Compositions and methods for treating metabolic disorders and liver disease

Abstract

Disclosed herein are small molecule GIP / GLP-1 dual receptor agonist compositions, pharmaceutical compositions thereof, uses thereof, and preparations thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 139,676, filed January 20, 2021, which is incorporated herein by reference in its entirety. background

[0003] Invention Field

[0004] This disclosure generally relates to the field of treating metabolic disorders and fatty liver diseases. More specifically, this disclosure relates to the field of small molecule drugs for treating non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD).

[0005] Description of related technologies

[0006] Incretin peptides glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are metabolic hormones. Both GIP and GLP-1 are secreted within minutes of nutrient ingestion and promote the rapid processing of ingested nutrients. These two peptides have a shared effect on pancreatic β-cells, acting through structurally different but related receptors. Activation of incretin receptors leads to glucose-dependent insulin secretion, induces β-cell proliferation, and enhances resistance to apoptosis. GIP also promotes energy storage through direct action on adipose tissue. Conversely, GLP-1 regulates glucose by slowing gastric emptying and glucose-dependently inhibiting glucagon secretion. GLP-1 also promotes satiety; in preclinical and clinical studies, sustained GLP-1 receptor activation has been associated with weight loss.

[0007] Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the most common cause of chronic liver disease. NAFLD can progress to liver inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. GIP / GLP-1 dual receptor agonists have been developed for the treatment of NAFLD, NAFLD, diabetes, obesity, and other conditions. However, the use of GIP / GLP-1 dual receptor agonists is associated with nausea, vomiting, and / or diarrhea. For example, clinical trials of GIP / GLP-1 dual receptor agonist compounds have shown that tolerability at high doses is limited by gastrointestinal adverse events. Dose limitation associated with gastrointestinal adverse events can prevent the administration of the desired effective dose, jeopardize patient adherence to treatment, and limit the effectiveness of treatment regimens. Therefore, there is a need for novel GIP / GLP-1 dual agonist compounds for the treatment of fatty liver disease and other conditions. Invention Overview

[0008] Some of the embodiments disclosed herein include compounds having the general formula I structure:

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein:

[0011] R 1 Selected from –C(=O)(OZ) 1 ), –P(=O)(X)(Y) and by 1-2 R 7 Optionally substituted 5-10 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, wherein R 7 Independently selected from halogens, 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 heterocyclic;

[0012] R 2 Selected from –C(=O)(OZ) 2 ), –P(=O)(X)(Y) and by 1-2 R 7 Optionally substituted 5-10 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, wherein R 7 Independently selected from halogens, 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 heterocyclic;

[0013] Each R 7 It can be independently selected from halogens, 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 heterocyclic;

[0014] X and Y can be independently selected from –OR 4 NR 5 R 6 C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0015] Each R4 It can be independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-10 aryloxy groups and C 6-10 arylalkoxy;

[0016] Each R 5 It can be hydrogen or C independently. 1-6 alkyl;

[0017] Each R 6 It can be hydrogen or C independently. 1-6 Alkyl groups; and

[0018] Z 1 and Z 2 Each can be independently selected from hydrogen and 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,

[0019] The condition is Z 1 and Z 2 At least one of them is not hydrogen.

[0020] Other embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable excipient.

[0021] Other embodiments disclosed herein include methods for preventing, treating, or improving one or more fatty liver diseases in an individual by administering the disclosed compounds or pharmaceutically acceptable salts thereof to an individual in need. Fatty liver diseases include, but are not limited to, steatosis, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD).

[0022] Other embodiments disclosed herein include methods for preventing, treating, or improving one or more diseases or conditions in an individual by administering the disclosed compounds or their pharmaceutically acceptable salts to an individual in need. In some embodiments, the disease or condition is liver fibrosis, kidney fibrosis, biliary fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic 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. Detailed description

[0023] In some embodiments, compounds that are non-macrocyclic functionalized peptides are provided as GIP / GLP-1 dual receptor agonists. Various embodiments of these compounds include compounds having the structure of general formula I described above, or pharmaceutically acceptable salts thereof. The structure of general formula I includes all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0024]

[0025] In some embodiments of the compound of general formula I:

[0026] R 1 Selected from –C(=O)(OZ) 1 ), –P(=O)(X)(Y) and by 1-2 R 7 Optionally substituted 5-10 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, wherein R 7 Independently selected from halogens, 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 heterocyclic;

[0027] R 2 Selected from –C(=O)(OZ) 2 ), –P(=O)(X)(Y) and by 1-2 R 7 Optionally substituted 5-10 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, wherein R 7 Independently selected from halogens, 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 heterocyclic;

[0028] Each R 7 It can be independently selected from halogens, 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 heterocyclic;

[0029] X and Y can be independently selected from –OR 4 NR 5 R 6 C 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0030] Each R 4 It can be independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-10 aryloxy groups and C 6-10 arylalkoxy;

[0031] Each R 5 It can be hydrogen or C independently. 1-6 alkyl;

[0032] Each R 6 It can be hydrogen or C independently. 1-6 Alkyl groups; and

[0033] Z 1 and Z 2 Each can be independently selected from hydrogen and 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,

[0034] The condition is Z 1 and Z 2 At least one of them is not hydrogen.

[0035] Some embodiments of compounds of general formula I include compounds having the structure of general formula Ia:

[0036]

[0037] Or its pharmaceutically acceptable salt.

[0038] In some embodiments of compounds of general formula Ia or pharmaceutically acceptable salts 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 .

[0039] In some embodiments of compounds of general formula Ia or pharmaceutically acceptable salts thereof; Z1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 Alkoxy groups; and each R 4 It can be independently selected from hydrogen and C. 6-10 aryloxy groups and C 6-10 Arylalkoxy group.

[0040] In some embodiments of compounds of general formula Ia or pharmaceutically acceptable salts thereof; Z 1 For hydrogen, and each R 4 It can be hydrogen or C independently. 6-10 Arylalkoxy group.

[0041] In some embodiments of compounds of general formula Ia or pharmaceutically acceptable salts thereof; each R 4 It is hydrogen.

[0042] In some embodiments of compounds of general formula Ia or pharmaceutically acceptable salts thereof; Z 1 For hydrogen and each R 4 It is hydrogen.

[0043] Some embodiments of compounds of general formula I include compounds having the structure of general formula Ib:

[0044]

[0045] Or its pharmaceutically acceptable salt.

[0046] In some embodiments of compounds of general formula Ib or pharmaceutically acceptable salts 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 .

[0047] In some embodiments of compounds of general formula Ib or pharmaceutically acceptable salts thereof; Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy groups; and each R 4 It can be independently selected from hydrogen and C. 6-10 aryloxy groups and C 6-10 Arylalkoxy group.

[0048] In some embodiments of compounds of general formula Ib or pharmaceutically acceptable salts thereof; Z 2 It is hydrogen and each R 4It can be hydrogen or C independently. 6-10 Arylalkoxy group.

[0049] In some embodiments of compounds of general formula Ib or pharmaceutically acceptable salts thereof; each R 4 It is hydrogen.

[0050] In some embodiments of compounds of general formula Ib or pharmaceutically acceptable salts thereof; Z 2 It is hydrogen and each R 4 It is hydrogen.

[0051] Some embodiments of compounds of general formula I include compounds having the structure of general formula Ic:

[0052]

[0053] Or its pharmaceutically acceptable salt.

[0054] In some embodiments of compounds of general formula Ic or pharmaceutically acceptable salts thereof; X and Y are each –OR 4 .

[0055] In some embodiments of compounds of general formula Ic or pharmaceutically acceptable salts thereof; each R 4 It can be independently selected from hydrogen and C. 6-10 aryloxy groups and C 6-10 Arylalkoxy group.

