Heterocyclic GLP-1 agonist

Abstract

This invention provides compounds for treating type 2 diabetes in patients. [Solution] The following GLP-1 agonists (including pharmaceutically acceptable salts and solvates thereof) and pharmaceutical compositions containing the same are provided. JPEG2026076168000258.jpg4691

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of International Patent Application No. PCT / CN2020 / 075105, filed on 13 February 2020; and International Patent Application No. PCT / CN2020 / 075103, filed on 13 February 2020 (each of these is incorporated herein by reference in whole).

[0002] Technical field This disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of using them. [Background technology]

[0003] 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 gastric tubal peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, reduce gastric motility, and increase satiety.

[0004] Diabetes mellitus refers to a group of metabolic diseases characterized by persistently high blood sugar levels. The most common type, type 2 diabetes mellitus (T2DM), is an acquired disease that accounts for over 90% of diabetes cases. Typical onset occurs in obese or sedentary adults and begins with insulin resistance. While lifestyle changes can be helpful in managing the disease, T2DM patients may need to take diabetes medications, including, among others, dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0005] In a healthy individual, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) provide regulation of the insulin secretory response to glucose digestion. This incretin effect is markedly reduced in the case of T2DM (in all cases), but GLP-1 retains its insulin secretory properties even when the endocrine pancreatic response to GIP is effectively abolished. Thus, incretin mimetics and other GLP-1-based therapies can assist in activating insulin production in patients with T2DM.

Summary of the Invention

[0006] This application describes heterocyclic GLP-1 agonists and pharmaceutical compositions containing the compounds disclosed herein. Methods for treating diseases, disorders, and conditions related to GLP-1 are also provided.

[0007] Thus, formula I:

Chemical Formula

Chemical Formula

[0008] Formula II: [ka] Formula II [In the formula, [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from C, CH, and N, except X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2(C1-C6) alkyl which may be appropriately substituted with (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, and each of the (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is, 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R Y 5-6 member heteroarylenes which may be substituted as appropriate. Selected from the group consisting of, mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and Each R Yis independently selected from the group consisting of halogen, cyano, -OH, oxo, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, and (C1-C3) haloalkoxy; Ring B is

Chemical formula

[0009] Also provided herein is a pharmaceutical composition comprising a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0010] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method of treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0012] A method for treating diabetes in a patient is also provided, comprising: determining that the patient has type 2 diabetes; and then administering to the patient a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In one embodiment, the step of determining that the patient has type 2 diabetes includes performing an assay to determine the level of an analyte in a sample from a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof. In one embodiment, the HbA1c level is about 6.5% or higher. In one embodiment, the fasting blood glucose level is about 126 mg / dL or higher. In one embodiment, the non-fasting blood glucose level is about 200 mg / dL or higher.

[0013] 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 or having a body mass index (BMI) of approximately 30 kg / m². In one embodiment, the patient has a BMI of approximately 30 kg / m². 2 Having a BMI of or higher.

[0014] In one embodiment, the method for treating type 2 diabetes includes reducing fasting blood glucose levels. In one embodiment, the fasting blood glucose level is reduced to about 100 mg / dL or less.

[0015] In one embodiment, the treatment method for type 2 diabetes includes reducing the HbA1c level. In one embodiment, the HbA1c level is reduced to about 5.7% or less.

[0016] In one embodiment, the method for treating type 2 diabetes includes reducing glucagon levels.

[0017] In one embodiment, the method for treating type 2 diabetes includes reducing insulin levels.

[0018] In one embodiment, the treatment method for type 2 diabetes includes reducing BMI. In one embodiment, the BMI is approximately 25 kg / m². 2 Or reduce it to less than that.

