Compositions and Methods for the Treatment of Metabolic and Liver Disorders

Abstract

Small molecule GLP-1 receptor agonist compounds, pharmaceutical compositions, and their use and preparation are disclosed herein.

Description

Technical Field

[0001] Reference to Sequence Listing This application has been filed together with a sequence listing in electronic format. The sequence listing is provided as a file named VIKNG.023WO_ST_26.xml created on July 17, 2023, which is 2,791 bytes in size. The information in the electronic format of the sequence listing is hereby incorporated by reference in its entirety into this specification.

[0002] The present disclosure generally relates to the field of treatments for metabolic disorders and fatty liver diseases. More specifically, the present disclosure relates to the field of small molecule drugs for the treatment of metabolic disorders and fatty liver diseases.

Background Art

[0003] The incretin peptide glucagon-like peptide-1 (GLP-1) is a metabolic hormone. GLP-1 is secreted within minutes of oral nutrient intake and facilitates the rapid processing of orally ingested nutrients. Incretin receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GLP-1 exerts its glucose-regulatory effects via deceleration of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss in both preclinical and clinical studies.

[0004] 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 receptor agonists have been developed to treat NAFLD, non-alcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of GLP-1 receptor agonists is associated with nausea, vomiting, and other gastrointestinal side effects. Dose limitations associated with gastrointestinal adverse events can prevent dosing to the desired effective dose, can impair patient compliance with treatment, and can limit the effectiveness of the treatment regimen. Therefore, there is a need for novel GLP-1 agonist compounds that can be used to treat fatty liver disease and other diseases and disorders.

Prior Art Documents

Patent Documents

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Patent Document 1

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Summary of the Invention

Means for Solving the Problems

[0007] Some embodiments disclosed herein are of formula (I):

[0008]

Chemical Formula

[0009] A compound having the structure, or a pharmaceutically acceptable salt thereof, wherein: 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 is selected from the group consisting of 5- to 10-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, optionally substituted with one or two R 7 ; R 2 is selected from -C(=O)(OZ 2 ), -(CH2CH2) n 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 is selected from the group consisting of 5- to 10-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, optionally substituted with one or two R 7 ; Each R 7 can be independently selected from the group consisting of 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, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each -OR 4 , NR 5 R6 , C 1~6 alkyl and halo C 1~6 can be independently selected from the group consisting of; each R 4 is hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, C 6~10 aryloxy and C 6~10 can be independently selected from the group consisting of arylalkoxy; each R 5 is independently hydrogen or C 1~6 alkyl may be; each R 6 is independently hydrogen or C 1~6 alkyl may be; Z 1 and Z 2 are each 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 can be independently selected from the group consisting of aryl; n is 0, 1, 2, 3 or 4, provided that however, Z 1 and Z 2 at least one of which is the condition that it is not hydrogen.

[0010] Other embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

[0011] Other embodiments disclosed herein include methods of preventing, treating, or alleviating one or more fatty liver diseases in a subject by administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof. Fatty liver diseases include, but are not limited to, steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD).

[0012] Other embodiments disclosed herein include methods of preventing, treating, or alleviating one or more diseases or disorders in a subject by administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is liver fibrosis, kidney fibrosis, biliary 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. In some embodiments, the disease or disorder is a metabolic disorder or metabolic syndrome. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 true diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In some embodiments, compounds are provided that are non-macrocyclic functionalized peptides that act as GLP-1 receptor agonists. 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) includes all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0014]

CHEMICAL

[0015] In some embodiments of the compound of formula (I): R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C6~10 One or two Rs independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl 7 Selected from the group consisting of 5- to 10-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and 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 one or two Rs independently selected from 5- to 10-membered heterocyclyl 7 Selected from the group consisting of 5- to 10-membered heteroaryl containing one to four heteroatoms selected from N, O, and S, optionally substituted with 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, and can be independently selected from the group consisting of 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; X and Y are each independently selected from the group consisting of -OR 4 , NR 5 R 6 , C 1~6 alkyl, and haloC 1~6 alkyl; Each R 4 is hydrogen, C 1~6 alkyl, haloC 1~6 alkyl, C 6~10 aryloxy, and C 6~10 aralkyl and can be independently selected from the group; Each R 5 can independently be hydrogen or C 1~6 alkyl; Each R 6 is independently hydrogen or C 1~6 alkyl; Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 aryl, provided that n is 0, 1, 2, 3 or 4, provided that Z 1 and Z 2 are not both hydrogen.

[0016] Some embodiments of the compound of formula (I) include a compound having the structure of formula (I-a):

[0017]

Chemical formula

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments of the compound of formula (I-a) or a pharmaceutically acceptable salt thereof, Z 1 is selected from 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; X and Y are each -OR 4 respectively.

[0020] In some embodiments of the compound of formula (I-a) or a pharmaceutically acceptable salt thereof, Z 1 is selected from hydrogen, halo C 1~6 alkoxy and C 1~6 alkoxy; each R4 is independently selected from hydrogen, C 6~10 aryloxy and C 6~10 arylalkoxy.

[0021] In some embodiments of the compounds of formula (I-a) or their pharmaceutically acceptable salts; Z 1 is hydrogen, and each R 4 is independently hydrogen or C 6~10 arylalkoxy.

[0022] In some embodiments of the compounds of formula (I-a) or their pharmaceutically acceptable salts, each R 4 is hydrogen.

[0023] In some embodiments of the compounds of formula (I-a) or their pharmaceutically acceptable salts, Z 1 is hydrogen, and each R 4 is hydrogen.

[0024] In some embodiments of the compounds of formula (I-a) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In still other embodiments, n is 2. In yet other embodiments, n is 3. In some embodiments, n is 4.

[0025] Some embodiments of the compounds of formula (I) include those of formula (I-b):

[0026]

Chemical formula

[0027] compounds having the structure of or their pharmaceutically acceptable salts.

[0028] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 selected from aryl; X and Y are each -OR 4 respectively.

