCC oxidation of 10-bromo-1-decanol. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonic acid ester. Hydrolysis of the methyl carboxylate provides the desired INT 2 having terminal carboxylic acids and dibenzyl phosphonates.

[0307] [ka]

[0308] Synthesis of intermediate 2A (INT 2A) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. This salt is treated with 1 equivalent of NaHMDS to produce an ylide, which is immediately reacted in a Wittig reaction with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonic acid ester. Hydrolysis of the methyl carboxylate provides the desired INT 2A having terminal carboxylic acids and dibenzyl phosphonates.

[0309] [ka]

[0310] Synthesis of Intermediate 3 (INT 3) Octadecanedioic acid is coupled to benzyl alcohol using EDC·HCl and DMAP in THF to obtain INT 3 as a monobenzyl ester.

[0311] [ka]

[0312] Synthesis of Intermediate 4 (INT 4) t-butyl 4-hydroxybutanoate undergoes Swarn oxidation to obtain an aldehyde. The aldehyde condenses with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. The addition of a lithium salt of diethyl phosphite to THF generates an α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group, providing INT 4 having a free primary amine, a t-butyl ester, and a diethyl phosphonate. The optical purity of INT 4 is determined by Mosher amide analysis. 1 This was confirmed by 1H-NMR to be at least 96%.

[0313] [ka]

[0314] Synthesis of Intermediate 5 (INT 5) INT 2 is coupled with 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 5.

[0315] [ka]

[0316] Synthesis of intermediate 5A (INT 5A) INT 2A is coupled with 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 5A.

[0317] [ka]

[0318] Synthesis of Intermediate 5 (INT 5) INT 3 is coupled with INT 4 in the presence of HATU and triethylamine in DMF to prepare a new amide linkage. Cleavage of ethyl phosphonate using TMS-Br yields free phosphonate. Re-esterification of N,N'-diisopropylcarbamimidic acid using a large excess of benzyl ester provides the corresponding dibenzyl phosphonate. The t-butyl ester is cleaved using TFA to provide INT 6.

[0319] [ka]

[0320] Synthesis of Intermediate 7 (INT 7) INT 2, when coupled with INT 4 in the presence of HATU and triethylamine in DMF, provides a new amide linkage. Cleavage of benzyl and ethyl phosphonate esters using TMS-Br yields both free phosphonates. Re-esterification of N,N'-diisopropylcarbamimidic acid using a large excess of benzyl ester provides the corresponding tetrabenzyl diphosphonate ester. The t-butyl ester is cleaved using TFA to give INT 7.

[0321] [ka]

[0322] (Example 15) Synthesis of a common peptide skeleton The 31-amino acid peptide skeleton is constructed using solid-phase peptide synthesis techniques employing diimide, HATU, or HBTU activation for amide linkage synthesis on Rink resin. Reagent selection varies based on the identity of the linked amino acids. The R group of lysine-20 is extended with two PEG2 amide linkers. The entire skeleton is synthesized on the resin prior to coupling INT 5, INT 5A, INT 6, or INT 7 to the amino terminus of the lysine linking linker.

[0323] [ka]

[0324] (Example 16) Synthesis of Compound 24 The peptide backbone is coupled to INT 5 to obtain a protected compound 24 bound to the resin. Cleavage of the resin, protection of the peptide chain, and the benzyl ester of INT 5 using TFA provide compound 24, which is purified via HPLC.

[0325] [ka]

[0326] (Example 17) Synthesis of Compound 25 The peptide backbone is coupled to INT 6 to obtain a protected compound 24 bound to the resin. Cleavage of the resin, protection of the peptide chain, and the benzyl ester of INT 6 using TFA provide compound 24, which is purified via HPLC.

[0327] [ka]

[0328] (Example 18) Synthesis of Compound 26 The peptide backbone is coupled to INT 7 to obtain a protected compound 3 bound to the resin. Cleavage of the resin, protection of the peptide chain, and the benzyl ester of INT 7 using TFA provide compound 26, which is purified via HPLC.

[0329] [ka]

[0330] (Example 19) Synthesis of Compound 27 The peptide backbone is coupled to INT 5A to obtain a protected compound 27 bound to the resin. Cleavage of the resin, protecting the peptide chain, and the benzyl ester of INT 5A using TFA provide compound 27, which is purified via HPLC.

[0331] [ka]

[0332] (Example 20) Pharmacokinetic studies in dogs The pharmacokinetic properties of the selected compounds disclosed herein were determined after administration of oral dosage forms (tablets) to male beagle dogs. Prior to initial administration, the animals were acclimatized to the laboratory for a minimum of 3 days. Dogs (N=3) received a single oral tablet dose containing the compound. Plasma samples were collected before administration to the dogs, and at 15, 30, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 192 hours, and 240 hours after administration. The compositions administered to the dogs are shown in Table 1.

[0333] [Table 1]

[0334] Pharmacokinetic analysis was performed on plasma concentration-time data using the non-compartmental analysis function (linear trapezoidal method for AUC calculation) of Phoenix WinNonlin (v 8.3). Nominal dose values ​​and sample collection times were used for calculation. max and the corresponding T maxThe values ​​were determined by direct determination of concentration-time data. All AUC calculations were performed using the linear trapezoidal rule. Where the data allowed, the terminal rate constants (lambda z, λz) were determined. The value of λz was calculated from the slope of the natural logarithmic transformation of the concentration-time regression line, where the data points were randomly distributed around the line, and C max Use at least three of the following data points in the regression and calculate the correlation coefficient (R) of the regression. 2 The value was >0.90, and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0335] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF The value was calculated as follows: AUC last +(C last ( / λz). Cl / F value is dose / AUC INF The calculation is performed as follows: Vz / F value is calculated as dose / (AUC INF * AUC was calculated as λz). INF If the percentage of extrapolated area for is >20%, then AUC INF The values, Vz / F values, and CL / F values ​​were not reported. Terminal half-life (t 1 / 2 The following was calculated: ln(2) / λz. The span for defining the lambda z line is t 1 / 2 If it was less than twice that, 1 / 2 Value with an asterisk ( * ) was used as a marker and removed from summary statistics. Administration of compound 4, compound Z, and compound 24 to beagle dogs provided plasma concentration-versus-time profiles, as shown in Figure 1. The data showed the mean plasma concentrations of compound 4 and compound 24 with 300 mg of SNAC structure:

[0336] [ka]

[0337] This indicates that the level is higher than that of similar formulations of peptide compound Z, and that both compound 4 and compound 24 were detected in plasma 144 hours after administration.