[0056] In some embodiments of compounds of general formula Ic or pharmaceutically acceptable salts thereof; each R 4 It is hydrogen.

[0057] Some embodiments include compounds having structures selected from the following:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] And its pharmaceutically acceptable salts.

[0064] Some implementations include compounds in which "*" indicates a chiral carbon having an "S" configuration.

[0065] Some implementations include compounds in which "*" indicates a chiral carbon having an "R" configuration.

[0066] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of these isomers (including racemates). The isolation 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 within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise stated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic forms. Additionally, some of the compounds disclosed herein can form hydrates or solvates with water or common organic solvents. Unless otherwise stated, such solvates are included within the scope of the compounds disclosed herein.

[0067] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds, which can be represented by other chemical structures, even kinetically; and that such structures may represent only a very small fraction of samples of such compounds. Such compounds are considered to be within the structural range described, although such resonance forms or tautomers are not represented herein.

[0068] definition

[0069] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for terms used herein, the definitions provided in this section shall prevail unless otherwise stated.

[0070] "Solvate" refers to a compound formed through the interaction of a solvent with the compound described herein or its salt. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0071] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a compound and is not biologically or otherwise undesirable for its use in a pharmaceutical product. In many cases, the compounds described herein can form acidic and / or basic salts by the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed from 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, etc. 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, etc. Pharmaceutically acceptable base addition salts can be formed from 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, and aluminum; particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO87 / 05297, Johnston et al., published September 11, 1987 (the entire contents of which are incorporated herein by reference).

[0072] As used in this article, "C" a To C b "or "C a-b (where "a" and "b" are integers) refers to the number of carbon atoms in the specified group. That is, the group can contain "a" to "b" (inclusive) carbon atoms. Therefore, for example, "C1 to C4 alkyl" or "C 1-4 The "alkyl" group refers to all alkyl groups having 1 to 4 carbons, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0073] As used herein, the term "halogen" or "halogenated" refers to any radioactively stable atom in column 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine.

[0074] As used herein, “alkyl” refers to a fully saturated (i.e., free of double or triple bonds) straight-chain or branched hydrocarbon chain. An alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as “1 to 20” refers to each integer within the given range; for example, “1 to 20 carbon atoms” means that an alkyl group can consist of 1, 2, 3, etc., up to and including 20 carbon atoms, although this definition also covers the occurrence of the term “alkyl” without a specified numerical range). An alkyl group can also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group can also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group of a compound can be specified as “C…”. 1-4 "alkyl" or a similar designation. By way of example only, "C" 1-4 "Alkyl" indicates the presence of 1-4 carbon atoms in an alkyl chain, meaning 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, and hexyl.

[0075] As used herein, “haloalkyl” means a straight-chain or branched alkyl group having 1 to 12 carbon atoms in the chain in which one or more hydrogen atoms are replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that, in accordance with the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any of the foregoing examples.

[0076] As used herein, “alkoxy” refers to the formula –OR, where R is an alkyl group as defined above, such as “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.

[0077] The term "polyethylene glycol" as used in this article refers to... Where n is an integer greater than 1, and R is hydrogen or alkyl. The number of repeating units “n” can be indicated by referring to multiple members. Thus, 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.

[0078] As used herein, “heteroalkyl” refers to a straight-chain 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 main chain. Heteroalkyl can have 1 to 20 carbon atoms, although this definition also covers the use of the term “heteroalkyl” where no numerical range is specified. Heteroalkyl can also be a medium-sized heteroalkyl having 1 to 9 carbon atoms. Heteroalkyl can also be a lower heteroalkyl having 1 to 4 carbon atoms. In various embodiments, the heteroalkyl can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl of the compound can be designated as “C…”. 1-4 "Heteroalkyl" or a similar designation. Heteroalkyl 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 one or more additional heteroatoms in the main chain.

[0079] The term "aromatic" refers to a ring or ring system having a conjugated π-electron system, and includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent atomic pairs) groups, provided that the entire ring system is aromatic.

[0080] As used herein, “aryl” refers to an aromatic ring or ring system containing only carbon in its ring skeleton (i.e., two or more fused rings sharing two adjacent carbon atoms). When an aryl is a ring system, each ring in the system is aromatic. Aryl groups can have 6 to 18 carbon atoms, although this definition also covers the occurrence of the term “aryl” where no numerical range is specified. In some embodiments, the aryl group has 6 to 10 carbon atoms. Aryl groups can be designated as “C…” 6-10 "Aryl", "C6 or C" 10 "Aryl" or similar names. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulel, and anthracene.

[0081] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is an aryl group as defined above, such as "C 6-10 "Aryloxy" or "C" 6-10 "Arylthio" and others, including but not limited to phenoxy groups.

[0082] "Arylalkyl" or "arylalkyl" refers to an aryl group that is a substituent linked by an alkylene group, such as "C 7-14 Aryl alkyl groups, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthyl alkyl groups. In some cases, alkylene groups are lower alkylene groups (i.e., C12-C ... 1-4 (alkylene).

[0083] 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 its ring skeleton. When a heteroaryl is a ring system, each ring in the system is aromatic. A heteroaryl can have 5-18 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), although this definition also covers the occurrence of the term "heteroaryl" where no numerical range is specified. In some embodiments, a heteroaryl has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl can be designated as "5-7-membered heteroaryl," "5-10-membered heteroaryl," or similar names. In various embodiments, a heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl group contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furanyl, thiophene, phthalazinyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indole, isoindole, and benzothiophene.

[0084] "Heteroarylalkyl" or "heteroarylalkyl" refers to a heteroaryl group that is a substituent linked via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolithylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C16-C ... 1-4 (alkylene).

[0085] As used herein, a "carbocyclic group" refers to a non-aromatic ring or ring system containing only carbon atoms in its ring skeleton. When a carbocyclic group is a ring system, two or more rings may be connected together by fusion, bridging, or helical linkage. A carbocyclic group can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Therefore, carbocyclic groups include cycloalkyl, cycloalkenyl, and cycloynyl groups. A carbocyclic group can have 3 to 20 carbon atoms, although this definition also covers the occurrence of the term "carbocyclic group" where no numerical range is specified. A carbocyclic group can also be a medium-sized carbocyclic group having 3 to 10 carbon atoms. A carbocyclic group can also be a carbocyclic group having 3 to 6 carbon atoms. A carbocyclic group can be designated as "C 3-6 "Carbocyclic" or similar names. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octyl, adamantyl, and spiro[4.4]nonyl.

[0086] "(Carbocyclic)alkyl" refers to a carbocyclic group that is a substituent linked by an alkylene group, such as "C 4-10 "(Carbocyclo)alkyl" and others, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene group is a lower alkylene group.

[0087] As used herein, "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0088] As used in this article, "cycloalkenyl" refers to a carbocyclic ring or ring system having at least one double bond, wherein none of the rings in the ring system is aromatic. An example is cyclohexenyl.

[0089] As used herein, a "heterocyclic group" refers to a non-aromatic ring or ring system containing at least one heteroatom in its ring backbone. Heterocyclic groups can be connected together by fusion, bridging, or spirolinking. Heterocyclic groups can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms can be present in either non-aromatic or aromatic rings within the ring system. Heterocyclic groups can have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), although this definition also covers the occurrence of the term "heterocyclic group" where no numerical range is specified. Heterocyclic groups can also be of medium size with 3 to 10 ring members. Heterocyclic groups can also be heterocyclic groups with 3 to 6 ring members. Heterocyclic groups can be designated as "3-6 membered heterocyclic groups" or similar names.