[0029] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts; Z 2 is selected from hydrogen, halo C 1~6 alkoxy and C 1~6 alkoxy; each R 4 is independently selected from hydrogen, C 6~10 aryloxy and C 6~10 arylalkoxy.

[0030] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 is independently hydrogen or C 6~10 arylalkoxy.

[0031] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts; each R 4 is hydrogen.

[0032] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 is hydrogen.

[0033] In some embodiments of the compounds of formula (I-b) or their pharmaceutically acceptable salts, n is 0. In other embodiments, n is 1. In still other embodiments, n is 2. In yet other embodiments, n is 3. In some embodiments, n is 4.

[0034] Some embodiments of the compounds of formula (I) include formula (I-c):

[0035] [Chemical formula]

[0036] Compounds having the structure of or pharmaceutically acceptable salts thereof are included.

[0037] In some embodiments of the compounds of formula (I-c) or pharmaceutically acceptable salts thereof, X and Y are each -OR 4 respectively.

[0038] In some embodiments of the compounds of formula (I-c) or pharmaceutically acceptable salts thereof, each R 4 may be independently selected from hydrogen, C 6~10 aryloxy and C 6~10 arylalkoxy. In some embodiments of the compounds of formula (I-c) or pharmaceutically acceptable salts thereof, each R 4 is hydrogen.

[0039] In some embodiments of the compounds of formula (I-c) or pharmaceutically acceptable salts thereof, n is 0. In other embodiments, n is 1. In still other embodiments, n is 2. In yet other embodiments, n is 3. In some embodiments, n is 4.

[0040] Some embodiments include

[0041]

Chemical Structure

[0042]

Chemical Structure

[0043] and compounds having a structure selected from the group consisting of pharmaceutically acceptable salts thereof.

[0044] Some embodiments include " *Examples of compounds in which " " represents a chiral carbon having an "S" configuration.

[0045] In some embodiments, " * Examples of compounds in which " " represents a chiral carbon having an "R" configuration.

[0046] If the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers, including racemates, or as mixtures of such isomers. The separation of individual isomers or the selective synthesis of individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Further, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms, including any polymorphic forms, are included within the scope of the compounds disclosed herein. In addition, some of the compounds disclosed herein can form solvates (i.e., hydrates) with water or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0047] Those skilled in the art will recognize that some of the structures described herein can be resonance forms or tautomers of compounds that can be significantly represented by other chemical structures, even kinetically; those skilled in the art will recognize that such structures can only represent a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the structures shown, but such resonance forms or tautomers are not represented herein.

[0048] Definitions Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. In the case of multiple definitions for a term herein, the definition in this section shall control unless otherwise specified.

[0049] "Solvate" refers to a compound formed by the interaction of a solvent with a compound or a salt thereof described herein. Suitable solvates include hydrates and are pharmaceutically acceptable solvates.

[0050] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound and are not biologically or otherwise undesirable for pharmaceutical use. In many cases, the compounds herein can form salts of acids and / or bases due to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, and the like. Many such salts are known in the art as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0051] As used herein, "C" where "a" and "b" are integers a from C b " or "C a~b " refers to the number of carbon atoms in the specified group. That is, the group can contain from an inclusive "a" to "b" carbon atoms. Thus, for example, "C1 to C4 alkyl" or "C 1~4The term "alkyl" refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0052] As used herein, the term "halogen" or "halo" means any one of the radioactively stable atoms in column 7 of the periodic table, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0053] As used herein, "alkyl" refers to a straight-chain or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have from 1 to 20 carbon atoms (and whenever it appears herein, a numerical range such as "from 1 to 20" refers to each integer within the given range; e.g., "from 1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" when no numerical range is specified). The alkyl group may be a medium-sized alkyl having from 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having from 1 to 4 carbon atoms. The alkyl group of the compound may be designated as "C 1~4 alkyl" or a similar name. By way of example only, "C 1~4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0054] As used herein, "haloalkyl" refers to a straight or branched alkyl group having from 1 to 12 carbon atoms in the chain, wherein one or more hydrogens are replaced by halogen. 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 foregoing examples in light of the ordinary techniques in the art and the teachings provided herein.

[0055] As used herein, "alkoxy" refers to a formula -OR where R is alkyl as defined above, for example, including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, etc., to refer to "C 1~9 alkoxy".

[0056] As used herein, "polyethylene glycol" refers to the formula

[0057]

Chemical formula

[0058] wherein 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. Thus, for example, "2-member to 5-member 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.

[0059] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the backbone, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. A heteroalkyl group can have from 1 to 20 carbon atoms, but this definition also encompasses occurrences of the term "heteroalkyl" when no numerical range is specified. A heteroalkyl group can be a medium-sized heteroalkyl having from 1 to 9 carbon atoms. A heteroalkyl group can also be a lower heteroalkyl having from 1 to 4 carbon atoms. In various embodiments, a heteroalkyl can have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compound can be designated as "C 1~4 heteroalkyl" or a similar name. A heteroalkyl group can contain one or more heteroatoms. By way of example only, "C 1~4 heteroalkyl" indicates that there are from 1 to 4 carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0060] 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.

[0061] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon in the ring backbone. When an aryl is a ring system, every ring in the system is aromatic. An aryl group can have from 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" when no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is "C 6~10 aryl", "C6 or C10 "Aryl", or can be designated by a similar name. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl and anthracenyl.

[0062] As used herein, "aryloxy" and "arylthio" are RO- and RS- where R is an aryl as defined above, for example, including, but not limited to, phenyloxy, "C 6~10 aryloxy" or "C 6~10 arylthio", etc.

[0063] "Aralkyl" or "arylalkyl" is an aryl group connected via an alkylene group as a substituent, for example, including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl, "C 7~14 aralkyl", etc. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 alkylene group).

