Compositions and methods for treating metabolic and liver conditions

Abstract

Disclosed herein are small molecule GLP-1 receptor agonist compounds, pharmaceutical compositions, and uses and preparation thereof.

Description

[0001] Reference sequence list

[0002] This application is submitted in electronic format along with a sequence listing. The sequence listing is provided as a file named VIKNG.023WO_ST_26.xml, created on July 17, 2023, and 2,791 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0003] background

[0004] field

[0005] The present disclosure relates generally to the field of treatments for metabolic disorders and fatty liver disease. More specifically, the present disclosure relates to the field of small molecule drugs for treating metabolic disorders and fatty liver disease.

[0006] Description of Related Technology

[0007] The incretin peptide glucagon-like peptide-1 (GLP-1) is a metabolic hormone. GLP-1 is secreted within minutes of nutrient intake and promotes rapid processing of ingested nutrients. Activation of incretin receptors leads to glucose-dependent insulin secretion, induction of β-cell proliferation and enhanced resistance to apoptosis. GLP-1 exerts glucose regulatory effects by slowing gastric emptying and glucose-dependent inhibition of glucagon secretion. In preclinical and clinical studies, GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss.

[0008] Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and is the most common cause of chronic liver disease. NAFLD may progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GLP-1 receptor agonists have been developed for the treatment of NAFLD, non-alcoholic fatty liver disease (NASH), diabetes, obesity and other diseases. However, the use of GLP-1 receptor agonists is associated with nausea, vomiting and other gastrointestinal side effects. The dose restrictions associated with gastrointestinal adverse events may prevent administration to the desired effective dose, may damage the patient's compliance with treatment, and may limit the effectiveness of the treatment regimen. Therefore, there is a demand for novel GLP-1 agonist compounds that can be used to treat fatty liver disease and other diseases and conditions.

[0009] Overview

[0010] Some embodiments disclosed herein include compounds having the structure of Formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] R 1 Selected from –C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0014] R 2 Selected from –C(=O)(OZ 2 ),–(CH2CH2) n P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0015] Each R 7 can be independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0016] X and Y can each independently be selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0017] Each R 4 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryloxy and C6-10 Arylalkoxy;

[0018] Each R 5 can be independently hydrogen or C 1-6 alkyl;

[0019] Each R 6 can be independently hydrogen or C 1-6 alkyl;

[0020] Z 1 and Z 2 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl;

[0021] n is 0, 1, 2, 3, or 4,

[0022] The condition is Z 1 and Z 2 At least one of them is not hydrogen.

[0023] Other embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.

[0024] Other embodiments disclosed herein include methods of preventing, treating or improving one or more fatty liver diseases in a subject by administering a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. Fatty liver diseases include, but are not limited to, steatosis, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).

[0025] Other embodiments disclosed herein include preventing, treating or improving one or more diseases or conditions in a subject by administering a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, the disease or condition is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic fatty hepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis. In some embodiments, the disease or condition is a metabolic disorder or metabolic syndrome. In some embodiments, the disease or condition is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity or Prader-Willi syndrome.

[0026] Details

[0027] In some embodiments, compounds of non-macrocyclic functionalized peptides as GLP-1 receptor agonists are provided. 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:

[0028]

[0029] In some embodiments of compounds of Formula (I):

[0030] R 1 Selected from –C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0031] R 2 Selected from –C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0032] Each R 7 can be independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0033] X and Y can each independently be selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0034] Each R 4 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryloxy and C 6-10 Arylalkoxy;

[0035] Each R 5 can be independently hydrogen or C 1-6 alkyl;

[0036] Each R 6 can be independently hydrogen or C 1-6 alkyl;

[0037] Z 1 and Z 2 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl;

[0038] n is 0, 1, 2, 3, or 4,

[0039] The condition is Z 1 and Z 2 At least one of them is not hydrogen.

[0040] Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ia):

[0041]

[0042] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0044] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 can be independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

[0045] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen, and each R 4 can be independently hydrogen or C 6-10 Arylalkoxy.

[0046] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, each R 4 It's hydrogen.

[0047] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen and each R 4 It's hydrogen.

[0048] In some embodiments of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In some embodiments, n is 4.

[0049] Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ib):

[0050]

[0051] or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, Z 2 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0053] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C1-6 alkoxy; and each R 4 can be independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

[0054] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, Z 2 is hydrogen and each R 4 can be independently hydrogen or C 6-10 Arylalkoxy.

[0055] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, each R 4 It's hydrogen.

[0056] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, Z 2 is hydrogen and each R 4 It's hydrogen.

[0057] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In some embodiments, n is 4.

[0058] Some embodiments of compounds of formula (I) include compounds having the structure of formula (Ic):

[0059]

[0060] or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments of the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, X and Y are each -OR 4 .

[0062] In some embodiments of the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, each R 4 can be independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 In some embodiments of the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, each R 4 It's hydrogen.

[0063] In some embodiments of the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In some embodiments, n is 4.

[0064] Some embodiments include compounds having a structure selected from the group consisting of:

[0065]

[0066]

[0067] and pharmaceutically acceptable salts thereof.

[0068] Some embodiments include compounds wherein "*" represents a chiral carbon having an "S" configuration.

[0069] Some embodiments include compounds wherein "*" represents a chiral carbon having an "R" configuration.

[0070] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). The separation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise stated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise stated, all such forms are included in the scope of the compounds disclosed herein (including any polymorphic forms). In addition, some compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise stated, such solvates are included in the scope of the compounds disclosed herein.