[0090] In various embodiments, the heterocyclic group contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclic group contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In a preferred six-membered monocyclic heterocyclic group, the heteroatom is selected from one to at most three O, N, or S atoms; in a preferred five-membered monocyclic heterocyclic group, the heteroatom is selected from one or two heteroatoms selected from O, N, or S atoms. Examples of heterocyclic groups include, but are not limited to, azaheptatrienyl, acridine, carbazole, cyclolinyl, dioxolane, imidazolinyl, imidazoalkyl, morpholinyl, ethylene oxide, hexyl oxide, thioheptatrienyl, piperidinyl, piperazinyl, dioxolane, pyrrolyl, pyrrolidone, pyrrolidone-keto, 4-piperidinone, pyrazolinyl, pyrazolyl, 1,3-dioxacyclohexenyl, 1,3-dioxacyclohexenyl, 1,4-dioxacyclohexenyl, 1,4-dioxacyclohexenyl, 1,3-oxothiohexenyl, 1,4-oxothiohexenyl, 1,4-oxothiohexane. The following compounds are listed: 2H-1,2-oxazinyl, trioxazolidinyl, hexahydro-1,3,5-triazinyl, 1,3-dioxazopentenyl, 1,3-dioxopentenyl, 1,3-dithiocyclopentadienyl, 1,3-dithiocyclopentaneyl, isoxazolinyl, isoxazolinyl, oxazolinyl, oxazolinyl, oxazolidinone, thiazolinyl, thiazolinyl, 1,3-oxothiocyclopentaneyl, dihydroindolyl, isodihydroindolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiaranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl, and tetrahydroquinoline.

[0091] "(Heterocyclic)alkyl" refers to a heterocyclic group that is a substituent linked by an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0092] As used in this article, "acyl" refers to -C(=O)R, where R is hydrogen, C is oxygen, and C is hydrogen. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Carbocyclic, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0093] The "O-carboxyl" group refers to the "-OC(=O)R" group, where R is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7Carbocyclic, aryl, 5-10 heteroaryl and 5-10 heterocyclic, as defined herein.

[0094] The "C-carboxyl" group refers to the "-C(=O)OR" group, where R is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Carbocyclic, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic groups, as defined herein. Non-limiting examples include carboxyl groups (i.e., -C(=O)OH).

[0095] The "cyano" group refers to the "-CN" group.

[0096] The "cyanoyl" group refers to the "-OCN" group.

[0097] The "isocyanate" group refers to the "-NCO" group.

[0098] The "thiocyanate" group refers to the "-SCN" group.

[0099] The "isothiocyanate" group refers to the "-NCS" group.

[0100] The "sulfinyl" group refers to the "-S(=O)R" group, where R is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0101] The "sulfonyl" group refers to the "-SO2R" group, where R is selected from hydrogen, C... 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbonyl group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0102] The "S-sulfonamide" group refers to "-SO2NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0103] The "N-sulfonamide" group refers to "-N(R)". A SO2R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0104] The "O-carbamoyl" group refers to "-OC(=O)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0105] The "N-carbamoyl" group refers to "-N(R)". A )OC(=O)R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0106] The "O-thiocarbamoyl" group refers to "-OC(=S)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0107] The "N-thiocarbamoyl" group refers to "-N(R A )OC(=S)R B "group, wherein RA and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0108] The "C-amide" group refers to "-C(=O)NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0109] The "N-amide" group refers to "-N(R)". A )C(=O)R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0110] The "amino" group refers to "-NR". A R B "group, wherein R A and R B Each is independently selected from hydrogen and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 carbon cyclo group, C 6-10 Aryl, 5-10 heteroaryl and 5-10 heterocyclic groups, as defined herein.

[0111] The "aminoalkyl" group refers to an amino group linked by an alkylene group.

[0112] The "alkoxyalkyl" group refers to an alkoxy group linked by an alkylene group, such as "C". 2-8 "Alkoxyalkyl", etc.

[0113] As used herein, "natural amino acid side chain" refers to the substituents on the side chain of naturally occurring amino acids. Naturally occurring amino acids have substituents attached to the α-carbon. Naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0114] As used in this article, "non-natural amino acid side chain" refers to the substituents on the side chain of amino acids that do not exist naturally. Non-natural amino acids include β-amino acids (β... 3 and β 2 ( ), high-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, cyclic-substituted phenylalanine and tyrosine derivatives, linear core amino acids, and N-methyl amino acids. Exemplary non-natural amino acids are available from Sigma-Aldridge and are listed under “Non-natural Amino Acids & Derivatives”. See also Travis S. Young and Peter G. Schultz, “Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon,” J. Biol. Chem. 2010 285:11039-11044, the full text of which is incorporated herein by reference.

[0115] As used herein, a substituted group is derived from an unsubstituted parent group, wherein there is an exchange of one or more hydrogen atoms with another atom or group. Unless otherwise stated, when a group is considered “substituted,” it means that the group is substituted by one or more substituents independently selected from: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocycloyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclo-C1-C6-alkyl (substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). Optional substitution), 5-10 membered heterocyclic groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclic -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(C1-C6)alkyl (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... The following groups are substituted with halogen, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups), 5-10-membered heteroaryl (C1-C6)alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy groups), halogen, cyano, hydroxy, C1-C6 alkoxy, and C1-C6 alkoxy (C1-C6)alkyl (i.e., ether). Aryloxy, thiohydro (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyanoyl, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted," the group can be substituted by the substituents listed above.

[0116] In some embodiments, the substituted group is replaced by one or more substituents, which are individually and independently selected from C1-C4 alkyl, amino, hydroxyl, and halogen groups.

[0117] It should be understood that certain group naming conventions may include mono- or bi-molecular groups, depending on the context. For example, when a substituent requires two connection points with the rest of the molecule, the substituent should be understood as bi-molecular. For example, substituents of alkyl groups identified as requiring two connection points include bi-molecular groups, such as –CH2–, –CH2CH2–, –CH2CH(CH3)CH2–, etc. Other group naming conventions clearly indicate that the group is a di-group, such as “alkylene” or “alkenylene”.

[0118] When two R groups are considered to form a ring (e.g., a carbocyclic, heterocyclic, aryl, or heteroaryl ring) "together with the atoms they are attached to," it means that the unit unit of the atom and the two R groups is the ring. The ring, when used alone, is not limited by the definition of each R group. For example, when the following substructures exist:

[0119]

[0120] And R 1 and R 2 Defined as selected from hydrogen and alkyl, or R 1 and R 2 Together with the nitrogen atoms they are attached to, they form heterocyclic groups, which means that R 1 and R 2 It may be selected from hydrogen or alkyl, or optionally, the substructure has the following structure:

[0121]

[0122] Wherein ring A is a heterocyclic ring containing the nitrogen.

[0123] Similarly, when two “adjacent” R groups are considered to form a ring “together with the atoms they are attached to,” this means that the unit unit consisting of the atom, the intervening bond, and the two R groups is the ring. For example, this occurs when the following substructure is present:

[0124]

[0125] And R 1 and R 2 Defined as selected from hydrogen and alkyl, or R 1 and R 2 Together with the atoms they are attached to, they form aryl or carbocyclic groups, which means R 1 and R 2 It may be selected from hydrogen or alkyl, or optionally, the substructure has the following structure:

[0126]

[0127] Wherein A is an aryl ring or a carbocyclic group containing the double bond.

[0128] When a substituent is described as bimolecular (i.e., having two connection points with the rest of the molecule), it should be understood that, unless otherwise stated, the substituent can be connected in any directional configuration. Thus, for example, a substituent described as -AE- or The substituents include those that are oriented such that A is attached to the leftmost attachment point of the molecule, and those that are attached to the rightmost attachment point of the molecule.