[0064] 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, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur, in the ring backbone. When heteroaryl is a ring system, every ring in the system is aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the occurrence of the term "heteroaryl" when no numerical range is specified. In some embodiments, the heteroaryl group has 5 to 10 ring members, or 5 to 7 ring members. The heteroaryl group can be designated as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or similar designations. In various embodiments, heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0065] "Heteroalkyl" or "heteroarylalkyl" is a heteroaryl group connected 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).

[0066] As used herein, "carbocyclic" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system skeleton. When the carbocyclic is a ring system, two or more rings may be joined together in a fused, bridged, or spiro-connected manner. The carbocyclic can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, examples of carbocyclic include cycloalkyl, cycloalkenyl, and cycloalkynyl. The carbocyclic group can have from 3 to 20 carbon atoms, but this definition also includes the occurrence of the term "carbocyclic" when no numerical range is specified. The carbocyclic group may be a medium-sized carbocyclic having from 3 to 10 carbon atoms. The carbocyclic group can also be a carbocyclic having from 3 to 6 carbon atoms. The carbocyclic group can be designated as "C 3~6 carbocyclic" or a similar name. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclic [2.2.2] octanyl, adamantyl, and spiro [4.4] nonanyl.

[0067] "(Carbocyclic)alkyl" refers to a carbocyclic group connected via an alkylene group as a substituent, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc., but is not limited thereto, "C 4-10 such as "(carbocyclic)alkyl". In some cases, the alkylene group is a lower alkylidene group.

[0068] As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0069] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, where the rings in the ring system are not aromatic. An example is cyclohexenyl.

[0070] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring skeleton. Heterocyclyl may be joined together in a fused, bridged, or spiro-connected manner. Heterocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in either the non-aromatic ring or the aromatic ring in the ring system. The heterocyclyl group can have from 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 occurrence of the term "heterocyclyl" when no numerical range is specified. The heterocyclyl group can be a medium-sized heterocyclyl having from 3 to 10 ring members. The heterocyclyl group can also be a heterocyclyl having from 3 to 6 ring members. The heterocyclyl group can be designated as "3- to 6-membered heterocyclyl" or a similar name.

[0071] In various embodiments, the heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains from 1 to 4 nitrogen atoms, from 1 to 3 nitrogen atoms, from 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In a preferred 6-membered monocyclic heterocyclyl, the heteroatom is selected from up to 3 O, N or S, and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom is selected from 1 or 2 heteroatoms selected from O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0072] "(Heterocyclyl)alkyl" is a heterocyclyl group connected via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0073] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.

[0074] The "O-carboxy" group refers to the "-OC(=O)R" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 selected from carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0075] The "C-carboxy" group refers to the "-C(=O)OR" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 selected from carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0076] The "cyano" group refers to the "-CN" group.

[0077] The "cyanato" group refers to the "-OCN" group.

[0078] The "isocyanate" group refers to the "-NCO" group.

[0079] The "thiocyanato" group refers to the "-SCN" group.

[0080] The "isothiocyanato" group refers to the "-NCS" group.

[0081] The "sulfinyl" group refers to the "-S(=O)R" group, where R is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0082] The "sulfonyl" group refers to the "-SO2R" group, where R is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0083] The "S-sulfonamide" group refers to the "-SO2NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0084] The "N-sulfonamide" group refers to the "-N(R A )SO2R B " group, where RA and R b are each independently hydrogen, C as defined herein 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0085] The "O-carbamyl" group refers to the "-OC(=O)NR A R B " group, where R A and R B are each independently hydrogen, C as defined herein 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0086] The "N-carbamyl" group refers to the "-N(R A )OC(=O)R B " group, where R A and R B are each independently hydrogen, C as defined herein 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0087] The "O-thiocarbamyl" group refers to the "-OC(=S)NR A R B " group, where R A and R B are each independently hydrogen, C as defined herein 1~6 alkyl, C 2~6 alkenyl, C 2~6Alkynyl, C 3~7 Carbocyclic, C 6~10 Selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0088] The "N-thiocarbamyl" group refers to the "-N(R A )OC(=S)R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0089] The "C-amide" group refers to the "-C(=O)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0090] The "N-amide" group refers to the "-N(R A )C(=O)R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0091] The "amino" group refers to the "-NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclic as defined herein.

[0092] The "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0093] The "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as "C 2~8 alkoxyalkyl", etc.

[0094] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be “substituted,” the group is independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,It is meant to be substituted with one or more substituents selected from C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanate, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O). When a group is described as "optionally substituted", the group may always be substituted with the above substituents.,

[0095] In some embodiments, the substituted group is individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy and halogen.,

[0096] Certain group naming conventions should be understood to be able to include either a mono-group or a di-group depending on the context. For example, when a substituent requires two attachment points to the rest of the molecule, the substituent is understood to be a di-group. For example, substituents identified as alkyl that require two attachment points include di-groups such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a di-group such as "alkylene" or "alkenylene".

[0097] When two R groups are stated to "together with the atoms to which they are attached" form a ring (e.g., a carbocyclic ring, a heterocyclic ring, an aryl ring or a heteroaryl ring), the set unit of the atoms and the two R groups is meant to be the ring listed. The ring, when taken individually, is not otherwise limited by the definition of each R group. For example, the following substructures exist:

[0098]

Chemical formula

[0099] R 1 and R 2 are defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R2 When they combine with the nitrogen to which they are attached to form a heterocyclyl, R 1 and R 2 are meant to be selectable from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0100]

Chemical formula

[0101] wherein ring A is a heterocyclic ring containing the nitrogen shown.

[0102] Similarly, when it is stated that two "adjacent" R groups "together with the atoms to which they are attached" form a ring, the atoms, intervening bonds, and the set unit of the two R groups are meant to be the ring listed. For example, the following substructures exist:

[0103]

Chemical formula

[0104] R 1 and R 2 are defined as being selected from the group consisting of hydrogen and alkyl, or when R 1 and R 2 combine with the atoms to which they are attached to form an aryl or carbocyclic ring, R 1 and R 2 are meant to be selectable from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0105]

Chemical formula

[0106] wherein A is an aryl ring or a carbocyclic ring containing the double bond shown.

