heterocyclic agonists

Abstract

The present invention generally relates to GLP-1 agonists and pharmaceutical compositions containing them, as well as methods for treating GLP-1-related diseases, disorders, or conditions.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of international patent application PCT / CN2023 / 105088, filed on 30 June 2023, which is incorporated herein by reference in its entirety.

[0002] field The present invention relates to a GLP-1 agonist, a pharmaceutical composition, and a method of using the same. [Background technology]

[0003] background Incretin-metabolizing hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are crucial for regulating glucose homeostasis. Drugs targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, reduce gastric motility, and increase satiety.

[0004] Diabetes mellitus is a group of metabolic disorders characterized by persistently high blood sugar levels. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition, accounting for over 90% of diabetes cases. Typical onset is in obese or otherwise sedentary adults, beginning with insulin resistance. While lifestyle changes can be helpful in managing this disorder, patients with T2DM may require the use of antidiabetic drugs, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

[0005] In healthy individuals, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem regulation of insulin secretion in response to glucose intake. While this incretin effect is significantly reduced (if present at all) in T2DM, GLP-1 maintains its insulin-secreting properties even when the endocrine pancreatic response to GIP is efficiently terminated. Therefore, incretin mimetic agents and other GLP-1-based therapies may help stimulate insulin production in T2DM patients. [Overview of the project]

[0006] overview This application describes pharmaceutical compositions comprising heterocyclic GLP-1 agonists and the compounds disclosed herein. Also provided are methods for treating GLP-1-related diseases, disorders, and conditions.

[0007] The present invention also provides pharmaceutical compositions comprising one or more of the compounds described herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives.

[0008] Pharmaceutical compositions comprising one or more of the compounds described herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable additives are also provided herein.

[0009] A method for treating type 2 diabetes in a patient requiring treatment is also provided herein, comprising administering to the patient a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0010] A method for treating type 2 diabetes in a patient is also provided herein, comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] A method for treating diabetes in a patient is also provided herein, comprising determining that the patient has type 2 diabetes; and administering to the patient a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the step of determining that the patient has type 2 diabetes comprises performing an assay to determine the level of a sample in a sample from the patient, wherein the sample is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In one embodiment, the level of HbA1c is about 6.5% or higher. In one embodiment, the level of fasting plasma glucose is about 126 mg / dL or higher. In one embodiment, the level of non-fasting plasma glucose is about 200 mg / dL or higher.

[0012] In one embodiment, the method further includes obtaining a sample from the patient. In one embodiment, the sample is a bodily fluid sample. In one embodiment, the patient is about 40 to about 70 years old and is overweight or obese. In one embodiment, the patient weighs about 22 kg / m². 2 The patient has a Body Mass Index (BMI) of approximately 30 kg / m². In one embodiment, the patient has a BMI of approximately 30 kg / m². 2 They have the above BMI.

[0013] In one embodiment, a method for treating type 2 diabetes includes reducing fasting plasma glucose levels. In one embodiment, fasting plasma glucose levels are reduced to about 100 mg / dL or less.

[0014] In one embodiment, a method for treating type 2 diabetes includes reducing HbA1c levels. In one embodiment, HbA1c levels are reduced to about 5.7% or less.

[0015] In one embodiment, a method for treating type 2 diabetes includes reducing glucagon levels.

[0016] In one embodiment, a method for treating type 2 diabetes includes increasing insulin levels.

[0017] In one embodiment, a method of treating type 2 diabetes includes reducing BMI. In one embodiment, BMI is approximately 25 kg / m². 2 It will decrease to the following:

[0018] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof are administered orally.

[0019] In one embodiment, a method for treating type 2 diabetes further includes administering a further treatment or therapeutic agent to the patient. In one embodiment, the further treatment or therapeutic agent is selected from the group consisting of antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatment agents, antiemetics, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In one embodiment, the antidiabetic agent is selected from the group consisting of biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinide, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinopropyl alcohol (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitors, or any combination thereof. In one embodiment, the biguanide is metformin. In one embodiment, the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human islet precursor peptides (HIPs), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonin agonists, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, or any combination thereof. In one embodiment, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In one embodiment, the NASH treatment agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof. In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures of stereoisomers, or their pharmaceutical compositions, and further therapeutic agents are administered sequentially in any order in separate doses.

[0020] A method for regulating insulin levels in a patient requiring such regulation is also provided herein, comprising administering to the patient an effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition thereof. In one embodiment, the regulation increases the insulin level.

[0021] A method for regulating glucose levels in a patient requiring such regulation is also provided herein, comprising administering to the patient an effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition thereof. In one embodiment, the regulation reduces the glucose level.

[0022] A method for treating a GLP-1-related disease, disorder, or condition is also provided herein, comprising administering an effective amount of one or more of the compounds described herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition thereof, to a patient in need thereof. In some embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity, weight gain due to the use of other drugs, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, Adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, FEFF vascular compliance disorder, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial stipemia, The following conditions are selected from the group consisting of metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In one embodiment, a disease, disorder, or condition is type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial stipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder The following conditions are selected from the group consisting of insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In some embodiments, a disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial stipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0023] All publications, patents, and patent applications described herein are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is specifically and individually incorporated herein by reference. Where any publication or patent or patent application incorporated herein by reference conflicts with any description contained herein, the specification shall prevail and / or be given weight over any such conflicting material.

[0024] description Before describing the compounds and methods, it should be understood that the present invention is not limited to the methods, protocols, cell lines, assays, and reagents described herein, as these may vary. It should also be understood that the terms used herein are intended to describe embodiments of the present invention and are not intended to limit the scope of the present invention as set forth in the claims in any sense.

[0025] definition A heterocyclic GLP-1 agonist is provided here for use in the management of T2DM and other conditions where activation of GLP-1 activity is beneficial.

[0026] Before describing the compounds and methods, it should be understood that the present invention is not limited to the methods, protocols, cell lines, assays, and reagents described herein, as these may vary. It should also be understood that the terms used herein are intended to describe embodiments of the present invention and are not intended to limit the scope of the present invention as set forth in the claims in any sense.

[0027] definition The following description illustrates exemplary embodiments of the present technology. However, it should be recognized that such descriptions are not intended to limit the scope of the invention, but rather are provided as illustrative embodiments.

[0028] In this specification, the following words, phrases, and symbols are intended to have the meanings set forth below, unless otherwise indicated by the context in which they are used.

[0029] A dash ("-") not between two letters or symbols indicates a substituent bond point. For example, -C(O)NH2 is bonded via a carbon atom. Dashes before or after a chemical group are for convenience; a chemical group may be written with or without one or more dashes without losing its usual meaning. Dashed or dashed lines that cross lines in a structure indicate a specific bond point of the group. Directionality or stereochemistry is not indicated unless chemically or structurally necessary, or is implied by the order in which chemical groups are written or named.

[0030] Prefix “C” u-v " indicates that the subsequent group has u to v carbon atoms. For example, "C 1-6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0031] The “approximate” values ​​or parameters described herein include (and are described) embodiments relating to the value or parameter itself. In one embodiment, the term “approximate” includes the indicated amount ± 10%. In another embodiment, the term “approximate” includes the indicated amount ± 5%. In yet another embodiment, the term “approximate” includes the indicated amount ± 1%. Also, the term “approximate X” includes the description of “X”. Furthermore, singular expressions include plural subjects unless the context clearly indicates otherwise. Thus, for example, the description of “compound” includes multiple such compounds, and the description of “assay” includes one or more assays and their equivalents known to those skilled in the art.

[0032] The term “substantially” as used herein is intended to mean more than approximately 35%, or approximately 40%, or approximately 45%, or approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95%.

[0033] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. The alkyl used here refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12(alkyl), 1 to 8 carbon atoms (i.e., C 1-8 (alkyl), 1 to 6 carbon atoms (i.e., C 1-6 (alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 (alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by chemical name or identified by molecular formula, all positional isomers of that number of carbon atoms may be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0034] "Alkenyl" refers to an alkyl group containing at least 1 (e.g., 1 to 3, or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 (alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 (alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 (alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 (alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 (alkenyl). Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0035] "Alkynyl" refers to an alkyl group containing at least 1 (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 (alkynyl), 2 to 12 carbon atoms (i.e., C 2-12Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) or 2-4 carbon atoms (i.e., C 2-4 This refers to an alkyl group having an alkynyl group. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0036] A different, commonly used chemical name may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be called "alkylene" or "alkylenyl" groups, and "arylene" or "aryleneyl" groups, respectively.

[0037] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0038] "Alkoxyalkyl" refers to the alkyl group defined above, where the hydrogen atom is replaced by the alkoxy group defined here.

[0039] A "haloalkyl" is an alkyl group defined as unbranched or branched, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens. For example, when a residue is substituted with more than one halogen, it may be named using a prefix corresponding to the number of halogen moieties bonded. Dihaloalkyls and trihaloalkyls are alkyls substituted with two ("di") or three ("tri") halo groups, which may but are not necessarily the same halogens. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0040] A "haloalkoxy" is an alkoxy group as defined above, in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halo group that is independently selected.

[0041] "Haloalkoxyalkyl" refers to the alkyl group defined above, where the hydrogen atom is replaced by the haloalkoxy group defined here.

[0042] "Hydroxyalkyl" refers to the alkyl group defined above, in which one or more hydrogen atoms (for example, 1 to 6 or 1 to 3) are replaced by hydroxyl atoms.

[0043] "Cyanoalkyl" refers to the alkyl group defined above, where one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by cyano atoms.

[0044] "Alkylthio" refers to the group "alkyl-S-".

[0045] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be substituted as desired, as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0046] "Amide" is the group -C(O)NR y R z The "C-amide" group and the group -NR y C(O)R z This refers to both of the "N-amide" groups, where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of them may be substituted as desired as defined herein, or R y and R zThese together form a cycloalkyl or heterocycline; each of which may be substituted as desired, as defined herein.

[0047] "Amino" is the base -NR y R z This refers to, and here, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired, as defined herein.

[0048] "Amidino" is -C(NR y )(NR z 2) Here, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired, as defined herein.

[0049] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a condensed system (e.g., bicyclic or tricyclic). The aryl group used here has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6-12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 It contains an aryl group. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl never encompasses or overlaps with heteroaryls as defined below. When one or more aryl groups condense with a heteroaryl, the resulting ring system is heteroaryl regardless of the bond site. When one or more aryl groups condense with a heterocyclyl, the resulting ring system is heterocyclyl regardless of the bond site. When one or more aryl groups condense with a cycloalkyl, the resulting ring system is cycloalkyl regardless of the bond site.

[0050] "Carbamoyl" is based on the base -OC(O)NR y R z The "O-carbamoyl" group and the -NR group are referred to as such. y C(O)OR z This refers to both of the "N-carbamoyl" groups, where R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired, as defined herein.

[0051] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x This refers to both, and here, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired as defined herein.

[0052] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having multiple rings, including monocyclic, condensed, crosslinked, and spirocyclic systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 It contains a carbocyclic fused ring system with carbon atoms (i.e., at least one non-aromatic ring). The cycloalkyl used here has 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6They have cycloalkyl groups. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbolonyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can condense to an aryl ring, regardless of its bond site to the rest of the molecule. Moreover, cycloalkyl also includes "spirocycloalkyl" groups, which have two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0053] "Cycloalkylalkyl" refers to the alkyl group defined above, where the hydrogen atom is replaced by the cycloalkyl group defined here.

[0054] "Imino" is base-C(NR y )R z This refers to, and here, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired, as defined herein.

[0055] "Imide" is the group -C(O)NR y C(O)R z or -N(C(O)R y )C(O)R z This refers to, and here, R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of them may be substituted as desired as defined herein, or R y and R z Together, they form a heterocycline that can be optionally substituted as defined herein.

[0056] "Halogen" or "halo" refers to atoms that occupy group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[0057] A "heteroalkyl" is an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by identical or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by identical or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be substituted as desired. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be substituted as desired. The heteroalkyl groups used here include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0058] A "heteroaryl" refers to an aromatic group having a monocyclic or fused ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroaryl used here has 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl group comprises a heteroaryl group and one to five ring heteroatoms, one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently comprising one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranil, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranil, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranil, dibenzothienyl, furanil, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, This includes isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl, and tri-α-dinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bonded via any of the rings. Any aromatic ring having a monocyclic or multiple fused rings containing at least one heteroatom can be considered a heteroaryl (i.e., via any of the fused rings), regardless of its bond to the rest of the molecule. Heteroaryls do not encompass or overlap with the aryls defined above.

