Pharmaceutical Formulations and Methods for the Treatment of Metabolic and Liver Disorders - Patent application

Abstract

Disclosed herein are formulations of small molecule GIP / GLP-1 dual receptor agonists and uses thereof.

Description

[Technical field]

[0001] The present disclosure generally relates to the field of treatments for metabolic disorders and fatty liver disease. More specifically, the present disclosure relates to the field of formulations of small molecule drugs for the treatment of diseases including non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD). [Background technology]

[0002] The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are metabolic hormones. Both GIP and GLP-1 are secreted within minutes of nutrient ingestion, facilitating rapid disposal of ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct but related receptors. Incretin receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage through direct actions on adipose tissue. In contrast, GLP-1 exerts glucoregulatory effects through slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss in both preclinical and clinical studies.

[0003] Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the most common cause of chronic liver disease. NAFLD can progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GIP / GLP-1 dual receptor agonists have been developed to treat NAFLD, nonalcoholic steatohepatitis (NASH), diabetes, obesity, and other diseases. However, the use of GIP / GLP-1 dual receptor agonists is associated with nausea, vomiting, and / or diarrhea. For example, clinical trials of GIP / GLP1 dual receptor agonist compounds have found that tolerability at high doses was limited by gastrointestinal adverse events. Dose limitations associated with gastrointestinal adverse events may prevent dosing to a desired effective dose, impair patient compliance to treatment, and limit the effectiveness of treatment regimens. Thus, there is a need for novel GIP / GLP1 dual agonist compound formulations that can be used to treat fatty liver disease and other diseases and disorders. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 87 / 05297, Johnston et al., published September 11, 1987 [Non-patent literature]

[0005] [Non-Patent Document 1] Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238~311 [Non-Patent Document 2] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287~332 [Non-Patent Document 3] Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon", J. Biol. Chem. 2010 285: pp. 11039-11044 [Non-Patent Document 4] Protective Groups in Organic Chemistry (edited by JFW McOmie, Plenum Press, 1973) [Non-Patent Document 5] PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999) [Non-Patent Document 6] R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 [Non-Patent Document 7] L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995. [Non-Patent Document 8] Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991) [Non-Patent Document 9] Rodd's Chemistry of Carbon Compounds, vols. 1-5 [Non-Patent Document 10] Supplementals (Elsevier Science Publishers, 1989)

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[0006] Some embodiments disclosed herein include a pharmaceutical formulation for administration to a subject in need thereof, wherein the pharmaceutical formulation comprises a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable diluent, and any combination of the foregoing; and a compound represented by Formula I:

[0007] [ka]

[0008] or a pharma- ceutically acceptable salt thereof, wherein R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with Each R 7 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 may be independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 arylalkoxy; Each R 5 are independently hydrogen or C 1~6 may be alkyl; Each R 6 are independently hydrogen or C 1~6 may be alkyl; Z 1 and Z 2 are hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; However, Z 1 and Z 2At least one of the above must not be hydrogen.

[0009] Other embodiments disclosed herein include a pharma- ceutically acceptable carrier comprising at least 10% by weight propylene glycol.

[0010] Other embodiments disclosed herein include a pharma- ceutically acceptable diluent that is a pH buffer. In some embodiments, the pharma- ceutically acceptable diluent is present in the formulation at a weight percentage of about 20% or greater.

[0011] Other embodiments disclosed herein include a method for preventing, treating or improving one or more fatty liver diseases in a subject by administering to the subject in need thereof the pharmaceutical formulations disclosed herein.Fatty liver diseases include, but are not limited to, steatosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD).

[0012] Other embodiments disclosed herein include a method for preventing, treating or improving one or more diseases or disorders in a subject by administering the pharmaceutical formulations disclosed herein to a subject in need thereof.In some embodiments, the disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.In some embodiments, the disease or disorder is metabolic disorder or metabolic syndrome.In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In some embodiments, pharmaceutical formulations are provided for administration to a subject in need thereof. Various embodiments of these pharmaceutical formulations include a pharma- ceutically acceptable carrier, a pharma-ceutically acceptable excipient, a pharma-ceutically acceptable diluent, and any combination of the above. Some embodiments of the pharmaceutical formulations include a therapeutically effective dose of a compound as described elsewhere herein, or a pharma-ceutically acceptable salt thereof. Some embodiments of the pharmaceutical formulations are administered for the prevention, treatment, or improvement of one or more fatty liver diseases in a subject. Fatty liver diseases include, but are not limited to, steatosis, nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD).

[0014] In some embodiments, the pharmaceutical formulations include compounds that are non-macrocyclic functionalized peptides that act as dual GIP / GLP-1 receptor agonists. Various embodiments of these compounds include compounds having the structure of Formula I, as described above, or a pharma- ceutically acceptable salt thereof. The structure of Formula I encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0015] [ka]

[0016] In some embodiments of the compounds of formula I: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with Each R 7 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 may be independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 arylalkoxy; Each R 5 are independently hydrogen or C 1~6 may be alkyl; Each R 6 are independently hydrogen or C 1~6 may be alkyl; Z 1 and Z 2 are hydrogen, C 1~6 Alkyl, haloC1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; However, Z 1 and Z 2 At least one of these must not be hydrogen.

[0017] Some embodiments of the compounds of formula I include those of formula Ia:

[0018] [ka]

[0019] or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; X and Y are each selected from -OR 4 It is.

[0021] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, haloC 1~6 Alkoxy and C 1~6 alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0022] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, and each R4 are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0023] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0024] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, and each R 4 is hydrogen.