[0129] The term "mammal" is used in its usual biological sense. Therefore, it specifically includes, but is not limited to, primates, including apes (chimpanzees, monkeys) and humans, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, as well as many other species.

[0130] The terms “pharmaceutically acceptable carrier” or “pharmaceuticalally acceptable excipient” include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and reagents for the active pharmaceutical ingredient is well known in the art. This excludes the intended use in therapeutic compositions of any conventional media or reagent that is incompatible with the active ingredient. Furthermore, various excipients commonly used in the art may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, the entire contents of which are incorporated herein by reference.

[0131] As used in this article, “individual” refers to humans or non-human mammals, such as dogs, cats, mice, rats, cattle, sheep, pigs, goats, non-human primates or birds, such as chickens, as well as any other vertebrates or invertebrates.

[0132] As used herein, “effective dose” or “therapeutic effective dose” means, to some extent, an effective relief of one or more symptoms of a disease or condition or a reduction in the likelihood of the onset of one or more symptoms of a disease or condition, and includes the amount of a therapeutic agent that cures a disease or condition. “Cure” means the elimination of symptoms of a disease or condition; however, even after a cure, some long-term or permanent effects may remain (e.g., extensive tissue damage).

[0133] As used herein, “treat,” “treatment,” or “treatment” refers to the administration of a pharmaceutical composition for preventative and / or therapeutic purposes. The term “preventative treatment” refers to treating an individual who has not yet shown symptoms of a disease or condition but is susceptible to or at risk of developing such a disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to treatment given to an individual who already has a disease or condition.

[0134] Preparation method

[0135] The compounds disclosed herein can be synthesized by the methods described below or by modifications thereof. Methods for improving the methodology include, among other things, temperature, solvents, reagents, etc., as is known to those skilled in the art. Typically, during any method used to prepare the compounds disclosed herein, it may be necessary and / or desired to protect any sensitive or reactive groups on the relevant molecule. This can be achieved by conventional protecting groups, such as those described in *Protective Groups in Organic Chemistry* (ed. J.F.W. McOmiie, Plenum Press, 1973); and *PGM Green, TW. Utts, *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 at convenient subsequent stages using methods known in the art. Synthetic chemical transformations for synthesizing applicable compounds are known in the art, including, 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 hereby incorporated in their entirety by reference. The routes shown and described herein are merely illustrative and are neither intended nor intended to limit the scope of the claims in any way. Those skilled in the art will recognize modifications to the disclosed synthesis and will be able to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0136] The reason for choosing protecting groups for oxygen atoms in the following schemes is their compatibility with the necessary synthetic steps and the compatibility of the introduction and deprotection steps with the overall synthetic scheme (PGMGreen, TWutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0137] If the compounds of this technique contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as mixtures enriched with stereoisomers. Unless otherwise stated, all such stereoisomers (and mixtures enriched with stereoisomers) are included within the scope of this technique. Pure stereoisomers (or mixtures enriched with stereoisomers) 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.

[0138] The starting materials used in the following reactions are typically known compounds or can be prepared by known processes or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other methods can be used to prepare the materials through procedures 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).

[0139] In one embodiment, the method disclosed herein may include constructing a 39-amino acid peptide backbone using solid-phase peptide synthesis technology to provide 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 intermediate (II) and a suitably substituted carboxylic acid (III) to provide a resin-bound intermediate (IV). In one embodiment, the method includes hydrolyzing intermediate (IV) under acidic conditions and then purifying it to give the final product (I). (Scheme 1).

[0140] Option 1:

[0141]

[0142] The exemplary schemes described above are provided for the reader's guidance and collectively represent exemplary methods for preparing the compounds included herein. Furthermore, other methods for preparing the compounds described herein will be apparent to those skilled in the art based on the following reaction schemes and examples. Unless otherwise stated, all variables are as defined above.

[0143] Application and pharmaceutical composition

[0144] The compounds are administered at therapeutically effective doses. While human dose levels for the compounds described herein have not been optimized, typical daily doses may be about 0.0125 mg / kg body weight to about 120 mg / kg body weight or more, about 0.025 mg / kg body weight or less to about 70 mg / kg body weight, about 0.05 mg / kg body weight to about 50 mg / kg body weight, or about 0.075 mg / kg body weight to about 10 mg / kg body weight. Therefore, for administration to a 70 kg person, the dose range may be about 0.88 mg / day to about 8000 mg / day, about 1.8 mg / day or less to about 7000 mg / day or more, about 3.6 mg / day to about 6000 mg / day, about 5.3 mg / day to about 5000 mg / day, or about 11 mg / day to about 3000 mg / day. Of course, the dosage of the active compound will depend on the individual being treated and the disease state, the severity of the ailment, the method and schedule of administration, and the judgment of the prescribing physician.

[0145] The administration of the compounds disclosed herein or their pharmaceutically acceptable salts may be made by any acceptable method of administration for agents having similar efficacy, including but not limited to oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. Oral and parenteral administration are routine in treating the indications for which the subject matter is the preferred embodiment.

[0146] The compounds useful as described above can be formulated into pharmaceutical compositions for treating these conditions. Standard pharmaceutical formulation techniques, such as those disclosed in Remington's *The Science and Practice of Pharmacy*, 21st Ed., Lippincott Williams & Wilkins (2005), are incorporated herein by reference in their entirety. Thus, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the compounds described herein (including their enantiomers, diastereomers, tautomers, polymorphs, and solvates) or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0147] In addition to the useful compounds selected as described above, some embodiments also include compositions containing pharmaceutically acceptable carriers. The terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent incompatible with the active ingredient is contemplated for use in therapeutic compositions. Furthermore, various excipients commonly used in the art may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0148] 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 carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth gum; 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, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents, such as sodium dodecyl sulfate; colorants; flavoring agents; tableting aids; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0149] The choice of a pharmaceutically acceptable carrier for use in conjunction with the subject compound is largely determined by the manner of administration of the compound.

[0150] Preferably, the compositions described herein are provided in unit dosage forms. As used herein, a “unit dosage form” is a composition containing a certain amount of the compound, which, according to good medical practice, is suitable for administration to an animal (preferably a mammalian individual) at a single dose. However, the preparation of a single dosage form or unit dosage form does not imply that the dosage form is administered once daily or once per course of treatment. Such dosage forms are contemplated for administration once, twice, three times, or more daily, may be administered by infusion over a period of time (e.g., about 30 minutes to about 2-6 hours), or may be administered by continuous infusion, and may be given more than once during a course of treatment, although single administration is not specifically excluded. Those skilled in the art will recognize that the formulation is not specifically designed for the entire course of treatment, and such decisions are left to those skilled in the art of treatment rather than formulation.

[0151] The useful compositions described above can be any of a variety of suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, subcutaneous, or other parenteral routes. In some embodiments, the compositions can be in forms suitable for subcutaneous administration. Those skilled in the art will understand that oral and nasal compositions comprise compositions prepared by inhalation and 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, solubilizers, surfactants, and encapsulating substances. Optional pharmaceutically active substances may be included that do not substantially interfere with the inhibitory activity of the compound. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms that can be used 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).

[0152] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed, formulated, enteric-coated, sugar-coated, film-coated, or multi-compressed, containing suitable binders, lubricants, diluents, disintegrants, colorants, flavoring agents, flow inducers, and fluxes. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, fluxes, colorants, and flavoring agents.

[0153] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible excipients as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders, such as starch, gelatin, and sucrose; disintegrants, such as starch, alginate, and croscarmellose; and lubricants, such as magnesium stearate, stearic acid, and talc. Flow aids such as silica can be used to improve the flow properties of powder mixtures. Colorants, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavorings, are useful excipients for chewable tablets. Capsules typically contain one or more of the disclosed solid diluents. The selection of carrier components depends on secondary considerations, such as taste, cost, and storage stability, which are not critical and can be readily selected by those skilled in the art.

