Linear apelin receptor agonist

Abstract

Disclosed herein is a compound of formula (1): JPEG2023544899000069.jpg29150[where, Q, X, AA 1 , A.A. 2 , A.A. 3 , A.A. 4 , A.A. 5 , A.A. 6 , A.A. 7 , A.A. 8 , A.A. 9 , A.A. 10 , A.A. 11 , A.A. 12 , A.A. 13 , R 1 , R 2 and n is defined herein] and salts thereof, and their use in treating, preventing, ameliorating, controlling or reducing risk of disorders associated with apelin receptors.

Description

[Technical Field]

[0001] This invention relates to a class of novel peptide compounds, their salts, pharmaceutical compositions containing them, and their use in the treatment of the human body. In particular, this invention is directed to a class of compounds that are agonists of the apelin receptor. This invention also relates to the manufacture and use of these compounds and compositions in the prevention or treatment of diseases involving the apelin receptor.

[0002] This compound relates to metabolically stable apelin analogs covering a range of G protein-dependent and independent pharmacological profiles, as well as their use under short-term (acute) and long-term administration protocols for the prevention or treatment of apelin receptor-mediated diseases, particularly cardiovascular diseases (heart failure, renal failure, hypertension, pulmonary hypertension, acute and chronic kidney injury, and thrombotic diseases), diabetes, liver disease, and gastrointestinal diseases. [Background technology]

[0003] Aperin is the endogenous ligand for the aperin receptor (also known as APJ, APLNR, or angiotensin receptor-like 1). The aperin receptor is a class A GPCR located on chromosome 11 and consists of 377 amino acids. To date, only one aperin receptor has been identified in mammals, but two subtypes exist in amphibians and fish. There are no closely related (homologous) genes.

[0004] In humans, the APLN gene is located on the X chromosome and encodes a 77-amino acid precursor, preproporanin. This preproporanin is then proteolytically cleaved to produce several isoforms, namely apelin-36, apelin-17, apelin-13, and [Pyr1]apelin-13. Of these isoforms, [Pyr1]apelin-13 is the major isoform detected in human heart and plasma. However, given the very short plasma half-life of apelin (<5 minutes), it is possible that another short-lived isoform with an alternative structure and / or pharmacological properties exists that contributes to the physiological effects associated with the parent peptide apelin-36. The binding of aperin to the aperin receptor results in the activation of numerous intracellular signaling pathways mediated by Gαi / o, Gα13, and possibly Gαq G proteins, and can recruit several signaling cascades including phospholipase C (PLC), protein kinase C (PKC), AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, regulation of ERK1 / 2 phosphorylation, and PI3K / Akt / p70S6 kinase signaling (but not limited to these).

[0005] A 54-amino acid second peptide, Elabela / Toddler (also known as ELABELA, ELA, Toddler, or Apela), has been identified and also activates the apelin receptor. While the primary amino acid sequence of ELA does not show similarity to APJ, like APJ, ELA undergoes rapid proteolytic cleavage to produce shorter isoforms. Both ligands are important regulators of cardiovascular development and function.

[0006] Activation of the apelin receptor by endogenous ligands has also been shown to result in receptor internalization, desensitization, and initiation of downstream signaling by β-arrestin, a protein. Recruitment of β-arrestin leads to a clear short-term response and apelin receptors that are unresponsive to further ligand-mediated activation. In various embodiments, identified examples, either alone or in combination with β-arrestin recruitment, can bind to and / or activate G protein signaling, thus offering a unique pharmacological profile useful for treating diseases associated with apelin dysfunction.

[0007] Both apelin and APJ are relatively widely expressed in the central nervous system (CNS), peripheral tissues, and blood, suggesting they play a role in numerous complex physiological processes. Based on numerous literature publications, the apelin system is involved in CNS disorders, thermoregulation, glucose homeostasis, angiogenesis, diabetes, pancreatitis, cardiovascular function, liver and kidney function, and cancer (including, but not limited to, glioblastoma and colon cancer).

[0008] APJ receptors and their ligands (apelin and ELA) are involved in the pathophysiology of human heart failure. Apelin receptors are present in endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Early studies have identified apelin as one of the most potent inotropic agents to date, as it directly affects cardiomyocyte contraction without causing cardiac hypertrophy. Apelin has also been shown to increase left ventricular contractility.

[0009] Apelin expression has been shown to alter depending on the cardiovascular disease status. Increased apelin immunoreactivity is observed in the plasma of patients with early heart failure, but decreased in later, more severe stages. Furthermore, apelin receptor mRNA has been shown to be reduced in hypertrophic and failing hearts in rats. Apelin gene-deficient mice have been shown to develop impaired myocardial contractility and progressive heart failure associated with aging and pressure overload. Therefore, downregulation of the apelin system appears to coincide with a decline in cardiac function, increasing the possibility that apelin may be a protective agent for cardiac function.

[0010] Systemic injection of apelin into rodents and humans has been shown to significantly reduce blood pressure (BP) in rats due to nitric oxide production. These data indicate that apelin exerts an antihypertensive effect in vivo. However, these effects on blood pressure and inotropic cardiac output are short-lived, lasting only a few minutes, and lead to some degree of desensitization (also known as tachyphylaxis), making the apelin receptor unresponsive to further stimulation.

[0011] In chronic models of right heart failure, aperin exhibits inotropic effects, and long-term treatment resulted in improved right ventricular mass, reduced cardiac load, increased contractility, and hemodynamic improvements. As these findings suggest, aperin infusion has been shown to improve pulmonary vascular hemodynamics in numerous preclinical models of pulmonary hypertension (PAH), and these benefits have been confirmed to be transferable to PAH patients.

[0012] In zebrafish, ELA signaling is necessary for normal cardiac and vascular development; its deficiency leads to severe defects in cardiac development and lymphogenesis. In humans, ELA is expressed in adult embryonic stem cells and kidneys, and activates the human apelin receptor by suppressing cAMP production and inducing ERK1 / 2 phosphorylation and calcium mobilization. Functionally, Elabela stimulates angiogenesis in human HUVECs and relaxes the aortic vessels in mice.

[0013] In addition to the cardiovascular effects of aperin, aperin receptor mRNA was detected throughout the entire renal region, most abundantly in the inner zone of the outer layer and glomeruli, with moderate expression observed in all nephron segments, particularly in the collecting ducts. Consistent with this localization, intravenous (IV) injection of aperin at gradually increasing doses resulted in a dose-dependent increase in diuresis.

[0014] Apelin expression has also been confirmed in human endothelial tissue, where its primary role is to regulate fatty acid transport across the endothelium through apelin-induced inactivation of the transcription factor forkheadbox protein O1 (FOXO1) and subsequent inhibition of endothelial fatty acid-binding protein 4 (FABP4) expression. These actions are consistent with the predicted benefits for improved glucose utilization and insulin sensitivity in diseases such as type 2 diabetes mellitus (T2DM).

[0015] Apelin receptor agonists may be useful alone or in combination with current standard treatments in the treatment of pulmonary hypertension (PAH) by increasing cardiac output, lowering pulmonary vascular hypertension, reducing inflammation, improving lung tissue remodeling, and preserving right ventricular function. PAH is a rare, progressive disorder characterized by hypertension of the pulmonary arteries (pulmonary arteries) without apparent cause. Symptoms of PAH include shortness of breath (dyspnea), chest pain, and syncope, particularly during exercise. The exact cause of PAH is unknown, and although treatable, there is no known cure for the disease. PAH is twice as common in women as in men. Women between the ages of 30 and 60 are more susceptible. It is estimated that 1 to 2 new cases occur per million people annually in the United States. The incidence is estimated to be similar in Europe. Approximately 500 to 1,000 new cases of PAH are diagnosed annually in the United States. No ethnic or racial group is known to have a higher prevalence of PAH. Because PAH symptoms are often mild, nonspecific, or only appear during strenuous exercise, it can take years to be diagnosed. However, treating PAH is crucial because, without treatment, the high blood pressure in the lungs places a significant burden on the right heart, leading to weakening or failure of this heart muscle over time. The disease is progressive, meaning that while patients may initially experience only mild symptoms, they will eventually require treatment and medical care to maintain a normal life.

[0016] Apelin receptor agonists are useful drugs in the treatment of cardiovascular conditions such as heart failure, acute decompensated heart failure, congestive heart failure, cardiac myopathy, ischemia, ischemia / reperfusion injury, fluid homeostasis, renal failure, hypertension, pulmonary hypertension, polycystic kidney disease, hyponatremia, and SIADH, in order to increase cardiac output, improve cardiac function, stabilize cardiac function, limit further decline in cardiac function, reduce systemic hypertension and portal hypertension, promote angiogenesis and neovascularization in ischemic tissue, treat thrombosis and platelet dysfunction, and improve renal function and diuresis. Heart failure constitutes a major and growing health burden. There are at least 15 million people with heart failure in Europe and approximately 5,800,000 in the United States. The incidence of heart failure is approaching 10 per 1,000 people after the age of 65. In the United States, 280,000 people die annually from heart failure, and the direct and indirect costs of heart failure in 2010 were estimated at $39.2 billion. Treatment options depend on the type, cause, symptoms, and severity of heart failure, and include treatment of underlying conditions and lifestyle changes. Several medications are prescribed for heart failure, and most patients take two or more drugs. Apelin receptor agonists appear to be used in addition to existing medications. Despite advances made in medical therapy, the mortality rate from heart failure remains high. Nearly 50% of patients diagnosed with heart failure die within five years.