[0071] Those skilled in the art will recognize that some structures described herein may be resonance forms or tautomers of compounds, even though they may be reasonably represented kinetically by other chemical structures; the skilled artisan recognizes that such structures may represent only a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the described structures, even though such resonance forms or tautomers are not represented herein.

[0072] definition

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the case where there are multiple definitions for a term in this article, unless otherwise stated, the definitions in this section shall prevail.

[0074] "Solvate" refers to a compound formed by the interaction of a solvent with a compound described herein or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0075] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound, which is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds herein are capable of forming acid and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in Johnston et al. WO 87 / 05297, published September 11, 1987 (incorporated herein by reference in its entirety).

[0076] As used herein, “C a To C b " or "C a-b ” (where “a” and “b” are integers) refers to the number of carbon atoms in a given group. That is, the group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4 The term "alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0077] As used herein, the term "halogen" or "halo" means any of the radiostable atoms of column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0078] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in a given range; for example, "1 to 20 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also covers the occurrence of the term "alkyl" in the case of an unspecified numerical range). The alkyl group can also be a medium-sized alkyl group with 1 to 9 carbon atoms. The alkyl group can also be a low alkyl group with 1 to 4 carbon atoms. The alkyl group of a compound can be designated as "C 1-4 Alkyl" or similar designations. By way of example only, "C 1-4 "Alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0079] As used herein, "haloalkyl" refers to a straight or branched alkyl group having 1 to 12 carbon atoms in the chain, wherein a halogen replaces one or more hydrogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3 and other groups that would be considered equivalent to any one of the aforementioned examples according to those of ordinary skill in the art and the teachings provided herein.

[0080] As used herein, "alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl radical as defined above, e.g., "C 1-9 "Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, etc.

[0081] As used herein, "polyethylene glycol" refers to Wherein n is an integer greater than 1, and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by citing multiple members. Therefore, for example, "2 to 5-membered polyethylene glycol" means that n is an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0082] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the backbone. The heteroalkyl group can have 1 to 20 carbon atoms, but this definition also encompasses the appearance of the term "heteroalkyl" in the case of an unspecified numerical range. The heteroalkyl group can also be a medium-sized heteroalkyl group with 1 to 9 carbon atoms. The heteroalkyl group can also be a low-order heteroalkyl group with 1 to 4 carbon atoms. In various embodiments, the heteroalkyl group can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms or 1 heteroatom. The heteroalkyl group of a compound can be named "C 1-4 Heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means that there are 1 to 4 carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms are present in the backbone of the chain.

[0083] The term "aromatic" refers to a ring or ring system having a conjugated π electron system, and includes carbocyclic aromatics (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0084] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, each ring in the system is aromatic. Aryl groups can have 6 to 18 carbon atoms, but this definition also covers the occurrence of the term "aryl" in the case of an unspecified numerical range. In some embodiments, aryl groups have 6 to 10 carbon atoms. Aryl groups can be named "C 6-10 Aryl", "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0085] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is an aryl group as defined above, for example, "C 6-10 Aryloxy" or "C 6-10 "Arylthio" and the like, including but not limited to phenoxy.

[0086] "Aralkyl" or "arylalkyl" is an aryl group attached as a substituent through an alkylene group, for example "C 7-14 "Aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0087] 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, each ring in the system is aromatic. The heteroaryl group can have 5-18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the appearance of the term "heteroaryl" in the case of an unspecified numerical range. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group can be named "5-7 yuan heteroaryl", "5-10 yuan heteroaryl" or similar names. In various embodiments, the heteroaryl group includes 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. For example, in various embodiments, the heteroaryl group comprises 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0088] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group attached as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0089] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the main chain of the ring system. When the carbocyclyl is a ring system, two or more rings can be connected together in a fused, bridged or spirally connected manner. The carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Therefore, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. The carbocyclyl group can have 3 to 20 carbon atoms, but this definition also covers the occurrence of the term "carbocyclyl" in the case of an unspecified numerical range. The carbocyclyl group can also be a medium-sized carbocyclyl with 3 to 10 carbon atoms. The carbocyclyl group can also be a carbocyclyl with 3 to 6 carbon atoms. The carbocyclyl group can be named "C 3-6Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindane, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0090] "(Carbocyclyl)alkyl" is a carbocyclyl group attached as a substituent via an alkylene group, for example "C 4-10 "(Carbocyclyl)alkyl" and the like, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group.

[0091] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0092] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0093] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclyl group can be connected together in a fused, bridged or spirally connected manner. The heterocyclyl group 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 a non-aromatic ring or aromatic ring in the ring system. The heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the appearance of the term "heterocyclyl" in the case of an unspecified numerical range. The heterocyclyl group can also be a medium-sized heterocyclyl with 3 to 10 ring members. The heterocyclyl group can also be a heterocyclyl with 3 to 6 ring members. The heterocyclyl group can be named "3-6 heterocyclyl" or similar names.

[0094] In various embodiments, the heterocyclic radical contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclic radical contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred six-membered monocyclic heterocyclic radicals, the heteroatoms are selected from one to three of O, N, or S, and in preferred five-membered monocyclic heterocyclic radicals, the heteroatoms are selected from one or two 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-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,2-oxazinyl, , 3,5-triazine, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrophenylthio, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0095] "(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0096] As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0097] An "O-carboxyl" group refers to a "-OC(=O)R" group, wherein R is selected from hydrogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0098] A "C-carboxyl" group refers to a "-C(=O)OR" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0099] A "cyano" group refers to a "-CN" group.

[0100] A "cyanato" group refers to a "-OCN" group.

[0101] An "isocyanato" group refers to a "-NCO" group.