[0019] In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0020] In one embodiment, the method for treating type 2 diabetes further comprises administering a further therapy or therapeutic agent to the patient. In one embodiment, the further therapy or therapeutic agent is selected from the group consisting of antidiabetic drugs, anti-obesity drugs, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) drugs, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In one embodiment, the antidiabetic drug is selected from the group consisting of biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic polypeptides (GIPs), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-dependent glucose transporter 1 (SGLT1) inhibitors, or any combination thereof. In one embodiment, the biguanide is metformin. In one embodiment, the anti-obesity drug is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, or a human proislet peptide. The following are selected from the group consisting of (HIP) peptides (HIP), cannabinoid receptor 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, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modifiers, AMP-activated protein kinase (AMPK) activators, sodium-glucose transporter 1 (SGLT-1) inhibitors, 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 analog 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-regulated kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof. In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and further therapeutic agents are administered sequentially in any order as separate formulations.

[0021] Also provided herein is a method for regulating insulin levels in a patient requiring regulation, comprising administering to the patient an effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In one embodiment, the regulation results in an increase in insulin levels.

[0022] Also provided herein is a method for regulating glucose levels in a patient requiring regulation, comprising administering to the patient an effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In one embodiment, the regulation results in a decrease in glucose levels.

[0023] Also provided herein are methods for treating GLP-1 related disorders, conditions, or diseases, comprising administering an effective amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, to a patient in need. In some embodiments, the disorders, conditions, or diseases include type 1 diabetes, type 2 diabetes, juvenile-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 intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, and kidney disease. Patients, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular diseases, 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 disorders, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hypertension The following conditions are selected from the group consisting of: dyslipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol intake 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, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic 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, the disease, disorder, or illness is type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other drugs, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, 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 hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism The following conditions are selected from the group consisting of: abnormalities, insulin resistance, hepatic insulin resistance, alcohol intake 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 ulcers, psoriasis, psychogenic 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, the diseases, disorders, or illnesses include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other drugs, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, 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 ulcers, or any combination thereof.

[0024] All publications, patents, and patent applications cited in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. Insofar as any incorporated publications, patents, and patent applications conflict with the disclosure contained herein, this specification shall prevail over and / or be superior to any such conflicting document.

[0025] Other features and advantages of the invention will be apparent from the following detailed description, drawings, and claims.

Mode for Carrying Out the Invention

[0026] Detailed Description Heterocyclic GLP-1 agonists for use in the treatment of T2DM and other diseases where activation of GLP-1 action is useful are provided herein.

[0027] Definitions When a numerical value is described as a range, all possible sub-ranges within such range, as well as descriptions of specific numerical values within such range, are understood to be included regardless of whether the specific numerical values or specific sub-ranges are explicitly indicated.

[0028] As used herein, the term "halo" or "halogen" means -F (also referred to herein as "fluoro" or "fluorine"), -Cl (also referred to herein as "chloro" or "chlorine"), -Br (also referred to herein as "bromo" or "bromine"), and -I (also referred to herein as "iodo" or "iodine").

[0029] As used herein, the term “alkyl” means a saturated linear or branched monovalent hydrocarbon group containing the indicated number of carbon atoms. For example, “C1-C6 alkyl” means a saturated linear or branched monovalent hydrocarbon group containing 1 to 6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0030] As used herein, the term “alkylene” means a divalent alkyl group containing the indicated number of carbon atoms. For example, “C1-C3 alkylene” means a divalent alkyl group having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-). Similarly, the terms “cycloalkylene,” “heterocycloalkylene,” “arylene,” and “heteroarylene” mean divalent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.

[0031] As used herein, the term “alkenyl” means a linear or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, “C2-C6 alkenyl” means a linear or branched monounsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkenyls include ethenyl, propenyl, butenyl, or pentenyl.

[0032] As used herein, the term “alkynyl” means a linear or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, “C2-C6 alkynyl” means a linear or branched diunsaturated hydrocarbon chain containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0033] As used herein, the term “cycloalkyl” means a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, “C3-C6 cycloalkyl” means a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl may also be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyl include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyl may contain multiple condensed and / or crosslinked rings. Non-limiting examples of condensed / crosslinked cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, and bicyclo[2.2.2]octane. Cycloalkyls also include spiro rings (e.g., spirocyclic birings in which two rings are simply bonded by one atom). Non-restrictive examples of spirocyclic cycloalkyl compounds include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, and spiro[5.5]undecane.