[0017] Platelet dysfunction is associated with a range of thrombotic diseases, including peripheral artery disease (PAD), acute coronary syndrome (ACS), myocardial infarction (MI), heart attack (HA), stroke, and atherosclerosis. Apelin and APJNR are expressed in human and mouse platelets, and apelin knockout mice exhibited a prothrombotic phenotype with increased platelet aggregation. Stimulation of platelets with apelin has been shown to involve signaling pathways related to the production of calcium, nitric oxide, and thromboxane, which is consistent with the expected benefits in these conditions.

[0018] Apelin receptor agonists are also useful in the treatment and management of diabetes and associated metabolic conditions, diabetic complications (e.g., diabetic nephropathy, retinopathy, neuropathy, non-alcoholic fatty liver disease, non-alcoholic steatosis, portal hypertension), and conditions where stimulation and / or increase of muscle mass and / or endurance are considered beneficial. Apelin has been shown to be expressed in endothelial cells, improve glucose tolerance, enhance glucose utilization by muscles, increase insulin sensitivity in muscles, and improve angiogenesis in tissues with poor local blood supply. Apelin-neuroprotection, in which administration of apelin peptides promotes neuronal survival and / or neuronal number increase, is useful in neuronal loss conditions such as diabetic neuropathy.

[0019] The half-life of aperin in blood circulation is approximately 1 minute. The present invention aims to design, synthesize, and test novel, potent, and stable drugs that activate the aperin / aperin receptor pathway. Embodiments contained herein illustrate the possibility of specifically activating intracellular signaling pathways in a manner that sustainably activates the receptor, independently of β-arrestin activation and without desensitization and / or tachyphylaxis. Such compounds constitute novel therapeutic potential for treating aperin receptor-mediated diseases as described in the present invention. [Overview of the project]

[0020] This invention relates to novel compounds having agonist activity at the apelin receptor, pharmaceutical compositions containing these compounds, and the use of these compounds for the manufacture of pharmaceuticals for the treatment of diseases.

[0021] Therefore, in one embodiment, the present invention relates to formula (1):

[0022] [ka] [In the formula, Q is selected from phenyl or monocyclic heteroaryl rings, each of which has one or more R qmay be substituted with a base; or Q is a polyether chain of the formula -(OCH2CH2) m OCH3 (where m is 1 to 5); R q is selected from C 1-6 alkyl having an alkyl chain which may contain one or more heteroatoms selected from halogen, hydroxyl, amino, or O, N, or S; n is 1 to 3; R 1 and R 2 are independently selected from hydrogen or a C 1-6 alkyl group, or together with the carbon to which they are attached form a C 3-8 cycloalkyl or heterocyclic group; X is -DArg- or a bond; AA 1 is -NHCR 3a R 3b CO- or -N(Me)CR 3a R 3b CO-; where R 3a is hydrogen or C 1-3 alkyl; R 3b is -CH2(CH2) p CONH2 or -(CH2) p benzyl (where p is 0 or 1); AA 2 is an -Arg-, -DArg- or homoarginine residue; AA 3 is

[0023]

Chemical formula

[0024] [ka] and; AA 9 These are -Gly-, -Ala-, -DAla-, or N-methylglycine residues; AA 10 is a residue:

[0025] [ka] and; AA 11 -NHCHR 6 CO-; here, R 6 C 1-6 These are alkyl, benzyl, -CH2-naphthyl, or -CH2-biphenyl groups, which may be substituted with one or more halo groups; AA 12 teeth,

[0026] [ka] A residue selected from; AA 13 -NHCR7a R 7b CO- or -N(Me)CR 7a R 7b CO-; here, R 7a is hydrogen or C 1-3 It is alkyl, R 7b C 1-10 These are alkyl, -CH2-naphthyl, -CH2-biphenyl, or benzyl, and these are one or more R 8 It may be substituted with the base, where R 8 is selected from halo, -O-aryl, or -O-benzyl; AA 13 The present invention provides compounds of which the C-terminus is a carboxyl group or a carboxamide group, or tautomers or stereochemical isomers thereof, or prodrugs, salts, or zwitterions thereof. [Modes for carrying out the invention]

[0027] This invention relates to novel compounds. This invention also relates to the use of novel compounds as apelin receptor agonists. Furthermore, this invention relates to the use of novel compounds in the manufacture of pharmaceuticals for use as apelin receptor agonists or for the treatment of apelin receptor-related disorders.

[0028] The present invention also relates to compounds, compositions, and pharmaceuticals useful for treating disorders associated with the apelin receptor. Such disorders include cardiovascular diseases, acute decompensated heart failure, congestive heart failure, myocardial infarction, myocardial myopathy, ischemia, ischemia / reperfusion injury, pulmonary hypertension, diabetes mellitus, obesity, cancer, metastatic diseases, fluid homeostasis, pathological angiogenesis, retinopathy, HIV infection, treatment of pulmonary hypertension (PAH) that increases cardiac output, reduces pulmonary vascular hypertension, reduces inflammation, improves lung tissue remodeling, and preserves right ventricular function, heart failure, congestive heart failure, myocardial myopathy, ischemia, ischemia / reperfusion injury, fluid homeostasis, renal failure, hypertension, pulmonary hypertension, and polycystic kidney disease. Hyponatremia, SIADH, and platelet function are associated with a range of thrombotic disorders, including peripheral artery disease (PAD), acute coronary syndrome (ACS), myocardial infarction (MI), heart attack (HA), stroke, and atherosclerosis; and treatment and management of diabetes and associated metabolic conditions, diabetic complications (e.g., diabetic nephropathy, retinopathy, neuropathy, non-alcoholic fatty liver disease, non-alcoholic steatosis, portal hypertension), and conditions in which stimulation and / or increase of muscle mass and / or endurance are considered beneficial.

[0029] Another aspect of the present invention is a treatment for various forms of central nervous system disorders, such as dementia (including senile dementia and vascular dementia), depression, hyperactivity (microbrain injury) syndrome, impaired consciousness, anxiety disorders, schizophrenia, phobias, epilepsy, amyotrophic lateral sclerosis; disorders of growth hormone secretion and / or function, such as but not limited to bulimia, polyphagia, hypercholesterolemia, hyperglyceridemia, dyslipidemia, hyperprolactinemia, hypoglycemia, hypopituitarism, pituitary dwarfism; cancer, pancreatitis, kidney disease, Turner syndrome, rheumatoid arthritis, spinal cord injury, spinocerebellar deformity, fractures, wounds, atopic dermatitis, osteoporosis, asthma, infertility, arteriosclerosis, emphysema, pulmonary edema, and insufficient lactation; and it can also be used as a hypnotic sedative, a postoperative nutritional improvement agent, a preventive or therapeutic agent for HIV infection, AIDS, etc., and includes administering an apelin-acting polypeptide to a patient who needs it.

[0030] The diseases or conditions for which this compound may be beneficial include, but are not limited to, those selected from the group consisting of the treatment of pulmonary hypertension (PAH) in which increasing cardiac output, reducing pulmonary vascular hypertension, reducing inflammation, improving lung tissue remodeling, and preserving right ventricular function; heart failure, congestive heart failure, myocardial myopathy, ischemia, ischemia / reperfusion injury, fluid homeostasis, renal failure, hypertension, pulmonary hypertension, polycystic kidney disease, hyponatremia and SIADH; diabetes mellitus and associated metabolic conditions; diabetic complications (e.g., diabetic nephropathy, retinopathy, neuropathy, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, portal hypertension); and the treatment and management of conditions in which stimulation and / or increase of muscle mass and / or endurance are considered beneficial.

[0031] In a further aspect, the present invention provides the use of the compounds outlined above to manufacture a medicament for treating any of the above indications.