[0025] Some embodiments of the compounds of formula I include those of formula Ib:

[0026] [ka]

[0027] or a pharma- ceutically acceptable salt thereof.

[0028] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 aryl; X and Y are each selected from -OR 4 It is.

[0029] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, haloC 1~6 Alkoxy and C 1~6 alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0030] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, and each R 4 are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0031] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0032] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, and each R 4 is hydrogen.

[0033] Some embodiments of the compounds of formula I include those of formula Ic:

[0034] [ka]

[0035] or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof; X and Y are each -OR 4 It is.

[0037] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0038] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0039] In some embodiments:

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] and pharma- ceutically acceptable salts thereof.

[0045] In some embodiments, * " exhibits a chiral carbon having the "S" configuration.

[0046] In some embodiments, * " exhibits a chiral carbon having the "R" configuration.

[0047] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is achieved by application of various methods well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein, including any polymorphic forms. In addition, some of the compounds disclosed herein can form solvates (i.e., hydrates) with water or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.

[0048] Those skilled in the art will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that may be significantly represented, even dynamically, by other chemical structures; those skilled in the art will recognize that such structures may only represent a very small proportion of the samples of such compounds. Although such compounds are believed to be within the scope of the depicted structures, such resonance forms or tautomers are not represented herein.

[0049] The pharmaceutical formulation comprises at least one pharma- ceutically acceptable carrier. The term "pharma- ceutically acceptable carrier" as used herein is given its usual meaning to those skilled in the art. In some embodiments, the pharma- ceutically acceptable carrier comprises propylene glycol. In some embodiments, the pharma- ceutically acceptable carrier is present in the formulation at a mass percentage of about: 1%, 5%, 10%, 15%, 20%, 25%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38% 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 60%, 70%, 80%, 90%, 95%, or more than the ranges including and / or spanning the aforementioned values. In some embodiments, the pharma- ceutically acceptable carrier is present in the formulation in a weight percentage of about 10% to 90% by weight, hi some embodiments, the pharma-ceutically acceptable carrier is present in the formulation in a weight percentage of about 30% to 50% by weight.

[0050] The pharmaceutical preparation may include at least one pharma- ceutically acceptable diluent. The term "pharma-ceutically acceptable diluent" as used herein is given its ordinary meaning to those skilled in the art. In some embodiments, the pharma-ceutically acceptable diluent includes saline or sterile water. In some embodiments, the pharma-ceutically acceptable diluent includes a pH buffer. In some embodiments, the pharma- ceutically acceptable diluent is a tartrate, citrate, acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), Tris(hydrogen)sulfonic acid, or the like, in a suitable solvent (e.g., water). The pH buffer is selected from the group consisting of N-cyclohexyl-2-aminoethanesulfonic acid (CHES), 2-(bis(2-hydroxyethyl)amino)propanesulfonic acid (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate, and any combination of the foregoing. In some embodiments, the pharma- ceutically acceptable diluent has a pH of about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range including and / or spanning the foregoing values. In some embodiments, the pharma- ceutically acceptable diluent has a pH of about 3 to 7. In some embodiments, the pharma- ceutically acceptable diluent has a pH of about 4 to 6.8.In some embodiments, the concentration of the pharma- ceutically acceptable diluent is about: 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM, 1 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 70 mM, 100 mM, 200 mM, 500 mM, 1000 mM, or a range including and / or spanning the aforementioned values. In some embodiments, the concentration of the pharma-ceutically acceptable diluent is about 1 mM to 50 mM. In some embodiments, the concentration of the pharma-ceutically acceptable diluent is about 8 mM to 12 mM. In some embodiments, the pharma- ceutically acceptable diluent is present in the formulation at a weight percentage of about: 1%, 5%, 10%, 20%, 30%, 40%, 50%, 53%, 55%, 57%, 59%, 60%, 61%, 63%, 65%, 67%, 70%, 75%, 80%, 90%, 95%, or a range including and / or spanning the foregoing values ​​or more. In some embodiments, the pharma- ceutically acceptable diluent is present in the formulation at a weight percentage of about 20% to 95% by weight. In some embodiments, the pharma- ceutically acceptable diluent is present in the formulation at a weight percentage of about 50% to 70% by weight.

[0051] In some embodiments, the pharmaceutical formulation comprises propylene glycol and a pH buffer. In some embodiments, the pH buffer comprises tartrate in a suitable solvent (e.g., water). In some embodiments, the pH buffer comprises citrate in a suitable solvent (e.g., water). In some embodiments, the pH buffer comprises acetate in a suitable solvent (e.g., water). In some embodiments, the pH buffer comprises 2-(N-morpholino)ethanesulfonic acid (MES) in a suitable solvent (e.g., water). In some embodiments, the pH buffer comprises piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES) in a suitable solvent (e.g., water). In some embodiments, the pH buffer has a pH of about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range including and / or spanning the foregoing values. In some embodiments, the pH buffer has a pH of about 3 to 7. In some embodiments, the pH buffer has a pH of about 4 to 6.8. In some embodiments, the pH buffer has a pH of about 5 to 6.8. In some embodiments, the pH buffer has a concentration of about: 0.01 mM, 0.05 mM, 0.1 mM, 0.5 mM, 1 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 20 mM, 25 mM , 30 mM, 40 mM, 50 mM, 70 mM, 100 mM, 200 mM, 500 mM, 1000 mM, or ranges including and / or spanning the foregoing values. In some embodiments, the concentration of the pH buffer is about 1 mM to 50 mM. In some embodiments, the concentration of the pH buffer is about 8 mM to 12 mM. In some embodiments, the propylene glycol is present in the formulation at a weight percentage of about 10% or more, and the pH buffer is present in the formulation at a weight percentage of about 20% or more. In some embodiments, the propylene glycol is present in the formulation at a weight percentage of about 10% to 90%. In some embodiments, the propylene glycol is present in the formulation at a weight percentage of about 20% to 70%. In some embodiments, the propylene glycol is present in the formulation at a weight percentage of about 30% to 50%.In some embodiments, the pH buffer is present in the formulation at a weight percentage of about 20% to 95%. In some embodiments, the pH buffer is present in the formulation at a weight percentage of about 30% to 80%. In some embodiments, the pH buffer is present in the formulation at a weight percentage of about 50% to 70%. In some embodiments, the pH of the formulation is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range including and / or spanning the foregoing values. In some embodiments, the formulation has a pH of about 3 to 7. In some embodiments, the formulation has a pH of about 4 to 6.8. In some embodiments, the formulation has a pH of about 5 to 6.8.