[0107] When a substituent is depicted as a di-group (i.e., having two attachment points to the rest of the molecule), it should always be understood that the substituent may be attached in an arrangement in any orientation, unless otherwise indicated. Thus, for example, -AE- or

[0108]

Chemical formula

[0109] substituents depicted as, for example, include substituents where A is attached in a direction such that it is the leftmost attachment point of the molecule and where A is attached as the rightmost attachment point of the molecule.

[0110] The term "mammal" is used in its ordinary biological sense. Thus, it includes, without being specifically limited to, primates including monkeys (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, but also many other species.

[0111] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, except where any conventional media or agent is incompatible with the active ingredient. In addition, various adjuvants commonly used in the art may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is hereby incorporated by reference in its entirety.

[0112] "Subject", as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, and any other vertebrate or invertebrate animal.

[0113] "Effective amount" or "therapeutically effective amount", as used herein, refers to the amount of a therapeutic agent that is effective to alleviate to some extent one or more symptoms of a disease or disorder or to reduce the likelihood of its manifestation, and includes curing the disease or disorder. "Curing" means that the symptoms of the disease or disorder are eliminated; however, even after a cure has been obtained, certain long-term or permanent effects may exist (such as extensive tissue damage, etc.).

[0114] "Treating", "treatment" or "treatment thereof", as used herein, refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who no longer exhibits the symptoms of a disease or disorder but is susceptible to or at risk of a particular disease or disorder, such that the treatment reduces the likelihood that the subject will develop the disease or disorder. The term "therapeutic treatment" refers to administering a treatment to a subject who already suffers from a disease or condition.

[0115] Method of preparation The compounds disclosed herein can be synthesized by the methods described below or by modifications of these methods. Ways of modifying the methodology include, inter alia, temperatures, solvents, reagents, etc. known to those skilled in the art. In general, during any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules involved. This can be accomplished by means of conventional protecting groups, for example those described in Protective Groups in Organic Chemistry (edited by J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd Edition) Wiley, New York (1999), both of which are hereby incorporated by reference in their entirety. The protecting groups can be removed at a convenient subsequent stage using methods known from the art. Synthetic chemical transformations useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are hereby incorporated by reference in their entirety. The pathways shown and described herein are illustrative only and are not intended or to be construed in any way as limiting the scope of the claims. Those skilled in the art can recognize modifications of the disclosed syntheses and can devise alternative pathways based on the disclosure herein; all such modifications and alternative pathways are within the scope of the claims.

[0116] In the following schemes, the protecting groups for the oxygen atoms are selected for their compatibility with the required synthetic steps and for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd Edition) Wiley, New York (1999)).

[0117] If the compounds of the present technology contain 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 within the scope of the present technology unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0118] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by the procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 - 15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1 - 5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1 - 40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or obvious modifications thereof.

[0119] In one embodiment, the method disclosed herein can include providing intermediate (II) by constructing a 31 - amino acid peptide backbone using solid - phase peptide synthesis techniques. The peptide backbone contains two PEG2 amide linkers. The method includes providing resin - bound intermediate (IV) by an amide coupling reaction between the amine of the terminal PEG2 amide of intermediate (II) and a carboxylic acid (III) appropriately substituted. In one embodiment, the method involves obtaining the final product (I) by hydrolyzing intermediate (IV) under acidic conditions followed by subjecting it to purification. (Scheme 1).

[0120] [Chemistry]

[0121] The above scheme examples are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Further, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0122] Administration and Pharmaceutical Compositions The compound is administered at a therapeutically effective dose. Human dosage levels have not yet been optimized for the compounds described herein, but generally, the daily dose may be from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg, from about 0.05 mg / kg of body weight to about 50 mg / kg, or from about 0.075 mg / kg of body weight to about 10 mg / kg. Thus, for administration to a 70 kg human, the dosage range may be from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg per day or less to about 7000 mg per day or more, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg per day to about 3000 mg per day. The amount of active compound administered will, of course, depend on the subject being treated and the disease state, the severity of the affliction, the mode and schedule of administration, and the judgment of the prescribing physician.

[0123] Administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof may be via any of the acceptable modes of administration for agents useful in a similar manner, including but not limited to oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administrations are common when treating the indications that are the subject of the preferred embodiments.

[0124] As described above, the useful compounds can be formulated into pharmaceutical compositions for use in the treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety. Thus, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0125] In addition to the selected compounds useful as described above, some embodiments include compositions containing a pharmaceutically acceptable carrier. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent is contemplated for the therapeutic compositions, except where it is incompatible with the active ingredient. In addition, various adjuvants as commonly used in the art may be included. Considerations regarding the inclusion of the various components in the pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0126] Some examples of substances that can act as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tweens; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tabletting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0127] The selection of a pharmaceutically acceptable carrier to be used in conjunction with the subject compound is basically determined by the manner in which the compound is to be administered.

[0128] The compositions described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition containing an amount of a compound suitable for administration as a single dosage to an animal, preferably a mammalian subject, in accordance with good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is to be administered once a day or once per treatment cycle. Such dosage forms are contemplated to be administered once, twice, three times or more per day and can be administered by infusion over a time period (e.g., from about 30 minutes to about 2 - 6 hours) or by continuous infusion and can be given more than once during a treatment cycle, although single administration is not specifically excluded. One of ordinary skill in the art will recognize that the formulation does not specifically contemplate the entire treatment cycle and that such determination is left to the practitioner of the treatment rather than the formulation.

[0129] As described above, the useful compositions can be in any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, subcutaneous, or other parenteral routes of administration. In some embodiments, the composition can be in a form suitable for subcutaneous administration. One of ordinary skill in the art will recognize that oral and nasal compositions include compositions that are administered by inhalation and made using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound can be included. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, which are hereby incorporated by reference in their entirety: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0130] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorants, flow inducing agents, and melting agents, and can be compressed, powder tablets, enteric coated, sugar coated, film coated, or multi-compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and foaming preparations reconstituted from foaming granules, which contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorants.