[0034] As used herein, the term “heterocycloalkyl” means a monocyclic, dicyclic, tricyclic, or polycyclic non-aromatic ring group containing the indicated number of ring atoms, having 1 to 3 heteroatoms (for monocyclics), 1 to 6 heteroatoms (for dicyclics), or 1 to 9 heteroatoms (for tricyclics or polycyclics) (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered dicyclic, or an 11- to 14-membered tricyclic ring group), wherein the heteroatoms are selected from O, N, or S (e.g., for monocyclics, dicyclics, or tricyclics, a carbon atom and 1 to 3, 1 to 6, or 1 to 9 heteroatoms (N, O, or S) respectively), and 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. Non-limiting examples of partially unsaturated heterocycloalkyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, and dihydropyranyl. Heterocycloalkyls may contain multiple condensed and crosslinked rings.Non-limiting examples of condensed / crosslinked heterocyclils include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and 3-azabicyclo Examples include [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, and 3-oxabicyclo[3.2.1]octane. Heterocycloalkyls also include spiro rings (for example, spiro-type dicyclic rings in which two rings are simply joined by one atom).Non-restrictive examples of spiro ring heterocycloalkyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, and 2-oxaspiro[2 Examples include pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, and 3-oxa-9-azaspiro[5.5]undecane.

[0035] As used herein, the term "aryl" means a monocyclic, dicyclic, tricyclic, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, wherein at least one ring in the group is aromatic (e.g., C6 monocyclic, C6). 10 Biring, or C 14 This refers to a tricyclic aromatic ring group. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0036] As used herein, the term “heteroaryl” means a monocyclic, dicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms) and having 6, 10, or 14 pi electrons shared by a cyclic aryl, wherein at least one ring in the group is aromatic (it does not have to be a ring containing a heteroatom (e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)), and at least one ring in the group contains one or more heteroatoms independently selected from the group consisting of N, O, and S. The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, prinyl, thienopyridinyl, pyrido[2, Examples include [3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]diokine, benzo[d][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]xatiin, and isoindoline.

[0037] As used herein, the term “haloalkyl” means an alkyl group as defined herein in which one or more hydrogen atoms are substituted with one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0038] As used herein, the term “alkoxy” means an -O-alkyl group in which the group is located on an oxygen atom. For example, “C 1-6 "alkoxy" is -O-(C 1-6 The term "haloalkoxy" means an alkyl group in which the group is located on an oxygen atom. Examples of alkoxys include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" means an O-haloalkyl group in which the group is located on an oxygen atom.

[0039] As used herein, [ka] " indicates any single or double bond, such that the valence is acceptable. As used herein, [ka] The symbol '' indicates the bond point to the parent molecule.

[0040] As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown. Compounds identified by name or structure as one specific tautomer form herein include other tautomer forms unless otherwise specified.

[0041] As used herein, 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, thioazole, isoxazole, and isothiazole. When a ring group containing at least two rings is described as “aromatic,” it means that the ring group contains one or more aromatic rings. Therefore, when a ring group containing at least two rings is described as “non-aromatic,” it means that none of the constituent rings of the ring group are aromatic.

[0042] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more further degrees of unsaturation (in addition to the degree of unsaturation relating to 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, dihydrothiophene, and the like. When a ring group containing at least two rings is described as “partially unsaturated,” it means that the ring group contains one or more partially unsaturated rings, but none of the constituent rings of the ring group are aromatic.

[0043] As used herein, the term “carboxylic acid bioisoster” means a group that has chemical and physical similarities to a carboxylic acid, resulting in biological properties very similar to those of a carboxylic acid (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, p283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 25 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design: a initio Electronic Distributions In Bioisosteres"). Suitable carboxylic acid bioisosteres include sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, or heterocyclic phenols, such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.

[0044] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in an easily and rapidly equilibrium state. Compounds provided herein may be shown as different tautomers, and if a compound has tautomer forms, all tautomer forms are considered to be within the scope of the present invention. It is understood that the names of compounds do not exclude tautomers.