[0052] The pharmaceutical preparation comprises a therapeutically effective dosage. The term "therapeutically effective dosage" as used herein depends on the subject and disease state being treated, the severity of the affliction, the mode and schedule of administration, and the judgment of the prescribing physician. In some embodiments, the therapeutically effective dosage may be a daily dosage of about 0.0125mg / kg to about 120mg / kg or more of body weight, about 0.025mg / kg or less to about 70mg / kg of body weight, about 0.05mg / kg to about 50mg / kg, or about 0.075mg / kg to about 10mg / kg of body weight. Thus, for administration to a 70 kg human, the dosage range is from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg per day or less to about 7000 mg per day or more, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg per day to about 3000 mg per day. In some embodiments, the therapeutically effective dosage is about 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.12 mg / kg, 0.14 mg / kg, 0.15 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.19 mg / kg, 0.2 mg / kg, 0.21 mg / kg, 0.22 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.26 mg / kg, 0.28 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100v, 200 mg / kg, 500 mg / kg, or a range including and / or spanning the foregoing values. In some embodiments, the therapeutically effective dosage is about 0.01 mg / kg to about 5 mg / kg. In some embodiments, the therapeutically effective dosage is about 0.05 mg / kg to about 1 mg / kg. In some embodiments, the therapeutically effective dosage is about 0.15 mg / kg to about 0.25 mg / kg.

[0053] The pharmaceutical preparations have a half-life in the blood of a subject when they are administered.In some embodiments, the half-life is about: 5 hours, 10 hours, 20 hours, 40 hours, 60 hours, 80 hours, 90 hours, 100 hours, 110 hours, 115 hours, 118 hours, 120 hours, 122 hours, 125 hours, 128 hours, 130 hours, 150 hours, 180 hours, 200 hours, 250 hours, 300 hours, 500 hours, or more than the range including and / or spanning the above values.In some embodiments, the half-life is about 40 hours to 300 hours.In some embodiments, the half-life is about 60 hours to 150 hours.

[0054] The pharmaceutical formulation may be administered by a route of administration including, but not limited to, enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intrapulmonary, intravaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration is selected from the group consisting of enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal. In some embodiments, the pharmaceutical formulation is administered subcutaneously. In some embodiments, the pharmaceutical formulation is administered intravenously. In some embodiments, the pharmaceutical formulation is administered orally.

[0055] The pharmaceutical preparation can be provided in a dosage form. In some embodiments, the dosage form is selected from a solid form and a liquid form. Solid dosage forms include tablets, capsules, granules and bulk powders. Liquid dosage forms include solutions, emulsions and suspensions. In some embodiments, the dosage form is a solid form. In some embodiments, the dosage form is a liquid form.

[0056] In some embodiments, the pharmaceutical preparation comprises at least one pharma- ceutically acceptable excipient. The term "pharma-ceutically acceptable excipient" as used herein includes, but is not limited to, solvents, dispersants, coatings, antimicrobial agents, adjuvants, isotonic agents, and absorption retardants. In some embodiments, the pharma-ceutically acceptable excipients include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, sorb ... Examples of suitable excipients include, but are not limited to, ethanol, polyethylene glycol, alginic acid, emulsifiers and surfactants, such as Tween, wetting agents, such as sodium lauryl sulfate, colorants, flavorings, tableting agents, stabilizers, antioxidants, preservatives, such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acid, and phenylmercuric nitrate, tonicity adjusters, such as sodium chloride, potassium chloride, mannitol, and glycerin, vehicles, such as polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, and hydroxyethylcellulose, and pyrogen-free water. In some embodiments, the pharmaceutically acceptable excipients are selected based on the route of administration and can include solid or liquid fillers, diluents, hydrotropes, surface active agents, and encapsulating materials. For example, for intravenous administration, excipients can include gelatin; carbohydrates, such as dextrose, mannitol, and dextran; and antioxidants, such as sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA.In some embodiments, pharma- ceutically acceptable excipients include antimicrobial agents, such as phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol. Additional examples of suitable pharma-ceutically 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, each of which is incorporated herein by reference in its entirety.

[0057] In some embodiments, the pharmaceutical formulation is administered to a subject that is a mammal.

[0058] In some embodiments, the pharmaceutical formulation is administered to a human subject.

[0059] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless otherwise stated.