[0338] (Example 21) Pharmacokinetic assessment after oral administration The pharmacokinetic properties of various peptide compounds disclosed herein were determined after oral administration (tablets) to male beagle dogs. The test compounds were formulated with varying amounts of salcaprozate sodium (SNAC). Animals were acclimatized to the laboratory for a minimum of 3 days prior to initial administration. Dogs (N=6) received oral tablet doses containing the test compounds. Plasma samples were collected on day 1 before administration to the dogs, and subsequently at 15 minutes, 30 minutes, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. On day 3, samples were collected only before dose administration. On day 5, samples were collected before administering the medication to the dogs, and subsequently at 15, 30, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 192 hours, and 240 hours after administration. The formulations provided to the dogs and the administration groups are shown in Table 2.

[0339] [Table 2]

[0340] Pharmacokinetic analysis was performed on plasma concentration-time data using the non-compartmental analysis function (linear trapezoidal method for AUC calculation) of Phoenix WinNonlin (v 8.3). Nominal dose values ​​and sample collection times were used for calculation. max and the corresponding T maxThe values ​​were determined by direct determination of concentration-time data. All AUC calculations were performed using the linear trapezoidal rule. Where the data allowed, the terminal rate constants (lambda z, λz) were determined. The value of λz was calculated from the slope of the natural logarithmic transformation of the concentration-time regression line, where the data points were randomly distributed around the line, and C max Use at least three of the following data points in the regression and calculate the correlation coefficient (R) of the regression. 2 The value was >0.90, and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0341] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF The value was calculated as follows: AUC last +(C last ( / λz). Cl / F value is dose / AUC INF The calculation is performed as follows: Vz / F value is calculated as dose / (AUC INF * AUC was calculated as λz). INF If the percentage of extrapolated area for is >20%, then AUC INF The values, Vz / F values, and CL / F values ​​were not reported. Terminal half-life (t 1 / 2 The following was calculated: ln(2) / λz. The span for defining the lambda z line is t 1 / 2 If it was less than twice that, 1 / 2 Values ​​were marked with an asterisk (*) and removed from the summary statistics.

[0342] Table 3 below discloses the mean pharmacokinetic data obtained from each experiment using each of the groups 1-10. Various ratios of SNACs to peptide compounds were tested. For compound 24 (groups 2-4), compound 27 (groups 5-7), and compound 4 (groups 8-10), exposure was increased while increasing SNAC levels over the tested range from 200 mg to 450 mg.

[0343] [Table 3]

[0344] (Example 22) Pharmacokinetic assessment after oral administration The pharmacokinetic properties of various peptide compounds disclosed herein were determined after oral administration (tablets) to male beagle dogs. The test compounds were formulated with 450 mg of salcaprozate sodium (SNAC). Animals were acclimatized to the laboratory for a minimum of 3 days prior to initial administration. Dogs (N=6) received a single oral tablet dose containing the test compound. Plasma samples were collected on day 1 prior to administration to the dogs, and subsequently at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 24 hours after administration. On day 3, samples were collected only before dose administration. On day 5, samples were collected before administering the medication to the dogs, and subsequently at 15, 30, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 192 hours, and 240 hours after administration. The formulations provided to the dogs and the administration groups are shown in Table 4.

[0345] [Table 4]

[0346] Pharmacokinetic analysis was performed on plasma concentration-time data using the non-compartmental analysis function (linear trapezoidal method for AUC calculation) of Phoenix WinNonlin (v 8.3). Nominal dose values ​​and sample collection times were used for calculation. max and the corresponding T max The values ​​were determined by direct determination of concentration-time data. All AUC calculations were performed using the linear trapezoidal rule. Where the data allowed, the terminal rate constants (lambda z, λz) were determined. The value of λz was calculated from the slope of the natural logarithmic transformation of the concentration-time regression line, where the data points were randomly distributed around the line, and C maxUse at least three of the following data points in the regression and calculate the correlation coefficient (R) of the regression. 2 The value was >0.90, and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0347] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF The value was calculated as follows: AUC last +(C last ( / λz). Cl / F value is dose / AUC INF The calculation is performed as follows: Vz / F value is calculated as dose / (AUC INF * AUC was calculated as λz). INF If the percentage of extrapolated area for is >20%, then AUC INF The values, Vz / F values, and CL / F values ​​were not reported. Terminal half-life (t 1 / 2 The following was calculated: ln(2) / λz. The span for defining the lambda z line is t 1 / 2 If it was less than twice that, 1 / 2 Value with an asterisk ( * They were marked with ) and removed from the summary statistics.

[0348] Table 5 below shows the average pharmacokinetic data obtained from each experiment using groups 1-4. Good drug exposure was achieved with all test compounds.

[0349] [Table 5]

[0350] (Example 23) Pharmacokinetic assessment of compound 4 after oral administration The pharmacokinetic properties of compound 4 were determined after oral administration of compound 4 (20 mg per tablet) to male beagle dogs. The test compound was formulated with varying amounts of salcaprozate sodium (SNAC) or C10. Animals were acclimatized to the laboratory for a minimum of 3 days prior to initial administration. Dogs (N=5) received oral tablet doses containing the test compound. Plasma samples were collected on day 1 before administration to the dogs, and subsequently at 15 minutes, 30 minutes, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. On day 3, samples were collected only before dose administration. On day 5, samples were collected before administering the medication to the dogs, and subsequently at 15 minutes, 30 minutes, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 192 hours, and 240 hours after administration. The formulations provided to the dogs and the administration groups are shown in Table 6.

[0351] [Table 6]

[0352] Pharmacokinetic analysis was performed on plasma concentration-time data using the non-compartmental analysis function (linear trapezoidal method for AUC calculation) of Phoenix WinNonlin (v 8.3). Nominal dose values ​​and sample collection times were used for calculation. max and the corresponding T max The values ​​were determined by direct determination of concentration-time data. All AUC calculations were performed using the linear trapezoidal rule. Where the data allowed, the terminal rate constants (lambda z, λz) were determined. The value of λz was calculated from the slope of the natural logarithmic transformation of the concentration-time regression line, where the data points were randomly distributed around the line, and C max Use at least three of the following data points in the regression and calculate the correlation coefficient (R) of the regression. 2 The value was >0.90, and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0353] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF The value was calculated as follows: AUC last +(C last ( / λz). Cl / F value is dose / AUC INF The calculation is performed as follows: Vz / F value is calculated as dose / (AUC INF * AUC was calculated as λz). INF If the percentage of extrapolated area for is >20%, then AUC INF The Vz / F and CL / F values ​​were not reported. Terminal half-life (t 1 / 2 The following was calculated: ln(2) / λz. The span for defining the lambda z line is t 1 / 2 If it was less than twice, 1 / 2 Value with an asterisk ( * They were marked with ) and removed from the summary statistics.