[0059] A "heterocyclyl" is a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged-heterocyclyl groups, condensed-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be monocyclic or multi-cyclic, where the multi-cyclic rings may be condensed, bridged, or spiro, and have one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) atoms. - ) may include a portion. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring, regardless of its bonding to the rest of the molecule, is considered a heterocyclyl. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyls regardless of their bonding (i.e., they can be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, regardless of its bonding site to the rest of the molecule, whose ring may be fused with a cycloalkyl, aryl, or heteroaryl ring. The heterocyclyl as used here contains 2 to 20 ring carbon atoms (i.e., C 2-20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocycline), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocycline), 2-8 ring carbon atoms (i.e., C 2-8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclyl), 3-8 ring carbon atoms (i.e., C 3-8 Heterocyclyl), or ring carbon atoms with 3-6 atoms (i.e., C 3-6A heterocyclyl group has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindri This includes octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanil, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl," which has two substitution positions on the same carbon atom. Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be linked via any of the rings.

[0060] The "sulfonyl" group is -S(O)2R y This refers to, and here, R yThe elements are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired, as defined herein. Examples of sulfonyls include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0061] "Sulfinyl" is the base -S(O)R y This refers to, and here, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be substituted as desired as defined herein.

[0062] The terms “optional” or “at will” mean that the event or situation described thereafter may or may not occur, and this description includes both cases in which the event or situation occurs and cases in which it does not occur. The term “substituted at will” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms of the specified atom or group may or may not be replaced by the non-hydrogen portion.

[0063] The term "compound" as used herein is intended to include any and all stereoisomers, geometric isomers, tautomers, and isotopic enriched analogs (e.g., deuterated analogs) of the structure described. Compounds identified herein by name or structure as one of a particular tautomer form include other tautomer forms unless otherwise specified.

[0064] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both amide and imido acid tautomers. Therefore, an amide-containing compound is understood to contain its imido acid tautomer. Similarly, an imido acid-containing compound is understood to contain its amide tautomer.

[0065] Any compound or structure shown herein is also intended to represent the compound in unlabeled form and in isotopically labeled form. Compounds of these forms may also be referred to as "isotope-enriched analogs". Isotopically labeled compounds have the structures described herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present invention, for example 3 H and 14 C and the like incorporating radioactive isotopes. Such isotopically labeled compounds may be useful in metabolic studies, in studies of reaction kinetics, in detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in the radiation treatment of patients.

[0066] The term "isotope-enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms, such as hydrogen on a carbon atom, are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of certain compounds when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized using methods well known in this art, for example, from starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0067] Deuterium-labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may provide therapeutic advantages due to greater metabolic stability, such as extended in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F, 3 H, 11 14C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing unlabeled reagents with readily available isotope-labeled reagents, as disclosed in the scheme or examples and preparations below. It is understood that deuterium in this context is considered a substituent in the compounds described herein.

[0068] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Therefore, in the compounds of the present invention, any atom specifically designated as deuterium (D) represents deuterium.

[0069] In many cases, the compounds of the present invention can form acids and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0070] Pharmacologically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances useful in the manufacture of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0071] The term "pharmaceutically acceptable salt" of a compound means a salt that retains the biological efficacy and properties of the compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be drafted by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following the conventional procedure for producing acid addition salts from a base compound. Those skilled in the art will recognize the various synthetic methods that can be used to produce non-toxic pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be produced from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and others. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, as merely examples, sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include salts of NH3, or primary, secondary, and tertiary amines, e.g., derived from N-containing heterocyclic, N-containing heteroaryl, or of the formula N(R) N )3 (For example, HN + (R N )3 or (alkyl)N + (R N )3)(Here, each R NThe salts of amines include, but are not limited to, salts of amines in which each is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more substituents (e.g., 1 to 5 or 1 to 3) (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, just as examples, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0072] The term "substitution" means that one or more hydrogen atoms of a specified atom or group are replaced by one or more non-hydrogen substituents, but not exceeding the normal valence of the specified atom. One or more substituents include, but are not limited to, acyl, alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, amidino, amide, amino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkoxy, haloalkoxyalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydrazino, hydroxy, hydroxyalkyl, imide, imino, nitro, oxo, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0073] Polymers or similar non-specific structures (e.g., substituted aryl groups having a substituent with an infinitely increasing number of substituents) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used in the modification of chemical groups, the term “substituted” may refer to other chemical groups defined herein. Unless otherwise specified, when a group is described as being substituted as desired, any substituents on the group are themselves unsubstituted. For example, in one embodiment, the term “substituted alkyl” means an alkyl group having one or more substituents, including hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In another embodiment, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted. In yet another embodiment, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0074] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable additive" as used herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retardants, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in a therapeutic composition unless it is incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into the composition.

[0075] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0076] In this context, when a ring is described as "aromatic," it means that the ring has a continuous, delocalized π-electron system. Typically, the number of extraplane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, and isothiazole. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Therefore, when a ring system containing at least two rings is described as "non-aromatic," none of the rings constituting the ring system are aromatic.

[0077] In this context, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation inherent in the ring itself; for example, one or more double bonds between the constituent ring atoms), but the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene. When a ring system containing at least two rings is described as "partially unsaturated," it means that the ring system contains one or more partially unsaturated rings, but none of the rings constituting the ring system are aromatic.

[0078] The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure described. Unless otherwise specified, compounds identified by name or structure as a specific tautomer are intended to include other tautomers.

[0079] The term "tautomer" as used herein refers to a compound whose structure differs significantly due to the arrangement of atoms, but which exists in an easily and rapidly equilibrium state. The compounds provided herein can be described in terms of different tautomers, and when a compound has tautomer forms, it is intended that all tautomer forms are within the scope of the present invention. It is understood that the names of the compounds do not exclude any tautomers.

[0080] The terms "GLP-1R" or "GLP-1 receptor" as used herein include, but are not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0081] The term "GLP-1 related disease" as used herein means all diseases, disorders, or conditions in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0082] The terms "GLP-1 agonist" or "GLP-1 RA" used herein refer to agonists of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriate glucagon level increases in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1 RAs have been shown to treat type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, albiglutide (Tanzeum®), dulaglutide (LY2189265, Trulicity®), efpeglenatide, exenatide (Byetta®, Bydureon®, Exendin-4), liraglutide (Victoza®, NN2211), lixisenatide (Lyxumia®), semaglutide (Ozempic®), tilzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401.

[0083] The term "pharmaceutically acceptable" as used herein means that the compound, or its salt or composition thereof, is chemically and / or toxicologically compatible with the other components of the formulation and / or the subject treated therewith.

[0084] The term "administer" or "to administer" refers to a method of giving a dosage of a compound or pharmaceutical composition to vertebrates or invertebrates, including mammals, birds, fish, or amphibians. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0085] As used herein, “effective dose,” “effective dosage,” “pharmaceutical effective dose,” or “therapeutic effective dose” means that a sufficient amount of a chemical substance (e.g., one or more of the compounds described herein, or their stereoisomers or mixtures thereof) administered will reduce, to some extent, one or more symptoms of a disease or condition, and may include a cure of the disease. “Cure” means the elimination of symptoms of an active disease. Results include a reduction and / or mitigation of signs, symptoms, or causes of the disease, or any other desired modification of a biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing the compounds described herein that is necessary to provide a clinically significant reduction in disease symptoms. The appropriate “effective” dose for any individual case will be determined using any appropriate technique, such as a dose-escalation study. In some embodiments, the “therapeutic effective dose” of a compound provided herein means the amount of the compound that is effective as monotherapy or combination therapy.

[0086] The term “additive” or “pharmaceutically acceptable additive” means a pharmaceutically acceptable substance, composition, or medium, such as a liquid or solid extender, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in terms of being compatible with other components of a pharmaceutical formulation, suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0087] The term “pharmaceutical composition” means a mixture of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or concentrators (collectively referred to herein as “additives”). Pharmaceutical compositions facilitate the administration of compounds to living organisms. Multiple techniques for administering compounds exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, non-enteral, ocular, pulmonary, and topical administration.

[0088] In the context of treatment of a disease, disorder, or condition, the terms “treatment” and “to treat” mean the reduction or suppression of one or more symptoms of the disorder, disorder, or condition or associated with such disorder, disorder, or condition; or the slowing of the progression, spread, or worsening of one or more symptoms of the disease, disorder, or condition or its symptoms.

[0089] As used herein, the term "prevention" refers to the complete or partial prevention of the onset, recurrence, or spread of any disease, condition, or symptom described herein.

[0090] The terms “subject,” “patient,” or “individual” as used herein are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or necessary. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0091] The terms "treatment regimen" and "medication regimen" are interchangeable and refer to the dosage and timing of administration of each therapeutic agent in a combination.

[0092] The term "pharmaceutical combination" as used herein refers to a pharmaceutical treatment resulting from the mixture or combination of one or more active ingredients, and includes both immobilized and unimmobilized combinations of active ingredients.

[0093] The term “combination therapy” as used herein refers to a drug regimen of two different therapeutic agents (i.e., combination components or combination partners) which are administered together or separately, in accordance with the form prescribed by a healthcare professional or in accordance with the regulatory authorities as defined herein.

[0094] As used herein, the terms “regulation” or “to regulate” mean control or adjustment (e.g., increase or decrease), and may include, for example, agonism, partial agonism, or antagonism.

[0095] compound The present invention relates to heterocyclic GLP-1 agonists and pharmaceutical compositions containing them.

[0096] In one embodiment, formula I: [ka] [During the ceremony: R 1 and R 2 Each is independently C 1-3 It is alkyl or cyclopropyl. A compound thereof, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided.

[0097] One reason, R 1 -OH: [ka] A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided.

[0098] One reason, R 1 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein the compound is methyl.

[0099] One reason, R 2 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein the compound is methyl.

[0100] One reason, R 1A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is provided, wherein the compound is ethyl.

[0101] One reason, R 2 A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is provided, wherein the compound is ethyl.

[0102] One reason, R 1 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein n-propyl is provided.

[0103] One reason, R 2 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein n-propyl is provided.

[0104] One reason, R 1 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein i-propyl is provided.

[0105] One reason, R 2 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein i-propyl is provided.

[0106] One reason, R 1 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein is cyclopropyl.

[0107] One reason, R 2 A compound of formula I, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided, wherein is cyclopropyl.

[0108] One reason, R1 A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is provided, wherein is methyl or ethyl.

[0109] One reason, R 1 is methyl or ethyl; and R 2 A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided, wherein is ethyl, n-propyl, i-propyl, or cyclopropyl.

[0110] One reason, R 1 -OH: [ka] A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided.

[0111] One reason, R 1 is methyl; and R 2 A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided, wherein is ethyl, n-propyl, i-propyl, or cyclopropyl.

[0112] One reason, R 1 is ethyl; and R 2 A compound of formula I, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided, wherein is ethyl, n-propyl, i-propyl, or cyclopropyl.

[0113] In one embodiment, compound IA and compound IB: [ka] A compound selected from there, or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, is provided.

[0114] In one embodiment, compound IA: [ka] Alternatively, stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided.

[0115] In one embodiment, compound IB: [ka] Alternatively, stereoisomers or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof are provided.

[0116] One explanation, [ka] Compounds selected from or pharmaceutically acceptable salts thereof are provided.

[0117] In one embodiment, the compound disclosed herein, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is substantially isolated.

[0118] As used herein, the term “substantially isolated” is intended to mean that the compound described herein, or its stereoisomers or mixtures of stereoisomers, or its pharmaceutically acceptable salts, is at least partially or substantially separated from the environment in which it was formed. Partial isolation may include, for example, a composition in which the compound, or its stereoisomers or mixtures of stereoisomers, or its pharmaceutically acceptable salts is concentrated. Substantially isolated may include a composition containing at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 97%, or at least about 99% by weight of the compound, or its stereoisomers or mixtures of stereoisomers, or its pharmaceutically acceptable salts.

[0119] In some embodiments, one or more of the compounds disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof are substantially isolated, where a mixture of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof may exist.