[0060] "Solvate" refers to the compound formed by the interaction of a solvent with a compound described herein, or a salt thereof. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0061] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical product. In many cases, the compounds herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium 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., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

[0062] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a From C b " or "C a~b " refers to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, "C1 to C4 alkyl" or "C 1~4An "alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0063] The term "halogen" or "halo" as used herein means any one of the radioactive stable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0064] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition encompasses the occurrence of the term "alkyl" even when no numerical range is specified). The alkyl group can be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compound can be a "C 1~4 By way of example only, "C 1~4 "Alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0065] As used herein, "haloalkyl" refers to a straight or branched chain alkyl group having from 1 to 12 carbon atoms in the chain in which one or more hydrogens are replaced with halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that would be considered equivalent to any one of the foregoing examples in light of ordinary skill in the art and the teachings provided herein.

[0066] As used herein, "alkoxy" refers to a group of the formula -OR where R is alkyl as defined above, including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. 1~9 Refers to "alkoxy".

[0067] As used herein, "polyethylene glycol" refers to a compound of the formula

[0068] [ka]

[0069] where n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by a number of members. Thus, for example, "2- to 5-membered polyethylene glycol" refers to n being an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0070] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the chain backbone, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. Heteroalkyl groups can have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" when no numerical range is specified. Heteroalkyl groups can be medium size heteroalkyls having 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having 1 to 4 carbon atoms. In various embodiments, heteroalkyls can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl groups of the compounds are defined as "C 1~4 A heteroalkyl group may be designated as "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" means that the heteroalkyl chain has 1 to 4 carbon atoms and, additionally, one or more heteroatoms in the backbone of the chain.

[0071] The term "aromatic" refers to a ring or ring system having a conjugated pi-electron system, and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0072] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, every ring in the system is aromatic. An aryl group can have from 6 to 18 carbon atoms, although this definition also encompasses occurrences of the term "aryl" when no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is defined as "C 6~10 Aryl, C6 or C10 The aryl group may be designated as "aryl" or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0073] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, including, but not limited to, phenyloxy. 6~10 aryloxy" or "C 6~10 "Arylthio" etc.

[0074] "Aralkyl" or "arylalkyl" refers to an aryl group connected as a substituent through an alkylene group, such as, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl, "C 7~14 In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0075] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms in the ring backbone, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, every ring in the system is aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" when no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members, or 5 to 7 ring members. Heteroaryl groups can be designated as "5-membered to 7-membered heteroaryl," "5-membered to 10-membered heteroaryl," or similar designations. In various embodiments, heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0076] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0077] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. Carbocyclyl groups can have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" when no numerical range is specified. Carbocyclyl groups may be medium-sized carbocyclyls having 3 to 10 carbon atoms. Carbocyclyl groups can also be carbocyclyls having 3 to 6 carbon atoms. Carbocyclyl groups are defined as "C 3~6 Carbocyclyl may be designated as "carbocyclyl" or a similar designation. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclic [2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0078] "(Carbocyclyl)alkyl" refers to a carbocyclyl group connected as a substituent via an alkylene group, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. 4-10 (carbocyclyl)alkyl." In some cases, the alkylene group is a lower alkylene group.

[0079] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0080] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, where no ring in the ring system is aromatic. An example is cyclohexenyl.

[0081] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged, or spiro-connected fashion. Heterocyclyls can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in either the non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have from 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclyl" when no numerical range is specified. Heterocyclyl groups may be medium-sized heterocyclyls having from 3 to 10 ring members. Heterocyclyl groups can also be heterocyclyls having from 3 to 6 ring members. Heterocyclyl groups can be designated as "3- to 6-membered heterocyclyl" or similar designations.

[0082] In various embodiments, the heterocyclyl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to up to 3 O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2H-1,2-oxazinyl, trioxadiyl, 1H-1,2-oxazin ... nyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0083] "(Heterocyclyl)alkyl" is a heterocyclyl group connected as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0084] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl and acryl.

[0085] An "O-carboxy" group refers to a "-OC(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0086] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, C(=O)O, or C(=O)O, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0087] A "cyano" group refers to a "-CN" group.

[0088] A "cyanato" group refers to a "-OCN" group.

[0089] An "isocyanato" group refers to a "-NCO" group.

[0090] A "thiocyanato" group refers to a "-SCN" group.

[0091] An "isothiocyanato" group refers to a "-NCS" group.

[0092] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0093] A "sulfonyl" group refers to a "-SO2R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0094] The "S-sulfonamide" group is "-SONR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0095] An “N-sulfonamide” group is defined as “-N(R A )SO2R B " group, where RA and R b each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0096] The "O-carbamyl" group is "-OC(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0097] The "N-carbamyl" group is defined as "-N(R A )OC(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0098] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0099] The "N-thiocarbamyl" group is defined as "-N(R A )OC(=S)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0100] A "C-amide" group is defined as "-C(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0101] An "N-amide" group is defined as "-N(R A )C(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0102] The "amino" group is "-NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0103] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0104] An "alkoxyalkyl" group is an alkoxy group connected via an alkylene group, e.g., "C 2~8 "Alkoxyalkyl" and the like.

[0105] As used herein, "natural amino acid side chain" refers to a side chain substituent of a naturally occurring amino acid. Naturally occurring amino acids have a substituent attached to the α-carbon. 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.

[0106] As used herein, "unnatural amino acid side chain" refers to the side chain substituents of a non-naturally occurring amino acid. Unnatural amino acids include β-amino acids (β 3 and β 2), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids and N-methyl amino acids. Illustrative unnatural amino acids are available from Sigma-Aldridge, listed under "Unnatural Amino Acids & Derivatives." See also Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in its entirety.