[0154] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers used in syrups, elixirs, emulsions, and suspensions include ethanol, glycerin, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragali gum, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as the sweeteners, flavoring agents, and coloring agents disclosed above.

[0155] Such compositions can also be coated using conventional methods, typically with pH-dependent or time-dependent coatings, to prolong the desired action by releasing the subject compound in the vicinity of the desired topical application or at different times in the gastrointestinal tract. Such dosage forms typically include, but are not limited to, one or more cellulose acetate phthalates, polyvinyl acetate phthalates, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

[0156] The compositions described herein may optionally include other pharmaceutically active substances.

[0157] Other compositions for achieving systemic delivery of the subject compound include sublingual, oral, and nasal dosage forms. Such compositions typically comprise one or more soluble filler substances, such as sucrose, sorbitol, and mannitol; and binders, such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. They may also include the flow aids, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above.

[0158] Liquid compositions for topical ophthalmic use are formulated so that they can be applied topically to the eye. Comfort should be maximized as much as possible, although optimal comfort may not always be achievable due to formulation considerations (e.g., drug stability). Where maximizing comfort cannot be achieved, the liquid should be formulated tolerable for patients using it topically. Furthermore, ophthalmologically acceptable liquids should be packaged for single use or contain preservatives to prevent contamination from repeated use.

[0159] For ophthalmic applications, physiological saline solutions or medications are typically prepared using this primary medium. Preferably, the ophthalmic solution is maintained at a comfortable pH using a suitable buffer system. The formulation may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0160] 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 media can be used in the ophthalmic formulations disclosed herein. These media include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0161] Tension modulators may be added as needed or conveniently. These include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerol, or any other suitable ophthalmologically acceptable tension modulators.

[0162] Various buffer solutions and pH adjustment methods can be used, as long as the resulting formulation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Therefore, buffer solutions include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. The pH of these formulations can be adjusted using acids or bases as needed.

[0163] Similarly, ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0164] Other excipients that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium ethylenediaminetetraacetate, although other chelating agents may be used instead or in combination with it.

[0165] For topical applications, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are used. Topical formulations typically consist of a drug carrier, a cosolvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0166] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextran solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the final composition has a pH of 2-8, or preferably 4-7. Antioxidant excipients may include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, bisulfite, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextran, mannitol, and dextran anhydride. 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, which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to obtain antibacterial or antifungal solutions, including but not limited to phenylmercuric nitrate, thimerosal, benzyl chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0167] Compositions for intravenous administration may be provided to the caregiver in one or more solid forms, which are reconstituted with a suitable diluent such as sterile water, saline, or glucose solution shortly before administration. In other embodiments, the composition is provided as a solution prepared for parenteral administration. In other embodiments, the composition is provided as a solution further diluted before administration. In embodiments comprising administration of a combination of the compound described herein and another pharmaceutical agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents before administration, or the two agents may be administered separately.

[0168] The actual dosage of the active compounds described herein depends on the specific compound and the condition to be treated; the selection of an appropriate dosage is entirely within the knowledge of those skilled in the art.

[0169] If desired, the compounds and compositions described herein may be contained in a packaging or dispenser device comprising one or more unit dosage forms containing the active ingredient. Such packaging or device may include, for example, metal or plastic foil, such as blister packs, or glass, and a rubber stopper, such as in a vial. The packaging or dispenser device may be accompanied by instructions for use. The compounds and compositions described herein may be formulated in a compatible pharmaceutical carrier, or prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0170] The amount of the compound in the formulation can vary within the full range employed by those skilled in the art. Typically, based on weight percentage (wt%), the formulation will contain approximately 0.01 wt% to 99.99 wt% of the compound of the present technology based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of approximately 1-80 wt%. Representative pharmaceutical formulations are described below.

[0171] Formulation Examples

[0172] The following are representative pharmaceutical preparations containing compounds of general formula I.

[0173] Formulation Example 1 - Tablet Formulation

[0174] Mix the following ingredients tightly and compress them into single-score tablets.

[0175]

[0176] Formulation Example 2 - Capsule Formulation

[0177] Mix the following ingredients tightly and encapsulate them into hard-shell gelatin capsules.

[0178]

[0179] Formulation Example 3 - Suspension Formulation

[0180] Mix the following ingredients to form a suspension for oral administration.

[0181]

[0182]

[0183] Formulation Example 4 - Injectable Formulation

[0184] Mix the following ingredients to form an injectable formulation.

[0185]

[0186] Formulation Example 5 - Suppository Formulation

[0187] The suppository, with a total weight of 2.5g, is produced by combining the compound of this technology with... It is prepared by mixing H-15 (saturated plant fatty acid triglycerides; Riches-Nelson, Inc., New York) and has the following composition:

[0188]

[0189] Treatment

[0190] The compounds disclosed herein, or their tautomers and / or pharmaceutically acceptable salts thereof, can effectively act as GIP / GLP1 dual receptor agonists. Some embodiments provide pharmaceutical compositions comprising one or more of the compounds disclosed herein and pharmaceutically acceptable excipients.

[0191] Some implementations provide methods for preventing, treating, or improving one or more fatty liver diseases in an individual. In some implementations, the method includes administering one or more compounds disclosed herein to an individual in need. In some implementations, the method includes administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to an individual in need.

[0192] Some implementations provide methods for preventing, treating, or improving steatosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. In some implementations, the methods include administering one or more compounds disclosed herein to an individual in need. In some implementations, the methods include administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to an individual in need.

[0193] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the prevention, treatment, or improvement of fibrosis, fibrotic conditions, or fibrotic symptoms. In some embodiments, the method includes administering a pharmaceutically acceptable salt of one or more of the compounds disclosed herein.

[0194] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a variety of conditions caused by fibrosis or inflammation, specifically including conditions associated with myofibroblast differentiation. Exemplary conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic, and hereditary chronic diseases), renal fibrosis (e.g., caused by chronic inflammation, infection, or type II diabetes), pulmonary fibrosis (idiopathic or caused by environmental damage including toxic particles, sarcoidosis, asbestosis, allergic pneumonia, bacterial infections including tuberculosis, drugs, etc.), interstitial fibrosis, systemic scleroderma (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), and splenic fibrosis (caused by sickle cell anemia). Fibrosis caused by blood and other blood disorders, cardiac fibrosis (caused by infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, renal systemic fibrosis, diabetic nephropathy, non-alcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, cirrhosis, surgical fibrotic complications, chronic allogeneic transplant vascular disease 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.

[0195] In some embodiments, the method of administering one or more compounds disclosed herein results in a reduction in the amount of extracellular matrix proteins present in one or more tissues of the individual. In some embodiments, the method includes administering a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0196] In some embodiments, the method of administering one or more compounds disclosed herein results in a reduction in the amount of collagen present in one or more tissues of the individual. In some embodiments, the method includes administering a pharmaceutically acceptable salt of one or more compounds disclosed herein.

[0197] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a reduction in the amount of type I, Ia, or III collagen present in one or more tissues of the individual. In some embodiments, the method includes administering a pharmaceutically acceptable salt of one or more of the compounds disclosed herein.

[0198] Some implementations provide methods for preventing, treating, or improving one or more of the following in an individual: liver fibrosis, kidney fibrosis, biliary fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis. In some implementations, the method includes administering one or more of the compounds disclosed herein to an individual in need. In some implementations, the method includes administering a pharmaceutically acceptable salt of one or more of the compounds disclosed herein to an individual in need.