[0354] Table 7 below discloses the mean pharmacokinetic data obtained from each experiment using each of groups 1-17 at the end of the study. Tests for groups 8, 9, and 10 show that increasing SNAC levels lead to increased and then decreased exposure to compound 4. The data also includes AUC for days 1 and 5. INF The values ​​are illustrated in Figure 2. For both days, doses containing 450 mg of SNAC resulted in higher exposure than 300 mg of SNAC or 700 mg of SNAC. Groups 1-3 did not show measurable plasma levels of the drug. Therefore, an appropriate mixture of compound 4 and SNAC in the formulation is important for achieving effective concentrations of the drug in plasma.

[0355] [Table 7A]

[0356] [Table 7B]

[0357] (Example 24) Pharmacokinetic evaluation of compounds 4, 15, 18, and 23 after oral administration. The pharmacokinetic properties of compounds 15, 18, and 23 were determined after administration of oral dosage forms (20 mg of compound 15, 18, or 23 per tablet and 450 mg of salcaprozate sodium (SNAC)) to male beagle dogs. Animals were acclimatized to the laboratory for a minimum of 3 days prior to initial administration. Dogs (N=6) received oral tablet doses containing the test compounds. Plasma samples were collected on day 1 before administration to the dogs, and subsequently at 15 minutes, 30 minutes, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. On day 3, samples were collected only before dose administration. On the fifth day, samples were collected before administering the medication to the dogs, and subsequently at 15 minutes, 30 minutes, 45 minutes, and 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 192 hours, and 240 hours after administration.

[0358] Pharmacokinetic analysis was performed on plasma concentration-time data using the non-compartmental analysis function (linear trapezoidal method for AUC calculation) of Phoenix WinNonlin (v 8.3). Nominal dose values ​​and sample collection times were used for calculation. max and the corresponding T max The values ​​were determined by direct determination of concentration-time data. All AUC calculations were performed using the linear trapezoidal rule. Where the data allowed, the terminal rate constants (lambda z, λz) were determined. The value of λz was calculated from the slope of the natural logarithmic transformation of the concentration-time regression line, where the data points were randomly distributed around the line, and C max Use at least three of the following data points in the regression and calculate the correlation coefficient (R) of the regression. 2 The value was >0.90, and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0359] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF The value was calculated as follows: AUC last +(C last ( / λz). Cl / F value is dose / AUC INF The calculation is performed as follows: Vz / F value is calculated as dose / (AUC INF * AUC was calculated as λz). INF If the percentage of extrapolated area for is >20%, then AUC INF The values, Vz / F values, and CL / F values ​​were not reported. Terminal half-life (t 1 / 2 The following was calculated: ln(2) / λz. The span for defining the lambda z line is t 1 / 2 If it was less than twice, 1 / 2 Values ​​were marked with an asterisk (*) and removed from the summary statistics. Figure 3 shows the mean plasma concentration versus time profiles for compounds 15, 18, and 23, and also includes the profile for compound 4. Each formulation of the compounds demonstrated adequate drug exposure over 72 hours.

[0360] (Example 25) Tablet formulation Wet granulation method - Tablet A A batch of tablets (tablet A) containing compound 4 as the active ingredient was prepared by a wet granulation process. The amounts of each component are shown in Table 8 below, expressed as mg / tablet and total mg in a 17-gram batch.

[0361] [Table 8]

[0362] Each component was passed through a #35 mesh sieve. Compound 4 and SNAC were weighed and blended in a mortar and pestle. Separately, polyvinylpyrrolidinone was weighed and dissolved in water at a concentration of 65 mg / mL in a total volume of 5.1 mL. The polyvinylpyrrolidinone solution was wet-granulated together with the blend of Compound 4 and SNAC. The granules were dried in a fluidized bed dryer at 30-35°C to ensure that the water content was 4% or less. The resulting granules were passed through a #35 mesh sieve and then combined with microcrystalline cellulose and magnesium stearate and mixed in a rotator. The resulting granules were then pressurized into tablets to achieve the desired hardness and thickness.

[0363] Dry granulation method #1 - Tablet B A batch of tablets (tablet B) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component are shown per tablet and per 17g batch in Tables 9 and 10 below.

[0364] [Table 9]

[0365] [Table 10]

[0366] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture.

[0367] Microcrystalline cellulose was weighed in a separate stainless steel bowl and then diluted 2x with the final magnesium stearate / SNAC mixture to form a premix. The premix was then added to the remaining final magnesium stearate / SNAC mixture and mixed manually for at least 60 seconds until visually homogeneous. The resulting mixture was then mixed in a v-blender at 25 rpm for 10 minutes. The resulting powder was pressurized into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0368] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0369] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0370] Dry granulation method #2 - Tablet C A batch of tablets (tablet C) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component are shown in Tables 11 and 12 below, per tablet and per 17g batch.

[0371] [Table 11]

[0372] [Table 12]

[0373] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0374] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0375] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0376] Dry granulation method #2 - Tablet D A batch of tablets (tablet D) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 13 below.

[0377] [Table 13]

[0378] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0379] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0380] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0381] Dry granulation method #2 - Tablet E A batch of tablets (tablet E) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 14 below.

[0382] [Table 14]

[0383] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0384] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0385] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0386] Dry granulation method #2 - Tablet F A batch of tablets (tablet F) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 15 below.

[0387] [Table 15]

[0388] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0389] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, PVP-VA, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into large tablets and crushed in a mortar and pestle to form the second fraction granule.

[0390] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0391] Dry granulation method #2 - Tablet G A batch of tablets (tablet G) containing compound 15 as the active ingredient was prepared by a dry granulation process. The amounts of each component, shown per tablet, are found in Table 16 below.

[0392] [Table 16]

[0393] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0394] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 15, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into large tablets and crushed in a mortar and pestle to form the second fraction granule.

[0395] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0396] Dry granulation method #2 - Tablet H A batch of tablets (tablet H) containing compound 18 as the active ingredient was prepared by a dry granulation process. The amounts of each component, shown per tablet, are found in Table 17 below.

[0397] [Table 17]

[0398] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was then added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0399] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 18, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0400] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0401] Dry granulation method #2 - Tablet J A batch of tablets (tablet J) containing compound 23 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 18 below.

[0402] [Table 18]

[0403] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0404] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 23, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0405] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0406] Dry granulation method #2 - Tablet K A batch of tablets (tablet K) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 19 below.

[0407] [Table 19]

[0408] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0409] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, Primellose, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into large tablets and crushed in a mortar and pestle to form the second fraction granule.

[0410] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0411] Dry granulation method #2 - Tablet L A batch of tablets (tablet L) containing compound 4 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 20 below.

[0412] [Table 20]

[0413] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0414] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0415] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0416] Dry granulation method #2 - Tablet M A batch of tablets (tablet M) containing compound 23 as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 21 below.

[0417] [Table 21]

[0418] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0419] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 23, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0420] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0421] Dry granulation method #2 - Tablet N A batch of tablets (tablet N) containing compound 4 (20 mg) as the active ingredient was prepared by a dry granulation process. The amounts of each component per tablet are shown in Table 22 below.