[0131] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders, such as starch, gelatin, and sucrose; disintegrants, such as starch, alginic acid, and croscarmellose; lubricants, such as magnesium stearate, stearic acid, and talc. Flow promoting agents such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavorants, such as aspartame, saccharin, menthol, peppermint, and fruit flavorings, are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as insignificant taste, cost, and storage stability, and can be readily made by those skilled in the art.

[0132] Oral compositions include, among others, solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavoring agents and coloring agents disclosed above.

[0133] Such compositions can also be coated by conventional methods, typically with pH- or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract, in the vicinity of the desired topical application or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0134] The compositions described herein can optionally contain other active drugs.

[0135] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions typically include a soluble filler substance, such as sucrose, sorbitol and mannitol; and one or more binders, such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. They can also include the flow promoters, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above.

[0136] Liquid compositions formulated for topical ophthalmic use are formulated such that they can be topically administered to the eye. Comfort should be maximized as much as possible, although sometimes formulation considerations (e.g., drug stability) may be required over optimal comfort. If comfort cannot be maximized, the liquid should be formulated such that it is tolerable for the patient for topical ophthalmic use. Additionally, the ophthalmically acceptable liquid should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0137] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the main vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulation can also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0138] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0139] Tonicity adjusters can be added when required or convenient. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0140] As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting the pH can be used. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. An acid or base can be used to adjust the pH of these formulations when required.

[0141] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0142] Other excipient components that can be included in the ophthalmic preparation are chelating agents. A useful chelating agent is sodium edetate, but other chelating agents can also be used instead of or in combination with it.

[0143] For topical use, creams, ointments, gels, solutions, suspensions, etc. containing the compounds disclosed herein are used. Topical formulations can generally be composed of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0144] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as physiological saline or a dextrose solution. Suitable excipients can include, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238 - 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, both of which are incorporated herein by reference in their entirety. Antimicrobial agents can also be included, but are not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol to achieve a bacteriostatic or fungistatic solution.

[0145] Compositions for intravenous administration can be provided to the caregiver in one or more solid forms that are reconstituted immediately prior to administration with a suitable diluent, such as sterile water, saline, or dextrose in water. In other embodiments, the composition is provided in a solution that is ready for parenteral administration. In still other embodiments, the composition is provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of the compounds and another agent described herein, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0146] The actual dosage of the active compounds described herein depends on the particular compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of a skilled artisan.

[0147] The compounds and compositions described herein can be provided, if desired, in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such pack or device can include, for example, a metal or plastic foil, such as a blister pack, or glass and rubber stoppers in vials, etc. The pack or dispenser device can be accompanied by instructions for administration. The compounds and compositions described herein can be formulated in a pharmaceutically acceptable carrier, also prepared for the treatment of the indicated condition, placed in a suitable container, and labeled.

[0148] The amount of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains the compound of the present science and technology from about 0.01 wt% to 99.99 wt% based on the total formulation on a weight percent (wt%) basis, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 wt% to 80 wt%. Representative pharmaceutical formulations are described below.

[0149] Formulation Examples The following are representative pharmaceutical preparations containing the compound of formula (I).

[0150] Formulation Example 1 - Tablet Formulation The following components were intimately mixed and compressed into single scored tablets.

[0151] [Table 1]

[0152] Formulation Example 2 - Capsule Formulation The following components were intimately mixed and filled into hard shell gelatin capsules.

[0153] [Table 2]

[0154] Formulation Example 3 - Suspension Formulation The following components are mixed to form a suspension for oral administration.

[0155] [Table 3]

[0156] Formulation Example 4 - Injectable Formulation The following components are mixed to form an injectable formulation.

[0157] [Table 4]

[0158] Formulation Example 5 - Suppository Formulation Suppositories with a total mass of 2.5 g were prepared by mixing the compound of the present science and technology with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition:

[0159] [Table 5]

[0160] Treatment method The compounds disclosed herein, or their tautomers and / or their pharmaceutically acceptable salts, act effectively as GLP-1 receptor agonists. Some embodiments provide a pharmaceutical composition comprising one or more of the compounds disclosed herein and a pharmaceutically acceptable excipient.

[0161] Some embodiments provide a method of preventing, treating or alleviating one or more fatty liver diseases in a subject. In some embodiments, the method comprises administering to a subject in need thereof one or more of the compounds disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutically acceptable salts of the compounds disclosed herein.

[0162] Some embodiments provide a method of preventing, treating or alleviating obesity, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In some embodiments, the method comprises administering to a subject in need thereof one or more of the compounds disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutically acceptable salts of the compounds disclosed herein.

[0163] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the prevention, treatment or alleviation of fibrosis, fibrotic conditions or fibrotic symptoms. In some embodiments, the method comprises administering one or more of the pharmaceutically acceptable salts of the compounds disclosed herein.

[0164] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a host in a condition, including but not limited to, conditions resulting from fibrosis or inflammation and associated with myofibroblast differentiation. Exemplary conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic, and genetic chronic diseases), kidney fibrosis (e.g., resulting from chronic inflammation, infection, or type II diabetes), lung fibrosis (idiopathic, or environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, drugs, etc.), interstitial fibrosis, systemic sclerosis (an autoimmune disease where many organs become fibrotic), macular degeneration (a fibrotic disease of the eye), pancreatic fibrosis (e.g., resulting from alcohol abuse and chronic inflammatory diseases of the pancreas), splenic fibrosis (from sickle cell anemia, other blood disorders), cardiac fibrosis (resulting from infection, inflammation, and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, non-alcoholic fatty liver disease, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemia-reperfusion injury-related fibrosis, injection-induced fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0165] In some embodiments, a method of administering one or more of the compounds disclosed herein results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the method comprises administering one or more pharmaceutically acceptable salts of one or more of the compounds disclosed herein.