[0199] Some implementations provide methods for preventing, treating, or improving one or more of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis in an individual. In some implementations, the method includes administering one or more compounds disclosed herein to an individual in need. In some implementations, the method includes administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to an individual in need.

[0200] Some implementations provide methods for preventing, treating, or improving one or more metabolic disorders or metabolic syndromes. In some implementations, the disorder or condition is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. In some implementations, the method includes administering one or more compounds disclosed herein to an individual in need. In some implementations, the method includes administering a pharmaceutically acceptable salt of one or more compounds disclosed herein to an individual in need.

[0201] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the activation of glucose-dependent insulinotropic peptide (GIP) receptors. In some embodiments, the method of administering one or more of the compounds disclosed herein results in the activation of glucagon-like peptide-1 (GLP-1) receptors. In some embodiments, the method of administering one or more of the compounds disclosed herein results in the activation of both GIP and GLP-1 receptors.

[0202] Some embodiments involve co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with other drugs. "Co-administration" means that two or more agents can be present simultaneously in the patient's bloodstream, 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 via the same route, such as oral administration. In another embodiment, the agents are administered via different routes, such as one subcutaneous administration, another oral administration, and another intravenous administration.

[0203] To further illustrate the invention, the following embodiments are included. These embodiments should not be construed as specifically limiting the invention. Variations of these embodiments within the scope of the claims are within the skill of the art and are considered to fall within the scope of the invention described and claimed herein. The reader will recognize that those skilled in the art, upon acquiring this disclosure and their skills, can prepare and use the invention without exhaustive embodiments. The following embodiments will further describe the invention and are for illustrative purposes only, and should not be considered restrictive.

[0204] Example

[0205] General Program

[0206] Those skilled in the art will understand that methods for preparing precursors and functional groups associated with the compounds claimed herein are generally described in the literature. Variations known to those skilled in the art in these reactions may also be used, but are not described in more detail. Based on the literature and this disclosure, those skilled in the art are fully capable of preparing any compound.

[0207] It should be recognized that those skilled in the art of organic chemistry can readily perform these operations without further instruction; that is, performing these operations is within the scope and practice of those skilled in the art. These include the reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, electrophilic substitution and nucleophilic substitution, etherification, esterification and saponification, etc. These operations are discussed in standard textbooks, such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in its entirety), etc. Unless otherwise stated, all intermediate compounds of this invention are used without further purification.

[0208] Those skilled in the art will readily understand that when other functional groups in a molecule are masked or protected, it is preferable 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 protecting groups to achieve this increased yield or avoidance of undesirable reactions. These reactions are present in the literature and are within the scope of those skilled in the art. Many examples of these operations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0209] The following examples are provided for the reader's guidance and represent preferred methods for preparing the exemplary compounds described herein. These methods are not limiting, and it will be apparent that other approaches can 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 using the methods given in the literature and this disclosure. The compound numbers used in the synthetic schemes described below are only for those specific schemes and should not be construed as the same numbers used in other parts of this application or as being confused with the same numbers.

[0210] The trademarks used herein are merely examples and reflect exemplary materials used in the course of this invention. Those skilled in the art will recognize that variations in batch size, manufacturing processes, etc., can be expected. Therefore, the embodiments and the trademarks used therein are non-limiting and are not intended to be restrictive, but merely exemplary illustrations of how those skilled in the art may choose to carry out one or more embodiments of the invention.

[0211] The following abbreviations have the meanings specified below:

[0212] Aib = Aminoisobutyric acid

[0213] Bn = benzyl

[0214] Boc = tert-butoxycarbonyl

[0215] Bu = Butyl

[0216] DMF = dimethylformamide

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

[0218] Et = Ethyl

[0219] HATU = Azabenzotriazole tetramethylurea hexafluorophosphate

[0220] HBTU = Benzotriazole tetramethylurea hexafluorophosphate

[0221] HMDS = Hexamethyldisilazane

[0222] HPLC = High Performance Liquid Chromatography

[0223] Me = methyl

[0224] NaHMDS = Sodium hexamethyldisilamide

[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 examples are provided for the reader's guidance and collectively represent the methods for preparing the compounds provided herein. Furthermore, other methods for preparing the compounds described herein will be apparent to those skilled in the art based on the following reaction schemes and examples. Unless otherwise stated, all variables are as defined above.

[0234] Example 1

[0235] intermediate 1(INT1) Synthesis

[0236] 7-Bromoheptanoate methyl ester was treated with triphenylphosphine to form the corresponding phosphonate salt. This salt was treated with 1 equivalent of NaHMDS to prepare ylide, which reacts immediately with an aldehyde oxidized from PCC of 12-bromo-1-dodecanool in a Wittig reaction. The resulting bromoalkene was hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonate ester. Hydrolysis of the carboxylic acid methyl ester provided the desired INT 1 with terminal carboxylic acid and dibenzyl phosphonate esters.

[0237]

[0238] intermediate 2(INT2) Synthesis

[0239] Using EDC·HCl and DMAP, docosanoic acid was coupled with benzyl alcohol in THF to obtain INT 2, which is a monobenzyl ester.

[0240]

[0241] intermediate 3 (INT 3) Synthesis

[0242] 4-Hydroxybutyrate tert-butyl ester undergoes Swern oxidation to yield an aldehyde. This aldehyde condenses with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. Addition of a lithium salt of diethyl phosphite to THF produces an α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group, yielding INT 3 containing a free primary amine, tert-butyl ester, and diethyl phosphonate. The optical purity of INT 3 was confirmed by 1H NMR, according to Mosher's amide analysis, to be at least 96%.

[0243]

[0244] intermediate 4 (INT 4) Synthesis

[0245] In the presence of HATU and triethylamine, INT 1 was coupled with 1-tert-butyl ester of D-glutamic acid in DMF to obtain INT 4.

[0246]

[0247] intermediate 5 (INT5) Synthesis

[0248] In the presence of HATU and triethylamine, INT 2 and INT 3 were coupled in DMF to prepare a novel amide linkage. Ethyl phosphonate was cleaved with TMS-Br to obtain free phosphonic acid. Re-esterification with a large excess of benzyl phosphonate of N,N'-diisopropylaminoimino acid yielded the corresponding dibenzyl phosphonate. Tert-butyl ester was cleaved with TFA to provide INT 5.

[0249]

[0250] intermediate 6 (INT 6) Synthesis

[0251] In the presence of HATU and triethylamine, INT 1 and INT 3 were coupled in DMF to provide a novel amide linker. Cleavage of benzyl phosphonate and ethyl phosphonate with TMS-Br yielded two free phosphonates. Re-esterification with a large excess of benzyl N,N'-diisopropylaminoimino acid gave the corresponding tetrabenzyl bisphosphonate. Cleavage of tert-butyl ester with TFA yielded INT 6.

[0252]

[0253] Example 2

[0254] Synthesis of common peptide backbone

[0255] A 39-amino acid peptide backbone was constructed on Rink resin using solid-phase peptide synthesis techniques, activated with diimides, HATU, or HBTU for amide linkage synthesis. The choice of reagents varied depending on the characteristics of the amino acid being linked. The R group of lysine-19 was extended with two PEG2 amide linkers. The entire backbone was synthesized on the resin before coupling INT 4, INT 5, or INT 6 to the amino terminus of the lysine-linked linker.

[0256]

[0257] Example 3

[0258] Synthesis of Compound 4

[0259] The peptide backbone was coupled with INT 4 to obtain resin-bound, protected compound 4. Compound 4 was provided by TFA cleavage of the resin, the protecting group on the peptide chain, and benzyl ester of INT 4, and was purified by HPLC.