[0102] A "thiocyanato" group refers to a "-SCN" group.

[0103] An "isothiocyanato" group refers to a "-NCS" group.

[0104] A "sulfinyl" group refers to a "-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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0105] A "sulfonyl" group refers to a "-SO2R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0106] The "S-sulfonylamino" 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, C3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0107] An "N-sulfonylamino" group refers to an "-N(R A )SO2R 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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0108] An "O-carbamoyl" group refers to a "-OC(=O)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0109] An "N-carbamoyl" group refers to an "-N(R A )OC(=O)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0110] An "O-thiocarbamoyl" group refers to an "-OC(=S)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0111] An "N-thiocarbamoyl" group refers to an "-N(R A )OC(=S)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0112] A "C-amido" group refers to a "-C(=O)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0113] An "N-amido" group refers to an "-N(R A )C(=O)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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0114] An "amino" group refers to an "-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 group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0115] An "aminoalkyl" group refers to an amino group attached through an alkylene group.

[0116] An "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group, for example, "C 2-8 "Alkoxyalkyl" and the like.

[0117] As used herein, a substituted group is derived from an unsubstituted parent group in which there is an exchange of one or more hydrogen atoms with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", it means that the group is substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 assorted alkyl, C3-C7 carbocyclyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl ... C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5-10 membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether), aryloxy, mercapto (thiol), 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-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted", the group may be substituted by the above substituents.

[0118] In some embodiments, the substituted group is substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxyl, and halogen.

[0119] It is understood that certain radical naming conventions may include monoradicals or diradicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl group that requires two points of attachment includes a diradical, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

[0120] When two R groups are considered to form a "ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring)" together with the atoms to which they are attached, it is meant that the collective unit of the atoms and the two R groups is the ring. The ring is not limited by the definition of each R group when used alone. For example, when the following substructure is present:

[0121]

[0122] And R 1 and R 2 is defined as being selected from hydrogen and alkyl, or R 1 and R 2 Together with the nitrogen to which they are attached, they form a heterocyclic group, which means that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0123]

[0124] wherein Ring A is a heterocyclyl ring containing said nitrogen.

[0125] Similarly, when two "adjacent" R groups are considered to form a ring together with the atoms to which they are attached, this means that the collective unit of atoms, the intervening bond, and the two R groups is the ring. For example, when the following substructure is present:

[0126]

[0127] And R 1 and R 2 is defined as being selected from hydrogen and alkyl, or R 1 and R 2 Together with the atoms to which they are attached, they form an aryl or carbocyclic group, which means that R 1 and R 2can be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0128]

[0129] wherein A is an aryl ring or a carbocyclic group containing the double bond.

[0130] Where a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, a substituent depicted as -AE- or Substituents include substituents that are directed such that A is attached at the leftmost attachment point of the molecule, as well as cases where A is attached at the rightmost attachment point of the molecule.

[0131] The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates (including great apes (chimpanzees, apes, monkeys) and humans), cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

[0132] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except in the case where any conventional media or agents are incompatible with the active ingredient, they are contemplated for use in therapeutic compositions. In addition, various adjuvants commonly used in the art may be included. Considerations for 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 Ed., Pergamon Press, which are incorporated herein by reference in their entirety.

[0133] As used herein, "subject" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate.

[0134] As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to alleviate or reduce the likelihood of onset of one or more symptoms of a disease or condition to some extent, and includes a cure for the disease or condition. "Cure" means eliminating the symptoms of the disease or condition; however, even after a cure is achieved there may be certain long-term or permanent effects (e.g., extensive tissue damage).

[0135] As used herein, "treat," "treatment," or "treating" refers to the administration of a pharmaceutical composition for preventive and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet show symptoms of a disease or condition, but who is susceptible to or at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who already has a disease or condition.

[0136] Preparation method

[0137] Compounds disclosed herein can be synthesized by the methods described below or by improvements to these methods. The method of improving the method particularly includes temperature, solvent, reagent, etc. known to those skilled in the art. Generally, during any process for preparing compounds disclosed herein, it may be necessary and / or necessary to protect sensitive or reactive groups on any related molecules. This can be achieved by means of conventional protecting groups, such as Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are incorporated herein by reference in their entirety. Protecting groups can be removed using methods known in the art in appropriate subsequent stages. Synthetic chemical transformations for synthesizing appropriate compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are incorporated herein by reference in their entirety. The approaches shown and described herein are illustrative only and are neither intended nor should be construed as limiting the scope of the claims in any way. Those skilled in the art will be able to identify modifications to the disclosed synthesis and will be able to design alternative approaches based on the disclosure herein; all such modifications and alternative approaches are within the scope of the claims.

[0138] In the following schemes, protecting groups for oxygen atoms were chosen for their compatibility with the necessary synthetic steps and for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0139] If the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present technology. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0140] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or reasonable modifications thereof. For example, many starting materials can be obtained from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures or rational modifications thereof, which are described in standard reference textbooks, 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).

[0141] In one embodiment, the method disclosed herein may include using solid phase peptide synthesis technology to construct a 31 amino acid peptide backbone to provide an intermediate (II). The peptide backbone includes two PEG2 amide linkers. The method includes an amide coupling reaction between the amine of the terminal PEG2 amide of the intermediate (II) and a suitably substituted carboxylic acid (III) to provide a resin-bound intermediate (IV). In one embodiment, the method includes hydrolyzing the intermediate (IV) under acidic conditions, followed by purification to obtain a final product (I). (Scheme 1).