[0032] Therefore, in one embodiment, the present invention relates to formula (1):

[0033] [ka] [In the formula, Q is selected from phenyl or monocyclic heteroaryl rings, each of which has one or more R q It may be substituted with the base; or Q is the formula -(OCH2CH2) m It is a polyether chain of OCH3 (where m is 1 to 5); R q C has an alkyl chain which may contain halogen, hydroxyl, amino, or one or more heteroatoms selected from O, N, or S. 1-6 Selected from alkyl groups; n is between 1 and 3; R 1 and R 2 is hydrogen or C 1-6 Either independently selected from the alkyl group, or together with the carbon to which they are bonded, C 3-8 Forming cycloalkyl or heterocyclyl groups; X is -DArg- or a bond; AA 1 is -NHCR 3a R 3b CO- or -N(Me)CR 3a R 3b CO-; where R 3a is hydrogen or C 1-3 alkyl; R 3b is -CH2(CH2) p CONH2 or -(CH2) p benzyl (where p is 0 or 1); AA 2 is -Arg-, -DArg- or a homoarginine residue; AA 3 is

[0034]

Chemical formula

[0035] [ka] and; AA 9 These are -Gly-, -Ala-, -DAla-, or N-methylglycine residues; AA 10 is a residue:

[0036] [ka] and; AA 11 -NHCHR 6 CO-; here, R 6 C 1-6 These are alkyl, benzyl, -CH2-naphthyl, or -CH2-biphenyl groups, which may be substituted with one or more halo groups; AA 12 teeth,

[0037] [ka] A residue selected from; AA 13 -NHCR 7a R 7b CO- or -N(Me)CR 7a R 7b CO-; here, R 7a is hydrogen or C 1-3 It is alkyl, R 7b C 1-10 These are alkyl, -CH2-naphthyl, -CH2-biphenyl, or benzyl, and these are one or more R 8 It may be substituted with the base, where R 8 is selected from halo, -O-aryl, or -O-benzyl; AA 13The present invention provides compounds of which the C-terminus is a carboxyl group or a carboxamide group, or tautomers or stereochemical isomers thereof, or prodrugs, salts, or zwitterions thereof.

[0038] Q is,

[0039] [ka] You can choose from these.

[0040] Q can be an imidazole ring. Q is,

[0041] [ka] It is possible.

[0042] n can be 1. n can be 2. n can be 3.

[0043] R 1 and R 2 is hydrogen or C 1-6 It can be selected independently of alkyl groups. 1 is hydrogen or C 1-6 It can be an alkyl group. 2 is hydrogen or C 1-6 It can be an alkyl group. 1 and R 2 Both can be methyl. 1 It can be methyl. 2 It can be methyl.

[0044] X can be -DArg-. X can be a combination.

[0045] AA 1 This includes glutamine residues, D-glutamine residues, homophenylalanine residues, or formulas:

[0046] [ka] It could be an N-methylglutamine residue.

[0047] AA 1 This could be a glutamine residue.

[0048] AA 2 It can be -Arg-. AA 2 It can be -DArg-. AA 2 This could be a homoarginine residue.

[0049] AA 3 teeth,

[0050] [ka] It is possible.

[0051] AA 3 teeth,

[0052] [ka] It is possible.

[0053] AA 4 It can be -Arg-. AA 4 It can be -DArg-.

[0054] AA 5 This can be a leucine residue, a D-leucine residue, a tert-butylalanine residue, a cyclobutylalanine residue, or an N-methylleucine residue. AA 5 This could be a leucine residue.

[0055] AA 6 It can be -Aib-. AA 6 It can be -DAla-. AA 6 It can be -Ser-.

[0056] AA 7 This can be a 2-aminoisobutyric acid residue, a histidine residue, a 4-bromophenylalanine residue, or

[0057] [ka] These are residues selected from among them.

[0058] AA 7 This could be a histidine residue.

[0059] AA 9 It can be -Gly-. AA 9 It can be -Ala-. AA 9 It can be -DAla-. AA 9 This could be an N-methylglycine residue.

[0060] AA 11 This can be a phenylalanine residue, a 2-naphthylalanine residue, a 3-chlorophenylalanine residue, a 4-bromophenylalanine residue, a 4-chlorophenylalanine residue, a norleucine residue, or a 4-phenylphenylalanine residue. AA 11 This could be a 4-bromophenylalanine residue.

[0061] AA 12 teeth,

[0062] [ka] It is possible.

[0063] AA 12 teeth,

[0064] [ka] It is possible.

[0065] AA 13This can be an O-benzyl-D-tyrosine residue, a 4-bromo-D-phenylalanine residue, a 4-phenoxy-D-phenylalanine residue, a 2-naphthyl-D-alanine residue, a 4-phenyl-D-phenylalanine residue, an N-methyl 4-phenyl-D-phenylalanine residue, or a beta-cyclohexyl-D-alanine residue. AA 13 This can be a 4-phenyl-D-phenylalanine residue.

[0066] AA 13 The C-terminus may be a carboxamide group. AA 13 The C-terminus can be a carboxyl group.

[0067] portion

[0068] [ka] Special examples include caps 1-7 shown below, where the COOH group is AA when peptide X or X is bound. 1 It is bonded to the amine.

[0069] [ka] The compound may be selected from any one of Examples 1 to 62 shown in Table 1.

[0070] Specific examples of compounds include those possessing apelin receptor agonist activity.

[0071] The compounds of the present invention can be used in pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0072] The compounds of the present invention can be used in pharmaceuticals.

[0073] The compounds of the present invention can be used to treat the above-mentioned disorders related to the apelin receptor. The embodiments of the present invention also include the following: Embodiment 1 Compounds containing the sequence of formula (1):

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[0074] definition In this application, unless otherwise indicated, the following definitions apply.

[0075] The terms “alkyl,” “aryl,” “halogen,” “cycloalkyl,” “heterocyclyl,” and “heteroaryl” are used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated.

[0076] In connection with the use of any of the compounds described herein, including the compound of formula (1), the term “treatment” is used to describe any form of intervention involving the administration of the compound to a subject who has, is at risk of, or is potentially at risk of having, the disease or disorder in question. Accordingly, the term “treatment” covers both preventative (prophylactic) treatment and treatment when measurable or detectable symptoms of the disease or disorder are present.

[0077] As used herein, the term “effective therapeutic dose” (for example, in relation to a treatment for a disorder, disease, or condition) refers to the amount of compound effective in producing a desired therapeutic effect. For example, if the condition is pain, the effective therapeutic dose is the amount sufficient to provide the desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or reduction in the severity of pain.

[0078] To the extent that any compound described herein has a chiral center, the present invention extends to all optical isomers of such compounds, whether in the form of racemic compounds or divided enantiomers. The inventions described herein relate to all crystalline forms, solvates, and hydrates of any of the disclosed compounds (regardless of how they are prepared). To the extent that any compound disclosed herein has an acid or base center such as a carboxylic acid or amino group, all salt forms of such compounds are included in the present invention. For pharmaceutical applications, the salts should be considered pharmaceutically acceptable salts.

[0079] Salts that may be mentioned or pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means. For example, by reacting the free acid or free base form of a compound with one equivalent or more of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., under vacuum, by freeze-drying, or by filtration). Salts can also be produced by exchanging the counterion of the compound in salt form with another counterion, for example, using a suitable ion exchange resin.

[0080] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral and organic acids, and salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0081] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acid (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, and camphor- Sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D- Glucuronic acid, glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphate, methanesulfonic acid, 1- It includes acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0082] Any solvates of the compounds and their salts are also included. Suitable solvates are solvates formed by incorporating molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent) into the solid structure (e.g., crystal structure) of the compounds of the present invention. Examples of such solvents are water, alcohols (e.g., ethanol, isopropanol and butanol) and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the present invention from a solvent or a mixture of solvents containing the solvating solvent. Whether a solvate is formed in any given case can be determined by subjecting the crystals of the compound to analysis using well-known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystal structure analysis.

[0083] Solvates can be stoichiometric or non-stoichiometric solvates. A particular solvate can be a hydrate, examples of hydrates including hemihydrate, monohydrate and dihydrate. For a more detailed description of solvates and the methods used for their preparation and characterization, see Bryn et al., Solid-State Chemistry of Drugs, 2nd Edition, published by SSCI, Inc, West Lafayette, Indiana, USA, 1999, ISBN 0-967-06710-3.

[0084] In the context of the present invention, the term "pharmaceutical composition" means a composition containing an active drug and additionally one or more pharmaceutically acceptable carriers. Depending on the mode of administration and the nature of the dosage form, the composition may further contain components selected, for example, from diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersing agents. The composition can take the form of, for example, tablets, coated tablets, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, troches, emulsions, solutions, cachets, granules, capsules and suppositories, and liquid injection preparations including liposome preparations.

[0085] The compounds of the present invention may contain one or more isotope substitutions, and reference to a particular element includes all isotopes of that element within its scope. For example, reference to hydrogen includes 1 H, 2 H (D), and 3 H (T) within its scope. Similarly, reference to carbon and oxygen includes 12 C, 13 C and 14 C as well as 16 O and 18 O within their scope. Similarly, reference to a particular functional group also includes isotope variations within its scope, unless otherwise indicated in the context. For example, reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations where one or more hydrogen atoms within the group are in the form of deuterium or tritium isotopes, such as an ethyl group (perdeuteroethyl group) where all 5 hydrogen atoms are in the deuterium isotope form or a methoxy group (trideutero-methoxy group) where all 3 hydrogen atoms are in the deuterium isotope form. Isotopes may be radioactive or non-radioactive.