[0045] As used herein, the terms “GLP-1R” or “GLP-1 receptor” 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, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0046] As used herein, the term “GLP-1 related disease” includes, but is not limited to, all diseases, disorders, or illnesses in which modulation of glucagon-like peptide 1 (GLP-1) receptor signaling alters the pathophysiology and / or symptoms and / or progression of the disease.

[0047] As used herein, the terms “GLP-1 agonist” or “GLP-1RA” refer to agonists of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels 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-1RAs have been shown to treat type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, albiglutide (TANZEMM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXMMIA®), semaglutide (OZEMPIC®), tilzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. For example, U.S. Patent Nos. 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE453 See also further GLP-1 receptor agonists described in publications 13; and international publications WO2019 / 239319; WO2019 / 239371; WO2020 / 103815; WO2020 / 207474; WO20202 / 34726; WO2020 / 044266; WO2020117987; and WO2020263695.

[0048] As used herein, the term “pharmaceutically acceptable” means that a compound, or a salt thereof, or a composition thereof, is chemically and / or toxicologically compatible with other components, including the formulation, and / or the patient being treated.

[0049] As used herein, the term “therapeutic compound” includes, but is not limited to, all compounds of formula I or II, or their pharmaceutically acceptable salts or solvates (e.g., any one of formulas IA and IB, or any one of formulas IIA, IIB, and IIC, or their pharmaceutically acceptable salts or solvates), as well as all compositions (e.g., pharmaceutical compositions) in which a compound of formula I or II or its pharmaceutically acceptable salt or solvate (e.g., any one of formulas IA and IB, or any one of formulas IIA, IIB, and IIC, or their pharmaceutically acceptable salt or solvate) is a component of the composition.

[0050] The term "administer" or "to administer" means a method for imparting a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can be varied depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0051] As used herein, the terms “effective dose,” “effective dosage,” “pharmaceutically effective amount,” or “therapeutic effective dose” mean a sufficient amount of a chemical substance administered (e.g., a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB, or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof)) that may reduce to some extent one or more symptoms of the disease or illness being treated, and may include curing the disease. “Cure” means that the active symptoms of the disease are eliminated. Such results include reduction and / or mitigation of the signs, symptoms or etiology of the disease, or any other desired change in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” dose in each case is determined using any appropriate technique, such as a dose escalation study. In one embodiment, the “therapeutic effective amount” of a compound provided herein means the amount of the compound that is effective as monotherapy or in combination therapy.

[0052] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid extender, diluent, carrier, solvent, or capsule material. In some embodiments, each component is “pharmaceutically acceptable” in the sense that it is compatible with the other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and with a reasonable balance of benefits / risks. 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.

[0053] The term “pharmaceutical composition” means a mixture of a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB, or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) and other chemical components (collectively referred to herein as “excipients”), such as carriers, stabilizers, diluents, dispersants, suspenders, and / or fillers. Pharmaceutical compositions facilitate the administration of compounds to living organisms. Many techniques for administering compounds exist, including, but are not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0054] In the context of treating a disease, disorder, or illness, the terms “to treat,” “treating,” and “treatment” include reducing or suppressing one or more symptoms of the disorder, disorder, or illness, or associated with the said disorder, disorder, or illness; or slowing the progression, spread, or worsening of the disease, disorder, or illness, or one or more symptoms thereof.

[0055] As used herein, the term “prevent” means to prevent the onset, recurrence, or spread of a disease or illness described herein, or any symptom thereof, in whole or in part.

[0056] As used herein, the terms “subject,” “patient,” or “individual” are interchangeable and mean any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the terms “subject” mean, in particular, a mammalian subject for which diagnosis, prognosis, or treatment is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease, disorder, or illness for which treatment and / or prevention is desired.

[0057] The terms “treatment plan” and “medication regimen” are interchangeable to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0058] As used herein, the term “medical combination” means a medical treatment which involves mixing or combining one or more active ingredients, and includes both fixed and unfixed combinations of active ingredients. As used herein, the term “combination therapy” means a drug regimen of two different therapeutic active agents (i.e., components of the combination or partners of the combination), wherein the therapeutic active agents are administered together or separately in a manner desired by the healthcare professional or in accordance with regulatory authorities, as defined herein.