[0142] Scenario 1:

[0143]

[0144] The above exemplary schemes are provided for the guidance of the reader and collectively represent exemplary methods for preparing the compounds included herein. In addition, other methods for preparing the compounds described herein will be apparent to those of ordinary skill in the art based on the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0145] Administration and pharmaceutical compositions

[0146] Compound is administered with therapeutically effective dose. Although human dosage level has not been optimized for compounds described herein, generally, daily dose can be about 0.0125mg / kg to about 120mg / kg body weight or more, about 0.025mg / kg or less to about 70mg / kg, about 0.05mg / kg to about 50mg / kg body weight or about 0.075mg / kg to about 10mg / kg body weight. Therefore, for people administered to 70kg, dosage range will be about 0.88mg / day to about 8000mg / day, about 1.8mg / day or less to about 7000mg / day or more, about 3.6mg / day to about 6000mg / day, about 5.3mg / day to about 5000mg / day or about 11mg / day to about 3000mg / day. Of course, the amount of active compound administered will depend on the object and disease state treated, the severity of the pain, the mode of administration and schedule and the judgment of the prescribing physician.

[0147] The administration of the compounds disclosed herein or their pharmaceutically acceptable salts can be carried out via any acceptable mode of administration for medicaments of similar utility, including but not limited to oral administration, subcutaneous administration, intravenous administration, intranasal administration, topical administration, transdermal administration, intraperitoneal administration, intramuscular administration, intrapulmonary administration, vaginal administration, rectal or intraocular administration. Oral and parenteral administration are generally used to treat the indications of the objects of the preferred embodiments.

[0148] The compounds useful as described above can be formulated into pharmaceutical compositions for treating these conditions. Standard pharmaceutical preparation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which are incorporated by reference in their entirety. Therefore, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, tautomers, polymorphs and solvates thereof) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

[0149] In addition to the selected compounds useful as described above, some embodiments also include compositions comprising a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except in the case where any conventional media or agents are incompatible with the active ingredient, it is considered to be used in therapeutic compositions. In addition, various adjuvants commonly used in the art may be included, for example. Considerations regarding the inclusion of various components in pharmaceutical compositions are described in, for example, Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which are incorporated herein by reference in their entirety.

[0150] Some examples of substances that can be used 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 carboxymethylcellulose, ethylcellulose and methylcellulose; 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 cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline and phosphate buffered solutions.

[0151] The choice of a pharmaceutically acceptable carrier for use in conjunction with a subject compound is essentially determined by the manner in which the compound is to be administered.

[0152] Compositions as described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition comprising a compound of an amount suitable for being administered to an animal (preferably a mammalian subject) in a single dose according to good medical practice. However, the preparation of a single or unit dosage form does not mean that the dosage form is administered once a day or once per course of treatment. It is expected that such dosage forms are administered once, twice, three times or more a day, and can be administered as an infusion within a period of time (e.g., about 30 minutes to about 2-6 hours), or as a continuous infusion, and can be given more than once in a course of treatment, although single administration is not particularly excluded. Those skilled in the art will recognize that the preparation does not specifically consider the entire course of treatment, and such a decision is left to the technical staff of the therapeutic field rather than the preparation.

[0153] As described above, useful compositions can be any of various suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intracapsular, intraarterial, intravenous, intramuscular, subcutaneous or other parenteral routes of administration. In some embodiments, the composition can be in a form suitable for subcutaneous administration. It will be appreciated by those skilled in the art that oral and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the specific 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 substances may be included that do not substantially interfere with the inhibitory activity of the compound. The amount of the carrier used in conjunction with the compound is sufficient to provide the material for the actual amount of the compound used for administration per unit dose. Techniques and compositions for preparing dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., 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).

[0154] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet grinding, enteric coating, sugar coating, film coating or multiple compression, including suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, flow inducers and melting agents (melting agent). Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstructed by non-effervescent granules and effervescent preparations reconstructed by effervescent granules, which include suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0155] Pharmaceutically acceptable carriers suitable for preparing 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 cross-linked sodium carboxymethylcellulose; lubricants, such as magnesium stearate, stearic acid and talc. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of the powder mixture. Colorants, such as FD&C dyes, may be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, mint and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents disclosed above. The choice of carrier components depends on secondary considerations, such as taste, cost and storage stability, which are not critical and can be easily made by those skilled in the art.

[0156] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also include one or more components, such as sweeteners, flavoring agents, and coloring agents disclosed above.

[0157] Such compositions may also be coated by conventional methods, typically using pH or time-dependent coatings, so that the subject compound is released in the gastrointestinal tract near the desired local application or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, acrylic resin coatings, waxes, and shellac.

[0158] The compositions described herein may optionally contain other pharmaceutically active substances.

[0159] Other compositions for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions generally include soluble filler materials, such as sucrose, sorbitol and mannitol; and binders, such as one or more of gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavorings disclosed above may also be included.

[0160] Liquid compositions (which are configured for topical ophthalmic use) are formulated so that they can be topically applied to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In the case where comfort cannot be maximized, liquids should be formulated so that liquids for topical ophthalmic use are tolerable to the patient. In addition, ophthalmologically acceptable liquids should be packaged for single use, or contain preservatives to prevent contamination from multiple uses.

[0161] For ophthalmic applications, physiological saline solution is usually used as the main vehicle to prepare solutions or medicines. It is preferred that the ophthalmic solution is maintained at a comfortable pH with an appropriate buffer system. The preparation may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0162] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate, and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0163] Tonicity adjusting agents may be added as required or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerol or any other suitable ophthalmologically acceptable tonicity adjusting agent.