[0086] The therapeutic dosage may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound being used. Determination of the appropriate dosage for a particular situation is within the scope of the skill in the art. Generally, treatment is initiated at a dosage less than the optimal dosage of the compound. Thereafter, the dosage is increased gradually until the optimal effect under the circumstances is reached. For convenience, the total daily dosage may, if desired, be divided and administered in divided amounts during the day.

[0087] The effective dose of a compound naturally varies depending on the severity of the condition being treated, as well as the specific compound and its route of administration. Selecting an appropriate dose is within the capabilities of those skilled in the art without undue burden. Generally, the daily dose range can be about 10 μg to 30 mg per kg of body weight of humans and non-human animals, preferably about 50 μg to 30 mg per kg of body weight of humans and non-human animals, for example, about 50 μg to 10 mg per kg of body weight of humans and non-human animals, for example, about 100 μg to 30 mg per kg of body weight of humans and non-human animals, for example, about 100 μg to 10 mg per kg of body weight of humans and non-human animals, and most preferably about 100 μg to 1 mg per kg of body weight of humans and non-human animals.

[0088] Pharmaceutical preparations While the active compound can be administered alone, it is preferable to provide it as a pharmaceutical composition (e.g., a formulation).

[0089] Therefore, in another embodiment of the present invention, a pharmaceutical composition is provided comprising at least one compound of formula (1) as defined above, along with at least one pharmaceutically acceptable excipient.

[0090] This composition may be suitable for injection. The injection may be intravenous (IV) or subcutaneous. This composition may be supplied in a sterile buffer or as a solid that can be suspended or dissolved in a sterile buffer for injection.

[0091] pharmaceutically acceptable excipients(s) may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; liquid diluents such as solvents and co-solvents), granulators, binders, flow aids, coatings, release control agents (e.g., release-delaying polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antimicrobial agents, antioxidants, buffers, tension modifiers, thickeners, flavoring agents, sweeteners, colorants, plasticizers, taste masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions.

[0092] As used herein, “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is appropriate for use in contact with the tissue of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic reaction, or other problems or complications, and that is commensurate with a reasonable benefit-to-risk ratio. Each excipient must also be “acceptable” in the sense that it is compatible with the other components of the formulation.

[0093] Pharmaceutical compositions containing the compound of formula (1) can be formulated according to known techniques. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company (Easton, Pennsylvania, USA).

[0094] A suitable formulation typically contains 0–20% (w / w) buffer, 0–50% (w / w) co-solvent, and / or 0–99% (w / w) water for injection (WFI) (depending on the dose and if lyophilized). Intramuscular depot formulations may also contain 0–99% (w / w) oil.

[0095] The compound of formula (1) is generally provided in a single dosage form and thus typically contains an amount of the compound sufficient to provide the desired level of biological activity. For example, the formulation may contain from 1 nanogram to 2 grams of the active ingredient, such as from 1 nanogram to 2 milligrams of the active ingredient. Within these ranges, certain sub-ranges of the compound are from 0.1 milligram to 2 grams of the active ingredient (more usually from 10 milligrams to 1 gram, such as from 50 milligrams to 500 milligrams), or from 1 microgram to 20 milligrams (such as from 1 microgram to 10 milligrams, such as from 0.1 milligram to 2 milligrams of the active ingredient).

[0096] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount (effective amount) sufficient to achieve the desired therapeutic effect. The exact amount of the compound to be administered can be determined by the supervising physician according to standard procedures.

Example

[0097] Next, the present invention will be described non - limitatively by reference to the specific embodiments described in the following examples.

[0098] Examples 1-62

Table A - 1

[0099]

Table A - 2

[0100]

Table A - 3

[0101]

Table A - 4

[0102]

Table A - 5

[0103] Table A-6

[0104] Table A-7

[0105] Table A-8

[0106] Table A-9

[0107] Table A-10

[0108] Table A-11

[0109] Table A-12

[0110] Table A-13

[0111] Table A-14

[0112] Table A-15

[0113] [Table A-16]

[0114] The compounds of Examples 1 to 62, shown in Table 1 below, were prepared. Their LCMS properties and the methods used for their preparation are shown in Table 2. Unless otherwise specified, the starting materials for each example are commercially available products.

[0115] [Table 1-1]

[0116] [Table 1-2]

[0117] [Table 1-3] Where appropriate, Table 1 uses standard amino acid symbols. If standard symbols are unavailable, the following notations are used. [Table B]

[0118] Where appropriate, Table 1 uses standard amino acid symbols. If standard symbols are unavailable, the following notations are used. [Table C-1]

[0119] [Table C-2]

[0120] General procedure If the preparation route is not included, the intermediate is a commercially available product. Commercial reagents were used without further purification. Room temperature (rt) refers to approximately 20-27°C. 1 ¹H NMR spectra were recorded at 400 MHz using a Bruker instrument. Chemical shift values ​​are expressed in parts per million (ppm), i.e., (δ) values. The following abbreviations are used for the multiplicity of the NMR signal: s = single line, br = broad line, d = double line, t = triple line, q = quadruple line, quint = quintle line, td = triple line of double lines, tt = triple line of triple lines, qd = quadruple line of double lines, ddd = double line of double lines, ddt = double line of triple lines, m = multiplicity. Coupling constants are stated as J values ​​measured in Hz. NMR and mass spectrometry results were corrected for background peaks. Chromatography refers to column chromatography performed using silica gel with a mesh size of 60 to 120 mesh under nitrogen pressure (flash chromatography) conditions.

[0121] Analysis method LC-MS analysis of the compounds was performed under electrospray conditions.

[0122] LCMS method A Instrument: Waters Acquity UPLC, Waters 3100 PDA detector, SQD; Column: Acquity HSS-T3, 1.8 micron, 2.1 × 100 mm; Gradient [time (min) / solvent B in solvent A (%)]: 0.00 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10; Solvent: Solvent A = 0.1% trifluoroacetic acid aqueous solution; Solvent B = acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm; Column temperature 30°C; Flow rate 0.3 mL / min.

[0123] Analysis method B MS ions were determined using the LCMS method described below under electrospray conditions, and the retention time (R) of HPLC was determined. TThe purity is determined using the HPLC method described below, and unless otherwise specified, the purity is >95% by HPLC.

[0124] LCMS: Agilent 1200 HPLC & 6410B triple quadrupole, column: Xbridge C18 3.5μm 2.1*30mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 0.9 / 80, 1.5 / 90, 8.5 / 5, 1.51 / 10. (Solvent A = 1 mL TFA in 1000 mL of water; Solvent B = 1 mL TFA in 1000 mL of MeCN); injection volume 5 μL (variable); UV detection 220 nm, 254 nm, 210 nm; column temperature 25°C; 1.0 mL / min.

[0125] HPLC: Agilent Technologies 1200, Column: Sepax GP-C18 5μm 120A 4.6*150mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 40, 20 / 55, 20.1 / 90, 23 / 90. (Solvent A = 1 mL of TFA in 1000 mL of water; Solvent B = 1 mL of TFA in 1000 mL of 80% MeCN + 20% H2O); Injection volume 30 μL (variable); UV detection 220 nm; Column temperature 25°C; 1.0 mL / min.

[0126] Analysis method C MS ions were determined using the LCMS method described below under electrospray conditions, and the retention time (R) of HPLC was determined. T The purity is determined using the HPLC method described below, and unless otherwise specified, the purity is >95% by HPLC.

[0127] LCMS: Agilent 1200 HPLC & 6410B triple quadrupole, column: Xbridge C18 3.5um 2.1*30mm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 0.9 / 80, 1.5 / 90, 8.5 / 5, 1.51 / 10. (Solvent A = 1 mL TFA in 1000 mL of water; Solvent B = 1 mL TFA in 1000 mL of MeCN); injection volume 5 μL (variable); UV detection 220 nm, 254 nm, 210 nm; column temperature 25°C; 1.0 mL / min.

[0128] HPLC: Agilent Technologies 1200, Column: Gemini-NX C18 5um 110A 150*4.6mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 30, 20 / 60, 20.1 / 90, 23 / 90. (Solvent A = 1 mL of TFA in 1000 mL of water; Solvent B = 1 mL of TFA in 1000 mL of MeCN); Injection volume 5 μL (variable); UV detection 220 nm 254 nm; Column temperature 25°C; 1.0 mL / min.

[0129] Analysis method D Instrument: Thermo Scientific Orbitrap Fusion; Column: Phenomenex Kinetex Biphenyl 100 Å, 2.6 μm, 2.1 x 50 mm; Gradient [Time (min) / Solvent B in Solvent A (%)]: 0.00 / 10, 0.30 / 10, 0.40 / 60, 1.10 / 90, 1.70 / 90, 1.75 / 10, 1.99 / 10, 2.00 / 10; Solvent: Solvent A = 0.1% formic acid in water; Solvent B = 0.1% formic acid in acetonitrile; Injection volume: 5 μL; Column temperature: 25°C; Flow rate: 0.8 mL / min.