[0120] In one embodiment, compound IA: [ka] Alternatively, its stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, have been substantially isolated.

[0121] In one embodiment, compound IB: [ka] Alternatively, its stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, have been substantially isolated.

[0122] In one embodiment, compound IA and compound IB: [ka] [ka] A mixture of the compounds or their respective stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof, is provided, wherein the mixture of compounds is substantially isolated.

[0123] In some embodiments, the compound, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is substantially solid. The solid does not need to be isolated as a solid, and may, where appropriate, be a suspension of the compound in which at least a portion of the compound is solid. In some embodiments, the compound, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is isolated and in solid form.

[0124] In one embodiment, a composition is provided comprising the compound described herein, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, having a purity of more than 35%, or more than 40%, or more than 45%, or more than 50%, or more than 55%, or more than 60%, or more than 65%, or more than 70%, or more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or a purity of about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%.

[0125] In one embodiment, a composition comprising the compound disclosed herein, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof, wherein the compound, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof is present in the composition in an amount greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 35%, greater than 40%, greater than 45%, or greater than 50%, A composition is provided which is present in an amount of approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% by weight, or approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% by weight.

[0126] In one embodiment, the composition comprises one or more of the compounds disclosed herein, their stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

[0127] In one embodiment, the compounds disclosed herein, their stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof are produced ex vivo.

[0128] In one embodiment, an ex vivo formulation of the compound described herein, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided. In one embodiment, an ex vivo formulation of the compound described herein, its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof is provided, having a purity of more than 35%, or more than 40%, or more than 45%, or more than 50%, or more than 55%, or more than 60%, or more than 65%, or more than 70%, or more than 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or a purity of about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%.

[0129] In general, the term "ex vivo" as used herein is intended to refer to a compound or composition that is outside of a living organism or body (e.g., outside the human body). The term "ex vivo formulation" as used herein is intended to refer to a compound or composition that is synthesized ex vivo, or outside of a living organism or body (e.g., outside the human body).

[0130] In one embodiment, an ex vivo composition comprising the compound disclosed herein, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof, wherein the compound, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof is present in an amount greater than 0.1%, greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 35%, or greater than 40%, greater than 45%, or greater than 50%, or A composition is provided which is present in a purity of approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95%, or in an amount of approximately 40%, or approximately 45%, or approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95% by weight.

[0131] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0132] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0134] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0135] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the structure: [ka] An ex vivo composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0141] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0142] In one embodiment, the structure: [ka] A pharmaceutical composition is provided comprising a compound having or a pharmaceutically acceptable salt thereof.

[0143] In one embodiment, the pharmaceutical composition is an ex vivo composition.

[0144] The compounds disclosed herein include pharmaceutically acceptable salts thereof. Furthermore, the compounds disclosed herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts but may be useful as intermediates in the manufacture and / or purification of the compounds and / or in the separation of enantiomers. Non-limiting examples of pharmaceutically acceptable salts include trifluoroacetate salts.

[0145] It is further recognized that the compounds disclosed herein or their salts can be isolated in the form of solvates, and therefore any such solvates are included within the scope of the present invention. For example, the compounds disclosed herein can exist in unsolvated forms as well as in solvated forms formed with pharmaceutically acceptable solvents such as water and ethanol.

[0146] Pharmaceutical composition and administration When used as a pharmaceutical, the compounds described herein (e.g., one or more of the compounds described herein, or their stereoisomers or mixtures of stereoisomers) can be administered in the form of pharmaceutical compositions. These compositions can be manufactured by methods well known in the pharmaceutical field and can be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epithelial, intraocular and intranasal, vaginal and rectal delivery, including mucosal delivery), pulmonary (e.g., inhalation or blowing of powder or aerosol, including by nebulizer; intratracheal or intranasal), oral, or non-enteral. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Non-enteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Non-enteral administration may be a single bolus dose or obtained, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, droplets, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, and thickeners may be necessary or desirable.

[0147] Pharmaceutical compositions are also provided herein that, in combination with one or more pharmaceutically acceptable additives (carriers), contain one or more of the compounds described herein, or their stereoisomers or mixtures thereof, as active ingredients. For example, a pharmaceutical composition prepared using one or more of the compounds described herein, or their stereoisomers or mixtures thereof.

[0148] In one embodiment, a pharmaceutical composition is provided comprising the compound disclosed herein, or a stereoisomer or stereoisomer mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In one embodiment, a pharmaceutical composition comprising the compound disclosed herein, or a stereoisomer or stereoisomer mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the pharmaceutical composition contains the compound, or a stereoisomer or stereoisomer mixture thereof, or a pharmaceutically acceptable salt thereof in an amount of about 0.1%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 35%, or about 40%, or about 45%, and A pharmaceutical composition is provided in which the substance is present in a purity of approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95%, or in an amount of approximately 40%, or approximately 45%, or approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95% by weight.

[0149] In some embodiments, the composition is suitable for topical administration. In the preparation of the compositions provided herein, the active ingredient is mixed with typical additives, diluted with additives, or encapsulated in carriers in the form of capsules, sachets, paper, or other containers. When the additive serves as a diluent, it may be a solid, semi-solid, or liquid substance that can act as a solvent, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as tablets or capsules.

[0150] Further, pharmaceutical compositions are provided comprising one or more of the compounds described herein, or their stereoisomers or mixtures thereof, and pharmaceutically acceptable additives. Pharmaceutical compositions comprising one or more of the compounds described herein, or their stereoisomers or mixtures thereof, as active ingredients can be prepared by tightly mixing one or more of the compounds described herein, or their stereoisomers or mixtures thereof, with a pharmaceutical carrier, according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, non-enteral). In one embodiment, the composition is a solid oral composition.

[0151] A pharmaceutical composition further comprising one or more of the compounds described herein, or their stereoisomers or mixtures thereof, and a pharmaceutically acceptable additive in combination with one or more further therapeutic agents, wherein the further therapeutic agent is: [ka] [ka] A pharmaceutical composition is provided.

[0152] Suitable pharmaceutically acceptable carriers are well known in this field. Some of these pharmaceutically acceptable carriers are described in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0153] Methods for formulating pharmaceutical compositions are described in numerous publications, including *Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3*, edited by Lieberman et al. and published by Marcel Dekker, Inc.; *Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2*, edited by Avis et al.; and *Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2*, edited by Lieberman et al.

[0154] In some embodiments, a compound or pharmaceutical composition may be administered in combination with one or more conventional pharmaceutical additives. Pharmaceutically acceptable additives include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical administration forms such as Tweens, poloxamer or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, electrolytes such as water, salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, wax, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder being non-toxic additives. The intended compositions may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, of the chemicals provided herein. Practical methods for producing such dosage forms are known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0155] In one embodiment, the compounds and pharmaceutical compositions described herein, or the pharmaceutical compositions thereof, may be administered to a patient in need by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, sinus, tracheal, enteral, epidural, interstitial, abdominal, arterial, bronchial, sacral, intracerebral, cisternal, coronary, dermal, ductal, duodenal, intradural, intraepithelial, esophageal, gastric, gingival, ileal, lymphatic, spinal cord, meningeal, intramuscular, ovarian, abdominal, prostate, lung, intrathecal, intrathecal, synovial, testicular, intrathecal, tubular, tumor, uterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, non-enteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, percutaneous, transmucosal, tracheal, ureter, urethra, and vaginal. In one embodiment, the route of administration is non-enteral (e.g., intratumoral).

[0156] In some embodiments, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, or pharmaceutical compositions thereof, can be formulated for non-enteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions can be prepared as injectable liquid solutions or suspensions; solid forms suitable for use in preparing solutions or suspensions by adding liquids before injection can also be prepared; and formulations can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of this disclosure. In some embodiments, devices are used for non-enteral administration. For example, such devices may include needle syringes, microneedle syringes, needleless syringes, and infusion technologies.

[0157] In one embodiment, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In one embodiment, the form must be sterile and fluid enough to be easily injected. In one embodiment, the form must be stable under manufacturing and storage conditions and protected against contamination by the action of microorganisms such as bacteria and fungi.

[0158] In some embodiments, the carrier may also be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In some embodiments, adequate fluidity may be maintained, for example, by the use of a coating such as lecithin, in the case of a dispersion, by maintaining the required particle size, and by the use of a surfactant. In some embodiments, prevention of microbial activity may be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In some embodiments, isotonic agents, such as sugars or sodium chloride, may be included. In some embodiments, long-term absorption of the injectable composition may be achieved by using absorption-delaying agents in the composition, such as aluminum monostearate and gelatin.

[0159] In one embodiment, a sterile injection solution is prepared by incorporating one or more of the compounds described herein, or their stereoisomers or mixtures thereof, in a suitable solvent, along with various other components listed above as needed, and then sterilizing by filtration. In another embodiment, a dispersion is prepared by incorporating various sterilizing active ingredients into a sterile medium containing a basic dispersion medium and other necessary components listed above. In another embodiment, a sterile powder is used to prepare a sterile injection solution. In yet another embodiment, the preparation method is vacuum drying and freeze-drying, which yields a powder of the active ingredients and further desired ingredients from a pre-filtered solution.

[0160] In one embodiment, pharmacogally acceptable additives that can be used in a rectal composition as a gel, cream, enema, or rectal suppository include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, and anoxide. SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, Carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocapric acid, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymethabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, and any one or more vitamins, such as vitamins A and E and potassium acetate.

[0161] In one embodiment, a suppository can be prepared by mixing one or more of the compounds described herein, or their stereoisomers or mixtures thereof, or the pharmaceutical composition described herein, with a suitable non-irritating additive or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In one embodiment, the composition for rectal administration is in the form of an enema.

[0162] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures of stereoisomers, or pharmaceutical compositions thereof, are formulated for oral administration or local delivery to the digestive or GI tract (e.g., in solid or liquid administration form).

[0163] In one embodiment, the solid dosage form for oral administration includes capsules, tablets, pills, powders, and granules. In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, one or more pharmaceutically acceptable additives, e.g., sodium citrate or dicalcium phosphate and / or: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g. The solid composition may be mixed with agar, calcium carbonate, potato or tapioca starch, alginic acid, silicic acid of Alshu, and sodium carbonate; e) a dissolution retarder, e.g., paraffin; f) an absorption enhancer, e.g., a quaternary ammonium compound; g) a wetting agent, e.g., cetyl alcohol and glycerol monostearate; h) an absorbent, e.g., kaolin and bentonite clay; and i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets and pills, the dosage form may also include a buffer. In some embodiments, a similar type of solid composition may also be used as a filler in soft or hard-filled gelatin capsules with the addition of lactose or lactose and high molecular weight polyethylene glycol.

[0164] In some embodiments, the pharmaceutical composition takes the form of a unit dosage form such as a pill or tablet, and therefore the composition may include, together with one or more of the compounds provided herein, or their stereoisomers or mixtures thereof, diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate, etc.; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, other solid dosage forms, powders, marblings, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). In some embodiments, unit dosage forms in which one or more of the compounds provided herein and the pharmaceutical composition or further activators are physically separated are also intended; for example, capsules of granules of each drug (or tablets in capsules); two-layer tablets; two-compartment gel caps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also intended.

[0165] In one embodiment, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives particularly useful for preventing the growth or activity of microorganisms. For example, various preservatives are well known and include, for instance, phenol and ascorbic acid.

[0166] In one embodiment, the additives are sterile and generally undesirable. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In another embodiment, sterility is not required for additives in various oral dosage forms, such as tablets and capsules. For example, the United States Pharmacopeia / National Pharmacopoeia (USP / NF) standards may suffice.

[0167] In some embodiments, one or more of the compounds described herein, or their stereoisomers or mixtures of stereoisomers, or pharmaceutical compositions thereof, are formulated for ophthalmic administration. In some embodiments, the ophthalmic composition comprises, but is not limited to, one or more of the following: biscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0168] In some embodiments, one or more of the compounds described herein, or their stereoisomers or mixtures of stereoisomers, or pharmaceutical compositions thereof, are formulated for topical administration to the skin or mucous membranes (e.g., skin or transdermally). In some embodiments, topical compositions may include ointments and creams. In some embodiments, the ointment is typically a semi-solid formulation based on petrolatum or other petroleum derivatives. In some embodiments, the cream containing the selected surfactant is typically a viscous liquid or a semi-solid emulsion, often oil-in-water or water-in-oil. For example, the cream base is typically washable with water and comprises an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase may be referred to as the “internal” phase and generally consists of petrolatum and fatty alcohols such as cetyl or stearyl alcohol; the aqueous phase, though not necessarily, usually exceeds the volume of the oil phase and generally contains a wetting agent. In some embodiments, the emulsifier of the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In one embodiment, like other carriers or media, the ointment base must be inert, stable, non-irritating, and non-sensitizing.