[0164] Various buffers and means for adjusting pH can be used, as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used as needed to adjust the pH of these preparations.

[0165] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0166] Other excipient components that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used in place of or in combination with it.

[0167] For topical use, creams, ointments, gels, solutions or suspensions, etc. containing the compounds disclosed herein are used. Topical formulations can generally be composed of pharmaceutical carriers, co-solvents, emulsifiers, penetration enhancers, preservative systems, and emollients.

[0168] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to reach the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid. In various embodiments, the pH range of the final composition is 2 to 8, or preferably 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium phosphate or potassium phosphate, citric acid, tartaric acid, gelatin and carbohydrates, such as dextrose, mannitol and dextran. Other 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 may also be included to obtain a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol.

[0169] Compositions for intravenous administration can be provided to a caregiver in the form of one or more solids, which are reconstituted in water with a suitable diluent (e.g., sterile water, saline or dextrose) shortly before administration. In other embodiments, the composition is provided in a solution prepared for parenteral administration. In other embodiments, the composition is provided in a solution further diluted before administration. In embodiments including the combination of a compound as described herein and another medicament, the combination can be provided to a caregiver as a mixture, or the caregiver can mix two medicaments before administration, or two medicaments can be administered separately.

[0170] The actual dosage of the active compounds described herein depends on the specific compound and the condition to be treated; selection of the appropriate dosage is well within the knowledge of those skilled in the art.

[0171] If desired, the compounds and compositions described herein may be present in a package or dispenser device containing one or more unit dosage forms containing the active ingredient. Such packages or devices may, for example, include metal or plastic foil, such as blister packs or glass, and rubber stoppers, such as in vials. The package or dispenser device may be accompanied by instructions for administration. The compounds and compositions described herein are formulated in a compatible pharmaceutical carrier, and may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0172] The amount of the compound in the preparation can vary within the full range used by those skilled in the art. Typically, based on weight percentage (wt%), the preparation will contain about 0.01-99.99wt% of the compound of the present technology based on the total preparation, and the remainder is one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80wt%. Representative pharmaceutical preparations are described below.

[0173] Preparation Examples

[0174] The following are representative pharmaceutical formulations comprising a compound of formula (I).

[0175] Formulation Example 1 - Tablet Formulation

[0176] The following ingredients are intimately mixed and compressed into single scored tablets.

[0177]

[0178] Formulation Example 2 - Capsule Formulation

[0179] The following ingredients are mixed intimately and filled into hard shell gelatin capsules.

[0180]

[0181] Formulation Example 3 - Suspension Formulation

[0182] The following ingredients are mixed to form a suspension for oral administration.

[0183]

[0184] Formulation Example 4 - Injectable Formulation

[0185] The following ingredients are mixed to form an injectable preparation.

[0186]

[0187] Formulation Example 5 - Suppository Formulation

[0188] By combining the compound of the present technology with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5 g and having the following composition:

[0189]

[0190] Treatment

[0191] The compounds disclosed herein or their tautomers and / or their pharmaceutically acceptable salts may effectively act as GLP-1 receptor agonists.Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.

[0192] Some embodiments provide methods for preventing, treating or ameliorating one or more fatty liver diseases in a subject. In some embodiments, the method comprises administering one or more compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to a subject in need thereof.

[0193] Some embodiments provide methods for preventing, treating or ameliorating steatosis, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. In some embodiments, the method comprises administering one or more compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to a subject in need thereof.

[0194] In some embodiments, the methods of administering one or more compounds disclosed herein result in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom. In some embodiments, the methods comprise administering a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0195] In some embodiments, the compounds and compositions comprising the compounds described herein are useful for treating a number of conditions resulting from fibrosis or inflammation, including in particular those conditions associated with myofibroblast differentiation. Example conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic, and genetic chronic diseases), renal fibrosis (e.g., caused by chronic inflammation, infection, or type II diabetes), pulmonary fibrosis (idiopathic or caused by environmental insults, including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections (including tuberculosis), drugs, etc.), interstitial fibrosis, systemic sclerosis (an autoimmune disease in which many organs become fibrotic), macular degeneration (a fibrotic disease of the eye), pancreatic fibrosis (caused by, for example, alcohol abuse and chronic inflammatory diseases of the pancreas), splenic fibrosis (due to sickle cell anemia, other blood disorders), cardiac fibrosis (caused by infection, inflammation, and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, nonalcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, cirrhosis), fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or conditions.

[0196] In some embodiments, the methods of administering one or more compounds disclosed herein result in a decrease in the amount of extracellular matrix proteins present in one or more tissues of the subject. In some embodiments, the methods include administering a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0197] In some embodiments, the methods of administering one or more compounds disclosed herein result in a decrease in the amount of collagen present in one or more tissues of the subject. In some embodiments, the methods include administering a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0198] In some embodiments, the method of administering one or more compounds disclosed herein results in a decrease 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 a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0199] Some embodiments provide a method for preventing, treating or improving one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis in a subject. In some embodiments, the method comprises administering one or more compounds disclosed herein to a subject in need. In some embodiments, the method comprises administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to a subject in need.

[0200] Some embodiments provide a method of preventing, treating or ameliorating one or more of nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis or primary biliary cirrhosis in a subject. In some embodiments, the method comprises administering one or more compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to a subject in need thereof.

[0201] Some embodiments provide methods for preventing, treating or improving one or more metabolic disorders or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more compounds disclosed herein to a subject in need. In some embodiments, the method comprises administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to a subject in need.

[0202] In some embodiments, the methods of administering one or more compounds disclosed herein result in the compound activating the glucagon-like peptide-1 (GLP-1) receptor.