[0130] Synthesis of intermediates and compounds The following embodiments are provided to illustrate preferred aspects of the present invention and are not intended to limit the scope of the invention.

[0131] Synthesis of intermediates With the exception of intermediates 1-7, all Fmoc-amino acids are commercially available. The synthesis of intermediates 1-7 is outlined below.

[0132] Synthesis of 3-((4-fluorobenzyl)amino)-2,2-dimethyl-3-oxopropanoic acid (intermediate 1)

[0133] [ka] Step 1: Synthesis of 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (2) :2,2-dimethyl-1,3-dioxane-4,6-dione( 1To a solution of 20.0 g, 138.8 mmol) of 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione (2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione) in 200 mL of ACN, K2CO3 (96 g, 694.0 mmol) and MeI (26 mL, 416.6 mmol) were added at room temperature, and the reaction mixture was refluxed for 10 hours. After completion, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with siRNA (3 x 50 mL). The organic layer was washed with 10% aqueous Na2S2O3 (100 mL), dried to (Na2SO4), and concentrated under vacuum to obtain 2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione ( 2 21g, 88% was obtained as a yellow solid. The crude residue was used in the next step without further purification. 1 H-NMR (400 MHz; CDCl3): δ1.63 (s, 6H), 1.73 (s, 6H).

[0134] Step 2: Synthesis of 3-((4-fluorobenzyl)amino)-2,2-dimethyl-3-oxopropanoic acid (intermediate 1) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione( 2 A stirred solution of (9.9 g, 57.0 mmol) in toluene (60 mL) was heated at 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (34.6 mL, 240 mmol) and (4-fluorophenyl)methaneamine ( 1 A solution of 6g, 48.0 mmol) in toluene (60 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at the same temperature for 16 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was pulverized with diethyl ether (70 mL) and the ether was decanted. The obtained material was dried under vacuum and 3-((4-fluorobenzyl)amino)-2,2-dimethyl-3-oxopropanoic acid ( Intermediate 1 1.58 g, 14%) was obtained as a yellow solid. LCMS (Method A): m / z 240.13 [M+H] + (ES + ), 4.77 minutes, 98.85%. 1H-NMR (400 MHz; DMSO-d6): δ 1.31 (s, 6H), 4.25 (d, J = 5.8 Hz, 2H), 7.07 - 7.15 (m, 2H), 7.20 - 7.30 (m, 2H), 8.23 ​​(br s, 1H), 12.49 (br s, 1H).

[0135] Synthesis of 2,2-dimethyl-3-oxo-3-(phenethylamino)propanoic acid (intermediate 2)

[0136] [ka] Step 1: Synthesis of 2,2-dimethyl-3-oxo-3-(phenethylamino)propanoic acid (intermediate 2) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione( 1 A stirred solution of (5.1 g, 29.7 mmol) in toluene (30 mL) was heated at 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (16.4 mL, 123.7 mmol) and 2-phenylethane-1-amine ( 2 A solution of 3.1 g, 24.7 mmol) in toluene (50 mL) was added dropwise over 10 minutes. The resulting mixture was further stirred at the same temperature for 3 hours. After the starting material was consumed, the reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was pulverized with diethyl ether (80 mL) and the ether was decanted. The resulting material was dried under vacuum to obtain 2,2-dimethyl-3-oxo-3-(phenethylamino)propanoic acid ( Intermediate 2 3.2 g, 55%) was obtained as a white solid. LCMS (Method A): m / z 236.18 [M+H] + (ES + ), at 5:01 minutes past the hour, 99.61%. 1 H-NMR (400 MHz; DMSO- d6): δ 1.24 (s, 6H), 2.70 (t, J = 7.6 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 7.17 - 7.20 (m, 3H), 7.26 - 7.29 (m, 2H), 7.72 (br s, 1H), 12.48 (br s, 1H).

[0137] Synthesis of 2,2-dimethyl-3-oxo-3-((2-(pyridine-2-yl)ethyl)amino)propanoic acid (intermediate 3)

[0138] [ka] Step 1: Synthesis of 2,2-dimethyl-3-oxo-3-((2-(pyridine-2-yl)ethyl)amino)propanoic acid (intermediate 3) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione( 1 A stirred solution of (3.3 g, 19.6 mmol) in toluene (30 mL) was heated at 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (11.4 mL, 81.9 mmol) and 2-(pyridine-2-yl)ethane-1-amine ( 2 A solution of 2g, 16.4 mmol) in toluene (50 mL) was added dropwise over 10 minutes. The reaction mixture was then stirred at the same temperature for 3 hours. After the starting material was consumed, the reaction mixture was concentrated under vacuum to obtain the crude material, which was pulverized with diethyl ether (50 mL) and the ether was decanted. The obtained material was dried under vacuum to obtain 2,2-dimethyl-3-oxo-3-((2-(pyridine-2-yl)ethyl)amino)propanoic acid ( Intermediate 3 A 1.9g, 50% solution was obtained as a white solid. LCMS (Method A): m / z 237.23 [M+H] + (ES + ), at 4:07 minutes past the hour, 97.85%. 1 H-NMR (400 MHz; DMSO-d6): δ 1.22 (s, 6H), 2.80 - 2.90 (m, 2H), 3.33 - 3.43 (m, 2H), 7.18 - 7.22 (m, 2H), 7.61 - 7.71 (m, 1H), 7.79 (br s, 1H), 8.45 (d, J = 4.4 Hz, 1H), 12.00 (br s, 1H).

[0139] Synthesis of 2,2-dimethyl-3-oxo-3-((3-(1-trityl-1H-imidazole-4-yl)propyl)amino)propanoic acid (intermediate 4)

[0140] [ka] Step 1: Synthesis of 1-trityl-1H-imidazole-4-carbaldehyde (2):1H-imidazole-4-carbaldehyde ( 1 To a solution of 10.0 g (104 mmol) in DCM (100 mL), Et3N (28.9 mL, 110 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes, and trityl chloride (34.7 g, 124.0 mmol) was added at the same temperature. The resulting mixture was stirred for a further 16 hours. After completion, water was added, and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the crude material. The obtained material was pulverized with hexane (200 mL) and the hexane was decanted off. The obtained material was dried under vacuum to obtain 1-trityl-1H-imidazole-4-carbaldehyde ( 2 11.2 g, 32%) was obtained as an off-white solid. 1 H NMR (400 MHz; DMSO-d6): δ 7.06 - 7.18 (m, 6H), 7.37 - 7.50 (m, 9H), 7.65 (s, 1H), 7.79 (s, 1H), 9.72 (s, 10H).

[0141] Step 2: Synthesis of (1-trityl-1H-imidazole-4-yl)methaneamine (3) :1-Trityl-1H-imidazole-4-carbaldehyde ( 2 (1-Trityl-1H-imidazole-4-yl)methaneamine (1-trityl-1H-imidazole-4-yl) was dissolved in EtOH (100 mL) and transferred to a parr apparatus. Then Raney Ni (1.5 g) was added, followed by ethanolic ammonia (100 mL). The resulting mixture was stirred under an H2 atmosphere (72 Psi) at 45°C for 10 hours. After the starting material was consumed, the reaction mixture was filtered through a Celite pad, washed with MeOH, and concentrated under vacuum to obtain (1-trityl-1H-imidazole-4-yl)methaneamine ( 3 4.1 g, 99% was obtained. This was used in the next step of the reaction without purification. MS (ESI +ve): 341.24 1H NMR (400 MHz; DMSO-d6): δ 3.40 - 3.50 (m, 2H), 4.08 (br s, 2H), 6.71 (s, 1H), 7.00 - 7.11 (m, 6H), 7.24 (s, 1H), 7.30 - 745 (m, 9H).

[0142] Step 3: Synthesis of 2,2-dimethyl-3-oxo-3-(((1-trityl-1H-imidazole-4-yl)methyl)amino)propanoic acid (intermediate 4) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione( 4 A stirring solution of (3.1 g, 18.1 mmol) in toluene (30 mL) was heated to 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (8.4 mL, 60.4 mmol) and (1-trityl-1H-imidazole-4-yl)methaneamine ( 3 A solution of 4.1 g, 12.1 mmol) in toluene (50 mL) was added dropwise over 10 minutes. The reaction mixture was continued at the same temperature for 3 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was dissolved in chloroform (80 mL) and washed with a 10% aqueous citric acid solution (pH approximately 6-6.5). The organic layer was dried over Na2SO4 and concentrated under vacuum. The resulting residue was pulverized with diethyl ether / n-hexane (35 mL) and the suspension was stirred at room temperature for 16 hours. The solid was filtered, washed with methanol (30 mL), and dried under vacuum to obtain 2,2-dimethyl-3-oxo-3-((3-(1-trityl-1H-imidazole-4-yl)propyl)amino)propanoic acid ( Intermediate 4 1.7 g, 43%) was obtained as a white solid. LCMS (Method A): m / z 454.26 [M+H] + (ES + ), 4.73 minutes, 99.42%. 1 H-NMR (400 MHz; DMSO- d6): δ 1.20 (s, 6H), 4.11 (d, J = 4.8 Hz, 2H), 6.68 (s, 1H), 6.98 - 7.10 (m, 6H), 7.25 (s, 1H), 7.30 - 7.50 (m, 2H), 8.00 (br s, 1H), 12.33 (br s, 1H).