[0059] As used herein, the term “regulation” means regulation or adjustment (e.g., increase or decrease), and may include, for example, receptor activating, partial receptor activating, or antagonistic effects.

[0060] compound In one embodiment, Equation I: [ka] Equation I [In formula: [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from C, CH, and N, except X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7, and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2 (C3-C6)alkyl may be appropriately substituted with (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, (C1-C6)alkoxy, CN, or (C2-C4)alkynyl, and each of the (C3-C6)cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is, Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys; and A partially unsaturated monocyclic 5-8 membered heterocycloalkylene, which may be appropriately substituted with 1 to 4 substituents selected independently from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys. Selected from the group consisting of; mm is L 2 The linkage point to ring B is shown, and nn indicates the linkage point to ring B; Ring B is, [ka] It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; B 1 B 2 , and B 3 Each of them is independent of CR 1 Selected from the group consisting of and N; B 4 and B 5 Each of these is independently N, NR 1 , C, CR 1 The group is selected from the group consisting of , O, and S, however, B 4 and B 5 The ring containing is a heteroaryl; R 1 It is selected from the group consisting of H, halogens, and (C1-C6)alkyl groups; Each R a These are independently (C1-C6)alkyl, (C1-C3)alkyl(C3-C6)cycloalkyl, (C1-C3)alkyl(3-5 member heterocycloalkyl), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2and R 3 These are independently selected from the group consisting of H and (C1-C6) alkyl groups; a is an integer selected from 0 to 3; Z 1 is -O- or -NH-; Each R c These are independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Compounds represented by or pharmaceutically acceptable salts or solvates thereof are provided herein.

[0061] In one embodiment, formula I: [ka] Equation I [In formula: [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from C, CH, and N, except X 1 , X 2 , X 3 , X 4 , X 5 , X6 , X 7 , and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2 (C1-C6) alkyl which may be appropriately substituted with (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, and each of the (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is, Partially unsaturated monocyclic (C5-C8) cycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys; and Selected from the group consisting of partially unsaturated monocyclic 5-8 membered heterocycloalkylenes, which may be appropriately substituted with 1-4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys; mm is L 2 The linkage point to ring B is shown, and nn indicates the linkage point to ring B; Ring B is, [ka] It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; B 1 B 2 , and B 3 Each of them is independent of CR 1 and selected from N; B 4 and B 5 Each of these is independently N, NR 1 , C, CR 1 Selected from O and S, however, B 4 and B 5 The ring containing is a heteroaryl; R 1 It is selected from the group consisting of H, halogens, and (C1-C6)alkyl groups; Each R a These are independently (C1-C6)alkyl, (C1-C3)alkyl(C3-C6)cycloalkyl, (C1-C3)alkyl(3-5 member heterocycloalkyl), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2 and R 3These are independently selected from the group consisting of H and (C1-C6) alkyl groups; a is an integer selected from 0 to 3; Z 1 is -O- or -NH-; Each R c These are independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Compounds represented by or pharmaceutically acceptable salts or solvates thereof are provided herein.

[0062] Embodiments of Formula I may include one or more of the features described below and / or in the claims.

[0063] For one reason, X 8 C is C; and X 5 It is C.

[0064] For one reason, X 3 It is C.

[0065] For one reason, X 2 It is N.

[0066] For one reason, X 4 It is N.

[0067] For one reason, X 3 C is X 2 is N; and X4 It is N.

[0068] For one reason, X 7 It is CH.

[0069] For one reason, X 8 C is X 5 C is C; and X 7 It is CH.

[0070] For one reason, X 8 , X 5 , and X 3 C is X 2 and X 4 is N and X 7 CH is; and X 1 and X 6 It is independently CH or N. For example, X 1 and X 6 is CH. As another non-restrictive example, X 1 is N; and X 6 CH is. As yet another non-restrictive example, X 1 CH is; and X 6 It is N.