[0203] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with another drug. "Co-administering" means that two or more agents can be present in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, co-administration is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered by the same route, such as orally. In another embodiment, the agents are administered by different routes, such as one subcutaneously, another orally, and another intravenously.

[0204] To further illustrate the present disclosure, the following examples are included. These examples should certainly not be construed as specifically limiting the present disclosure. Variations of these examples within the scope of the claims are within the purview of those skilled in the art and are considered to fall within the scope of the present disclosure as described and claimed herein. The reader will recognize that those skilled in the art who understand the present disclosure and have mastered the technology in the art are able to prepare and use the present disclosure without the detailed examples. The following examples will further describe the present disclosure and are used for illustrative purposes only and should not be considered limiting. Example

[0205] General Procedure

[0206] It will be apparent to those skilled in the art that methods for preparing precursors and functional groups associated with the compounds claimed herein are generally described in the literature. In these reactions, variants may also be used, which are known to those of ordinary skill in the art but are not mentioned in more detail. In view of the literature and this disclosure, those skilled in the art are fully capable of preparing any compound.

[0207] It should be appreciated that those skilled in the art of organic chemistry can easily perform the operations without further guidance, that is, it is entirely within the scope and practice of those skilled in the art to perform these operations. These include reducing carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions (electrophilic and nucleophilic), etherifications, esterifications, and saponifications, etc. These operations are discussed in standard textbooks, e.g., March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein in their entirety by reference), etc. Unless otherwise noted, all intermediate compounds of the present disclosure are used without further purification.

[0208] Those skilled in the art will readily appreciate that when other functional groups in the molecule are masked or protected, it is best to carry out certain reactions to avoid any undesirable side reactions and / or increase the yield of the reaction. Those skilled in the art typically utilize blocking groups to achieve such increased yields or to avoid undesirable reactions. These reactions are present in the literature and are also within the scope of those skilled in the art. Many examples of these operations can be found in, for example, T.Greene and P.Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), which are incorporated herein by reference in their entirety.

[0209] The following example schemes are provided to guide the reader and represent preferred methods for preparing the compounds exemplified herein. These methods are not restrictive, and other approaches can obviously be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Those skilled in the art are fully capable of preparing these compounds by providing those methods of the literature and the present disclosure. The compound numbers used in the synthetic schemes described below are only used for those specific schemes and should not be interpreted as being the same numbering in other parts of the application or being confused with the same numbering.

[0210] The trademarks used herein are examples only and reflect the illustrative material used in the present disclosure. Those skilled in the art will recognize that variations in batches, manufacturing processes, etc. can be expected. Therefore, the examples and the trademarks used therein are non-limiting, and they are not intended to be limiting, but are merely illustrative of how one skilled in the art might choose to perform one or more embodiments of the present disclosure.

[0211] The following abbreviations have the designated meanings:

[0212] Aib = aminoisobutyric acid

[0213] Bn=Benzyl

[0214] Boc=tert-butyloxycarbonyl

[0215] Bu=Butyl

[0216] DMF = dimethylformamide

[0217] EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0218] Et=ethyl

[0219] HATU = tetramethyluranium hexafluorophosphate azabenzotriazolyl

[0220] HBTU = benzotriazolyl tetramethyluranium hexafluorophosphate

[0221] HMDS = Hexamethyldisilazane

[0222] HPLC = High Performance Liquid Chromatography

[0223] Me = methyl

[0224] NaHMDS = sodium hexamethyldisilazide

[0225] NMR = Nuclear Magnetic Resonance

[0226] PCC = Pyridinium Chlorochromate

[0227] PEG = Polyethylene glycol

[0228] Ph = Phenyl

[0229] tBu=tert-butyl

[0230] TFA = trifluoroacetic acid

[0231] THF = Tetrahydrofuran

[0232] TMS = trimethylsilyl

[0233] The following example schemes are provided to guide the reader and collectively represent example methods for preparing the compounds provided herein. In addition, other methods for preparing the compounds described herein will be apparent to those of ordinary skill in the art based on the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0234] Example 1

[0235] Synthesis of Intermediate 1 (INT1)

[0236] 7-bromoheptanoic acid methyl ester is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to prepare ylides, which are immediately reacted with aldehydes from PCC oxidation of 10-bromo-1-decanol in the Wittig reaction. The resulting bromoolefin is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonate. The hydrolysis of the carboxylic acid methyl ester provides the desired INT1 with terminal carboxylic acid and dibenzyl phosphonate.

[0237]

[0238] Synthesis of Intermediate 1A (INT 1A)

[0239] Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to prepare the ylide, which reacts immediately with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol in a Wittig reaction. The resulting bromoolefin is hydrogenated and treated with dibenzyl phosphite in a weak base to form the phosphonate. Hydrolysis of the carboxylic acid methyl ester provides the desired INT 1A with a terminal carboxylic acid and a dibenzyl phosphonate.

[0240]

[0241] Synthesis of Intermediate 2 (INT 2)

[0242] Octadecanedioic acid was coupled with benzyl alcohol using EDC·HCl and DMAP in THF to afford INT 2 as the monobenzyl ester.

[0243]

[0244] Synthesis of Intermediate 3 (INT 3)

[0245] Tert-butyl 4-hydroxybutyrate undergoes Swern oxidation to give the aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. Addition of a lithium salt of diethyl phosphite in THF produces an α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group and provides INT 3 with a free primary amine, a tert-butyl ester, and diethyl phosphonate. The optical purity of INT 3 was confirmed to be at least 96% by 1H-NMR by Mosher amide analysis.