[0169] In any of the embodiments described herein, the pharmaceutical composition may comprise one or more of the following: lipids, interlayer crosslinked multilayer vesicles, biodegradable poly(D,L-milk-coglycolic acid) (PLGA)-based or polyanhydride-based nanoparticles or microparticles, and nanopore particle-supporting lipid bilayers.

[0170] The amount of compound in a pharmaceutical composition or formulation can vary within the range used by those skilled in the art. Typically, a formulation contains about 0.01 to 99.99 wt% of the compound of the present invention, based on the total formulation, on a weight percentage (wt%) basis, with the remainder being one or more suitable pharmaceutical additives. In some embodiments, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are listed below.

[0171] Formulation Example 1 - Tablet Formulation The following ingredients are closely mixed and compressed into a single-scored tablet. [Table 1]

[0172] Formulation Example 2 - Capsule Formulation The following ingredients are tightly mixed and filled into hard-shelled gelatin capsules. [Table 2]

[0173] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form an oral suspension. [Table 3]

[0174] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable preparation. [Table 4]

[0175] Formulation Example 5 - Suppository Formulation A suppository weighing 2.5 g in total is prepared by mixing the compound of the present invention with Uitepzol® H-15 (saturated plant fatty acid triglyceride; Riches-Nelson, Inc., New York) and has the following composition: [Table 5]

[0176] In some embodiments, the dosage of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, is determined based on several factors, including, but not limited to, the patient's type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or its pharmaceutically acceptable salt or solvate. In some embodiments, the appropriate dosage for a particular situation may be determined by a person skilled in the medical art. In some embodiments, the total daily dose may be divided and administered by means of providing small doses throughout the day or continuous delivery.

[0177] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, are administered in doses ranging from approximately 0.01 to approximately 1000 mg. For example, approximately 0.1 to approximately 30 mg, approximately 10 to approximately 80 mg, approximately 0.5 to approximately 15 mg, approximately 50 mg to approximately 200 mg, approximately 100 mg to approximately 300 mg, approximately 200 to approximately 400 mg, approximately 300 mg to approximately 500 mg, approximately 400 mg to approximately 600 mg, approximately 500 mg to approximately 800 mg, approximately 600 mg to approximately 900 mg, or approximately 700 mg to approximately 1000 mg. In one embodiment, the dose is a therapeutically effective dose.

[0178] In certain embodiments, one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof described herein, are administered at a dosage of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0002 mg / Kg to about 1 mg / Kg; about 0.0002 mg / Kg to about 0.5 mg / Kg; about 0.0002 mg / Kg to about 0.1 mg / Kg; about 0.001 mg / Kg to about 50 mg / Kg; about 0.001 mg / Kg to about 25 mg / Kg; about 0.001 mg / Kg to about 10 mg / Kg; about 0.001 mg / Kg to about 5 mg / Kg; about 0.001 mg / Kg to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg). In certain embodiments, one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof described herein, are administered at a dosage of about 100 mg / Kg.

[0179] In certain embodiments, the dosage of one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof, may be administered on a daily basis (e.g., as a single dose or as multiple divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, every two weeks, once a month).

[0180] In one embodiment, the duration of administration of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the period during which administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, there is a period during which one or more of the compounds described herein, or their stereoisomers or mixtures thereof, are administered to a patient for a certain period, followed by a period during which administration of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, is discontinued. In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, are administered during a first period, followed by a second period, during which administration is stopped, followed by a third period in which administration of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, is started, followed by a fourth period in which administration is stopped. For example, the period of administration of one or more of the compounds described herein, or their stereoisomers or mixtures thereof, followed by the period of administration cessation, is repeated for a predetermined or indefinite period. In one instance, the duration of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.In certain embodiments, the period of treatment interruption is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0181] In certain embodiments, one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof, are administered orally to a patient one or more times per day (e.g., once a day, twice a day, three times a day, four times a day or a single daily dose).

[0182] In certain embodiments, one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof, are administered parenterally to a patient one or more times per day (e.g., 1 - 4 times, once a day, twice a day, three times a day, four times a day or a single daily dose).

[0183] In certain embodiments, one or more of the compounds described herein, or stereoisomers or mixtures of stereoisomers thereof, are administered parenterally to a patient once a week.

[0184] Method of treatment In certain embodiments, the present invention relates to a method of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of the GLP - 1R (e.g., inhibition or impairment and / or up - regulation or unwanted GLP - 1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include or further include treating one or more co - existing or secondary conditions associated with any one or more of the conditions described herein.

[0185] A method for treating a GLP-1 related disease, disorder, or condition is provided herein, comprising administering to a patient in need one or more of the compounds described herein, or a mixture of stereoisomers or stereoisomers thereof, or a pharmaceutical composition disclosed herein, in an effective amount.

[0186] In one embodiment, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, Kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial fat This includes, but is not limited to, diabetes, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0187] In one embodiment, a disease, disorder, or condition is type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial stipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, i This includes, but is not limited to, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0188] In some embodiments, a disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial stipemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0189] In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating a patient induce one or more of the following: a decrease in blood glucose (e.g., a decrease in blood glucose levels), a decrease in blood hemoglobin A1c (HbA1c) levels, an increase in insulin synthesis, an increase in β-cell mass, a regulation of gastric acid secretion, a regulation of gastric emptying, a decrease in body mass index (BMI), and / or a decrease in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating a patient stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Methods for making such regulation in a patient requiring regulation of glucose or insulin levels are also provided herein, comprising administering to the patient an effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition disclosed herein.

[0190] In one embodiment, a method is provided for reducing the risk of major adverse cardiovascular events (MACE) in a patient requiring treatment (e.g., by about 20%, 30%, 40%, 50%, 60%, 70%, or 80%), comprising administering to the patient an effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes mellitus (T2D). In one embodiment, the patient is an adult diagnosed with heart disease. In one embodiment, the patient is an adult diagnosed with both type 2 diabetes mellitus (T2D) and heart disease. In one embodiment, the patient is an adult with type 2 diabetes mellitus (T2D). In one embodiment, the patient is an adult with heart disease. In one embodiment, the patient has both type 2 diabetes mellitus (T2D) and heart disease.

[0191] Indications obesity In some embodiments, a condition, disease, or disorder is obesity and any condition, disease, or disorder associated with or related to obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal steatosis). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence Moon-Beadle syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea, or β-blocker-induced obesity).

[0192] In some embodiments, a condition, disease, or disorder is associated with obesity. Examples of such conditions, diseases, or disorders include, but are not limited to, impaired glucose tolerance, diabetes mellitus (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), stroke (e.g., cerebral thrombosis, transient ischemic attack), bone or joint diseases (e.g., osteoarthritis of the knee, osteoarthritis of the hip, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick's syndrome), menstrual disorders (e.g., menstrual cycle abnormalities, menstrual flow and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome. In some embodiments, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting symptoms of both obesity and insulin deficiency.

[0193] diabetes In one embodiment, the condition, disease, or disorder is diabetes mellitus. Non-limiting examples of diabetes mellitus include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-assisted type 2 diabetes mellitus, sulfonylurea-assisted type 2 diabetes mellitus, acute type 2 diabetes mellitus, long-term insulin-assisted type 2 diabetes mellitus), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes mellitus, obesity-related diabetes mellitus, autoimmune diabetes mellitus, and prediabetes. In one embodiment, the condition, disease, or disorder is type 2 diabetes mellitus (e.g., diet-assisted type 2 diabetes mellitus, sulfonylurea-assisted type 2 diabetes mellitus, acute type 2 diabetes mellitus, long-term insulin-assisted type 2 diabetes mellitus).

[0194] A method for treating diabetes in a patient is provided herein, comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition disclosed herein.

[0195] A method for treating type 2 diabetes in a patient is provided herein, comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition disclosed herein.

[0196] Furthermore, a method for treating type 2 diabetes in a patient requiring treatment is provided, comprising administering to the patient a therapeutically effective amount of one or more of the compounds described herein, or a stereoisomer or mixture thereof, or a pharmaceutical composition disclosed herein.

[0197] In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions described herein and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) reduce BMI.

[0198] In one embodiment, a decrease of approximately 5% to 95% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 15% to 80% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 25% to 60% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In another embodiment, a decrease of fasting plasma glucose levels to approximately 126 mg / dL or less, approximately 110 mg / dL or less, or approximately 90 mg / dL or less indicates treatment for type 2 diabetes.

[0199] In certain embodiments, a decrease of about 5% to about 95% in non-fasting plasma glucose level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 15% to about 80% in non-fasting plasma glucose level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 25% to about 60% in non-fasting plasma glucose level indicates treatment of type 2 diabetes. In certain embodiments, a decrease in non-fasting plasma glucose level to about 200 mg / dL or less, about 150 mg / dL or less, or about 130 mg / dL or less indicates treatment of type 2 diabetes.

[0200] In certain embodiments, a decrease of about 5% to about 95% in HbA1c level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 15% to about 80% in HbA1c level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 25% to about 60% in HbA1c level indicates treatment of type 2 diabetes. In certain embodiments, a decrease in HbA1c level to about 6.5% or less, about 6.0% or less, or about 5.0% or less indicates treatment of type 2 diabetes.

[0201] In certain embodiments, a decrease of about 5% to about 95% in glucagon level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 15% to about 80% in glucagon level indicates treatment of type 2 diabetes. In certain embodiments, a decrease of about 25% to about 60% in glucagon level indicates treatment of type 2 diabetes. In certain embodiments, an increase of about 5% to about 95% in insulin level indicates treatment of type 2 diabetes. In certain embodiments, an increase of about 15% to about 80% in insulin level indicates treatment of type 2 diabetes. In certain embodiments, an increase of about 25% to about 60% in insulin level indicates treatment of type 2 diabetes.

[0202] In one embodiment, a decrease of approximately 5% to 95% in BMI indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 15% to 80% in BMI indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 25% to 60% in BMI indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% in BMI indicates treatment for type 2 diabetes. In another embodiment, a decrease of approximately 40 or less, approximately 30 or less, or approximately 20 or less indicates treatment for type 2 diabetes.

[0203] In some embodiments, a condition, disease, or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular complications, osteopenia, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hyperacusis, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0204] Other non-limiting examples of disorders associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic disorders in which GLP-1R activation is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0205] In one embodiment, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In one embodiment, the compounds described herein are also useful for improving the therapeutic efficacy of metformin.

[0206] Damage to metabolically important tissues In one embodiment, the condition, disease, or disorder is a disorder of metabolically important tissues. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0207] In one embodiment, the condition, disease, or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease due to hepatitis, fatty liver disease due to obesity, fatty liver disease due to diabetes, fatty liver disease due to insulin resistance, fatty liver disease due to hypertriglyceridemia, abetalipoproteinemia, glycogen depletion disorders, Weber-Christian disease, Wolmann disease, gestational acute fatty liver, and steatosis.

[0208] Non-alcoholic fatty liver disease (NAFLD) represents a diverse range of disorders that occur without alcohol abuse and are typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children, eventually leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, isolated, and primarily macrodroplet steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In one embodiment, the patient is a pediatric patient. The term "pediatric patient" as used herein refers to a patient under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (from birth to 1 month old); infants (1 month to 2 years old); children (2 years to 12 years old); and adolescents (12 years to 21 years old (up to their 22nd birthday, but not including it)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In one embodiment, the pediatric patient is between birth and 28 days old, 29 days old and under 2 years old, 2 years old and under 12 years old, or 12 years old and under 21 years old (up to but not including the 22nd birthday).In one embodiment, the pediatric patient is born to 28 days old, 29 days old to under 1 year old, 1 month old to under 4 months old, 3 months old to under 7 months old, 6 months old to under 1 year old, 1 year old to under 2 years old, 2 years old to under 3 years old, 2 years old to under 7 years old, 3 years old to under 5 years old, 5 years old to under 10 years old, 6 years old to under 13 years old, 10 years old to under 15 years old, or 15 years old to under 22 years old. In one embodiment, the patient is an adult patient.