[0071] For one reason, X 8 , X 5 , and X 3 C is X 7 and X 6 CH is; X 1 is N; and X 2 and X 4 It is N.

[0072] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0073] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0074] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0075] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0076] One appeal, T 1 This is C(=O)OH.

[0077] One appeal, T 1 It is a carboxylic acid bioisoster.

[0078] One example (T 1 However, if it is a carboxylic acid bioisoster, T 1This is a five-membered heteroaryl compound comprising 2 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein the heteroaryl compound may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen.

[0079] One appeal, T 1 This is a tetrazolyl compound that may be appropriately substituted with one or two substituents independently selected from the group consisting of hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] It is selected from the group consisting of the following.

[0080] One appeal, T 1 This is a triazolyl or oxadiazolyl compound, which may be appropriately substituted with one or two substituents independently selected from (C1-C6) alkyl and hydroxyl compounds. For example, T 1 teeth, [ka] That is the case.

[0081] One appeal, T 1 This is a ring (e.g., a 4-6 membered ring, e.g., a 5-membered ring) containing 0-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the ring is substituted with 1-2 oxos and may be further appropriately substituted with 1-2 substituents independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] That is the case.

[0082] One appeal, T 1 is a (C1-C6) alkyl group substituted with 1 to 3 hydroxyls, and may be further substituted with 1 to 10 fluorols as appropriate. In any of these embodiments, T 1 These are (C1-C6) alkyl groups substituted with 1 to 3 hydroxyls, and further substituted with 1 to 10 fluorols. For example, T 1 teeth, [ka] That is the case.

[0083] One appeal, T 1 This is C(=O)NHS(O)2(C1-C4)alkyl. For example, T 1 This is C(=O)NHS(O)2Me.

[0084] One appeal, T 1 The following: [ka] It is selected from the group consisting of the following.

[0085] One appeal, T 2 These are (C1-C3) alkyl groups substituted with (C3-C6) cycloalkyl groups, 3-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups.

[0086] One appeal, T 2 This is a (C1-C3) alkyl group substituted with a (C3-C6) cycloalkyl group or a 3- to 6-membered heterocycloalkyl group.

[0087] One appeal, T 2 It is a (C1-C3) alkyl group substituted with a 3- to 6-membered heterocycloalkyl group.

[0088] One appeal, T 2It is a (C1-C3) alkyl group substituted with a 4-6 member heterocycloalkyl group.

[0089] One appeal, T 2 It is a (C1-C3) alkyl group substituted with oxetanyl.

[0090] One appeal, T 2 teeth, [ka] In one example, T 2 teeth, [ka] and; as well as T 2 The center of the solid has an (S)-configuration.

[0091] One appeal, T 2 is a (C1-C3) alkyl substituted with a (C3-C6) cycloalkyl, wherein the (C3-C6) cycloalkyl has 1 to 4 R x It may be replaced as appropriate. In one embodiment, T 2 is a (C1-C3) alkyl group substituted with cyclopropyl, wherein the cyclopropyl may be appropriately substituted with CN (for example, CN-substituted cyclopropyl). For example, T 2 teeth, [ka] It is possible. As another non-restrictive example, T 2 teeth, [ka] It is possible.

[0092] One appeal, T 2 is a (C1-C3) alkyl substituted with a (C1-C6) alkoxy. In one embodiment, T 2is a (C1-C3) alkyl group substituted with methoxy. For example, T 2 This could be -CH2CH2OCH3.

[0093] One appeal, T 2 is a (C1-C6) alkyl group substituted with CN. In one embodiment, T 2 This is a branched (C3-C6) alkyl group substituted with CN. For example, T 2 teeth, [ka] It is possible.

[0094] One appeal, T 2 This is a (C1-C3) alkyl group substituted with a (C2-C4) alkynyl group. For example, T 2 teeth, [ka] It is possible.

[0095] As a non-limiting example, the above [ka] The part is, [ka] It is possible.