[0246]

[0247] Synthesis of Intermediate 4 (INT 4)

[0248] INT 1 was coupled with 1-tert-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0249]

[0250] Synthesis of Intermediate 4A (INT 4A)

[0251] INT 1A was coupled with 1-tert-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4A.

[0252]

[0253] Synthesis of Intermediate 5 (INT 5)

[0254] INT 2 was coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare a new amide bond. Cleavage of the ethyl phosphonate with TMS-Br gave the free phosphonic acid. Re-esterification of the benzyl ester with a large excess of N,N'-diisopropylcarbamide afforded the corresponding dibenzyl phosphonate. Cleavage of the tert-butyl ester with TFA afforded INT 5.

[0255]

[0256] Synthesis of Intermediate 6 (INT 6)

[0257] INT 1 was coupled with INT 3 in the presence of HATU and triethylamine in DMF to provide a new amide bond. Cleavage of the benzyl and ethyl phosphonates with TMS-Br afforded the free phosphonic acids of both. Re-esterification of the benzyl ester with a large excess of N,N'-diisopropylcarbamide afforded the corresponding tetrabenzyl diphosphonate. Cleavage of the tert-butyl ester with TFA afforded INT 6.

[0258]

[0259] Example 2

[0260] Synthesis of the common peptide backbone

[0261] A 31 amino acid peptide backbone was constructed using solid phase peptide synthesis techniques using imide, HATU or HBTU activation for the synthesis of amide bonds on Rink resin. Reagent selection varied depending on the identity of the amino acid being attached. The R group of lysine-20 was extended with 2 PEG2 amide linkers. The entire backbone was synthesized on resin and then INT 4, INT 4A, INT 5 or INT 6 was coupled to the amino terminus of the lysine-bound linker.

[0262]

[0263] Example 3

[0264] Synthesis of compound 1

[0265] The peptide backbone was coupled to INT 4 to give the resin-bound protected compound 1. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT4 with TFA provided compound 1 which was purified by HPLC.

[0266]

[0267] Example 4

[0268] Synthesis of compound 2

[0269] The peptide backbone was coupled to INT 5 to give the resin-bound protected compound 2. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 5 with TFA provided compound 2, which was purified by HPLC.

[0270]

[0271] Example 5

[0272] Synthesis of compound 3

[0273] The peptide backbone was coupled to INT 6 to give the resin-bound protected compound 3. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 6 with TFA provided compound 3, which was purified by HPLC.

[0274]

[0275] Example 6

[0276] Synthesis of compound 4

[0277] The peptide backbone was coupled with INT 4A to give the resin-bound protected compound 4. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 4A with TFA provided compound 4, which was purified by HPLC.

[0278]

[0279] Example 7

[0280] In vitro GLP-1 binding activity

[0281] use Binding assay and HEK293 cell line assay for ligand binding competition activity at the human GLP-1 receptor. Compounds were tested in duplicate at the following nanomolar concentrations: 3, 10, 30, 100, 300, 1,000, 3,000 and 10,000 nM. Each compound was tested individually, and the agonist activity of the test compound in the presence of 2% HSA was expressed as the reference agonist at its IC 100 The activity percentages at the concentrations are shown in Table 1.

[0282] Table 1: In vitro GLP-1 binding activity of selected compounds

[0283]

[0284] Example 8

[0285] Pharmacokinetic study of the preparation

[0286] Male cynomolgus monkeys were administered subcutaneous (SC) administration of the compound in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline. The designated dose groups were: 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 was prepared by formulating the compound (e.g., Compound 1 or Compound 4) in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline. Formulation 2 was prepared by formulating the compound in 40% propylene glycol and 60% 10 mM pH 6 citrate buffer solution. The designated dose groups were administered Semaglutide (0.2 mg / kg) or Compound 4 (0.2 mg / kg) over 21 days.

[0287] Selected pharmacokinetic data for the two formulations are shown in Table 2. The data show that administration of Compound 4 in Formulation 1 and Formulation 2 resulted in significantly greater persistence in the bloodstream compared to administration of semaglutide in the same formulation. The mean half-life of Compound 4 in Formulation 1 was 150% greater than semaglutide. Formulation 2 resulted in a 150% greater mean half-life for Compound 4 when compared to semaglutide. In addition, Compound 4 showed greater drug exposure than Compound 1 for both Formulation 1 and Formulation 2.

[0288] Table 2: Selected pharmacokinetic data

[0289]

[0290] Example 9

[0291] Biological effects of compounds in mice

[0292] NASH was induced in mice by feeding mice Gubra amylin NASH (GAN) diet, as described in Boland et al. World J Gastroenterol. 2019, 25 (33): 4904-4920. One week before the first dose of the compound was administered, the mice were weighed and randomized, and their food intake was measured. The mice were randomly assigned to dosing groups, with 12 mice in each group. The designated dose 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 treated with vehicle simulation only as a control. Compound dose adjustment (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 (starting from day 6).

[0293] After two weeks, the animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), plasma total triglycerides and plasma total cholesterol were measured, and terminal necropsy of each liver was performed to determine the relative liver weight as a percentage of body weight, analyze the full range of liver biochemistry (including liver total triglycerides, plasma insulin and liver total cholesterol) and histological evaluation of galectin-3 and α-smooth muscle actin.

[0294] Although some embodiments have been illustrated and described, those of ordinary skill in the art, after reading the foregoing description, may make changes, substitutions of equivalents or other types of changes to the compounds of the present technology described herein or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures. Each aspect and embodiment described above may also include or incorporate such changes or aspects disclosed with respect to any or all other aspects and embodiments.