[0107] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group is independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 5- to 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); 5- to 10-membered heteroaryl(C1-C6)alkyl (halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy); and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,It is meant to be substituted with one or more substituents selected from C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo (=O). Whenever a group is described as "optionally substituted", that group may be substituted with the above-mentioned substituents.

[0108] In some embodiments, substituted groups are individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0109] It should be understood that certain group naming conventions can include either mono or di groups, depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, the substituent is understood to be a di group. For example, a substituent identified as an alkyl requiring two points of attachment includes di groups such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a di group, such as "alkylene" or "alkenylene".

[0110] When two R groups are described as "together with the atoms to which they are attached" forming a ring (e.g., a carbocyclyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring), the collective unit of the atoms and the two R groups is meant to be the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, the following substructures exist:

[0111] [ka]

[0112] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R2 together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0113] [ka]

[0114] where Ring A is the nitrogen-containing heterocyclyl ring as shown.

[0115] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," the collective unit of the atoms, intervening bonds, and two R groups is meant to be the recited ring. For example, the following substructure exists:

[0116] [ka]

[0117] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0118] [ka]

[0119] where A is an aryl ring or carbocyclyl containing the double bond shown.

[0120] Whenever a substituent is depicted as a digroup (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or

[0121] [ka]

[0122] Substituents depicted as include those where A is oriented such that it is attached at the leftmost attachment point of the molecule, and those where A is attached at the rightmost attachment point of the molecule.

[0123] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

[0124] "Subject", as used herein, means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0125] An "effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent that is effective to alleviate to some extent one or more of the symptoms of a disease or condition or to reduce the likelihood of its occurrence, as well as to cure the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated; however, even after a cure is obtained, certain long-term or permanent effects may exist (such as extensive tissue damage).

[0126] "Treat", "treatment" or "treating" as used herein refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who no longer exhibits symptoms of the disease or condition, but who is susceptible or otherwise at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering a treatment to a subject who is already suffering from a disease or condition.

[0127] Method of preparation The compounds disclosed herein can be synthesized by the methods described below or by modification of these methods. The manner of modifying the methodology includes, among others, temperature, solvent, reagents, etc., known to those skilled in the art. In general, during any of the processes for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd Edition) Wiley, New York (1999), both of which are hereby incorporated by reference in their entirety. The protecting groups can be removed at a convenient subsequent stage using methods known from the art. Synthetic chemical transformations useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 19955, both of which are hereby incorporated by reference in their entirety. The routes shown and described herein are exemplary only and are in no way intended or to be construed as limiting the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and may undertake alternative routes based on the disclosures herein; all such modifications and alternative routes are within the scope of the claims.

[0128] In the schemes below, protecting groups are selected for their compatibility with the synthetic steps required, and for compatibility of the installation and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0129] If the compounds of the present technology contain one or more chiral centers, these compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents that are well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0130] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0131] In one embodiment, the method disclosed herein can include constructing a 39-amino acid peptide backbone using solid-phase peptide synthesis techniques 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 an appropriately substituted carboxylic acid (III) to provide resin-bound intermediate (IV). In one embodiment, the method involves hydrolysis of intermediate (IV) under acidic conditions followed by purification to obtain final product (I). (Scheme 1).

[0132] [ka]

[0133] The above example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0134] The pharmaceutical formulations disclosed herein can be prepared using standard pharmaceutical formulation techniques, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, each of which is incorporated herein by reference in its entirety. In some embodiments, the pharmaceutical formulations can be prepared as unit dosage forms. Techniques and compositions for preparing unit dosage forms are described in Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004), each of which is incorporated herein by reference in its entirety.

[0135] Treatment Method The pharmaceutical formulation disclosed herein comprises a compound or its tautomer and / or its pharma- ceutical acceptable salt that can effectively act as a GIP / GLP1 dual receptor agonist. The pharmaceutical formulation further comprises one or more pharma- ceutical acceptable carriers and one or more pharma- ceutical acceptable diluents.

[0136] Some embodiments provide a method for preventing, treating or improving one or more fatty liver diseases in a subject.In some embodiments, the method comprises administering one or more of the pharmaceutical preparations disclosed herein to a subject in need thereof.

[0137] Some embodiments provide a method for preventing, treating or ameliorating steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutical preparations disclosed herein.

[0138] In some embodiments, the methods of administering one or more of the pharmaceutical formulations disclosed herein result in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom.

[0139] In some embodiments, the pharmaceutical formulations described herein can be used to treat a host of pathologies, including those resulting from fibrosis or inflammation and specifically associated with myofibroblast differentiation.Exemplary pathologies include, but are not limited to, progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic and genetic chronic diseases), renal fibrosis (e.g., due to chronic inflammation, infection or type II diabetes), pulmonary fibrosis (idiopathic or due to environmental insults, including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections, including tuberculosis, drugs, etc.), interstitial fibrosis, systemic sclerosis (autoimmune disease that causes many organs to become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (e.g., due to alcohol abuse and chronic inflammatory disease of the pancreas), These include splenic fibrosis (from sickle cell anemia, other blood disorders), cardiac fibrosis (due to infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, nonalcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemia-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0140] In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of extracellular matrix protein present in one or more tissues of said subject.

[0141] In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of collagen present in one or more tissues of said subject.

[0142] In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

[0143] Some embodiments provide the method of preventing, treating or improving one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis in a subject.In some embodiments, the method comprises administering one or more of the pharmaceutical preparations disclosed herein to a subject in need thereof.

[0144] Some embodiments provide a method for preventing, treating or improving one or more of non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis or primary biliary cirrhosis in a subject.In some embodiments, the method comprises administering one or more of the pharmaceutical preparations disclosed herein to a subject in need thereof.