[0422] [Table 22]

[0423] Magnesium stearate was weighed and passed through a 355 μm sieve. The magnesium stearate was diluted 2x with SNAC in a stainless steel bowl. The remaining SNAC was added to a v-blender and mixed at 25 rpm for 2 minutes. The magnesium stearate / SNAC mixture was added to the v-blender and the contents were mixed at 25 rpm for 20 minutes to form the final magnesium stearate / SNAC mixture. The resulting powder was pressed into large tablets, crushed in a mortar and pestle, and passed through a 180 μm mesh sieve to form the first fraction granules.

[0424] A second fraction granule was prepared by weighing appropriate amounts of microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone into a stainless steel bowl. The contents of the bowl were manually mixed for 3 minutes until visually homogeneous, then transferred to a v-blender and tumbling for 1 minute. The resulting powder was pressurized into a large tablet and crushed in a mortar and pestle to form the second fraction granule.

[0425] The first fraction granules, followed by the second fraction granules, were added to a v-blender and mixed at 32 rpm for 5 minutes. Magnesium stearate was then added to the resulting mixture and blended at 32 rpm for 30 seconds. The resulting granules were then pressed into tablets to achieve the desired hardness and thickness.

[0426] (Example 26) Pharmaceutical research The pharmacokinetics of different formulations of compound 4 were studied in male cynomolgus monkeys. Animals were acclimatized to the laboratory for a minimum of 3 days prior to the start of drug administration. Monkeys were administered one tablet per day in the study. Blood samples (0.5 mL) were collected from the monkeys on day 1 (pre-dose only), day 2 (pre-dose only), and day 3 (pre-dose, and 1, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 hours after administration). Sample analysis was performed using LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions for monkey pharmacokinetic studies. All samples from the study were stored at -80°C until ready for analysis as a single batch. Pharmacokinetic parameters were calculated using Phoenix® WinNonlin® software (version 8.3) with non-compartmental analysis.

[0427] The monkeys were administered either tablet A, tablet B, or tablet C as described in the previous example, or an oral solution of compound 4 (blend 1) containing 25 mg of compound 4 and 500 mg of SNAC.

[0428] [Table 23]

[0429] The mean plasma concentration-time data for compound 4 after repeated oral administration in male cynomolgus monkeys are shown in Figure 4. Tablet formulation C resulted in the highest mean exposure to compound 4 compared to tablet formulations A, B, and C. All tablet formulations resulted in a higher mean exposure to compound 4 compared to blend 1.

[0430] (Example 27) Additional formulation research The pharmacokinetics of different formulations of various peptide compounds were studied in male cynomolgus monkeys. Animals were acclimatized to the laboratory for a minimum of 3 days before the start of drug administration. Monkeys were administered one tablet per day in the study. Blood samples (0.5 mL) were collected from monkeys on days 1, 2, and 3 (pre-dose and at 1, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 hours after administration). Sample analysis was performed using LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions for monkey pharmacokinetic studies. All samples from the study were stored at -80°C until ready for analysis as a single batch. Pharmacokinetic parameters were calculated using Phoenix® WinNonlin® software (version 8.3) with non-compartmental analysis.

[0431] Tablet formulation C, described in the previous example, containing 25 mg of compound 4 and 500 mg of SNAC, was administered to monkeys. Compounds 15, 18, and 23 were administered as formulations G, H, and J, respectively. Mean plasma concentration-time data and AUC data for compounds 4, 15, 18, and 23 are provided in Table 24. Formulation C provides adequate drug exposure for all four compounds.

[0432] [Table 24]

[0433] (Example 28) Pharmacokinetic studies using permeability enhancers The study in this example was designed to evaluate the pharmacokinetics of the compounds herein by adding absorption enhancers (SNAC, C10, lauroyl-L-carnitine chloride, and Labrasol) to PBS as intraduodenal (ID) administration. Male Sprague Dawley rats were socially housed in individual ventilated cages (IVG) at a rate of 3 rats per cage for acclimatization for 3–7 days, with alpha dri bedding, water free, 2016 Teklad solid feed free, and enrichment. The room temperature was 72+ / -2°F, relative humidity 30–70%, and the light cycle was 12 hours. Animals were housed individually immediately before the start of the study, and food and water were free throughout the duration of the study. The rats were administered a dose of the specific compound at a dose level of 5 mg / kg on day 1 of the study. Blood samples (0.5 mL) were collected from rats before dose administration and at 0.25, 0.6, 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration. Groups 1-4 were administered compound 24 together with SNAC, C10, lauroyl-L-carnitine chloride, and Labrasol, respectively; groups 5-8 were administered compound 27 together with SNAC, C10, lauroyl-L-carnitine chloride, and Labrasol, respectively; and groups 9-12 were administered compound 4 together with SNAC, C10, lauroyl-L-carnitine chloride (LCC), and Labrasol, respectively. There were 3 rats per test group.

[0434] Sample analysis was performed using LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions for rat pharmacokinetic studies. All samples from the study were stored at -80°C until ready for analysis.

[0435] Excipient stock solution Phosphate-buffered saline (PBS): A solution was prepared at pH 7.4 (calcium-free, magnesium-free). For Labrasol, an 80 mg / mL stock solution was prepared on the day of administration by weighing 800 mg of Labrasol into a vial, adding 9.2 ml of PBS, and vortexing.

[0436] C10: A 200 mM solution of C10 in PBS was prepared. Before use, the solution was heated to 37°C in a water bath until clear. The solution was allowed to cool to room temperature before adding any test compound.

[0437] SNAC: A 200 mM solution was prepared in PBS. The solution was prepared on the day of administration.

[0438] Lauroyl carnitine chloride (LCC): 100 mM solution of LCC in PBS solution (15 ml). The LCC solution was prepared in advance and frozen in 5 mL aliquots.

[0439] Compound drug solution Labrasol® and test compound: A dose was prepared at a concentration of 1 mg / mL of the compound (total 6 mL). 3 mL of PBS was added to a glass container of appropriate size. 6 mg of the compound (corrected for purity) was then added to 3 mL of PBS and vortexed. 3 mL of Labrasol® stock solution was vortexed into the above compound solution. Animals were administered the formulation at a dose of 5 mL / kg.

[0440] C10 and Test Compound: A 1 mg / mL solution of the test compound was prepared by warming 3 mL of C10 stock solution to 37°C until the solution became clear. The solution was allowed to return to room temperature before adding the test compound. In a glass container of appropriate size, 3 mL of PBS was added, followed by 6 mg of the test compound (corrected for purity). Subsequently, 3 mL of room temperature C10 stock solution was vortexed into the test compound solution.

[0441] SNAC and test compound: A 1 mg / mL solution of the test compound was prepared by adding 6 mg of the test compound (corrected for purity) to 3 mL of PBS in an appropriate-sized glass container. Subsequently, 3 mL of room-temperature SNAC stock solution was vortexed into the test compound solution.