[0295] The present technology is also not limited to the specific aspects described herein, which are intended to be a single description of the individual aspects of the present technology. Without departing from the spirit and scope of the present technology, many modifications and changes can be made to the present technology, which will be obvious to those skilled in the art. In addition to those methods listed herein, functionally equivalent methods within the scope of the present technology will be obvious to those skilled in the art from the previous description. Such modifications and changes are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds or biological systems, which can certainly be changed. It should also be understood that the terms used herein are only used for the purpose of describing specific aspects and are not intended to be restrictive. Therefore, this specification is intended to be considered as merely exemplary, and the breadth, scope and spirit of the present technology are indicated only by the appended claims, the definitions therein and any equivalents thereof.

[0296] The embodiments illustratively described herein may be appropriately practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and not restrictively. In addition, the terms and expressions used herein have been used as descriptive and not restrictive terms, and when such terms and expressions are used, it is not intended to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications may be made within the scope of the claimed technology. In addition, the phrase "essentially consisting of..." will be understood to include those elements specifically enumerated and those additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any element that is not specified.

[0297] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also forms part of the present technology. This includes the general description of the present technology with any subject proviso or negative limitation removed from the genus, regardless of whether the excised material is specifically enumerated herein.

[0298] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) mentioned in this specification are incorporated herein by reference, as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated herein by reference in its entirety. Definitions contained in text incorporated by reference will be excluded to the extent they conflict with definitions in this disclosure.

[0299] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0300] While the present disclosure has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made therein without departing from the spirit and scope of the present disclosure.

[0301] All references, issued patents, and patent applications cited within the subject matter of this specification are hereby incorporated by reference in their entirety for all purposes.

[0302] Although the present disclosure has been described with reference to embodiments and examples, it should be understood that many and various modifications can be made without departing from the spirit of the present disclosure. Therefore, the present disclosure is limited only by the appended claims.

Claims

1. A compound having the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from –C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; R 2 Selected from –C(=O)(OZ 2 ),–(CH2CH2) n P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryloxy and C 6-10 Arylalkoxy; Each R 5 are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 alkyl; Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 aryl; and n is 0, 1, 2, 3, or 4, Where Z 1 and Z 2 At least one of them is not hydrogen.

2. The compound according to claim 1, which has the structure of formula (Ia): or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

4. The compound according to claim 2 or 3, wherein Z 1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

5. The compound of any one of claims 2 to 4, wherein Z 1 is hydrogen, and each R 4 are independently hydrogen or C 6-10 Arylalkoxy.

6. A compound as described in any one of claims 2 to 5, wherein each R 4 It's hydrogen.

7. A compound as described in any one of claims 2 to 6, wherein Z 1 is hydrogen and each R 4 It's hydrogen.

8. The compound of any one of claims 2 to 7, wherein n is 1.

9. The compound of any one of claims 2 to 7, wherein n is 2.

10. The compound according to claim 1, which has the structure of formula (Ib): or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, wherein Z 2 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

12. The compound of claim 10 or 11, wherein Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

13. A compound as claimed in any one of claims 10 to 12, wherein Z 2 is hydrogen, and each R 4 is hydrogen or C 6-10 Arylalkoxy.

14. A compound as described in any one of claims 10 to 13, wherein each R 4 It's hydrogen.

15. The compound of any one of claims 10 to 13, wherein Z 2 is hydrogen and each R 4 It's hydrogen.

16. The compound of any one of claims 10 to 15, wherein n is 1.

17. The compound of any one of claims 10 to 15, wherein n is 2.

18. The compound of claim 1, which has the structure of formula (Ic): or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein X and Y are each -OR 4 .

20. The compound of claim 19, wherein each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

21. The compound of claim 19 or 20, wherein each R 4 It's hydrogen.

22. The compound of any one of claims 18 to 21, wherein n is 1.

23. The compound of any one of claims 18 to 21, wherein n is 2.

24. The compound of claim 1 having a structure selected from the group consisting of: and pharmaceutically acceptable salts thereof.

25. The compound of any one of claims 1 to 24, wherein "*" represents a chiral carbon with an "S" configuration.

26. A compound as described in any one of claims 1 to 24, wherein "*" represents a chiral carbon with an "R" configuration.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable excipient.

28. A method for preventing, treating or ameliorating one or more fatty liver diseases in a subject, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the fatty liver disease is selected from the group consisting of steatosis, nonalcoholic steatohepatitis, and nonalcoholic fatty liver disease.

30. The method of claim 28 or 29, wherein the administration of the compound results in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a symptom of fibrosis.

31. The method of any one of claims 28 to 30, wherein the administration of the compound results in a decrease in the amount of extracellular matrix protein present in one or more tissues of the subject.

32. The method of any one of claims 28 to 31, wherein the administration of the compound results in a decrease in the amount of collagen present in one or more tissues of the subject.

33. The method of claim 32, wherein the administration of the compound results in a decrease in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

34. A method for preventing, treating or ameliorating one or more diseases or conditions in a subject, comprising administering to a subject in need thereof a compound of any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is a metabolic disorder, liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

35. The method of claim 34, wherein the disease or condition is nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis.

36. The method of claim 34, wherein the disease or condition is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome.

37. The method of any one of claims 28 to 36, wherein the compound activates the glucagon-like peptide-1 (GLP-1) receptor.

38. The method of any one of claims 28 to 37, wherein the subject is a mammal.

39. The method of any one of claims 28 to 38, wherein the subject is a human.

40. The method of any one of claims 28 to 39, wherein the route of administration is selected from enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal.

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