[0143] Synthesis of 2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl)amino)propanoic acid (intermediate 5)

[0144] [ka] Step 1: Synthesis of 2,2,2-trifluoro-N-(2-(1-trityl-1H-imidazole-4-yl)ethyl)acetamide (2) :2-(1H-imidazole-4-yl)ethane-1-amine dihydrochloride ( 1 To a solution of 25.0 g (136.6 mmol) of ethyl trifluoroethyl acetate in 100 mL of MeOH, 67 mL (464.4 mmol) was added at room temperature, and the reaction mixture was cooled to 0°C. A solution of 20 mL (164.0 mmol) of ethyl trifluoroethyl acetate in 50 mL of MeOH was added to the reaction mixture over 30 minutes at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. This reaction mixture was diluted with 200 mL of dry DCM and 60 mL (409.8 mmol), and the reaction mixture was cooled to 0°C. 76 g (273.2 mmol) of Tr-Cl was added little by little, and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with water (300 mL), and the aqueous layer was extracted with chloroform (3 x 150 mL). The organic layers were combined, dried, and concentrated under vacuum using (Na2SO4). The crude residue is ground with n-hexane and 2,2,2-trifluoro-N-(2-(1-trityl-1H-imidazole-4-yl)ethyl)acetamide ( 2 50.10 g, 81%) was obtained as a white solid. MS (ESI +ve): 450 1 H-NMR (400 MHz; CDCl3): δ 2.75 (t, J = 5.9 Hz, 2H), 3.60 - 3.65 (m, 2H), 6.61 (s, 1H), 7.08 - 7.15 (m, 6H), 7.31 - 7.38 (m, 9H), 7.40 (s, 1H), 8.41 (br s, 1H).

[0145] Step 2: Synthesis of 2-(1-trityl-1H-imidazole-4-yl)ethane-1-amine (3) :2,2,2-trifluoro-N-(2-(1-trityl-1H-imidazole-4-yl)ethyl)acetamide( 2To a solution of 50.0 g, 111.3 mmol of 2-(1-trityl-1H-imidazole-4-yl)ethane-1-amine in 150 mL of THF and 180 mL of MeOH, 22.0 g, 556.7 mmol of NaOH in 100 mL of water was gradually added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was quenched with 300 mL of water, and the aqueous layer was extracted with chloroform (3 x 150 mL). The organic layers were combined, dried, and concentrated under vacuum to obtain 2-(1-trityl-1H-imidazole-4-yl)ethane-1-amine ( 3 34.0 g, 86% was obtained as a yellowish, sticky solid. The crude residue was used in the next step without further purification. MS (ESI +ve): 354 1 H-NMR (400 MHz; CDCl3):δ 1.53 (bs, 2H), 2.65 (t, J = 6.5 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 6.58 (s, 1H), 7.11 - 7.16 (m, 6H), 7.28 - 7.38 (m, 10H).

[0146] Step 4: Synthesis of 2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl)amino)propanoic acid (intermediate 5) :2-(1-trityl-1H-imidazole-4-yl)ethane-1-amine( 3 A solution of 2,2,5,5-tetramethyl-1,3-dioxan-4,6-dione (8.0 g, 22.6 mmol) and Et3N (16.0 mL, 113.0 mmol) in toluene (100 mL) is prepared. 55.8 g (29.76 mmol) of 2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl)amino)propanoic acid(2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl))propyl)) was added dropwise to a solution in 50 mL of toluene at 75°C for 60 minutes. The reaction mixture was stirred at the same temperature for 3 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was dissolved in 100 mL of chloroform and washed with 75 mL of n-hexane, and the suspension was stirred at room temperature for 16 hours. The solid was filtered, washed with chloroform:n-hexane (1:1, 2 x 50 mL), and dried under vacuum to obtain 2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl)amino)propanoic acid()propanoic acid(2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl))propanoic acid(2,2-dimethyl-3-oxo-3-((2-(1-trityl-1H-imidazole-4-yl)ethyl))propanoic acid(2,2-dimethyl-3-oxo-3-((2-(1-trityl- Intermediate 5 6.8 g, 64%) was obtained as a white solid. LCMS (Method A): m / z 468 [M+H] + (ES + ), 5:38 minutes, 99.31% 1 H-NMR (400 MHz; DMSO-d6):δ 1.21 (s, 6H), 2.57 (t, J = 6.8 Hz, 2H), 3.22 - 3.27 (m, 2H), 6.66 (s, 1H), 7.06 - 7.11 (m, 6H), 7.28 (s, 1H), 7.35 - 7.42 (m, 8H), 7.64 (t, J = 5.4 Hz, 1H), 8.31 (s, 1H), 12.44 (br s, 1H).

[0147] Synthesis of 2,2-dimethyl-3-oxo-3-((3-(1-trityl-1H-imidazole-4-yl)propyl)amino)propanoic acid (intermediate 6)

[0148] [ka] Step 1: Synthesis of methyl 3-(1H-imidazole-4-yl)propanoate HCl(2) :3-(1H-imidazole-4-yl)propanoic acid ( 2A mixture of 5g, 38.7 mmol of methyl 3-(1H-imidazole-4-yl)propanoate was added to 80mL of MeOH at 0°C. After allowing the reaction mixture to stand at room temperature, the reaction was heated under reflux for a further 5 hours. After completion, the reaction mixture was concentrated under vacuum, and the reaction mixture was pulverized with diethyl ether (200mL) to obtain methyl 3-(1H-imidazole-4-yl)propanoate.HCl( 2 7g, 97%) was obtained as a white solid. MS (ESI +ve): 155.14.

[0149] Step 2: Synthesis of methyl 3-(1-trityl-1H-imidazole-4-yl)propanoate (3) :Methyl 3-(1H-imidazole-4-yl)propanoate HCl salt ( 2 To a solution of (7g, 44.02 mmol) in DCM (80 mL), Et3N (19 mL, 132 mmol) was added. After stirring at 0°C for 10 minutes, trityl chloride (18.3 g, 66 mmol) was added at the same temperature, and the reaction was stirred for a further 2 hours. After completion, water was added, and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried on Na2SO4, and concentrated under vacuum. The crude material was pulverized with hexane (200 mL), and the hexane was decanted off. The obtained material was dried under vacuum, and methyl 3-(1-trityl-1H-imidazole-4-yl)propanoate ( 3 15g, 88%) was obtained as a white solid. MS (ESI +ve): 397 1 H NMR (400 MHz; DMSO-d6): δ 2.51 - 2.73 (m, 4H), 3.52 (s, 3H), 6.60 (s, 1H), 7.00 - 7.11 (m, 6H), 7.17 - 745 (m, 10H).

[0150] Step 3: Synthesis of 3-(1-trityl-1H-imidazole-4-yl)propan-1-ol (4) :Methyl 3-(1-trityl-1H-imidazole-4-yl)propanoate ( 3To a solution of 15g, 37.8 mmol of LAH (2.5M in THF, 60mL, 151.2 mmol) in 300mL of THF, LAH was gradually added at 0°C. After stirring at 0°C for 10 minutes, the reaction was allowed to warm to room temperature for 2 hours. After completion, the reaction was quenched with saturated NH4Cl solution (60mL), the solid suspension was filtered through a Celite pad, and washed with ethyl acetate (200mL). The filtrate was concentrated under vacuum to obtain 3-(1-trityl-1H-imidazole-4-yl)propan-1-ol ( 4 10.2 g, 73%) was obtained as a white solid. This was used in the next reaction step without purification. MS (ESI -ve): 367 1 H NMR (400 MHz; DMSO-d6): δ 1.60 - 1.70 (m, 2H), 2.40 - 2.53 (m, 2H), 3.30 - 3.42 (m, 2H), 4.40 (bs, 1H), 6.57 (s, 1H), 7.00 - 7.11 (m, 6H), 7.24 (s, 1H), 7.30 - 745 (m, 9H).

[0151] Step 4: Synthesis of 3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (5) :3-(1-trityl-1H-imidazole-4-yl)propan-1-ol( 4 To a solution of 10g (27.1 mmol) of 3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate (3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate ( 5 A crude product (14 g) was obtained as a viscous liquid. This was used in the next step of the reaction without purification.