[0442] LCC and test compound: A 1 mg / mL solution of the test compound was prepared by adding 6 mg of the test compound (corrected for purity) to 3 mL of PBS in an appropriate-sized glass container. Subsequently, 3 mL of room temperature LCC stock solution was vortexed into the test compound solution.

[0443] The plasma concentrations of each compound using each excipient are shown in Figures 5A to 5C. While trace levels are not shown for compound 24 using SNAC as the plasma level for compound 24 with various excipients, the highest initial concentration using C10 was below the limit of quantification (Figure 5A). Similar phenomena are observed for compound 27 and C10 (Figure 5B) and compound 4 and SNAC (Figure 5C). However, for the combination of compound 4 and SNAC, the plasma level of compound 4 exceeded the limit of quantification.

[0444] (Example 29) Additional tablet formulations Spray drying dispersion method - Tablet O A batch of tablets (tablet O) using the compounds disclosed herein as active ingredients is prepared by a spray-drying dispersion method. The compounds disclosed herein are combined in a solvent with any of the following to form a solution for spray drying: (a) hydroxypropyl methylcellulose acetate succinate type M (HPMCAS-M); (b) hydroxypropyl methylcellulose acetate succinate type L (HPMCAS-L); (c) polyvinylpyrrolidinone-vinyl acetate copolymer (PVP-VA64); or (d) Eudragit® L100. The solution is then dried with a stream of heated nitrogen and recovered using a cyclone. The spray-dried material is then combined with microcrystalline cellulose, magnesium stearate, and additional fillers and disintegrants and pressurized into tablets.

[0445] Wet granulation method #2 - Tablet P A batch of tablets (tablet P) using the compounds disclosed herein as active ingredients is prepared by a wet granulation method. The compounds disclosed herein are combined with microcrystalline cellulose and hydroxypropyl cellulose. The mixture of materials is wet-granulated using purified water as the granulation liquid. The wet granules are dried in a fluidized bed dryer. The dried granules are then milled and blended for 10 minutes. Magnesium stearate is sieved and added to the blend mixture, and blended for an additional 5 minutes. The mixture is then compressed into tablets.

[0446] While some embodiments have been illustrated and described, persons with ordinary art in the art may, after reading the foregoing specification, bring about changes, substitutions of equivalents, and other types of modifications to the compounds or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof of the Art as described herein. Each of the embodiments described above may also include or incorporate with respect to any or all of the other embodiments.

[0447] Furthermore, this technology should not be limited to the specific embodiments described herein, which are intended as single examples of individual aspects of this technology. Many modifications and variations of this technology can be carried out without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of this 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. This technology should be understood as not being limited to any particular methods, reagents, compounds, compositions, labeled compounds, or biological systems, which may naturally vary. Furthermore, the terminology used herein should be understood as being for the purpose of describing only specific embodiments and not intended to be limiting. Accordingly, this specification is intended to be considered as illustrative only, and the scope, scope, and spirit of this technology are indicated solely by the appended claims, their definitions and any equivalents.

[0448] The embodiments described herein as exemplary may be put into practice as appropriate without any elements (singular or plural) or limitations (singular or plural) not specifically disclosed herein. Therefore, terms such as “include,” “contain,” and “contain” should be read broadly and without limitation. In addition, the terms and expressions used herein are for descriptive purposes only and are not intended to exclude any equivalents of the indications and described features or parts thereof, although it is recognized that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase “essentially consisting of” should be understood to include elements such as those specifically enumerated, as well as additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase “consisting of” excludes any elements not specifically identified.

[0449] In addition, where any feature or aspect of this disclosure is described in relation to the Markush Group, a person skilled in the art will recognize that this disclosure also describes any individual member of the Markush Group or any subgroup of its members. Each of the narrower species and subgenera classifications that fall within the comprehensive disclosure also forms part of the Art. This includes comprehensive descriptions of the Art that have provisos or negative limitations that exclude any subject matter from a class concept, regardless of whether the deleted material is specifically enumerated herein.

[0450] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are incorporated herein by reference as specifically and individually indicated, each individual publication, patent application, issued patent, or other document is incorporated in whole by reference. Definitions contained in the texts incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.

[0451] Other embodiments are described in the following claims together with the entire scope of equivalents to which such claims are granted.

[0452] While this disclosure has been shown and described with particular reference to preferred embodiments 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 within this disclosure without departing from the spirit and scope of this disclosure.

[0453] All references, issued patents, and patent applications listed within the body of this Specified Specification are incorporated by reference herein in their entirety for all purposes.

[0454] While this 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 this disclosure. Accordingly, this disclosure is limited only by the following claims.

Claims

1. Permeability enhancers; and Therapeutic effective dose of compounds that are GLP-1 agonists or GLP / GIP dual agonists Includes, The mass of the permeability enhancer is greater than 300 mg. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the compound is a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In formula: R 1 is selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two R independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; and optionally contains one or two heteroatoms selected from N, O and S substituted by one or two R 7 selected from the group consisting of 5- to 10-membered heteroaryl; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 6～10 They can be independently selected from the group consisting of aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines; X and Y are each -OR 4 , NR 5 R 6 , C 1～6 Alkyl and Halo C 1～6 It can be independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, C 6～10 Aryloxy and C 6～10 It can be independently selected from the group consisting of arylalkoxys; Each R 5 These are independently hydrogen or C 1～6 It may be alkyl; Each R 6 These are independently hydrogen or C 1～6 It may be alkyl; Z 1 and Z 2 These are hydrogen and C, respectively. 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 [It can be independently selected from the group consisting of aryls.]

3. Z 1 and Z 2 The pharmaceutical composition according to claim 2, wherein at least one of the elements is not hydrogen.

4. The compound is given by formula (Ia): 【Chemistry 2】 The pharmaceutical composition according to claim 2 or 3, which is a compound having the structure of, or a pharmaceutically acceptable salt thereof.

5. Z 1 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y are each -OR 4 The pharmaceutical composition according to claim 4.

6. Z 1 However, hydrogen, halo C 1～6 Alkoxy and C 1～6 Selected from the group consisting of alkoxys; each R 4 Hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 4 or 5, selected from the group consisting of arylalkoxys.

7. Z 1 is hydrogen, and each R 4 Independently, hydrogen or C 6～10 A pharmaceutical composition according to any one of claims 4 to 6, wherein the composition is an arylalkoxy.

8. Each R 4 A pharmaceutical composition according to any one of claims 4 to 7, wherein is hydrogen.

9. Z 1 is hydrogen, and each R 4 A pharmaceutical composition according to any one of claims 4 to 8, wherein is hydrogen.

10. The compound is given by formula (Ib): 【Transformation 3】 The pharmaceutical composition according to claim 2, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

11. Z 2 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y are each -OR 4 The pharmaceutical composition according to claim 10.