[0209] Other non-limiting examples of disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism, including osteoporosis, such as postmenopausal osteoporosis, decreased bone density, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteogenesis imperfecta in liver disease and altered bone metabolism due to renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and nutritional deficiencies; polycystic ovary syndrome; renal diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In one embodiment, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or preventing catabolic reactions caused by surgical trauma.

[0210] Cardiovascular and vascular diseases In one embodiment, the condition, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, hypertension (e.g., ≥130 / 85 mmHg), and prothrombotic conditions (exemplified by high blood fibrinogen levels or plasminogen activator inhibitors).

[0211] In some embodiments, the condition, disease, or disorder is related to a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, nephropathy, and neuropathy.

[0212] Neurological disorders In some embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity, mania, Parkinson's disease, Steel-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain injury, vascular amyloidosis, cerebral hemorrhage with amyloidosis I, encephalitis, ataxia of Friedreich, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndromes). See, for example, US2006 / 0275288A1.

[0213] Non-limiting examples of mental disorders include substance dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful in improving behavioral responses to addictive substances, reducing substance dependence, preventing relapse of substance abuse, and alleviating anxiety caused by the absence of a particular addictive substance. See, for example, US2012 / 0021979A1.

[0214] In one embodiment, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, and also for preserving dopamine neurons and motor function in Parkinson's disease.

[0215] Insulin-related conditions and disorders In one embodiment, the condition, disease, or disorder is poor fasting blood glucose (IFG), abnormal fasting blood glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemic state, insulin resistance syndrome, paresthesia due to hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagon-producing tumors, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and associated coma endpoints with insulin.

[0216] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression to diabetes mellitus, including prediabetes, poor fasting blood glucose levels, or abnormal fasting blood glucose levels.

[0217] autoimmune disorders In some embodiments, the condition, disease, or disorder is an autoimmune disorder. Non-exclusive examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease. See, for example, US20120148586A1.

[0218] Stomach and intestinal disorders In one embodiment, the condition, disease, or disorder is a gastrointestinal or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption disorders, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac pruritus, hypogammaglobulinemia pruritus, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexies (e.g., cancerous cachexies, tuberculous cachexies, cachexies associated with hematological disorders, cachexies associated with endocrine disorders, cachexies associated with infectious diseases, and cachexies caused by acquired immunodeficiency syndromes).

[0219] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce body weight (e.g., overweight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in patients (e.g., patients in need). In some embodiments, weight gain in patients may be due to excessive food intake or unbalanced diet, or due to concomitant medications (e.g., insulin sensitizers having PPARγ agonist-like activity such as troglitazone, rosiglitazone, englitazone, siglitazone, pioglitazone, etc.). In some embodiments, weight gain may be weight gain before becoming obese, or weight gain in obese patients. In some embodiments, weight gain may also be drug-induced weight gain or weight gain after quitting smoking.

[0220] In one embodiment, the condition, disease, or disorder is an eating disorder such as bulimia, binge eating episodes, bulimia nervosa, or compulsive eating.

[0221] inflammatory diseases In one embodiment, the condition, disease, or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include rheumatoid arthritis, spondylitis degenerative, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, bloating, neuralgia, pharyngolaryngitis, cystitis, pneumonia, pancreatitis, colitis, inflammatory bowel disease (including inflammatory bowel disease), inflammation of metabolically important tissues including the liver, fat, pancreas, kidneys, and intestines, and pro-inflammatory conditions (e.g., elevated levels of pro-inflammatory cytokines or inflammatory C-reactive protein markers in the blood).

[0222] cancer In one embodiment, the condition, disease, or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor) Stromas of the liver) Cancer (e.g., primary liver cancer, extrahepatic cholangiocarcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer) This includes adenomatous carcinoma, parathyroid carcinoma, nasal cavity carcinoma, paranasal sinus carcinoma, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0223] Hypothalamic-pituitary dysfunction In one embodiment, the condition, disease, or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is related to the hypothalamic-pituitary-ovarian axis. In other examples, the condition, disease, or disorder is related to the hypothalamic-pituitary-testicular axis. Disorders of the hypothalamic-pituitary-gonadal axis include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, anterior pituitary insufficiency, sexual dysfunction, and Cushing's disease.

[0224] In one embodiment, a condition, disease, or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0225] Lung disease In one embodiment, the condition, disease, or disorder is related to a lung disease. Lung diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hyperpnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0226] In one embodiment, the condition, disease, or disorder associated with diabetes is a lung disease.

[0227] Combination therapy In one embodiment, the present invention intends both monotherapy regimens and combination therapy regimens.

[0228] In one embodiment, the method described herein further comprises the administration of one or more additional therapeutic agents (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compound described herein.

[0229] In one embodiment, the method described herein includes administration of the compound described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary adjustment.

[0230] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, can be administered in combination with one or more further therapeutic agents.

[0231] Representative further therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapy, immunotherapy, anti-inflammatory drugs, antithrombotic agents, antioxidants, therapeutic agents for osteoporosis, vitamins, anti-dementia drugs, erectile dysfunction drugs, therapeutic agents for frequent urination or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for voiding disorders, and antiemetics.

[0232] In one embodiment, one or more further therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensin), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., berneperit), cannabinoid receptor antagonists ( For example, limonabant, taranaban), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylates inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacityl Glycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturates inhibitors, microsomal triglyceride transport protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR Agonists (e.g., GFT-505, DRF-11605, gemfibrozil and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, troduskemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821,Compounds described in W0008 / 136428 and W0008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving agents, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., plumrintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinate, TM-30339, TM-30335), oxintomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF2 extracted from bovine or porcine pancreas). 1. Formulations; including genetically synthesized human FGF21 formulations using E. coli or yeast (fragments or derivatives of FGF21), anorexia stimulants (e.g., P-57), human island precursor peptides (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0233] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, may be administered in combination with one or more further therapeutic agents, the further therapeutic agents being selected from the compounds in WO2021 / 155841.

[0234] In one embodiment, one or more of the compounds described herein, or their stereoisomers or mixtures thereof, can be administered in combination with one or more further therapeutic agents, wherein the further therapeutic agents are: [ka] [ka] That is the case.

[0235] In one embodiment, one or more further therapeutic agents include, for example, those useful as antidiabetic agents.Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or its salts), biguanides (e.g., metformin, buformin or its salts (e.g., hydrochloride, fumarate, succinate)), glucagon analogue Glucagon (e.g., any of the glucagon analogs listed in WO2010 / 011439), drugs that antagonize or reduce the secretion of glucagon, sulfonylureas (e.g., chlorpropamide, trazamide, glycirazide, glimepiride, tolbutamide, glibenclamide, glycirazide, acetohexamide, glyclopyramide, glibzol, glibride), thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate) ), insulin secretagogues, such as dietary glucose regulators (sometimes called "short-acting secretagogues"), such as meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, aviglutide, tacrine This includes spoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adgliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0236] In one embodiment, one or more further therapeutic agents include, for example, those useful for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, and ileal bile. This product contains acid transporter (IBAT) inhibitors, glycyrrhizin, schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylurea, alpha-glucosidase inhibitors, meglitinide, vitamins, tetrahydrolipustatin, milk thistle protein, antiviral agents, and antioxidants.

[0237] In one embodiment, one or more further therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion enhancers described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., mesylate This includes boxistaurine, AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridrine, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulated kinase-1 (ASK-1) inhibitors.

[0238] In one embodiment, one or more further therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]acetase The formulation includes [Tyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, synfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomole, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma-oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., Zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3 fatty acid ethyl ester 90).

[0239] In one embodiment, one or more further therapeutic agents include, for example, those useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0240] In one embodiment, one or more further therapeutic agents include, for example, those useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, meticlothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefluside, indapamide).

[0241] In one embodiment, one or more further therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering approaches (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0242] In one embodiment, one or more further therapeutic agents include, for example, those useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium); warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran); FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504). The formulation includes thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0243] In one embodiment, one or more further therapeutic agents include, for example, those useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmoncalcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate, and disodium risedronate. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Suitable examples of therapeutic agents for frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of therapeutic agents for voiding disorders include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

[0244] Further examples of therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs designed to treat complications of long-term hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemia agents such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), and cholestasis. Adrenaline, including cholesterol-lowering agents, bile acid scavenging agents (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogues, antioxidants (e.g., probucol), omega-3 fatty acids, beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers (e.g., labetalol). Antihypertensive agents including receptor antagonists, adrenergic receptor agonists including alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and calcium channel blockers such as benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone), central alpha agonists (e.g., clonidine), Centrally acting adrenaline drugs such as lonidine, diuretics (e.g., furosemide), antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and hemostatic modulators including direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel),Phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tyrofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenaline agents (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), Monoamine signaling modulators such as norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., troxatone and amyflamin), compounds described in W0007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 063 Compounds described in 729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), and other cachexia-improving agents, glucocorticoids (e.g., dexamethasone), Metoclopramide, tetrahydrocannabinol, drugs to improve lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexy inducer TNF-α, LIF, IL-6, and antibodies against oncostatin M, metabolically modified proteins or peptides such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711),Nerve regeneration-promoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trireptal, keppra, zonegran, pregabalin, harcoceride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), anesthetics Drug analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depletion treatments (e.g., anti-CD20 antibodies (e.g., rituximab), i-BLyS antibodies), and T cell migration Drugs that affect the drug (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), drugs that act on immunophyllines (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), and metaglidacen, AMG-131, paraglitazone, MBX-2044, riboglycan This includes Tazone, Allegritazar, Tigritazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, Exenatide, Exendin-4, Memantine, Midazolam, Ketoconazole, Ethyl Icosapentate, Clonidine, Azosemide, Isosorbide, Ethacrine, Pyretanide, Bumetanide, Etoposide, Piroxicam, NO donors (e.g., nitrate esters), and NO promoters (e.g., phosphodiesterase inhibitors).

[0245] In one embodiment, one or more additional therapeutic agents include, for example, those useful as antiemetics. As used herein, “antiemetic” means any agent that counteracts (e.g., reduces or eliminates) nausea or vomiting (the act of vomiting). When referring to a therapeutically effective dose of an antiemetic, it is understood that the amount administered is the amount necessary to counteract (e.g., reduce or eliminate) nausea or vomiting (the act of vomiting). While we do not wish to be bound by theory, it is understood that the administration of one or more antiemetics in combination with the compound of formula (I) described herein may allow for the administration of higher doses of the compound of formula (I), for example, because the patient is able to eat normally and thereby may respond more quickly to the treatment.

[0246] Non-exclusive examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0247] For example, antiemetics may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, anti-dopaminergic agents / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0248] In one embodiment, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-exclusive examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), drasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, allosetron, azasetron, bemethetron, zatisetron, batanoprid, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazine-1-yl)-2-quinoxaline carbononitrile maleate, zacoprid hydrochloride, and mirtazepine. Other non-exclusive examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include silancetron, clozapine, cyproheptadine, dazoprid, hydroxyzine, rerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, camosetron, ramosetron, ricasetron, risperidone, ziprasidone, and zatosetron.

[0249] In one embodiment, the 5HT-3 receptor antagonist is granisetron, drasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, allosetron, bemethetron, zatisetron, batanoprid, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL-72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxaline carbonitride, zacoprid hydrochloride, and mirtazepine.

[0250] In one embodiment, the 5HT-3 receptor antagonist is granisetron, drasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, allosetron, bemethetron, and zatisetron.

[0251] In one embodiment, the 5HT-3 receptor antagonist is granisetron, drasetron, and ondansetron.

[0252] In one embodiment, the 5HT-3 receptor antagonist is granisetron.

[0253] In one embodiment, the 5HT-3 receptor antagonist is ondansetron.

[0254] In one embodiment, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinates (dramanin, gravol); diphenhydramine; hydroxyzine; buclidine; and meclizine hydrochloride (Bonine, Antibart), doxylamine, and mirtazapine.

[0255] In one embodiment, the antiemetic is an anticholinergic agent (an inhibitor of acetylcholine receptors). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyostine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Disipal (Norflex orphenadyl hydrate), diphenhydramine, hydroxyzine, hyoscyamine, and Kemadrin (procyclidine hydrochloride).