[0145] Some embodiments provide a method for preventing, treating or improving one or more metabolic disorders or metabolic syndromes.In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome.In some embodiments, the method comprises administering one or more of the pharmaceutical preparations disclosed herein to a subject in need thereof.

[0146] In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in the activation of the glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in the activation of the glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, the method of administering one or more of the pharmaceutical formulations disclosed herein results in the activation of the GIP receptor and the GLP-1 receptor.

[0147] Some embodiments include co-administration of the pharmaceutical formulations and / or compounds or pharma- ceutically acceptable salts thereof described herein with additional pharmaceutical agents. By "co-administration" it is meant that two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, e.g., orally. In another embodiment, the agents are administered via different routes, e.g., one is administered subcutaneously, another is administered orally, and another is administered iv.

[0148] The following examples are included to further illustrate this disclosure. The examples should not be interpreted as specifically limiting this disclosure, of course. Variations of these examples within the scope of the claims are within the knowledge of a person skilled in the art and are considered to fall within the scope of this disclosure as described and claimed herein. The reader will recognize that a person skilled in the art, equipped with this disclosure and the skills in the art, can prepare and use this disclosure without using the exhaustive examples. The following examples further describe this disclosure and are used for illustrative purposes only and should not be interpreted as limiting. EXAMPLES

[0149] General Procedure It is clear to the skilled artisan that the methods for preparing the precursors and functional groups related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to utilize variants that are themselves known to the skilled artisan, but are not described in more detail. The skilled artisan, given the literature and this disclosure, is fully equipped to prepare any of the compounds.

[0150] It will be recognized that those skilled in the art of organic chemistry can readily perform the manipulations without further instruction, i.e., it is well within the scope and practice of the skilled artisan to perform these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification, and saponification, etc. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry, which are incorporated herein by reference in their entirety. All intermediate compounds in this disclosure were used without further purification unless otherwise specified.

[0151] Those skilled in the art will readily recognize that certain reactions are best performed when other functional groups are masked or protected in the molecule, thus avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, those skilled in the art will utilize protecting groups to achieve such increased yields or avoid undesired reactions. These reactions are found in the literature and are also well within the scope of those skilled in the art. Many examples of these manipulations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Edition, John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0152] The following example schemes are provided for the reader's guidance and represent preferred methods for making the compounds illustrated herein. It is clear that these methods are not limiting and other routes can be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Those skilled in the art are fully equipped to prepare these compounds by the methods provided in the literature and in this disclosure. The compound numbering used in the synthetic schemes illustrated below has meaning only for those specific schemes and should not be interpreted or confused with the same numbering in other sections of this application.

[0153] The trademarks used herein are only examples and reflect the exemplary materials used at the time of this disclosure. One of ordinary skill in the art will recognize that variations in lots, manufacturing processes, etc. are expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but merely illustrative of how one of ordinary skill in the art may select to perform one or more of the embodiments of the present disclosure.

[0154] The following abbreviations have the indicated meanings: Aib = aminoisobutyric acid Bn=benzyl Boc = tert-butoxycarbonyl Bu = butyl DMF = Dimethylformamide EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl HATU = Hexafluorophosphate azabenzotriazole tetramethyluranium HBTU = hexafluorophosphate benzotriazole tetramethyluranium HMDS = hexamethyldisilazane HPLC = High Performance Liquid Chromatography Me = methyl NaHMDS = sodium hexamethyldisilazide NMR=nuclear magnetic resonance PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl

[0155] The following example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0156] Example 1 Synthesis of Intermediate 1 (INT 1) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to generate the ylide, which is immediately reacted in a Wittig reaction with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in mild base to form the phosphonate. Hydrolysis of the methyl carboxylate provides the desired INT 1 with a terminal carboxylic acid and dibenzyl phosphonate.

[0157] [ka]

[0158] Synthesis of Intermediate 2 (INT 2) The docosanedioic acid is coupled to benzyl alcohol using EDC·HCl and DMAP in THF to give INT 2 as the monobenzyl ester.

[0159] [ka]

[0160] Synthesis of intermediate 3 (INT 3) t-Butyl 4-hydroxybutanoate undergoes Swern oxidation to give the aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form the imine. Addition of the lithium salt of diethyl phosphite in THF generates the α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group and provide INT 3 with a free primary amine, t-butyl ester, and phosphonic acid diethyl ester. The optical purity of INT 3 was confirmed to be at least 96% by 1H NMR via Mosher amide analysis.

[0161] [ka]

[0162] Synthesis of intermediate 4 (INT 4) INT 1 is coupled with 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0163] [ka]

[0164] Synthesis of Intermediate 5 (INT 5) INT 2 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare the new amide linkage. Cleavage of the phosphonic acid ethyl ester with TMS-Br gives the free phosphonic acid. Re-esterification with a large excess of the benzyl ester of N,N'-diisopropylcarbamimic acid provides the corresponding dibenzyl phosphonate. The t-butyl ester is cleaved with TFA to provide INT 5.

[0165] [ka]

[0166] Synthesis of intermediate 6 (INT 6) INT 1 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to provide the new amide linkage. Cleavage of the benzyl and phosphonic acid ethyl esters with TMS-Br gives both free phosphonic acids. Re-esterification with a large excess of the benzyl ester of N,N'-diisopropylcarbamimic acid provides the corresponding tetrabenzyl diphosphonate ester. The t-butyl ester is cleaved with TFA to give INT 6.