12. Z 2 However, hydrogen, halo C 1～6 Alkoxy and C 1～6 Selected from the group consisting of alkoxys; each R 4 Hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 10 or 11, selected from the group consisting of arylalkoxys.

13. Z 2 is hydrogen, and each R 4 However, hydrogen or C 6～10 The pharmaceutical composition according to claim 10 or 11, wherein it is an arylalkoxy.

14. Each R 4 A pharmaceutical composition according to any one of claims 10 to 13, wherein is hydrogen.

15. Z 2 is hydrogen, and each R 4 A pharmaceutical composition according to any one of claims 10 to 14, wherein is hydrogen.

16. The compound is given by formula (Ic): 【Chemistry 4】 The pharmaceutical composition according to claim 2, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

17. where each of X and Y is -OR 4 The pharmaceutical composition according to claim 16, wherein

18. Each R 4 However, hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 16 or 17, independently selected from the group consisting of arylalkoxys.

19. Each R 4 A pharmaceutical composition according to any one of claims 16 to 18, wherein is hydrogen.

20. The compound, [Chemistry 5A] 【Chem.5B】 【5C】 [5D Transformation] The pharmaceutical composition according to claim 2 or 3, wherein the compound has a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

21. The compound has the following structure: 【Transformation 6】 The pharmaceutical composition according to claim 20, which is a compound having or a pharmaceutically acceptable salt thereof.

22. " * The pharmaceutical composition according to any one of claims 2 to 21, wherein "" represents a chiral carbon having an "S" stereoconfiguration.

23. " * The pharmaceutical composition according to any one of claims 2 to 21, wherein "" represents a chiral carbon having an "R" stereoconfiguration.

24. The compound is given by formula (II) 【Transformation 7】 The pharmaceutical composition according to claim 1, which is a compound having the structure or a pharmaceutically acceptable salt thereof. [In formula: Aib is 2-aminoisobutyric acid; J 1 、 J 2 、 and J 3 each instance of is independently an amino acid selected from Aib, naturally occurring amino acids, and non-natural amino acids; 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 either a naturally occurring amino acid or a non-natural amino acid; Each of n1, n2, n3, n4, n5, n6, n7, and n8 is independently either 0 or 1, provided that the sum of n1 + n2 + n3 + n4 + n5 + n6 + n7 + n8 is 4; R 1 is -C(=O)(OZ 1 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from halogens, C, -P(=O)(X)(Y), and N, O, and S, the heteroaryl is a halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 It is replaced by optional selection; R 2 is -C(=O)(OZ 2 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from halogens, C, -P(=O)(X)(Y), and N, O, and S, the heteroaryl is a halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 It is replaced by optional selection; Each R 7 is halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 6～10 Independently selected from the group consisting of aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines; X and Y respectively are -OR 4 , NR 5 R 6 , C 1～6 Alkyl and Halo C 1～6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, C 6～10 Aryl and C 7～11 Independently selected from the group consisting of arylalkyls; Each R 5 These are independently hydrogen or C 1～6 It is alkyl; Each R 6 These are independently hydrogen or C 1～6 It is alkyl; Z 1 and Z 2 Each is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 [Selected independently from the group consisting of aryls.]

25. The pharmaceutical composition according to claim 24, wherein the compound is not one of the following: 【Transformation 8】

26. J 1 , J 2 , and J 3 The pharmaceutical composition according to claim 24 or 25, wherein each instance of is independently an amino acid selected from Aib and naturally occurring amino acids.

27. J 1 , J 2 , and J 3 The pharmaceutical composition according to any one of claims 24 to 26, wherein each instance of is independently an amino acid selected from Aib, A, F, N, R, and Q.

28. J 1 The pharmaceutical composition according to any one of claims 24 to 27, wherein the composition is Aib or F.

29. J 1 A pharmaceutical composition according to any one of claims 24 to 28, wherein F.

30. J 2 The pharmaceutical composition according to any one of claims 24 to 29, wherein the most common is N or Q.

31. J 2 A pharmaceutical composition according to any one of claims 24 to 30, wherein is N.

32. J 3 The pharmaceutical composition according to any one of claims 24 to 31, wherein the composition is A or R.

33. J 3 A pharmaceutical composition according to any one of claims 24 to 32, wherein R is present.

34. J 4 , J 5 , J 6 , and J 7 The pharmaceutical composition according to any one of claims 24 to 33, wherein each instance is independently an amino acid selected from A, I, K, R, Q, S, T, and V.

35. J 4 The pharmaceutical composition according to any one of claims 24 to 34, wherein the most common is K or R.

36. J 4 A pharmaceutical composition according to any one of claims 24 to 35, wherein R is present.

37. J 5 The pharmaceutical composition according to any one of claims 24 to 36, wherein the composition is I, T, or V.

38. J 5 The pharmaceutical composition according to any one of claims 24 to 37, wherein the composition is T or V.

39. J 6 The pharmaceutical composition according to any one of claims 24 to 38, wherein the composition is A or S.

40. J 6 A pharmaceutical composition according to any one of claims 24 to 39, wherein S is

41. J 7 A pharmaceutical composition according to any one of claims 24 to 40, wherein is Q or K.

42. J 8 , J 9 , J 10 , and J 11 The pharmaceutical composition according to any one of claims 24 to 41, wherein each instance is independently an amino acid selected from A, I, and Q.

43. J 8 The pharmaceutical composition according to any one of claims 24 to 42, wherein the composition is I or Q.

44. J 9 The pharmaceutical composition according to any one of claims 24 to 43, wherein the composition is A or Q.

45. J 10 A pharmaceutical composition according to any one of claims 24 to 44, wherein Q is Q.

46. J 11 A pharmaceutical composition according to any one of claims 24 to 45, wherein Q is Q.

47. J 1 However, it is selected from A, B, or F; J 2 However, it is selected from Q or N; J 3 However, it is selected from A or R; U 1 However, it is selected from -KVA-, -KIAQ- (sequence number 8), -KTAQ- (sequence number 9), -KTSQ- (sequence number 10), -KVAQ- (sequence number 11), -RIAQ- (sequence number 12), KIAK- (sequence number 13), -KISQ- (sequence number 14), or does not exist; U 2 However, it is selected from -Q-, -IAQQ- (sequence number 15), -IAQK- (sequence number 16), -VAQK (sequence number 17), or does not exist. A pharmaceutical composition according to any one of claims 24 to 27.

48. The pharmaceutical composition according to any one of claims 24 to 47, wherein each instance of n1, n2, n3, and n4 is zero.

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

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

51. Z 1 and Z 2 A pharmaceutical composition according to any one of claims 24 to 50, wherein at least one of the elements is not hydrogen.