[0256] In one embodiment, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, prednisone®, and trimethobenzamide (Tigan).

[0257] In one embodiment, the antiemetic is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezropitant, fosaprepitant, maropitant, netsupitant, lorapitant, and vestipitant.

[0258] Other non-limiting examples of NK1 receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (besilate / bepotastine chloride), LY 303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, and DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j. Benserazide and carbidopa k. TAK-637[(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazosino[2,1-g][1,7]naphthyridine-6,13-dione], PD Includes 154075, ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph), FK888, and (D-Pro4, D-Trp7,9,10,Phe11)SP4-11.

[0259] In one embodiment, the antiemetic is an anti-dopaminergic agent / dopamine receptor antagonist (e.g., dopamine receptor antagonists, e.g., D2 or D3 antagonists). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone); butyrophenones (e.g., haloperidol, droperidol); arizaprid, bromoprid, clevopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0260] In one embodiment, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), cannabinoid agonists, e.g., WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Sesamet)).

[0261] Other examples of antiemetics include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / antipsychotics (e.g., dixylazine, haloperidol, and prochlorperazine (Compadin®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (emetrol); bismuth subsalicylate (peptobismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0262] Further examples of antiemetics include those disclosed in US20120101089A1;US10,071,088B2;US6,673,792B1;US6,197,329B1;US10,828,297B2;US10,322,106B2;US10,525,033B2;WO2009080351A1;WO2019203753A2;WO2002020001A2;US8,119,697B2;US5,039,528;US20090305964A1; and WO2006 / 111169 (each of these is incorporated herein by reference).

[0263] In one embodiment, a further therapeutic agent or regimen is administered to the patient before contact with or administration of the compound and the pharmaceutical composition (for example, about 1 hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[0264] In one embodiment, a further therapeutic agent or regimen is administered to the patient almost simultaneously with contact with or administration of the compound and pharmaceutical composition. For example, the further therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in the same dosage form. In another example, the further therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in separate dosage forms.

[0265] Patient Selection In one embodiment, the method described herein further includes the step of identifying patients (e.g., subjects) who require such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0266] In one embodiment, the method described herein further includes the step of identifying a patient (e.g., a patient) having the disease, disorder, or condition provided herein (e.g., a GLP-1 related disease, disorder, or condition).

[0267] In one embodiment, the method described herein further includes the step of identifying a patient (e.g., a patient) who has type 2 diabetes. In one embodiment, the determination of whether a patient has type 2 diabetes includes performing an assay to determine the levels of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In one embodiment, the HbA1c level is about 6.5% to about 24.0%. In one embodiment, the HbA1c level is about 6.5% or higher. In one embodiment, the HbA1c level is about 8.0% or higher. In one embodiment, the HbA1c level is about 10.0% or higher. In one embodiment, the HbA1c level is about 12.0% or higher. In one embodiment, the HbA1c level is about 14.0% or higher. In one embodiment, the HbA1c level is about 16.0% or higher. In one embodiment, the HbA1c level is about 18.0% or higher. In one embodiment, the HbA1c level is approximately 20.0% or higher. In another embodiment, the HbA1c level is approximately 22.0% or higher. In yet another embodiment, the HbA1c level is approximately 24.0% or higher.

[0268] In one embodiment, the fasting plasma glucose level is approximately 120 mg / dL to approximately 750 mg / dL or higher. In another embodiment, the fasting plasma glucose level is approximately 200 mg / dL to approximately 500 mg / dL or higher. In yet another embodiment, the fasting plasma glucose level is approximately 300 mg / dL to approximately 700 mg / dL or higher.

[0269] In one embodiment, the non-fasting plasma glucose level is approximately 190 mg / dL to approximately 750 mg / dL or higher. In another embodiment, the non-fasting plasma glucose level is approximately 250 mg / dL to approximately 450 mg / dL or higher. In yet another embodiment, the non-fasting plasma glucose level is approximately 400 mg / dL to approximately 700 mg / dL or higher.

[0270] In one embodiment, the determination of whether or not a patient has type 2 diabetes further includes determining the patient's BMI. In one embodiment, the patient's BMI is approximately 22 kg / m². 2 ~about 100kg / m 2 That concludes the explanation. In one embodiment, the patient's BMI is approximately 30 kg / m². 2 ~about 90kg / m 2 That concludes the explanation. In one embodiment, the patient's BMI is approximately 40 kg / m². 2 ~about 80kg / m 2 That concludes the explanation. In one embodiment, the patient's BMI is approximately 50 kg / m². 2 ~about 70kg / m 2 That's all.

[0271] In one embodiment, further factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes include the patient's age and ethnicity. In one embodiment, the patient's age is approximately 10 years or older. In one embodiment, the patient's age is approximately 15 years or older. In one embodiment, the patient's age is approximately 20 years or older. In one embodiment, the patient's age is approximately 25 years or older. In one embodiment, the patient's age is approximately 30 years or older. In one embodiment, the patient's age is approximately 35 years or older. In one embodiment, the patient's age is approximately 40 years or older. In one embodiment, the patient's age is approximately 42 years or older. In one embodiment, the patient's age is approximately 44 years or older. In one embodiment, the patient's age is approximately 46 years or older. In one embodiment, the patient's age is approximately 48 years or older. In one embodiment, the patient's age is approximately 50 years or older. In one embodiment, the patient's age is approximately 52 years or older. In one embodiment, the patient's age is approximately 54 years or older. In one embodiment, the patient's age is approximately 56 years or older. In one embodiment, the patient's age is approximately 58 years or older. In one instance, the patient's age is approximately 60 years or older. In another instance, the patient's age is approximately 62 years or older. In another instance, the patient's age is approximately 64 years or older. In another instance, the patient's age is approximately 66 years or older. In another instance, the patient's age is approximately 68 years or older. In another instance, the patient's age is approximately 70 years or older. In another instance, the patient's age is approximately 72 years or older. In another instance, the patient's age is approximately 74 years or older. In another instance, the patient's age is approximately 76 years or older. In another instance, the patient's age is approximately 78 years or older. In another instance, the patient's age is approximately 80 years or older. In another instance, the patient's age is approximately 85 years or older. In another instance, the patient's age is approximately 90 years or older. In another instance, the patient's age is approximately 95 years or older.In one embodiment, the patient's ethnicity may be African American, Native American or Alaskan Native, Asian American, Latino or Latino, or Native Hawaiian or Pacific Islander.

[0272] General synthesis method The compounds of the present invention can be prepared, for example, from readily available starting materials using general methods and procedures. When certain method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is recognized that other method conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the reactants or solvent used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0273] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0274] Furthermore, the compounds of the present invention may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or concentrated mixtures of stereoisomers. All such stereoisomers (and concentrated mixtures) are included within the scope of the present invention unless otherwise specified. Pure stereoisomers (or concentrated mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0275] 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, CA, USA), EMKA-Chemie Gmbh & Co. KG (Eching, Germany), or Millipore Sigma (Burlington, MA, USA). Others can be found in 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 Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), and March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 th It can be manufactured by the procedures described in standard reference books such as Edition, 2001, and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or by obvious modifications thereof. [Examples]

[0276] The present invention is further understood by reference to the following embodiments, which are intended to be pure examples of the invention. The scope of the invention is not limited by exemplary embodiments intended only to describe one aspect of the invention. Any functionally equivalent method is within the scope of the invention. In addition to those described herein, various modifications of the invention will be obvious to those skilled in the art from the foregoing and the accompanying drawings. Such modifications fall within the scope of the accompanying claims.

[0277] Abbreviations (used here): [Table 6]

[0278] General Information: Total evaporation or concentration was performed using a rotary evaporator under reduced pressure. Analytical samples were dried under reduced pressure (1–5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100–200 mesh). Solvent systems were reported as volumetric mixtures. NMR spectra were recorded using a Bruker 400 or Varian (400 MHz) spectrometer. 1 The H chemical shift is reported as a δ value (ppm) using the deuterated solvent as an internal standard. The data is reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broad, m=multilet), coupling constant (Hz), and integral. LCMS spectra were obtained by electrospray ionization using a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series, 6110 or 6120 mass spectrometer, with the exception of those otherwise indicated.

[0279] Example A1 3-((1S,2S)-1-(2-((S)-3-(3-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 1, compound 102) 3-3-((1S,2S)-1-(2-((S)-3-(3-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 2, compound 103) [ka] [ka] Step A: Ethyl (4-bromo-2-fluorophenyl)phosphinate [ka] To a mixture of 4-bromo-2-fluoro-1-iodobenzene (10 g, 33.23 mmol) in THF (150 mL), i-PrMgCl (2 M, 16.62 mL) was added under Ar at -20°C. The solution was then stirred at -20°C for 1 hour. A solution of chloro(diethoxy)phosphan (4.75 mL, 33.23 mmol) in THF (10 mL) was slowly added at -20°C. After addition, the mixture was stirred at 20°C for 12 hours. The reaction mixture was adjusted to pH=2 with 1N HCl, stirred at 20°C for 10 minutes, and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with saturated aqueous solution NaHCO3 (80 mL x 3) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, 60 mL / min with a 0-100% ethyl acetate / petroleum ether gradient eluent) to obtain ethyl (4-bromo-2-fluorophenyl) phosphinate (5.0 g, 56% yield). 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.64 (m, 1H), 7.63 (d, J= 591.6 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 4.24 - 4.06 (m, 2H), 1.34 (t, J= 7.2 Hz, 3H). 31 1P NMR (CDCI3): δ15.1 (d).

[0280] Step B: (4-bromo-2-fluorophenyl)(ethyl)phosphine oxide [ka] To a mixture of EtMgBr (3M, 9.99mL) in THF (20mL), a solution of ethyl (4-bromo-2-fluorophenyl)phosphine (4g, 14.98 mmol) in THF (10mL) was slowly added at 0°C under N2 conditions. The solution was stirred at 20°C for 2 hours. The reaction mixture was quenched with saturated aqueous solution NH4Cl (30mL) and extracted with ethyl acetate (80mL x 3). The combined organic layers were washed with brine (60mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, 30mL / min with a 0-100% ethyl acetate / petroleum ether gradient eluent) to obtain (4-bromo-2-fluorophenyl)(ethyl)phosphine oxide (1.4g, 37% yield). 1 H NMR (400 MHz, CDCl3) δ 7.73 (td, J= 7.2, 12.4 Hz, 1H), 7.62 (d, J= 485.2 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.36 - 7.33 (m, 1H), 2.27 - 2.05 (m, 2H), 1.29 - 1.13 (m, 3H). 31 1P NMR (CDCI3): δ19.2 (s).

[0281] Step C: (4-bromo-2-fluorophenyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide [ka] To a mixture of (4-bromo-2-fluorophenyl)(ethyl)phosphine oxide (0.2 g, 796.71 μmol) in THF (5 mL), LDA (2 M, 438.19 μL) was added under N2 conditions at -70°C. After stirring at -70°C for 1 hour, tert-butyl-(2-iodoethoxy)-dimethyl-silane (296.45 mg, 1.04 mmol) was added to the mixture at -70°C. After addition, the mixture was stirred at 20°C for 12 hours, saturated aqueous solution NH4Cl (10 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (PE / EA = 1 / 1) to obtain (4-bromo-2-fluorophenyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (240 mg, 74% yield). LC-MS: m / z 409.1 (M+H) + .

[0282] Process D: 5-Bromo-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-N-methyl-aniline [ka] To a solution of (4-bromo-2-fluorophenyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (150 mg, 366.44 μmol) in toluene (1.5 mL), MeNH2 (2 M in THF, 5.50 mL) was added, and the reaction mixture was stirred at 130 °C for 1.5 hours using a Biotage Initiator microwave. After cooling, the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, PE / EA / MeOH = 1 / 2 / 0.1, 20 mL / min) to obtain 5-bromo-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-N-methyl-aniline (50 mg, 32% yield). 1H NMR (400 MHz, CDCl3) δ 7.49 (br s, 1H), 6.87 (dd, J= 8.4, 13.2 Hz, 1H), 6.78 - 6.68 (m, 2H), 4.04 - 3.97 (m, 1H), 3.84 -3.78 (m, 1H), 2.78 (d, J= 4.8 Hz, 3H), 2.25 - 2.17 (m, 2H), 2.12 - 1.93 (m, 2H), 1.15 (td, J= 7.6, 17.6 Hz, 3H), 0.89 - 0.85 (m, 9H), 0.04 (d, J= 4.8 Hz, 6H).LC-MS: m / z 420.1(M+H) + .