[0166] In some embodiments, a method of administering one or more of the compounds disclosed herein results in a reduction in the amount of collagen present in one or more tissues of the subject. In some embodiments, the method comprises administering one or more pharmaceutically acceptable salts of one or more of the compounds disclosed herein.

[0167] In some embodiments, a method of administering one or more of the compounds disclosed herein 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. In some embodiments, the method comprises administering one or more pharmaceutically acceptable salts of one or more of the compounds disclosed herein.

[0168] Some embodiments provide a method of preventing, treating, or alleviating one or more of liver fibrosis, kidney fibrosis, biliary 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 in a subject. In some embodiments, the method comprises administering to a subject in need thereof one or more of the compounds disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof one or more pharmaceutically acceptable salts of one or more of the compounds disclosed herein.

[0169] Some embodiments provide a method of preventing, treating, or alleviating one or more of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis in a subject. In some embodiments, the method comprises administering to a subject in need thereof one or more of the compounds disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof one or more pharmaceutically acceptable salts of one or more of the compounds disclosed herein.

[0170] Some embodiments provide a method of preventing, treating, or alleviating one or more metabolic disorders or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 true diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. In some embodiments, the method comprises administering to a subject in need thereof one or more of the compounds disclosed herein. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutically acceptable salts of the compounds disclosed herein.

[0171] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the glucagon-like peptide-1 (GLP-1) receptor.

[0172] Some embodiments include co-administering a compound, composition, and / or pharmaceutical composition described herein with an additional medicament. By "co-administering," it is meant that two or more agents can be found in the bloodstream of a patient at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, e.g., orally. In another embodiment, the agents are administered via different routes, e.g., one is administered subcutaneously, another is administered orally, and another is administered i.v.

[0173] To further illustrate this disclosure, the following examples are given. The examples, of course, should not be construed as specifically limiting this disclosure. Variations of these examples 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 this disclosure as described and claimed herein. The reader will recognize that this disclosure and a skilled artisan with the skills in the art can prepare and use this disclosure without using an exhaustive number of examples. The following examples further describe this disclosure and are used for illustrative purposes only and should not be construed as limiting.

Example

[0174] General Procedure It is apparent to those skilled in the art that methods for preparing the 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 per se to those skilled in the art but not described in more detail. Those skilled in the art given the literature and this disclosure are well equipped with the ability to prepare any of these compounds.

[0175] Those skilled in the art of organic chemistry will recognize that the operations can be readily carried out without further instruction, i.e., performing these operations is well within the scope and practice of those skilled enough. These include, for example, the reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification, and saponification, etc. These operations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (which are incorporated herein by reference in their entirety). All intermediate compounds of this disclosure were used without further purification unless otherwise specified.

[0176] Certain reactions are best carried out when other functional groups are masked or protected in the molecule, and thus it will be readily appreciated by one skilled in the art to avoid any unwanted side reactions and / or increase the yield of the reaction. Often, one skilled in the art will utilize protecting groups to achieve such yield increases or avoid undesired reactions. These reactions are found in the literature and are well within the scope of one skilled in the art. Many examples of these procedures can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Edition, John Wiley & Sons (2007), which is hereby incorporated by reference in its entirety.

[0177] The following scheme examples are provided for the reader's guidance and represent preferred methods for making the compounds illustrated herein. These methods are not limiting, and it is clear that other routes can be used to prepare these compounds. Such methods specifically include solid-phase based chemistry including combinatorial chemistry. One skilled in the art is fully equipped with the ability to prepare these compounds by methods as provided in the literature and this disclosure. The compound numbering used in the synthetic schemes illustrated below is meant for those particular schemes only and should not be construed or confused with the same numbering in other sections of this application.

[0178] The trademarks used herein are for example only and reflect the exemplary materials used at the time of this disclosure. One skilled in the art will recognize that variations in lots, manufacturing processes, etc. are to be expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but are merely illustrative of how one skilled in the art can select to carry out one or more of the embodiments of this disclosure.

[0179] The following abbreviations have the indicated meanings: Aib = aminoisobutyric acid Bn = benzyl Boc = tert-butoxycarbonyl Bu = butyl DMF = dimethylformamide EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU = O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HMDS = hexamethyldisilazane HPLC = high performance liquid chromatography Me = methyl NaHMDS = sodium hexamethyldisilazide NMR = nuclear magnetic resonance PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl

[0180] The following scheme examples are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Further, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0181] (Example 1) Synthesis of Intermediate 1 (INT 1) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with 1 equivalent of NaHMDS to generate an ylide, which is immediately reacted with the aldehyde from the PCC oxidation of 10-bromo-1-decanol in a Wittig reaction. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonate ester. Hydrolysis of the methyl carboxylate provides the desired INT 1 having a terminal carboxylic acid and dibenzyl phosphonate.

[0182]

Chemical formula

[0183] Synthesis of Intermediate 1A (INT 1A) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with 1 equivalent of NaHMDS to generate an ylide, which is immediately reacted with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol in a Wittig reaction. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonate ester. Hydrolysis of the methyl carboxylate provides the desired INT 1A having a terminal carboxylic acid and dibenzyl phosphonate.

[0184]

Chemical formula

[0185] Synthesis of Intermediate 2 (INT 2) Octadecanedioic acid is coupled to benzyl alcohol using EDC·HCl and DMAP in THF to obtain INT 2 as a monobenzyl ester.

[0186]

Chemical formula

[0187] Synthesis of Intermediate 3 (INT 3) t-Butyl 4-hydroxybutanoate undergoes Swern oxidation to give an aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. Addition of the lithium salt of diethyl phosphite in THF generates an α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group, providing INT 3 with a free primary amine, t-butyl ester, and diethyl phosphonate ester. The optical purity of INT 3 was confirmed to be at least 96% by 1H-NMR via Mosher amide analysis.