[0152] Step 5: Synthesis of 2-(3-(1-trityl-1H-imidazole-4-yl)propyl)isoindoline-1,3-dione (7) :3-(1-trityl-1H-imidazole-4-yl)propylmethanesulfonate ( 5A solution of 14g, 28 mmol) in DMF (50 mL) is mixed with NaI (1.2 g, 8.4 mmol) and potassium phthalimide ( 6 7.3g, 39.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. After the starting material was consumed, water was added and the solid was filtered. The filtrate was dried under vacuum to obtain 2-(3-(1-trityl-1H-imidazole-4-yl)propyl)isoindoline-1,3-dione ( 7 7.5 g, 51%) was obtained as a white solid. This was used in the next reaction step without purification. MS (ESI+-ve): 498.31 1 H NMR (400 MHz; DMSO-d6):δ 1.80 - 1.90 (m, 2H), 2.80 - 3.00 (m, 4H), 6.40 (s, 1H), 7.00 - 7.11 (m, 3H), 7.12 -7.47 (m, 16H), 7.82 (s, 1H).

[0153] Step 6: Synthesis of 3-(1-trityl-1H-imidazole-4-yl)propan-1-amine (8) :2-(3-(1-trityl-1H-imidazole-4-yl)propyl)isoindoline-1,3-dione( 7 To a solution of 7.5g, 15.1 mmol) of 3-(1-trityl-1H-imidazole-4-yl)propan-1-amine in EtOH:THF (2:1, 75mL), 9.4mL of hydrazine monohydrate was added dropwise, and the reaction was heated at 75°C for 4 hours. After completion, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography [normal phase, silica gel (100-200 mesh), gradient, 2% MeOH (saturated NH4OH) in DCM], and 3-(1-trityl-1H-imidazole-4-yl)propan-1-amine ( 8 3g, 54%) was obtained as a white solid. 1H NMR (400 MHz; DMSO-d6):δ 1.50 - 1.60 (m, 2H), 2.20 - 2.30 (m, 2H), 2.48 - 2.67 (m, 2H), 4.08 (bs, 2H), 6.56 (s, 1H), 7.00 - 7.12 (m, 6H), 7.22 (s, 1H), 7.32 -7.45 (m, 9H).

[0154] Step 7: Synthesis of 2,2-dimethyl-3-oxo-3-((3-(1-trityl-1H-imidazole-4-yl)propyl)amino)propanoic acid (intermediate 6) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione [1] ( 9 A stirred solution of (2.1 g, 12.2 mmol) in toluene (30 mL) was heated at 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (5.8 mL, 40.8 mmol) and 3-(1-trityl-1H-imidazole-4-yl)propan-1-amine ( 8 A 3g, 8.1 mmol solution in toluene (50 mL) was added over 10 minutes at 75°C. The reaction mixture was further stirred at the same temperature for 3 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was dissolved in chloroform (100 mL) and washed with 10% citric acid aqueous solution (pH approximately 6-6.5). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude material was washed with diethyl ether (50 mL) and the ether was decanted off. The obtained material was dried under vacuum and 2,2-dimethyl-3-oxo-3-((3-(1-trityl-1H-imidazole-4-yl)propyl)amino)propanoic acid ( Intermediate 6 1.7 g, 43%) was obtained as a white solid. LCMS (Method A): m / z 482.09 [M+H] + (ES + ), 4.98 minutes, 97.99%. 1 H-NMR (400 MHz; DMSO- d6):δ 1.24 (s, 6H), 2.70 (t, J = 7.6 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 7.17 - 7.24 (m, 3H), 7.23 - 7.33 (m, 2H), 7.72 (br s, 1H).

[0155] Synthesis of 19,19-dimethyl-18-oxo-2,5,8,11,14-pentaoxa-17-azaicosan-20-acid (intermediate 7)

[0156] [ka] Synthesis of 19,19-dimethyl-18-oxo-2,5,8,11,14-pentaoxa-17-azaicosan-20-acid (intermediate 7) :2,2,5,5-tetramethyl-1,3-dioxane-4,6-dione( 1 A stirred solution of 986 mg (5.73 mmol) in toluene (30 mL) was heated at 75°C. The reaction mixture was stirred at the same temperature for 10 minutes, and Et3N (3.0 mL, 23.4 mmol) and 2,5,8,11,14-pentaoxahexadecane-16-amine ( 2 A solution of 1.2 g (4.71 mmol) in toluene (30 mL) was added dropwise over 10 minutes. The reaction mixture was further stirred at the same temperature for 18 hours. After completion, the reaction mixture was concentrated under vacuum. The residue was pulverized with diethyl ether (50 mL) and the ether was decanted off. The obtained material was dried under vacuum to obtain 19,19-dimethyl-18-oxo-2,5,8,11,14-pentaoxa-17-azaicosan-20-acid ( Intermediate 7 A 1.9g, 90% solution was obtained as a yellow viscous liquid. LCMS (Method A): m / z 383.2 [M+H] + (ES + ), 3.85 minutes, 99.3%. 1 H-NMR (400 MHz; DMSO- d6):δ 1.04 (t, J = 7.1 Hz, 1H), 1.25 (s, 6H), 2.70 - 2.85 (m, 2H), 3.15 - 3.23 (m, 2H), 3.23 (s, 1H), 3.32 - 3.45 (m, 6H), 3.46 - 3.55 (m, 7H), 7.80 (br s, 1H), 12.00 (br s, 1H).

[0157] Synthesis of Examples 1-62 Linear peptides were synthesized using standard Fmoc solid-phase peptide synthesis (SPPS), then cleaved from the resin and purified.

[0158] General peptide synthesis methods : The peptides were synthesized using standard Fmoc chemistry.

[0159] Method a - Exemplify by the synthesis of Example 39 1) Add DCM to a container containing CTC resin (sub: 0.35 mmol / g, 5 mmol, 14.29 g) and allow to swell for 2 hours.

[0160] 2) Drain the water and wash the resin with DMF (5 times, draining after each wash).

[0161] 3) Add 20% piperidine solution to DMF and stir for 30 minutes while aerating with N2.

[0162] 4) Drain the water and rinse with DMF (5 times, draining after each rinse).

[0163] 5) Add Fmoc-amino acid solution (2.0 equivalents in DMF), mix for 30 seconds, then add activation buffer (HBTU (1.9 equivalents) and DIEA (4 equivalents) in DMF), and stir for 1 hour while ablating with N2.

[0164] 6) The coupling reaction was monitored by the ninhydrin test.

[0165] 7) If inefficient coupling occurs, repeat steps 4-5 for the same amino acid coupling if necessary.

[0166] 8) Repeat steps 2-6 for the next amino acid coupling.

[0167] Note: Different equivalent amounts and coupling agents were used for the amino acids in the table below. [Table D]

[0168] 9) The resin was washed three times with MeOH and dried under vacuum.

[0169] Peptide cleavage and purification : 1) Add the cleavage buffer (92.5% TFA / 2.5% EDT / 2.5% TIS / 2.5% H2O) to the flask containing the side-chain protective peptide on the resin at room temperature and stir for 3 hours.

[0170] 2) Precipitate the peptide with cold tert-butyl methyl ether and centrifuge (at 3000 rpm for 3 minutes).

[0171] 3) Filter the reaction mixture, collect the filtrate, and concentrate it under vacuum.

[0172] 4) Wash the residue with tert-butyl methyl ether (twice).

[0173] 5) Dry the crude peptide under vacuum for 2 hours.

[0174] 6) The crude peptide was purified by preparative HPLC (A: 0.5% ACOH in H2O, B: MeCN). Preparative HPLC conditions: Gilson 281. Solvent: A - 0.075% TFA in H2O, B - acetonitrile, Column: Luna C18 (200 × 25 mm; 10 μm) and Gemini C18 (150 × 30 mm; 5 μm) in series. Gradient [time (min) / solvent B (%)]: 0.0 / 25, 60.0 / 55, 60.1 / 90, 70 / 90, 70.1 / 10. Next, it was re-purified by preparative HPLC (A: 0.5% ACOH in H2O, B: MeCN). Preparative HPLC conditions: Instrument: Gilson 281. Solvent: 0.5% AcOH in A-H2O, B-acetonitrile. Columns: Luna C18 (200×25mm; 10μm) and Gemini C18 (150×30mm; 5μm) arranged in series. Gradient [time (min) / solvent B (%)]: 0.0 / 25, 60.0 / 55, 60.1 / 90, 70 / 90, 70.1 / 10. This yielded Example 39 (2.94g, yield 28.04%).

[0175] [Table 2-1]

[0176] [Table 2-2]

[0177] [Table 2-3]

[0178] [Table 2-4] biological activity The following embodiments are provided to illustrate preferred aspects of the present invention and are not intended to limit the scope of the invention.