[0260]

[0261] Example 4

[0262] Synthesis of Compound 8

[0263] The peptide backbone was coupled to INT 5 to obtain resin-bound, protected compound 8. The resin was cleaved with TFA to remove the protecting groups on the peptide chain and the benzyl ester of INT 4, yielding compound 8, which was purified by HPLC.

[0264]

[0265] Example 5

[0266] Synthesis of Compound 12

[0267] The peptide backbone was coupled to INT 6 to give resin-bound, protected compound 12. The resin was cleaved with TFA to remove the protecting groups on the peptide chain and the benzyl ester of INT 4, yielding compound 12, which was purified by HPLC.

[0268]

[0269] Example 6

[0270] In vitro GLP-1 and GIP binding activity

[0271] For the two human recombinant G protein-coupled receptors GLP-1 and GIP, using Binding data for Tirzepatide, compounds 4, 8, and 12 were obtained using a combination assay and Epics therapeutic cell line. The agonist activity of the test compounds is expressed as their IC50 values. 100 The percentage of activity of the reference agonist at the specified concentrations is shown in Table 1.

[0272] Table 1

[0273]

[0274] Example 7

[0275] Biological effects of compounds in mice

[0276] As described by Boland et al. World J Gastroenterol. 2019, 25(33): 4904-4920, NASH was induced in mice by feeding them a Gubra amylin NASH (GAN) diet. One week before administration of the first dose of the compound, mice were weighed and randomized, and their food intake was measured. Mice were randomly assigned to treatment groups of 12 mice each. The designated dose groups were: tesipatetide (10 mg / kg); compound 4 (10 mg / kg); compound 8 (10 mg / kg); compound 12 (10 mg / kg); and a control group treated only with a mediator. Compound dose titrations (nmol / kg) were: 0.6 (day 0), 1.2 (day 1), 2.4 (day 2), 4.8 (day 3), 4.8 (day 4), 12 (day 5), and 30.0 (starting from day 6).

[0277] Two weeks later, the animals were euthanized. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured. Terminal necropsy of each liver was performed, and the relative liver weight as a percentage of body weight was measured. Total liver biochemistry was measured, including total liver triglycerides, plasma insulin, and total liver cholesterol. Histological evaluation of galactagogue-3 and α-smooth muscle actin was also performed.

[0278] Hepatic triglyceride (TG) levels are shown in Table 2. Data showed that administration of compounds 4, 8, or 12 resulted in lower relative and total hepatic triglyceride levels compared to administration of tesipatide or its carrier alone. Hepatic galactagogue-3 (Gal-3) levels, measured by histological quantitative assessment, are shown in Table 2. Data showed that administration of compounds 4, 8, or 12 resulted in lower relative and total hepatic galactagogue-3 levels compared to administration of tesipatide or its carrier alone. α-Smooth muscle actin (α-SMA) levels, measured by histological quantitative assessment, are shown in Table 2. Data showed that administration of compounds 4, 8, or 12 resulted in lower relative and total hepatic α-smooth muscle actin levels compared to administration of tesipatide.

[0279] Table 2

[0280]

[0281] Example 8

[0282] HSA-regulated in vitro GLP-1 and GIP binding activity

[0283] The binding assays of compounds tesipatide (TRZ), 4, and 12 were repeated in Example 6, with and without 2% human serum albumin (HSA). The ratios of compound-receptor binding with 2% HSA to those with 0% HSA are listed in Table 3. For the GLP-1 receptor and GIP receptor, tesipatide had HSA ratios of 12.8 and 5.82, respectively. For the GLP-1 receptor and GIP receptor, compound 4 had HSA ratios of 6.42 and 1.25, respectively. For the GLP-1 receptor and GIP receptor, compound 12 had HSA ratios of 5.26 and 1.70, respectively. The larger HSA ratio of tesipatide compared to compounds 4 and 12 indicates that tesipatide has a greater binding affinity for albumin than compounds 4 or 12.

[0284] Table 3

[0285]

[0286]

[0287] Example 9

[0288] Pharmacokinetics of the compound in monkeys

[0289] Subcutaneous (SC) administration of the compounds to male cynomolgus monkeys in a phosphate-buffered saline medium of 0.1% bovine serum albumin was performed. The designated dose groups were: tesipatide (0.2 mg / kg); compound 4 (0.2 mg / kg); and compound 12 (0.2 mg / kg). Samples were obtained at 1, 4, 8, 12, 24, 48, 72, 96, 120, 168, 192, 240, and 336 hours after single-dose administration.

[0290] The mean half-life values ​​are shown in Table 4. The data show that administration of compound 4 or compound 12 resulted in significantly greater persistence in the bloodstream compared to administration of tesipatide. The mean half-life of compound 4 was almost twice as long as that of tesipatide.

[0291] Table 4

[0292]

[0293] Previous studies have observed a direct correlation between albumin-binding affinity and in vivo half-life; compounds with longer half-lives have shown greater albumin-binding affinity (Lau, J., et al. J. Med. Chem. 2015, 58, 7370-7380). As described above, the experiments in Example 8 demonstrate that tesipatide has a greater albumin-binding affinity than compound 4 or compound 12. In contrast, the pharmacokinetic experiments described in this example determined half-lives of tesipatide, compound 4, and compound 12 to be 63.2 h, 118 h, and 104 h, respectively. The longer half-lives of compounds 4 and 12 compared to tesipatide are due to unexpected results from previous studies. The smaller HSA ratios of compounds 4 and 12 suggest that compounds 4 and 12 are expected to have lower albumin-binding affinity and shorter half-lives relative to tesipatide. The longer half-life of compound 4 or compound 12 relative to tesipatide was contrary to expectations.

[0294] Example 10

[0295] Pharmacokinetic studies of the formulation

[0296] The SC dosing experiments described in Example 9 were repeated with different formulations of tesipatide and compound 4. Formulation 1 comprised the compound in a phosphate-buffered saline solution of 0.1% bovine serum albumin. Formulation 2 comprised the compound in a 40% propylene glycol and 60% 10mM pH 6 citrate buffer solution. The designated dose groups were administered either tesipatide (0.2 mg / kg) or compound 4 (0.2 mg / kg) over 21 days.

[0297] The mean half-lives of the two formulations are shown in Table 5. The data show that administration of compound 4 in formulations 1 and 2 resulted in significantly greater persistence in the bloodstream compared to administration of tesipatide in the same formulation. The mean half-life of compound 4 in formulation 1 was almost twice as long as that of tesipatide. When compared to tesipatide, formulation 2 resulted in a mean half-life of compound 4 that was twice as long.

[0298] Table 5

[0299]

[0300] When the compound was administered in formulations 1 and 2, the unexpected results described in Example 9 were also observed in this example. The longer half-lives of compound 4 in formulations 1 and 2, relative to tesipatide, contradicted the expected results based on the above HSA studies.

[0301] Example 11

[0302] solubility of compounds

[0303] 50 mM phosphate buffer was prepared according to the United States Pharmacopeia (USP) guidelines. A large volume of 27.22 g of potassium dihydrogen phosphate was diluted with water to prepare a 1000 mL solution. 250 mL of the potassium dihydrogen phosphate solution and 22.4 mL of 1 M NaOH solution were then diluted to 1000 mL with water. The pH of the resulting buffer solution was determined to be 6.83. Solubility studies were conducted under ambient conditions, designed to prepare solutions with a maximum concentration of approximately 20 mg / mL. An initial volume of 100 μL of buffer was added to approximately 1–4 mg of tesipatide (TRZ), compound 4, compound 8, and compound 12 samples, followed by vortexing or vortex mixing. Additional buffer was added in increments of less than 1 mL until a maximum of approximately 200 mL was reached. Quantitative solubility (QNT) was reported in mg / mL. Qualitative solubility (QLT) based on visual observation was described using the USP protocol. The results are listed in Table 6.