52. The compound is given by formula (II-a): 【Chemistry 9】 A pharmaceutical composition according to any one of claims 24 to 51, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

53. Z 1 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; each of X and Y is -OR 4 The pharmaceutical composition according to claim 52.

54. Z 1 is hydrogen, and each R 4 Independently, hydrogen or C 7～11 The pharmaceutical composition according to claim 51, wherein it is an arylalkyl.

55. Each R 4 The pharmaceutical composition according to claim 53 or 54, wherein is hydrogen.

56. Z 1 is hydrogen, and each R 4 The pharmaceutical composition according to claim 51, wherein is hydrogen.

57. The compound is given by formula (II-b): 【Chemistry 10】 A pharmaceutical composition according to any one of claims 23 to 51, comprising a compound having the structure or a pharmaceutically acceptable salt thereof.

58. Each R 4 However, hydrogen, C 6～10 Aryl and C 7～11 A pharmaceutical composition according to claim 57, independently selected from the group consisting of arylalkyls.

59. Each R 4 The pharmaceutical composition according to claim 58, wherein is hydrogen.

60. The compound, 【Chemical Engineering 11A】 【Chemical 11B】 【Chemical 11C】 The pharmaceutical composition according to claim 24 or 25, which is a compound having a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

61. The compound is given by formula (III) 【Chemistry 12】 A pharmaceutical composition according to claim 1, which is a compound having the structure of [formula: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ), -(CH 2 CH 2 ) n P(=O)(X)(Y), as well as halogens, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 6～10 Independently selected from the group consisting of aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines; X and Y respectively are -OR 4 , NR 5 R 6 , C 1～6 Alkyl and Halo C 1～6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, C 6～10 Aryloxy and C 6～10 Independently selected from the group consisting of arylalkoxys; Each R 5 These are independently hydrogen or C 1～6 It is alkyl; Each R 6 These are independently hydrogen or C 1～6 It is alkyl; Z 1 and Z 2 Each is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Independently selected from the group consisting of aryls; n is 0, 1, 2, 3, or 4.

62. Z 1 and Z 2 The pharmaceutical composition according to claim 61, wherein at least one of the is not hydrogen.

63. The compound is given by formula (III-a): 【Chemistry 13】 The pharmaceutical composition according to claim 61 or 62, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

64. Z 1 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y each have -OR 4 The pharmaceutical composition according to claim 63.

65. Z 1 However, hydrogen, halo C 1～6 Alkoxy and C 1～6 Selected from the group consisting of alkoxys; each R 4 Hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 63 or 64, selected from the group consisting of arylalkoxys.

66. Z 1 is hydrogen, and each R 4 Independently, hydrogen or C 6～10 A pharmaceutical composition according to any one of claims 63 to 65, wherein the composition is an arylalkoxy.

67. Each R 4 A pharmaceutical composition according to any one of claims 63 to 66, wherein is hydrogen.

68. Z 1 is hydrogen, and each R 4 A pharmaceutical composition according to any one of claims 63 to 67, wherein is hydrogen.

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

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

71. The compound is given by formula (III-b): 【Chemistry 14】 The pharmaceutical composition according to claim 59, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

72. Z 2 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y each have -OR 4 The pharmaceutical composition according to claim 71.

73. Z 2 However, hydrogen, halo C 1～6 Alkoxy and C 1～6 Selected from the group consisting of alkoxys; each R 4 Hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 71 or 72, selected from the group consisting of arylalkoxys.

74. Z 2 is hydrogen, and each R 4 However, hydrogen or C 6～10 A pharmaceutical composition according to any one of claims 71 to 73, wherein the composition is an arylalkoxy.

75. Each R 4 A pharmaceutical composition according to any one of claims 71 to 74, wherein is hydrogen.

76. Z 2 is hydrogen, and each R 4 A pharmaceutical composition according to any one of claims 71 to 75, wherein is hydrogen.

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

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

79. The compound is given by formula (III-c): 【Chemistry 15】 The pharmaceutical composition according to claim 61 or 62, which is a compound having the structure or a pharmaceutically acceptable salt thereof.

80. X and Y each have -OR 4 The pharmaceutical composition according to claim 79.

81. Each R 4 However, hydrogen, C 6～10 Aryloxy and C 6～10 A pharmaceutical composition according to claim 80, independently selected from the group consisting of arylalkoxys.

82. Each R 4 The pharmaceutical composition according to claim 80 or 81, wherein is hydrogen.

83. A pharmaceutical composition according to any one of claims 79 to 82, wherein n is 1.

84. A pharmaceutical composition according to any one of claims 79 to 82, wherein n is 2.

85. The compound, 【Chemistry 16】 The pharmaceutical composition according to claim 61 or 62, wherein the compound has a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

86. " * The pharmaceutical composition according to any one of claims 61 to 85, wherein " represents a chiral carbon having an "S" stereoconfiguration.

87. " * The pharmaceutical composition according to any one of claims 61 to 85, wherein "" represents a chiral carbon having an "R" stereoconfiguration.

88. The pharmaceutical composition according to any one of claims 1 to 87, wherein the mass of the permeability enhancer is approximately 350 mg to approximately 1000 mg.

89. The pharmaceutical composition according to any one of claims 1 to 87, wherein the mass of the permeability enhancer is approximately 400 mg to approximately 800 mg.

90. The pharmaceutical composition according to any one of claims 1 to 87, wherein the mass of the permeability enhancer is approximately 500 mg to approximately 750 mg.

91. The pharmaceutical composition according to any one of claims 1 to 87, wherein the mass of the permeability enhancer is about 500 mg; or the mass of the permeability enhancer is 450 mg.

92. The pharmaceutical composition according to any one of claims 1 to 91, wherein the permeability enhancer constitutes about 40% to about 90% by mass of the composition.

93. The pharmaceutical composition according to any one of claims 1 to 91, wherein the permeability enhancer constitutes about 50% to about 80% by mass of the composition.

94. The pharmaceutical composition according to any one of claims 1 to 91, wherein one or more permeability enhancers constitute about 70% to about 80% by mass of the composition.

95. A pharmaceutical composition according to any one of claims 1 to 91, wherein a permeability enhancer constitutes about 73% of the composition.

96. The pharmaceutical composition according to any one of claims 1 to 95, wherein the permeability enhancer is sodium salcaprozate (SNAC), sodium caprate (C10), or a combination thereof.

97. The pharmaceutical composition according to any one of claims 1 to 95, wherein the permeability enhancer is salcaprozate sodium.

98. The pharmaceutical composition according to any one of claims 1 to 95, wherein the permeability enhancer is sodium caprate.

99. The pharmaceutical composition according to any one of claims 1 to 95, wherein one or more permeability enhancers are a combination of sodium salcaprozate and sodium caprate.

100. A pharmaceutical composition according to any one of claims 1 to 99, comprising approximately 1 mg to approximately 50 mg of the compound.