[0179] Example A. In vitro pharmacological characterization of apelin peptide - Functional agonism and cAMP accumulation assay of the human apelin receptor : cAMP Functional Assay cAMP production was quantified using the Homogeneous Time-Resolved Fluorescence (HTRF) cAMP Dynamic-2 assay (Cisbio, France). CHO cells stably expressing the human apelin receptor were seeded at a density of 12,500 cells / well in solid-walled 96-well half-area plates (Costar). After incubation at 37°C for 16 hours, the medium was removed, and the cells were incubated at 37°C for 30 minutes in serum-free medium containing 500 μM IBMX (Tocris), 3 μM forskolin to increase cAMP levels, and a test agonist at an increasing concentration. After determining cAMP production according to the manufacturer's instructions, the plates were read using a PheraStar fluorescence plate reader (BMG LabTech) and EC (Emission Control Value) was calculated. 50 The values ​​were determined using Graphpad Prism. [Table E]

[0180] Example B. In vitro pharmacological characterization of apelin peptide - Functional agonism and β-arrestin accumulation assay of the human apelin receptor : β-Arrestin assayCHO-K1 cells (DiscoverRx) modified to overexpress human apelin receptor and β-arrestin were seeded at a density of 12,500 cells / well in a solid-walled 96-well half-area plate (Costar). After incubation at 37°C for 16 hours, the medium was removed and the cells were incubated in serum-free medium containing gradually increasing concentrations of the test agonist at 37°C for 90 minutes. The assay reaction was stopped by adding the detection reagent (DiscoverRx) and incubation in the dark for 60 minutes. Next, the level of receptor activation was measured using a PheraStar fluorescence plate reader (BMG LabTech) and EC2 was measured. 50 The values ​​were determined using Graphpad Prism. Emax values ​​are reported only for the active compound. [Table F]

Claims

1. Compounds containing the sequence of formula (1): 【Chemistry 1】 [In the formula, Q is selected from phenyl or monocyclic heteroaryl rings, each of which has one or more R ｑ It may be substituted with the base; or Q is formula - (OCH ２ CH ２ ) ｍ OCH ３ (wherein m is 1 to 5) is a polyether chain; R ｑ C has an alkyl chain which may contain halogen, hydroxyl, amino, or one or more heteroatoms selected from O, N, or S. １－６ Selected from alkyl; n is between 1 and 3; R １ and R ２ are each independently selected from hydrogen or a C １－６ alkyl group, or together with the carbon to which they are attached form a C ３－８ cycloalkyl or heterocyclic group; X is -DArg- or a combination; AA １ - NHCR ３ａ R ３ｂ CO- or -N(Me)CR ３ａ R ３ｂ CO-; here, R ３ａ is hydrogen or C １－３ It is alkyl; R ３ｂ is, -CH ２ (CH ２ ) ｐ CONH ２ or - (CH ２ ) ｐ It is benzyl (where p is 0 or 1); AA ２ is a -Arg-, -DArg-, or homoarginine residue; AA ３ teeth, 【Chemistry 2】 A residue selected from; AA ４ is -Arg- or -DArg-; AA ５ is -NHCH(CH ２ R ４ )CO- or -N(Me)CH(CH ２ R ４ ) CO-; here, R ４ C １－６ Alkyl, C １－６ Cycloalkyl or C １－６ It is branched alkyl; AA ６ is -Aib-, -DAla-, or -Ser-; AA ７ - NHCR ５ａ R ５ｂ CO- or -N(Me)CR ５ａ R ５ｂ CO-; here, R ５ａ is hydrogen or C １－３ It is alkyl, R ５ｂ C １－３ Alkyl, CH ２ - Aryl or CH ２ -A heteroaryl compound, where CH2-aryl or CH2-heteroaryl is one or more halo groups or C １－３ It may also be substituted with an alkyl group; AA ８ is, residue: 【Transformation 3】 And; AA ９ is a -Gly-, -Ala-, -DAla- or N-methylglycine residue; AA １０ is, residue: 【Chemistry 4】 And; AA １１ is, -NHCHR ６ CO-; here, R ６ C １－６ Alkyl, benzyl, -CH ２ -Naphthyl or -CH ２ - Biphenyls, which may be substituted with one or more halo groups; AA １２ teeth, 【Transformation 5】 A residue selected from; AA １３ - NHCR ７ａ R ７ｂ CO- or -N(Me)CR ７ａ R ７ｂ CO-; here, R ７ａ is hydrogen or C １－３ It is alkyl, R ７ｂ C １－１０ Alkyl, -CH ２ -Naphthyl, -CH ２ - Biphenyl or benzyl, which are one or more R ８ It may be substituted with the base, where R ８ is selected from halo, -O-aryl, or -O-benzyl; AA １３ The C-terminus of is a carboxyl group or a carboxamide group, or a tautomer or stereoisomer thereof, or a salt or zwitterion thereof.

2. Q is, 【Transformation 6】 A compound according to claim 1, selected from, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

3. Q is, 【Transformation 7】 The compound according to claim 2, or its tautomer or stereochemical isomer, or its salt or zwitterion.

4. The compound according to claim 3, wherein n is 2, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

5. R １ and R ２ However, hydrogen or C １－６ A compound according to any one of claims 1 to 4, independently selected from an alkyl group, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

6. R １ and R ２ The compound according to claim 5, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof, wherein both are methyl.

7. A compound according to any one of claims 1 to 6, wherein X is -DArg, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

8. A compound according to any one of claims 1 to 6, wherein X is a bond, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

9. AA １ However, glutamine residues, D-glutamine residues, homophenylalanine residues or formulas: 【Transformation 8】 A compound according to any one of claims 1 to 8, which is an N-methylglutamine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

10. AA １ The compound according to claim 9, wherein is a glutamine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

11. AA ５ The compound according to any one of claims 1 to 10, wherein the residue is a leucine residue, a D-leucine residue, a tert-butylalanine residue, a cyclobutylalanine residue, or an N-methylleucine residue, or a tautomer or stereoisomer thereof, or a salt or zwitterion thereof.

12. AA ５ The compound according to claim 11, wherein is a leucine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

13. AA ７ However, it is either a 2-aminoisobutyric acid residue, a histidine residue, or a 4-bromophenylalanine residue, 【Chemistry 9】 A compound according to any one of claims 1 to 12, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof, which is a residue selected from there.

14. AA ７ The compound according to claim 13, wherein the residue is a histidine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

15. AA １１ The compound according to any one of claims 1 to 14, wherein the residue is a phenylalanine residue, a 2-naphthylalanine residue, a 3-chlorophenylalanine residue, a 4-bromophenylalanine residue, a 4-chlorophenylalanine residue, a norleucine residue, or a 4-phenylphenylalanine residue, or a tautomer or stereoisomer thereof, or a salt or zwitterion thereof.

16. AA １１ The compound according to claim 15, wherein is a 4-bromophenylalanine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

17. AA １３ The compound according to any one of claims 1 to 16, wherein the residue is an O-benzyl-D-tyrosine residue, a 4-bromo-D-phenylalanine residue, a 4-phenoxy-D-phenylalanine residue, a 2-naphthyl-D-alanine residue, a 4-phenyl-D-phenylalanine residue, an N-methyl-4-phenyl-D-phenylalanine residue, or a beta-cyclohexyl-D-alanine residue, or a tautomer or stereoisomer thereof, or a salt or zwitterion thereof.

18. AA １３ The compound according to claim 17, wherein is a 4-phenyl-D-phenylalanine residue, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

19. AA １３ The compound according to any one of claims 1 to 18, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof, wherein the C-terminus of AA is a carboxyl group. 【Request Item 20】 【Chemistry 10-1】 【Chemistry 10-2】 A compound according to claim 1, or a tautomer, salt, or zwitterion thereof, selected from the above.

21. A compound according to any one of claims 1 to 20 having apelin receptor agonist activity, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof.

22. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 21, or a tautomer or stereochemical isomer thereof, or a salt or zwitterion thereof, and a pharmaceutically acceptable excipient.

23. The composition according to claim 22 for use in pharmaceuticals.

24. Cardiovascular disease, acute decompensated heart failure, congestive heart failure, myocardial infarction, myocardial myopathy, ischemia, ischemia / reperfusion injury, pulmonary hypertension, diabetes, obesity, cancer, metastatic disease, fluid homeostasis, pathological angiogenesis, retinopathy, treatment of HIV infection, treatment of pulmonary hypertension (PAH) to increase cardiac output, reduce pulmonary vascular hypertension, reduce inflammation, improve lung tissue remodeling, and preserve right ventricular function, heart failure, congestive heart failure, myocardial myopathy, ischemia, ischemia / reperfusion injury, fluid homeostasis, renal failure, hypertension, pulmonary hypertension, polycystic kidney disease, hyponatremia, SIADH, The composition according to claim 22 or 23 for use in the treatment and management of platelet function associated with a range of thrombotic diseases such as peripheral artery disease (PAD); acute coronary syndrome (ACS); myocardial infarction (MI); heart attack (HA); stroke; atherosclerosis; diabetes and associated metabolic conditions; diabetic complications (e.g., diabetic nephropathy, retinopathy, neuropathy, non-alcoholic fatty liver disease, non-alcoholic steatosis, portal hypertension); and conditions in which stimulation and / or increase of muscle mass and / or endurance are considered beneficial.

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