[0188] [Chemical Structure]

[0189] Synthesis of Intermediate 4 (INT 4) INT 1 is coupled with the 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0190] [Chemical Structure]

[0191] Synthesis of Intermediate 4A (INT 4A) INT 1A is coupled with the 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4A.

[0192] [Chemical Structure]

[0193] Synthesis of Intermediate 5 (INT 5) INT 2 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare a new amide linkage. Cleavage of the ethyl phosphonate with TMS-Br gives the free phosphonic acid. Trans-esterification using a large excess of the benzyl ester of N,N'-diisopropylcarbamimidic acid provides the corresponding dibenzyl phosphonate. The t-butyl ester is cleaved using TFA to give INT 5.

[0194]

Chemical Structure

[0195] Synthesis of Intermediate 6 (INT 6) INT 1 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to provide a new amide linkage. Cleavage of the benzyl and ethyl phosphonate with TMS-Br gives both free phosphonic acids. Trans-esterification using a large excess of the benzyl ester of N,N'-diisopropylcarbamimidic acid provides the corresponding tetrabenzyl diphosphonate ester. The t-butyl ester is cleaved using TFA to give INT 6.

[0196]

Chemical Structure

[0197] (Example 2) Synthesis of the Common Peptide Backbone The 31-amino acid peptide backbone is constructed using solid-phase peptide synthesis techniques using diimide, HATU or HBTU activation for amide bond synthesis on Rink resin. Reagent selection varies based on the identity of the amino acids being attached. The R-group of lysine-20 was extended with two PEG2 amide linkers. The entire backbone is synthesized on resin prior to coupling INT 4, INT 4A, INT 5 or INT 6 to the amino terminus of the lysine-linked linker.

[0198]

Chem.

[0199] (Example 3) Synthesis of Compound 1 The peptide backbone is coupled to INT 4 to obtain the protected Compound 1 bound to the resin. Cleavage of the resin, protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provide Compound 1, which is purified via HPLC.

[0200]

Chem.

[0201] (Example 4) Synthesis of Compound 2 The peptide backbone is coupled to INT 5 to obtain the protected Compound 2 bound to the resin. Cleavage of the resin, protecting groups on the peptide chain, and the benzyl ester of INT 5 using TFA provide Compound 2, which is purified via HPLC.

[0202]

Chem.

[0203] (Example 5) Synthesis of Compound 3 The peptide backbone is coupled to INT 6 to obtain the protected Compound 3 bound to the resin. Cleavage of the resin, protecting groups on the peptide chain, and the benzyl ester of INT 6 using TFA provide Compound 3, which is purified via HPLC.

[0204]

Chem.

[0205] (Example 6) Synthesis of Compound 4 The peptide backbone is coupled to INT 4A to obtain the protected compound 4 bound to the resin. Cleavage of the resin, protecting groups on the peptide chain, and the benzyl ester of INT 4A using TFA afford compound 4, which is purified via HPLC.

[0206] [Chemical formula]

[0207] (Example 7) In vitro GLP-1 binding activity Using the TagLite® binding assay and the HEK293 cell line, the ligand binding competition activity at the human GLP-1 receptor was determined. Compounds were tested in duplicate at the following nanomolar concentrations: 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1,000 nM, 3,000 nM, and 10,000 nM. Compounds were tested individually and in the presence of 2% HSA. The agonist activity of the test compounds is expressed as a percentage of the activity of the reference agonist at its IC 100 concentration as shown in Table 1 (Table 6).

[0208] [Table 6]

[0209] (Example 8) Pharmacokinetic study of the formulation Subcutaneous (SC) dosing of the compounds in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline aqueous solution was performed using male cynomolgus monkeys. The assigned dose groups were as follows: Formulation 1 semaglutide (0.2 mg / kg); Formulation 2 semaglutide (0.2 mg / kg); Formulation 1 compound 4 (0.2 mg / kg); and Formulation 2 compound 4 (0.2 mg / kg). Formulation 1 is prepared by formulating a compound (e.g., compound 1 or compound 4) in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline aqueous solution. Formulation 2 is prepared by formulating the compound in 40% propylene glycol and 60% 10 mM pH 6 citrate buffer solution. Semaglutide (0.2 mg / kg) or compound 4 (0.2 mg / kg) was administered to the assigned dose groups over 21 days.

[0210] Selected pharmacokinetic data for the two formulations are shown in Table 2 (Table 7). The data indicate that administration of compound 4 in Formulation 1 and Formulation 2 resulted in significantly higher persistence in the bloodstream when compared to administration of semaglutide in the same formulation. The mean half-life of compound 4 in Formulation 1 was 150% greater when compared to semaglutide. Formulation 2 resulted in a mean half-life of compound 4 that was 150% greater when compared to semaglutide. Additionally, compound 4 showed greater drug exposure than compound 1 for both Formulation 1 and Formulation 2.

[0211] [Table 7]

[0212] (Example 9) Biological effects of the compounds in mice As described by Boland et al. in World J Gastroenterol, 2019, 25(33): 4904 - 4920, NASH was induced in mice by administering the Gubra amylin NASH (GAN) diet therapy. One week before the administration of the first dose of the compound, the mice were weighed, randomized, and their food intake was measured. The mice were randomly assigned to the dosing groups, with 12 mice per group. The assigned dosing groups included: semaglutide (10 mg / kg); compound 1 (10 mg / kg); compound 2 (10 mg / kg); compound 3 (10 mg / kg); and compound 4 (10 mg / kg); one group was sham - treated with vehicle only as a control. Compound dose titration (nmol / kg): 0.6 (day 0), 1.2 (day 1), 2.4 (day 2), 4.8 (day 3), 4.8 (day 4), 12 (day 5), 30.0 (from day 6).

[0213] After 2 weeks, the animals are sacrificed. Plasma enzymes (P - ALT (alanine aminotransferase) and P - AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol are measured, and a terminal autopsy of each liver is performed to determine the relative liver mass as a percentage of body weight, and the total liver biochemistry including total liver triglycerides, plasma insulin, and total liver cholesterol is assayed, and similarly, histological evaluations of galectin - 3 and alpha - smooth muscle actin are performed.