[0304] Table 6

[0305]

[0306] Unlike TRZ, compounds 4 and 12 were observed to dissolve completely, and compound 12 had a quantitatively higher solubility than TRZ.

[0307] While some embodiments have been illustrated and described by way of example, those skilled in the art, upon reading the foregoing specification, can make equivalent changes and substitutions, as well as other types of variations, 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 combine variations or aspects disclosed with respect to any or all of the other aspects and embodiments.

[0308] This technology is not limited to the specific aspects described herein, which are intended as a single illustrative example of individual aspects of the technology. Many modifications and variations can be made to this technology without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of this technology, in addition to those listed herein, will also be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that this technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds, or biological systems, although such methods, reagents, compounds, compositions, labeled compounds, or biological systems can vary. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. Therefore, this specification is to be considered exemplary only, and the breadth, scope, and spirit of this technology are indicated solely by the appended claims, their definitions, and any equivalents thereof.

[0309] The embodiments illustrated herein may be practiced appropriately without any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be understood broadly and not restrictively. Furthermore, the terms and expressions used herein have been used as descriptive rather than restrictive terms, and in using such terms and expressions, no equivalents of the features shown and described or portions thereof are intended to be excluded, but it should be recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consistently composed of” will be understood to include those specifically listed elements and those additional elements that do not materially affect the essential and novel features of the claimed technology. The phrase “consisting of” excludes any unspecified elements.

[0310] Furthermore, where features or aspects of this disclosure are described according to the Markush Group, those skilled in the art will recognize that this disclosure is also described according to any individual member or subgroup of the Markush Group. Each of the narrower classes and subgeneral groupings falling within the general disclosure also forms part of this technology. This includes a general description of the technology, the conditions or negative limitations of which remove any subject matter from that class, regardless of whether the removed material is specifically described herein.

[0311] All publications, patent applications, granted 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, granted patent, or other document were specifically and individually indicated as being incorporated herein by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent that they contradict the definitions in this disclosure.

[0312] Other embodiments are set forth in the following claims, as well as the full scope of the equivalents authorized by these claims.

[0313] Although the invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.

[0314] For all purposes, all references, patents and patent applications cited in the body of this specification are incorporated herein by reference in their entirety.

[0315] Although the invention 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 invention. Therefore, the invention is defined only by the appended claims.

Claims

1. Compounds having the structure of formula Ia, Ib or Ic, or pharmaceutically acceptable salts thereof: Ia Ib Ic in: 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 Independently selected from hydrogen and C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Arylalkyl; Each R 5 Independently hydrogen or C 1-6 alkyl; Each R 6 Independently hydrogen or C 1-6 Alkyl groups; and Z 1 and Z 2 Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of general formula Ia: Ia Or its pharmaceutically acceptable salt.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl; and X and Y are each –OR 4 .

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Z 1 Selected from hydrogen, C 1-6 Alkyl and Halogenated C 1-6 Alkyl groups; and each R 4 Independently selected from hydrogen and C 6-10 Aryl and C 6-10 Arylalkyl.

5. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Z 1 For hydrogen, and each R 4 Independently hydrogen or C 6-10 Arylalkyl.

6. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each R 4 It is hydrogen.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Z 1 For hydrogen, and each R 4 It is hydrogen.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of general formula Ib: Ib Or its pharmaceutically acceptable salt.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z 2 Selected from hydrogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-10 cycloalkyl and C 6-10 Aryl; and X and Y are each –OR 4 .

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z 2 Selected from hydrogen, halogenated C 1-6 Alkyl and C 1-6 Alkyl groups; and each R 4 Independently selected from hydrogen and C 6-10 Aryl and C 6-10 Arylalkyl.

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z 2 For hydrogen, and each R 4 It is hydrogen or C 6-10 Arylalkyl.

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R 4 It is hydrogen.

13. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Z 2 For hydrogen, and each R 4 It is hydrogen.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the structure of general formula Ic: Ic Or its pharmaceutically acceptable salt.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein X and Y are each – OR 4 .

16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from hydrogen and C 6-10 Aryl and C 6-10 Arylalkyl.

17. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 4 It is hydrogen.

18. A compound or a pharmaceutically acceptable salt thereof having a structure selected from the following: 、 、 、 、 、 、 、 、 、 、 、 、 And its pharmaceutically acceptable salts.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, having the following structure: ， Or its pharmaceutically acceptable salt.

20. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, having the following structure: ， Or its pharmaceutically acceptable salt.

21. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, having the following structure: ， Or its pharmaceutically acceptable salt.

22. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, having the following structure: ， Or its pharmaceutically acceptable salt.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein " "" indicates a chiral carbon with an "S" configuration.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein " "" indicates a chiral carbon with an "R" configuration.

25. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. Use of any compound of claims 1-24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention, treatment or improvement of one or more fatty liver diseases.

27. The use according to claim 26, wherein the one or more fatty liver diseases are steatosis or non-alcoholic fatty liver disease.

28. The use according to claim 27, wherein the one or more fatty liver diseases are non-alcoholic fatty liver diseases, and the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

29. The use according to claim 26, wherein the administration of said compound or a pharmaceutically acceptable salt thereof results in the prevention, treatment or improvement of fibrosis, fibrotic condition or fibrotic symptoms.

30. The use according to claim 26, wherein the administration of said compound or a pharmaceutically acceptable salt thereof results in a reduction in the amount of extracellular matrix proteins present in one or more tissues of an individual.

31. The use according to claim 26, wherein the administration of said compound or a pharmaceutically acceptable salt thereof results in a reduction in the amount of collagen present in one or more tissues of an individual.

32. The use according to claim 31, wherein the administration of said compound or a pharmaceutically acceptable salt thereof results in a reduction in the amount of type I, Ia, or III collagen present in one or more tissues of an individual.

33. Use of any compound of claims 1-24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention, treatment or improvement of one or more diseases or conditions, wherein said one or more diseases or conditions are liver fibrosis, kidney fibrosis, biliary fibrosis, pancreatic fibrosis, non-alcoholic fatty liver disease, chronic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis.

34. The use according to claim 33, wherein one or more diseases or conditions are non-alcoholic fatty liver disease, and the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

35. The use according to claim 33, wherein the one or more diseases or conditions are chronic kidney disease, and the chronic kidney disease is diabetic nephropathy.

36. The use according to claim 33, wherein the one or more diseases or conditions are primary sclerosing cholangitis or primary biliary cirrhosis.

37. The use according to claim 26, wherein the compound or a pharmaceutically acceptable salt thereof activates a glucose-dependent insulinotropic polypeptide (GIP) receptor.

38. The use according to claim 26, wherein the compound or a pharmaceutically acceptable salt thereof activates the glucagon-like peptide-1 (GLP-1) receptor.

39. The use according to claim 26, wherein the compound or a pharmaceutically acceptable salt thereof activates glucose-dependent insulinotropic peptide (GIP) receptors and glucagon-like peptide-1 (GLP-1) receptors.

40. The use according to claim 26, wherein the drug is formulated for administration via enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, or mucosal administration.

41. Use of any compound of claims 1-24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention, treatment or improvement of one or more diseases or conditions, wherein the one or more diseases or conditions are metabolic disorders or metabolic syndromes selected from atherosclerosis, diabetes, dyslipidemia, obesity or Prader-Willi syndrome.

42. The use according to claim 41, wherein the metabolic disorder or metabolic syndrome is diabetes, and the diabetes is hyperglycemic diabetes or type 2 diabetes.

43. The use according to claim 41, wherein the metabolic disorder or metabolic syndrome is dyslipidemia, and the dyslipidemia is hypercholesterolemia or hyperlipidemia.

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