[0283] Process E: (4S)-3-[3-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-3-(methylamino)phenyl]-2-oxo-imidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate [ka] A mixture of 5-bromo-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-N-methyl-aniline (320 mg, 761.19 μmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (302.46 mg, 685.07 μmol) in NMP (25 mL) is mixed with K2CO3 (210.40 mg, 1.52 mmol), CuI (217.45 mg, 1.14 mmol), and (1S,2S)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (162.41 mg, 1.14 mmol) was added under Ar at 20°C. The mixture was then stirred at 130°C for 3 hours. After cooling, the reaction mixture was diluted with H2O (30 mL) and extracted with dimethylcyclohexane (80 mL x 3). The organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (PE / EA / MeOH = 1 / 2 / 0.1) to obtain tert-butyl (4S)-3-[3-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-3-(methylamino)phenyl]-2-oxo-imidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (350 mg, 59% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.59 (m, 1H), 7.35 (d, J= 3.2 Hz, 1H), 7.29 (dd, J= 8.4, 13.2 Hz, 1H), 7.10 (d, J= 6.4 Hz, 2H), 6.98 (br s, 1H), 6.90 - 6.89 (m, 1H), 6.88 - 6.86 (m, 1H), 5.25 - 5.02 (m, 1H), 4.35 - 4.14 (m, 1H), 3.93 - 3.82 (m, 1H), 3.81 - 3.71 (m, 1H), 3.27 - 2.91 (m, 1H), 2.79 - 2.60 (m, 5H), 2.28 - 2.20 (m, 2H), 2.18 (s, 6H), 1.98 - 1.92 (m, 2H), 1.43 (s, 9H), 1.18 - 1.16 (m, 3H), 0.98 (td, J= 7.6, 17.4 Hz, 3H), 0.79 (s, 9H), -0.02 (d, J= 4.8 Hz, 6H). 31 P NMR(DMSO-d6) δ48.6 (s). LC-MS: m / z 781.7(M+H) + .

[0284] Step F: tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (first eluted enantiomer: 2-1a) and tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (second enantiomer: 2-1b) [ka] tert-butyl (4S)-3-[3-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl-ethyl-phosphoryl]-3-(methylamino)phenyl]-2-oxo-imidazole-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (450 mg, 576.20 μmol) was purified by SFC (column: REGIS(S,S)WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase A (supercritical CO2), mobile phase B (EtOH (MeOH solution of 0.1% 7.0 M ammonia); B%: 40%, fixed composition elution mode) to obtain tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (first eluting enantiomer: 2-1a) (160 mg, 34% yield, 97% purity) eluted with a rapid eluent (R t =2.46min)(LC-MS: m / z 781.5(M+H) + ) and tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (second eluting enantiomer: 2-1b) (200 mg, 44% yield, 99% purity) as the second eluent (R t =2.78 min)(LC-MS: m / z 781.5(M+H) + ) was obtained as follows.

[0285] Process G: 1-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one [ka] A mixture of tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (first eluted enantiomer: 2-1a) (160.00 mg, 204.87 μmol) in dioxane (1 mL) was mixed with HCl / dioxane (4 M, 20 mL) at 20°C. The mixture was then stirred at 20°C for 12 hours. The reaction mixture was concentrated to obtain crude 1-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one (2-2a) (170 mg, HCl salt). LC-MS: m / z 567.3 (M+H) + .

[0286] Process H: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one enantiomer 1 (compound 102) [ka] 1-(4-((S)-ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one HCl salt (2-2a) (100.00 mg, 165.82 μmol) A mixture of 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-tetrahydropyran-4-ylindole-2-carboxylic acid (63.57 mg, 165.82 μmol) in DMF (4 mL) was mixed with DIEA (85.72 mg, 663.28 μmol) and HATU (75.66 mg, 198.98 μmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain a crude product. The crude product was subjected to preparative HPLC (column: Xtimate C18). The sample was purified using a 150*40mm*10μm mobile phase (water (0.1% formic acid)-CH3CN) gradient (52%~82% B over 7 minutes), and then 3-((1S,2S)-1-(2-((S)-3-(3-(4-((S)-ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro We obtained (-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one enantiomer 1 (compound 102) (40.5 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.60 (br s, 1H), 7.66 - 7.52 (m, 1H), 7.51 - 7.40 (m, 1H), 7.39 - 7.19 (m, 3H), 7.16 (d, J= 5.6 Hz, 2H), 7.05 - 6.62 (m, 4H), 5.68 - 5.12 (m, 1H), 4.59 - 4.35 (m, 1H), 3.96 (d, J= 10.4 Hz, 2H), 3.76 - 3.40 (m, 7H), 3.21 - 2.81 (m, 3H), 2.74 (s, 3H), 2.26 - 2.10 (m, 8H), 2.05 - 1.89 (m, 2H), 1.71 (br s, 7H), 1.54 - 1.31 (m, 3H), 1.14 (d, J= 5.6 Hz, 3H), 1.06 - 0.93 (m, 3H). 31 P NMR(DMSO-d6) δ49.0 (s). LC-MS: m / z 932.4(M+H) + .

[0287] Step I: 1-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one [ka] A mixture of tert-butyl (S)-3-(3-(4-((2-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (second enantiomer: 2-1b) (200 mg, 256.09 μmol) in dioxane (1 mL) was mixed with HCl / dioxane (4 M, 64.02 μL) at 20°C. The mixture was then stirred at 20°C for 12 hours. The reaction mixture was concentrated to obtain crude 1-(4-((R)-ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one(2-2b) (200 mg, HCl salt). LC-MS: m / z 567.2 (M+H) + .

[0288] Process J: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one enantiomer 2 (compound 103) [ka] 1-(4-((R)-ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one HCl salt (2-2b) (100.00 mg, 165.82 μmol) A mixture of 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-tetrahydropyran-4-ylindole-2-carboxylic acid (63.57 mg, 165.82 μmol) in DMF (3 mL) was mixed with DIEA (85.72 mg, 663.28 μmol) and HATU (75.66 mg, 198.98 μmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain a crude product. The crude product was subjected to preparative HPLC (column: Xtimate C18). 150*40mm*10μm; Mobile phase: [Water (0.1% formic acid)-CH3CN]; Gradient: 52%~82% B over 7 minutes) Purified, 3-((1S,2S)-1-(2-((S)-3-(3-(4-((R)-ethyl(2-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4- Fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (compound 103) (50.5 mg, 31% yield) was obtained. 11H NMR (400 MHz, DMSO-d6) δ 11.6 (br s, 1H), 7.67 - 7.53 (m, 1H), 7.51 - 7.40 (m, 1H), 7.40 - 7.21 (m, 3H), 7.19 - 7.07 (m, 2H), 7.06 - 6.64 (m, 4H), 5.77 - 5.16 (m, 1H), 4.79 - 4.56 (m, 1H), 3.96 (d, J = 10.4 Hz, 2H), 3.80 - 3.34 (m, 7H), 3.22 - 2.79 (m, 3H), 2.74 (d, J = 4.0 Hz, 3H), 2.22 (br s, 8H), 2.04 - 1.91 (m, 2H), 1.84 - 1.57 (m, 7H), 1.56 - 1.34 (m, 3H), 1.32 - 1.12 (m, 3H), 1.07 - 0.93 (m, 3H). 31 31P NMR (DMSO-d6) δ 49.0 (s). LC-MS: m / z 932.4 (M + H) + .

[0289] Example A2 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazo Lu-5(4H)-one (enantiomer 1, compound 105), 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)- 2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 2, compound 106), 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2 H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 3, compound 107) and 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 4, compound 108), [ka] [ka] [ka] Step A: (4-bromo-2-fluorophenyl)(ethyl)(1-hydroxyethyl)phosphine oxide [ka] To a mixture of (4-bromo-2-fluorophenyl)(ethyl)phosphine oxide (0.4 g, 1.59 mmol) in THF (10 mL), LDA (2 M, 876.38 μL) was added under N2 conditions at -70°C. After stirring at -70°C for 1 hour, acetaldehyde (5 M, 478.03 μL, 2.39 mmol in THF) was added at -70°C. After the addition, the reaction mixture was stirred at 20°C for 2 hours. Next, the mixture was quenched with saturated aqueous solution NH4Cl (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product (480 mg). The crude product was used directly in the next step.

[0290] Step B: (4-bromo-2-fluorophenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide [ka] To a mixture of (4-bromo-2-fluorophenyl)(ethyl)(1-hydroxyethyl)phosphine oxide (0.48 g, 1.63 mmol) and imidazole (221.48 mg, 3.25 mmol) in DMF (10 mL), tert-butyl-chloro-dimethyl-silane (367.76 mg, 2.44 mmol) was added at 0°C under N2. The resulting mixture was stirred at 45°C for 12 hours. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, 30 mL / min with a 0-100% siRNA / PE gradient eluent) to obtain (4-bromo-2-fluorophenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (0.2 g, 30% yield). 1 H NMR (400 MHz, CDCl3) δ 7.87 - 7.83 (m, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.30 - 7.28 (m, 1H), 4.25 -4.16 (m, 1H), 2.22 - 2.19 (m, 1H), 2.09 - 2.05 (m, 1H), 1.41 (dd, J= 6.8, 15.2 Hz, 1H), 1.19 - 1.11 (m, 3H), 0.88 (s, 9H), 0.04 (s, 3H), -0.09 (s, 3H). 31 1P NMR (CDCI3) δ43.6 (s).

[0291] Step C: (4-bromo-2-(methylamino)phenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide [ka] A mixture of DIEA (3.32 g, 25.65 mmol, 4.47 mL) and methaneamine hydrochloride (1.48 g, 21.99 mmol) in MeOH (4 mL) and DMSO (2 mL) was stirred at 20°C for 0.5 hours, and then (4-bromo-2-fluorophenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (300 mg, 732.88 μmol) was added under N2 at 20°C. The mixture was then stirred at 80°C for 1.5 hours. After cooling, the reaction mixture was diluted with H2O (30 mL) and extracted with ELISA (80 mL x 3). The organic layer was washed with brine (50 ml x 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, 30 mL / min with a 0-100% siRNA / PE gradient eluent) to obtain (4-bromo-2-(methylamino)phenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (60 mg, 5% yield).

[0292] Process D: (4-bromo-2-(methylamino)phenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (4 isomers, peak 1 is shown as 4-1a, peak 2 as 4-1b, peak 3 as 4-1c, and peak 4 as 4-1d) [ka] (4-bromo-2-(methylamino)phenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (590 mg, 1.17 mmol) was separated by SFC (conditions: column: Chiralpak IH, 250*30 mm, 10 μm; mobile phase A (supercritical CO2), mobile phase B (EtOH (MeOH solution of 0.1% 7.0 M ammonia); B%: 5%, fixed composition elution mode) to obtain 4-1a and 4-1b (peaks 1 and 2, 460 mg), and 4-1c (peak 3, R t= 1.427 mins, 36 mg) and 4-1 day (peak 4, R t A mixture of 1.622 mins (41 mg) was obtained.

[0293] The mixture of 4-1a and 4-1b (peaks 1 and 2, 460 mg) was further separated by SFC (conditions: column: Chiralpak IH, 250*30 mm, 10 μm; mobile phase A (supercritical CO2), mobile phase B (EtOH (MeOH solution of 0.1% 7.0 M ammonia); B%: 5%, fixed composition elution mode) to obtain 4-1a (peak 1, R t =1.160 min, 200 mg) and 4-1b (peak 2, R t A mixture of 1.202 mins (210 mg) was obtained.