[0167] [ka]

[0168] Example 2 Synthesis of the common peptide backbone The 39-amino acid peptide scaffold is constructed using solid-phase peptide synthesis techniques using diimide, HATU or HBTU activation for amide linkage synthesis on Rink resin. Reagent selection varies based on the identity of the amino acid being attached. The R-group of lysine-19 was extended with two PEG2 amide linkers. The entire scaffold is synthesized on resin prior to coupling of INT 4, INT 5 or INT 6 to the amino terminus of the lysine-linked linker.

[0169] [ka]

[0170] Example 3 Synthesis of compound 4 The peptide backbone is coupled to INT 4 to give resin-bound protected compound 4. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 with TFA provides compound 4, which is purified via HPLC.

[0171] [ka]

[0172] Example 4 Synthesis of compound 8 The peptide backbone is coupled to INT 5 to give resin-bound protected compound 8. Cleavage of the protecting groups on the resin, peptide chain, and benzyl ester of INT 4 with TFA provides compound 8, which is purified via HPLC.

[0173] [ka]

[0174] Example 5 Synthesis of compound 12 The peptide backbone is coupled to INT 6 to give resin-bound protected compound 12. Cleavage of the protecting groups on the resin, peptide chain, and benzyl ester of INT 4 with TFA provides compound 12, which is purified via HPLC.

[0175] [ka]

[0176] Example 6 Pharmacokinetic studies of formulations Male cynomolgus monkeys were used to administer subcutaneous (SC) dosing of tirzepatide and Compound 4 in two different formulations. Formulation 1 contained the compound in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline solution. Formulation 2 contained the compound in 40% propylene glycol and 60% 10 mM pH 6 citrate buffer solution. Tirzepatide (0.2 mg / kg) or Compound 4 (0.2 mg / kg) was administered to assigned dose groups over 21 days. Samples were obtained 1, 4, 8, 12, 24, 48, 72, 96, 120, 168, 192, 240, and 336 hours after administration of a single dose.

[0177] The mean half-life values ​​are shown in Table 1. The data show that administration of compound 4 in formulations 1 and 2 resulted in significantly greater persistence in the bloodstream when compared to administration of tirzepatide in the same formulation. Surprisingly, the half-life of compound 4 was higher in formulation 2 than in formulation 1. Even more surprising, the relative increase in the half-life of compound 4 compared to tirzepatide was greater in formulation 2 than in formulation 1. Formulation 2 resulted in a mean half-life of compound 4 that was twice as long when compared to tirzepatide.

[0178] [Table 1]

[0179] The binding assay of tirzepatide and compound 4 was carried out in the presence or absence of 2% human serum albumin (HSA). The ratio of compound-receptor binding with 2% HSA to compound-receptor binding with 0% HSA is listed in Table 2. Tirzepatide has HSA ratios of 12.8 and 5.82 for GLP-1 receptor and GIP receptor, respectively. Compound 4 has HSA ratios of 6.42 and 1.25 for GLP-1 receptor and GIP receptor, respectively. The larger HSA ratio of tirzepatide compared to compound 4 indicates that the binding affinity of tirzepatide to albumin is greater than that of compound 4.

[0180] [Table 2]

[0181] In previous studies, a direct correlation between albumin binding affinity and in vivo half-life was observed; compounds with longer half-life exhibited higher albumin binding affinity. (Lau, J. et al., J. Med. Chem. 2015, 58, 7370-7380). As described above, the binding affinity of tirzepatide to albumin is higher than that of compound 4. In contrast, the pharmacokinetic experiments described in this example determined the half-lives of tirzepatide and compound 4 to be 66.2 hours and 106 hours, respectively, in formulation 1. The half-lives of tirzepatide and compound 4 to be 59.8 hours and 120 hours, respectively, in formulation 2. The longer half-life of compound 4 in formulation 1 and formulation 2 compared to that of tirzepatide is an unexpected result in view of previous studies. The smaller HSA ratio of compound 4 indicates that compound 4 is expected to have a lower albumin binding affinity and a shorter half-life relative to tirzepatide. The longer half-life for compound 4 in formulation 1 and formulation 2 relative to tirzepatide is the opposite of the expected result.

[0182] Although some embodiments have been illustrated and described, a person of ordinary skill in the art, after reading the foregoing specification, may effect changes, equivalent substitutions, and other types of modifications to the compounds or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof of the present technology as described herein. Each aspect and embodiment described above may include or incorporate therewith variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0183] The present technology should not be limited in terms of the particular embodiments described herein, which are intended as single illustrations of individual embodiments of the technology. Many modifications and variations of the present technology can be made without departing from the spirit and scope thereof, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds, or biological systems, which may of course vary. Moreover, it should be understood that the terminology used herein is for the purpose of describing only particular embodiments, and is not intended to be limiting. Thus, it is intended that the specification be considered as illustrative only, with the breadth, scope, and spirit of the present technology being indicated only by the appended claims, definitions therein, and any equivalents thereof.

[0184] The embodiments illustratively described herein may be suitably practiced without any element(s), limitation(s) not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc. shall be read broadly and without limitation. In addition, the terms and expressions used herein are used as descriptive terms and not as limitations, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. In addition, the phrase "consisting essentially of" is understood to include the elements as specifically recited, as well as additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0185] In addition, where a feature or aspect of the disclosure is described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described in terms of any individual member of the Markush group or subgroup of members thereof. Each of the narrower species and subgeneric groupings that fall within the generic disclosure also form part of the technology. This includes the generic description of the technology with any provisos or negative limitations that remove any subject matter from the genus, regardless of whether the omitted material is specifically recited herein.