[0214] Although some embodiments have been illustrated and described, those of ordinary skill in the art, after reading the foregoing specification, may effect 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 present technology as described herein. Each aspect and embodiment described above may include or incorporate variant forms or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0215] Moreover, the technology should not be limited with respect to the specific embodiments described herein which are intended as a single illustration of individual aspects of the technology. As will be apparent to those skilled in the art, many modifications and variations of this technology can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent ways within the scope of the technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that this technology is not limited to the particular methods, reagents, compounds, compositions, labeled compounds or biological systems which can of course vary. Moreover, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Accordingly, this specification is intended to be considered as illustrative only, and the breadth, scope and spirit of the technology are indicated only by the appended claims, their definitions and any equivalents thereof.

[0216] The embodiments illustratively described herein can be suitably practiced without any element(s) (singular or plural), limitation(s) (singular or plural) not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. shall be read in a broad and non-limiting sense. In addition, the terms and expressions used herein are used as descriptive terms and not as limiting, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or a part thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. In addition, the phrase "consisting essentially of" is understood to include the elements as specifically recited, as well as additional elements that do not materially affect the basic and novel features of the claimed technology. The phrase "consisting of" excludes any element not specified.

[0217] In addition, when features or aspects of the present disclosure are described with respect to a Markush group, one of ordinary skill in the art will recognize that the present disclosure thereby also describes with respect to any individual member of the Markush group or a subgroup of its members. Each of the narrower species and subgeneric classifications that fall within the broad disclosure also forms part of this technology. This includes any disclaimer or negative limitation of the technology that excludes any subject matter from the genus concept, whether or not the excised material is specifically recited herein.

[0218] All publications, patent applications, issued patents, and other documents (e.g., academic journals, articles and / or textbooks) referred to in this specification are hereby incorporated by reference in their entirety as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference. Definitions contained in text incorporated by reference are excluded to the extent they contradict definitions in this disclosure.

[0219] Other embodiments are described in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0220] The present disclosure has been shown and described with respect to preferred embodiments and various alternative embodiments, but it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.

[0221] All references, issued patents, and patent applications enumerated in the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0222] The present disclosure has been described with reference to embodiments and examples, but it should be understood that numerous and various modifications can be made without departing from the spirit of the present disclosure. Accordingly, the present disclosure is limited only by the following claims.

Claims

1. Equation (I): 【Chemistry 1】 A compound having the structure, or a pharmaceutically acceptable salt thereof. [In formula: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and 1 to 2 R 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S, which may be substituted with; R 2 is -C(=O)(OZ 2 ), P(=O)(X)(Y), and 1 to 2 R 7 Selected from the group consisting of 5-10 membered heteroaryls containing 1-4 heteroatoms selected from N, O, and S, which may be substituted with; Each R 7 is independently selected from the group consisting of 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; 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 6～10 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, C 3～10 Cycloalkyl and C 6～10 Independently selected from the group consisting of aryls, n is 0, 1, 2, 3, or 4, Here, Z 1 and Z 2 If both exist, Z 1 and Z 2 At least one of them is not hydrogen, [* indicates a chiral carbon having an "S" or "R" stereoconfiguration.]

2. Equation (Ia): 【Chemistry 2】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

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

4. Z 1 However, it is hydrogen; each R 4 Hydrogen, C 6～10 Aryl and C 6～10 A compound according to claim 3, selected from the group consisting of arylalkyls.

5. Each R 4 Independently, hydrogen or C 6～10 The compound according to claim 4, wherein it is an arylalkyl.

6. The compound according to claim 2, wherein n is 1 or 2.

7. Formula (Ib): 【Transformation 3】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

8. Z 2 However, hydrogen, C 1～6 Alkyl, Halo C 1～6 Alkyl, C 3～10 Cycloalkyl and C 6～10 Selected from the group consisting of aryls; X and Y are each -OR 4 The compound according to claim 7.

9. Z 2 However, it is hydrogen; each R 4 Hydrogen, C 6～10 Aryl and C 6～10 The compound according to claim 8, selected from the group consisting of arylalkyls.

10. Each R 4 However, hydrogen or C 6～10 A compound according to claim 9, independently selected from arylalkyls.

11. The compound according to claim 7, wherein n is 1 or 2.

12. Formula (Ic): 【Chemistry 4】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

13. X and Y are each -OR 4; each R 4 However, hydrogen, C 6～10 Aryl and C 6～10 A compound according to claim 12, independently selected from the group consisting of arylalkyls.

14. The compound according to claim 12, wherein n is 1 or 2. 【Request Item 15】 【Chemistry 5A】 【Chem.5B】 The compound according to claim 1, having a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition according to claim 16 for use in a method for preventing, treating, or alleviating one or more fatty liver diseases in a subject, (i) The fatty liver disease may be selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD). (ii) Administration of the compound may result in the prevention, treatment, or relief of fibrosis, fibrotic conditions, or fibrotic symptoms. (iii) Administration of the compound may result in a reduction of the amount of extracellular matrix proteins present in one or more tissues of the subject, and / or (iv) Administration of the compound may result in a reduction in the amount of collagen present in one or more tissues of the subject, and administration of the compound may result in a reduction in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject. Pharmaceutical composition.

18. A pharmaceutical composition according to claim 16 for use in a method of preventing, treating or alleviating one or more diseases or disorders in a subject, wherein the one or more diseases or disorders are metabolic disorders, hepatic fibrosis, renal fibrosis, cholangiofibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis. The aforementioned one or more diseases or disorders may be non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis, or The aforementioned one or more diseases or disorders may be atherosclerosis, diabetes mellitus, hyperglycemic diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. Pharmaceutical composition.

19. The pharmaceutical composition according to claim 18, wherein the compound or a pharmaceutically acceptable salt thereof activates the glucagon-like peptide-1 (GLP-1) receptor.

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