[0294] Step E: tert-butyl (S)-3-(3-(4-((1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate 4-2a [ka] A mixture of (4-bromo-2-(methylamino)phenyl)(1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphine oxide (peak 1, 200.00 mg, 475.74 μmol) and tert-butyl (4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-1H-imidazole-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (189.04 mg, 428.17 μmol) in NMP (20 mL) contains K2CO3 (131.50 mg, 951.48 μmol), CuI (135.91 mg, 713.61 μmol), and (1S,2S)-N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (101.51 mg, 713.61 μmol) was added under Ar at 20°C. The mixture was then stirred at 130°C for 3 hours. After cooling, the reaction mixture was diluted with H2O (30 mL) and extracted with dimethylcyclohexane (80 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (PE / EA / MeOH = 1 / 2 / 0.1) to obtain tert-butyl(S)-3-(3-(4-((1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (230 mg, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 - 7.52 (m, 1H), 7.36 (d, J= 3.2 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.10 (d, J= 6.0 Hz, 2H), 6.98 (s, 1H), 6.89 - 6.88 (m, 2H), 5.22 - 5.20 (m, 1H), 4.20 - 4.14 (m, 2H), 3.14 (br s, 1H), 2.73 - 2.70 (m, 3H), 2.69 (br s, 1H), 2.19 - 2.17 (m, 7H), 2.07 - 2.00 (m, 1H), 1.98 - 1.95 (m, 1H), 1.32 (s, 9H), 1.28 - 1.27 (m, 3H), 1.19 - 1.17 (m, 3H), 1.06 - 1.03 (m, 3H), 0.82 (s, 9H), 0.00 (s, 3H), -0.18 (s, 3H). 31 1P NMR (CDCI3) δ 51.5 (s).

[0295] Process F: 1-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one 4-3a [ka] A mixture of tert-butyl (S)-3-(3-(4-((1-((tert-butyldimethylsilyl)oxy)ethyl)(ethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (190.00 mg, 243.28 μmol) in dioxane (1 mL) was mixed with HCl / dioxane (4 M, 20 mL) at 20 °C. The mixture was then stirred at 20 °C for 24 hours. The reaction mixture was concentrated to obtain crude 1-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazole-2-one (150 mg, HCl salt).

[0296] Process G: 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 1, compound 105) [ka] 1-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-yl)-1,3-dihydro-2H-imidazole-2-one HCl salt (100.00 mg, 165.82 μmol) and 1-[( To a mixture of 1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazole-3-yl)cyclopropyl]-5-tetrahydropyran-4-ylindole-2-carboxylic acid (63.57 mg, 165.82 μmol) in DMF (4 mL), DIEA (85.72 mg, 663.28 μmol) and HATU (75.66 mg, 198.98 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain the crude product. The crude product was subjected to preparative HPLC (column: Xtimate C18). 150*40mm*10μm; Mobile phase: [Water (0.1% formic acid)-CH3CN]; Gradient: 52%~82% B over 7 minutes) Purified, 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro- 3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 1, compound 105) (38 mg, 24% yield) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br s, 1H), 7.52 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.33 - 7.18 (m, 3H), 7.14 (d, J= 6.0 Hz, 2H), 6.85 (br s, 4H), 5.80 - 5.41 (m, 1H), 4.58 - 4.34 (m, 1H), 4.06 - 3.95 (m, 3H), 3.87 - 3.43 (m, 5H), 2.93 - 2.82 (m, 3H), 2.72 (br s, 3H), 2.22 (s, 6H), 2.09 - 1.96 (m, 2H), 1.83 - 1.59 (m, 7H), 1.43 (br s, 3H), 1.29 (dd, J= 7.2, 14.5 Hz, 4H), 1.17 (br s, 2H), 1.10 - 1.01 (m, 3H). 31 P NMR(DMSO-d6) δ 51.5 (s). LC-MS: m / z 932.2(M+H) + .

[0297] Example compounds 106, 107, and 108 were synthesized using appropriate materials and a procedure similar to that of Example compound 105.

[0298] 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 2, compound 106) Preparative HPLC conditions (Column: Xtimate C18 150*40mm*10μm; Mobile phase: [Water (0.1% formic acid)-CH3CN]; Gradient: 52%~82% B over 7 minutes).

[0299] 1H NMR (400 MHz, DMSO-d6) δ 11.45 (m, 1H), 7.69 (br s, 1H), 7.56 - 7.46 (m, 1H), 7.41 - 7.27 (m, 3H), 7.15 (d, J= 5.6 Hz, 2H), 7.05 - 6.77 (m, 4H), 5.55 (d, J= 7.3 Hz, 1H), 4.38 (d, J= 8.6 Hz, 1H), 4.01 - 3.92 (m, 3H), 3.67 - 3.35 (m, 5H), 2.87 (d, J= 19.6 Hz, 3H), 2.73 (s, 3H), 2.21 (br s, 6H), 2.04 - 1.97 (m, 2H), 1.76 - 1.65 (m, 6H), 1.62 (d, J= 4.8 Hz, 1H), 1.51 (d, J= 6.8 Hz, 1H), 1.37 (d, J= 6.2 Hz, 2H), 1.25 (dd, J= 6.8, 14.4 Hz, 4H), 1.14 (d, J= 5.6 Hz, 2H), 1.05 - 0.97 (m, 3H). 31 P NMR(DMSO-d6) δ 51.4 (s). LC-MS: m / z 932.4(M+H) + . 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 3, compound 107)

[0300] Preparative HPLC conditions (Column: Xtimate C18 150*40mm*10μm; Mobile phase: [Water (0.1% formic acid)-CH3CN]; Gradient: 52%~82% B over 7 minutes).

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.61 (br s, 1H), 7.51 (br s, 1H), 7.41 (d, J= 9.2 Hz, 1H), 7.34 (br s, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.14 (d, J= 5.6 Hz, 2H), 6.85 (br s, 4H), 5.42 (br s, 1H), 4.42 (br s, 1H), 4.06 (br s, 1H), 3.97 (d, J= 9.6 Hz, 2H), 3.75 - 3.15 (m, 5H), 2.86 (br s, 3H), 2.71 (br s, 3H), 2.21 (s, 6H), 2.06 - 1.96 (m, 2H), 1.74 (br s, 7H), 1.41 (br s, 3H), 1.30 - 1.23 (m, 4H), 1.21 (br d, J= 6.8 Hz, 2H), 1.06 (dd, J=7.6, 15.9 Hz, 3H). 31 P NMR(DMSO-d6) δ 52.8 (s). LC-MS: m / z 932.3(M+H) + .

[0302] 3-((1S,2S)-1-(2-((4S)-3-(3-(4-(ethyl(1-hydroxyethyl)phosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazole-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazole-5(4H)-one (enantiomer 4, compound 108) Preparative HPLC conditions (Column: Xtimate C18 150*40mm*10μm; Mobile phase: [Water (0.1% formic acid)-CH3CN]; Gradient: 52%~82% B over 7 minutes).

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (m, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 6.8 Hz, 1H), 7.26 (d, J= 8.8 Hz, 1H), 7.15 (d, J= 5.6 Hz, 2H), 6.86 (br s, 4H), 5.57 - 5.38 (m, 1H), 4.62 - 4.28 (m, 1H), 4.11 - 4.03 (m, 1H), 3.97 (d, J= 10.8 Hz, 2H), 3.73 - 3.11 (m, 5H), 3.04 - 2.81 (m, 3H), 2.71 (br s, 3H), 2.22 (s, 6H), 2.07 - 1.94 (m, 2H), 1.80 - 1.59 (m, 7H), 1.43 (br s, 3H), 1.23 (dd, J= 7.2, 15.0 Hz, 4H), 1.19 - 1.11 (m, 2H), 1.10 - 1.01 (m, 3H). 31 P NMR(DMSO-d6) δ 52.8 (s). LC-MS: m / z 932.3(M+H) + .

[0304] Biological examples Biological Example 1: CAMP Assay Activation of the GLP-1 receptor is known to stimulate cyclic AMP (cAMP) production in cells, which indicates primary coupling of the G protein heterotrimer complex to the Gαs subunit. Evidence suggests that signaling mediated by Gαs-induced cAMP stimulation triggers the desired pharmacological response for insulin release from pancreatic β-cells.

[0305] To optimize functional activity for Gαs coupling, we used the HEK293 / CRE-Luc cell line developed by HDBs that stably express the GLP-1 receptor. A 200× concentration compound working solution was prepared (Agilent Technologies Bravo) and serially diluted by 1 / 2 log in a 384-well Echo LDV plate (Labcyte, Cat#LP-0200). 50 nL / well of the 200× concentration compound working solution was transferred to a 384-well white low-volume plate (Greiner, Cat#784075) using Labcyte ECHO550. 1×10⁶ assay buffers prepared in DPBS containing 0.5 mM IBMX (Sigma, Cat#I5879) and 0.1% BSA (GENVIEW, Cat#FA016-100g) were used. 5 10 μL of the HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension was added to each well of a pre-prepared assay plate containing 50 nL of a 200× concentration compound using a ThermoFisher Multidrop Combi (1000 cells / well). The plate was sealed and incubated at 37°C in 5% CO2 for 30 minutes.

[0306] After incubation, cAMP assay signals were prepared using the cAMP dynamic 2 Kit (Cisbio). 5 μL of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-cryptate working solution, which was added to each well using a ThermoFisher Multidrop Combi. The mixture was incubated at room temperature for 1 hour in the dark. Fluorescence at 665 and 615 nm was read using a Reader PerkinElmer EnVision.

number

[0307] Table 3 shows the results of the GLP-1R agonist cAMP stimulation assay (EC 50 This shows the biological activity of the compound in ).

[0308] Table 6

Claims

1. Formula I: 【Chemistry 1】 [In the formula, R １ and R ２ Each is independently C １－３ It is alkyl or cyclopropyl. Compounds thereof, their stereoisomers or mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.

2. R １ The compound according to claim 1, wherein is methyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

3. R １ The compound according to claim 1, wherein is ethyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

4. R １ The compound according to claim 1, wherein n-propyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

5. R １ The compound according to claim 1, wherein i-propyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

6. R １ The compound according to claim 1, wherein is cyclopropyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

7. R ２ The compound according to any one of claims 1 to 6, wherein R is methyl, or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

8. R ２ A compound according to any one of claims 1 to 6, wherein is ethyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

9. R ２ A compound according to any one of claims 1 to 6, wherein n is n-propyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

10. R ２ A compound according to any one of claims 1 to 6, wherein i-propyl, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

11. R ２ A compound according to any one of claims 1 to 6, wherein is cyclopropyl, or a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

12. Compound IA: 【Chemistry 2】 The compound described in claim 1, or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

13. Compound IB: 【Transformation 3】 The compound described in claim 1, or its stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 4】 A compound selected from, or a pharmaceutically acceptable salt thereof.

15. The compound, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein the compound, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof is substantially isolated.

16. The compound, its stereoisomer or stereoisomer mixture, or its pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein the compound, its stereoisomer or stereoisomer mixture, or its pharmaceutically acceptable salt is substantially solid.

17. A composition comprising a compound according to any one of claims 1 to 16, having a purity of more than approximately 75%, or more than approximately 80%, or more than approximately 85%, or more than approximately 90%, or more than approximately 95%, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

18. A composition comprising a compound according to any one of claims 1 to 16, a stereoisomer or stereoisomer mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound, its stereoisomer or stereoisomer mixture, or a pharmaceutically acceptable salt thereof is present in the composition in an amount of more than 25%, more than 50%, or more than 75% by weight.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, a stereoisomer or mixture thereof, a pharmaceutically acceptable salt thereof, or a composition according to claim 17 or 18, and a pharmaceutically acceptable additive.

20. The pharmaceutical composition according to claim 19, wherein a compound, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof is present in the composition in an amount of more than about 0.1% by weight.

21. The pharmaceutical composition according to claim 19 or 20, wherein the pharmaceutical composition comprises a further therapeutic agent.

22. Further treatments 【Transformation 5】 The pharmaceutical composition according to claim 21.

23. A method for treating a GLP-1 related disease, disorder, or condition, comprising administering to a patient in need an effective amount of any one of claims 1 to 16, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the composition according to claim 17 or 18, or the pharmaceutical composition according to any one of claims 19 to 22.

24. The disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity, weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, or gestational diabetes. Kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial steatosis, metabolic a The method according to claim 23, selected from the group consisting of sidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

25. A method for reducing body weight, comprising administering to a patient in need of such reduction an effective amount of any one of claims 1 to 16, a stereoisomer or mixture thereof, a pharmaceutically acceptable salt thereof, a composition according to claim 17 or 18, or a pharmaceutical composition according to any one of claims 19 to 22.

26. The method according to any one of claims 23 to 25, further comprising administering a further therapeutic agent to the patient.

27. Further treatments: 【Transformation 6】 The method according to claim 26.

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