[0186] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the texts incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0187] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0188] While the present disclosure has been particularly shown and described with reference to preferred and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.

[0189] All references, issued patents and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0190] Although the present disclosure has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the disclosure. Accordingly, the present disclosure is limited only by the following claims.

Claims

1. 1. A pharmaceutical formulation for administration to a subject in need thereof, comprising: at least 10% by weight of propylene glycol; and A therapeutically effective dose of a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof a pharmaceutical preparation comprising 【Chemistry 1】 [In formula: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y) and 1 to 2 R 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y) and 1 to 2 R 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with Each R 7 is a halogen, C 1～6 Alkyl, HaloC 1～6 Alkyl, HaloC 1～6 Alkoxy, -OR 5 , C 3～10 Cycloalkyl, C 6～10 independently selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1～6 Alkyl and HaloC 1～6 independently selected from the group consisting of alkyl; Each R 4 is hydrogen, C 1～6 Alkyl, HaloC 1～6 Alkyl, C 6～10 Aryl and C 6～10 independently selected from the group consisting of arylalkyl; Each R 5 are independently hydrogen or C 1～6 is alkyl; Each R 6 are independently hydrogen or C 1～6 is alkyl; Z 1 and Z 2 are hydrogen and C 1～6 Alkyl, HaloC 1～6 Alkyl, C 3～10 Cycloalkyl and C 6～10 independently selected from the group consisting of aryl; When Z 1 and Z 2 are both present, Z 1 and Z 2 at least one of which is not hydrogen; "*" indicates a chiral carbon having either the "S" or "R" configuration].

2. The compound has formula Ia: 【Chemistry 2】 2. The pharmaceutical formulation of claim 1, having the structure:

3. Z 1 But hydrogen, C 1～6 Alkyl, HaloC 1～6 Alkyl, C 3～10 Cycloalkyl and C 6～10 aryl; X and Y are each selected from the group consisting of -OR 4 3. The pharmaceutical formulation of claim 2, wherein

4. Z 1 is hydrogen; each R 4 are independently hydrogen, C 6～10 Aryl and C 6～10 4. The pharmaceutical formulation of claim 3, wherein the aryl is selected from the group consisting of arylalkyl.

5. Each R 4 are independently hydrogen or C 6～10 5. The pharmaceutical formulation of claim 4, wherein the aryl is arylalkyl.

6. The compound has the formula Ib: 【Transformation 3】 2. The pharmaceutical formulation of claim 1, having the structure:

7. Z 2 But hydrogen, C 1～6 Alkyl, HaloC 1～6 Alkyl, C 3～10 Cycloalkyl and C 6～10 aryl; X and Y are each selected from the group consisting of -OR 4 7. The pharmaceutical formulation of claim 6, wherein

8. Each R 4 are independently hydrogen, C 6～10 Aryl and C 6～10 8. The pharmaceutical formulation of claim 7, wherein the aryl is selected from the group consisting of arylalkyl.

9. Each R 4 is hydrogen or C 6～10 9. The pharmaceutical formulation of claim 8, wherein the aryl is arylalkyl.

10. The compound has the formula Ic: 【Chemistry 4】 2. The pharmaceutical formulation of claim 1, having the structure:

11. Each X and Y is -OR 4 ; each R 4 But hydrogen, C 6～10 Aryl and C 6～10 11. The pharmaceutical formulation of claim 10, wherein the aryl is independently selected from the group consisting of arylalkyl.

12. The compound is: [Chemical 5A] 【Chem.5B】 【5C】 [5D Transformation] and pharmaceutically acceptable salts thereof.

13. " * 2. The pharmaceutical formulation of claim 1, wherein "" indicates a chiral carbon having an "S" configuration.

14. " * 2. The pharmaceutical formulation of claim 1, wherein " denotes a chiral carbon having the "R" configuration.

15. 10. The pharmaceutical formulation of claim 1, comprising a pharmaceutically acceptable aqueous carrier, wherein the aqueous carrier is water, an aqueous buffer solution, or saline.

16. 2. The pharmaceutical formulation of claim 1, wherein propylene glycol is present in the formulation in a weight percentage of 15% or more, or 15% to 90%, or 30% to 50%.

17. 10. The pharmaceutical formulation of claim 1, comprising a buffer.

18. Buffers include tartrate, citrate, acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 3-[N-tris(hydroxymethyl)methylamino] ]-2-hydroxypropanesulfonic acid (TAPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminomethane (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate, or any combination of the foregoing.

19. 2. The pharmaceutical formulation of claim 1, wherein the buffer is present in the formulation in a weight percentage of 20% or more, or 20% to 95%, or 50% to 70%.

20. The pharmaceutical formulation of claim 1, having a pH of 2 to 12.

21. 10. The pharmaceutical formulation of claim 1, wherein the therapeutically effective dose is from 0.01 mg / kg to 5 mg / kg.

22. 10. The pharmaceutical formulation of claim 1, which has a half-life of 40 to 300 hours when administered.

23. A pharmaceutical formulation according to any one of claims 1 to 22 for preventing, treating or ameliorating one or more fatty liver diseases in a subject.

24. 24. The pharmaceutical formulation of claim 23, wherein the one or more fatty liver diseases are selected from the group consisting of steatosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.

25. A pharmaceutical formulation described in any one of claims 1 to 22 for preventing, treating or ameliorating one or more diseases or disorders in a subject, wherein the one or more diseases or disorders are metabolic disorders or metabolic syndrome.

26. The pharmaceutical formulation of claim 25, wherein the one or more diseases or disorders are atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, obesity, or Prader-Willi syndrome.

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