101. A pharmaceutical composition according to any one of claims 1 to 99, comprising approximately 5 mg to approximately 40 mg of the compound.

102. A pharmaceutical composition according to any one of claims 1 to 99, comprising approximately 10 mg to approximately 30 mg of the compound.

103. A pharmaceutical composition according to any one of claims 1 to 99, comprising approximately 20 mg to approximately 30 mg of the compound.

104. A pharmaceutical composition according to any one of claims 1 to 99, comprising approximately 25 mg of the compound.

105. A pharmaceutical composition according to any one of claims 1 to 104, further comprising a disintegrant.

106. The pharmaceutical composition according to claim 105, wherein the disintegrant is croscarmellose sodium.

107. Pharmaceutical composition containing the following: Sodium salcaprozate; and The therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof: 【Chemistry 17】 [In formula: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 One or two R molecules independently selected from aryls, 5-10 membered heteroaryls, and 5-10 membered heterocyclines. 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-2 heteroatoms selected from N, O, and S which are optionally substituted; Each R 7 is halogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 6～10 Independently selected from the group consisting of aryls, 5- to 10-membered heteroaryls, and 5- to 10-membered heterocyclines; X and Y respectively are -OR 4 , NR 5 R 6 , C 1～6 Alkyl and Halo C 1～6 Independently selected from the group consisting of alkyl groups; Each R 4 is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, C 6～10 Aryl and C 6～10 Independently selected from the group consisting of arylalkyls; Each R 5 These are independently hydrogen or C 1～6 Alkyl Each R 6 These are independently hydrogen or C 1～6 It is alkyl; Z 1 and Z 2 Each is hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 [Selected independently from a group consisting of aryls]; Here, the mass of salcaprozate is greater than approximately 300 mg.

108. Z 1 and Z 2 A pharmaceutical composition according to any one of claims 1 to 107, wherein at least one of is not hydrogen.

109. A pharmaceutical composition according to any one of claims 1 to 107, wherein the composition further comprises one or more excipients.

110. The pharmaceutical composition according to claim 109, wherein one or more excipients are selected from the group consisting of microcrystalline cellulose, magnesium stearate, and polyvinylpyrrolidone.

111. The compound is, formula Ia: [Chemistry 18] A pharmaceutical composition according to any one of claims 1 to 110, having the structure of or a pharmaceutically acceptable salt thereof.

112. Z 1 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, Halo C 1～6 Alkoxy, C 1～6 Alkoxy, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y are each -OR 4 The pharmaceutical composition according to any one of claims 1 to 111.

113. Z 1 However, hydrogen, halo C 1～6 Alkoxy and C 1～6 Selected from the group consisting of alkoxys; each R 4 Hydrogen, C 6～10 Aryl and C 6～10 A pharmaceutical composition according to any one of claims 1 to 112, selected from the group consisting of arylalkyls.

114. Z 1 is hydrogen, and each R 4 Independently, hydrogen or C 6～10 A pharmaceutical composition according to any one of claims 1 to 113, wherein the composition is an arylalkyl group.

115. Each R 4 A pharmaceutical composition according to any one of claims 1 to 114, wherein is hydrogen.

116. The compound: 【Chemistry 19】 A pharmaceutical composition according to any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof.

117. A pharmaceutical composition according to any one of claims 1 to 116, formulated for oral administration.

118. Compounds in amounts ranging from approximately 1.0% by mass to approximately 5.0% by mass; Approximately 50% to 80% by mass of sodium salcaprozate; Microcrystalline cellulose in an amount of approximately 10% to 30% by mass; Approximately 1.0% to approximately 3.0% by mass of polyvinylpyrrolidinone; and Approximately 1.0% to 3.0% by mass of magnesium stearate A pharmaceutical composition according to any one of claims 1 to 117, comprising:

119. Approximately 3.6% by mass of the compound; Approximately 72.7% by mass of sodium salcaprozate; Approximately 19.4% by mass of microcrystalline cellulose; Approximately 1.9% by mass of polyvinylpyrrolidinone; and Approximately 2.3% by mass of magnesium stearate A pharmaceutical composition according to any one of claims 1 to 118, comprising:

120. A pharmaceutical composition according to any one of claims 1 to 119, wherein the composition is enterically coated.

121. A method for preventing, treating, or alleviating one or more metabolic disorders or metabolic syndromes in a subject, comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 120 to a subject in need thereof.

122. The method according to claim 119, wherein the metabolic disorder or metabolic syndrome is atherosclerosis, diabetes mellitus, hyperglycemic diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, hypothalamic obesity, or Prader-Willi syndrome.

123. The method according to claim 119 or 120, wherein the metabolic disorder or metabolic syndrome is obesity or hypothalamic obesity.

124. A method for preventing, treating, or alleviating one or more fatty liver diseases in a subject, comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 120 to a subject in need thereof.

125. The method according to claim 122, wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.

126. The method according to claim 122 or 125, wherein the administration of the pharmaceutical composition prevents, treats or alleviates fibrosis, a fibrous condition, or fibrous symptoms.

127. The method according to any one of claims 122 to 126, wherein the administration of the pharmaceutical composition results in a reduction in the amount of extracellular matrix proteins present in one or more tissues of the subject.

128. The method according to any one of claims 122 to 127, wherein the administration of the pharmaceutical composition results in a reduction in the amount of collagen present in one or more tissues of the subject.

129. The method according to claim 128, wherein the administration of the pharmaceutical composition 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.

130. A method for preventing, treating or alleviating one or more diseases or disorders in a subject, comprising the step of administering a pharmaceutical composition according to any one of claims 1 to 118 to a subject in need thereof, wherein the disease or disorder is hepatic fibrosis, renal fibrosis, cholangiofibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

131. The method according to claim 130, wherein the disease or disorder is non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis.

132. The method according to any one of claims 121 to 131, wherein the route of administration is orally.

133. (i) A step of forming first granules by combining sodium salcaprozate and magnesium stearate; (ii) A step of forming a second granule by combining microcrystalline cellulose, compound 4, and polyvinylpyrrolidinone. (iii) The step of forming a mixture by combining the first granules and the second granules; (iv) A step of forming a third granule by adding magnesium stearate to the mixture; (v) The process of pressurizing the third granule into a tablet. A method for preparing a pharmaceutical composition containing [a certain substance].

134. (i) A step of combining microcrystalline cellulose and the compounds disclosed herein in a first tank; (ii) The process of combining polyvinylpyrrolidinone and water in a second tank; (iii) A step of forming wet granules by adding the contents of the first tank to the second tank; (iv) A step of forming dry granules by drying the wet granules; (v) the step of combining dried granules with magnesium stearate; and (vi) A step of pressurizing the mixture obtained as a result of step (v) into granules. A method for preparing a pharmaceutical composition containing [a certain substance].

135. A pharmaceutical composition prepared by the method described in claim 133 or 134.

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