[0096] In one statement, L 2 It is a combination.

[0097] In one statement, L 2 It is -O-.

[0098] In one statement, L 1 This is 1 to 3 R L It is a (C1-C2) alkylene which may be substituted as appropriate.

[0099] In one statement, L 1 This is CH2.

[0100] In one statement, L 1 It is CH2CH2.

[0101] In one statement, L 1 This is 1 to 3 R L This is a CH2CH2 which may be substituted as appropriate.

[0102] In one statement, L 2 is a combination; and L 1 This is 1 to 3 R L C may be replaced as appropriate. 1-3 (For example, C1, C2, or C3) alkylenes.

[0103] In one statement, L 2 is a combination; and L 1 This is CH2.

[0104] In one statement, L 2 is a combination; and L 1 It is CH2CH2.

[0105] In one statement, L 2 is -O-; and L 1 This is 1 to 3 R L C may be replaced as appropriate. 1-2 It is an alkylene. As a non-restrictive example, L 2 is -O-; and L 1 This is CH2.

[0106] In one embodiment, mm is parametric with respect to nn.

[0107] In one embodiment, ring A is a partially unsaturated monocyclic (C5-C8) cycloalkylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys.

[0108] In one embodiment, ring A is a partially unsaturated monocyclic C6 cycloalkylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys.

[0109] In one embodiment, ring A is a cyclohexenylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys.

[0110] In one embodiment, ring A is an unsubstituted cyclohexenylene.

[0111] In one presentation, ring A is, [ka] That is the case.

[0112] In one embodiment, ring A is a partially unsaturated monocyclic 5-8 membered heterocycloalkylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys.

[0113] In one embodiment, ring A is a partially unsaturated monocyclic 5-6 membered heterocycloalkylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys.

[0114] In one embodiment, ring A is a tetrahydropyridinylene which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of halogens, (C1-C3)alkyls, (C1-C3)haloalkyls, (C1-C3)alkoxys, and (C1-C3)haloalkoxys. In another embodiment, ring A is an unsubstituted tetrahydropyridinylene.

[0115] In one presentation, ring A is, [ka] That is the case.

[0116] One appeal states that ring B is [ka] (BI) That is the case.

[0117] (BI) In one embodiment, B 2 It is N.

[0118] (BI) In one embodiment, B 1 and B 3 CR is independent. 1 That is the case.

[0119] (BI) In one embodiment, B 1 and B 3 One of them is N; as well as B 1 and B 3 The other one is CR 1 For example, B 1 is N; and B3 CR 1 As another non-restrictive example, B 1 CR 1 B is; and B 3 It is N.

[0120] One appeal states that ring B is [ka] That is the case.

[0121] One appeal states that ring B is [ka] That is the case.

[0122] One appeal states that ring B is [ka] That is the case.

[0123] One appeal states that ring B is [ka] (B-II) That is the case.

[0124] In one embodiment (B-II), B 2 CR 1 That is the case.

[0125] In one embodiment (B-II), B 2 It is N.

[0126] In one embodiment (B-II), B 1 It is N.

[0127] In one embodiment (B-II), B 1 CR 1 That is the case.

[0128] One appeal states that ring B is [ka] That is the case.

[0129] One appeal states that ring B is [ka] That is the case.

[0130] One appeal states that ring B is [ka] (B-IV) That is the case.

[0131] In one embodiment (B-IV), B 5 It is N.

[0132] In one embodiment (B-IV), B 4 , NR 1 Selected from the group consisting of , S, and O. For example, B 4 It can be S.

[0133] One appeal states that ring B is [ka] That is the case.

[0134] One way of doing this is for each R 1 These are independently either H or halogen.

[0135] One way of doing this is for each R 1 H is H.

[0136] In one example, a is 0.

[0137] A certain appeal, Z 1 It is -O-.

[0138] A certain appeal, Z 1 It is -NH-.

[0139] One way of doing this is for each R c H is H.

[0140] One way of doing this is for each R c This is an independently selected (C1-C6) alkyl or (C1-C3) haloalkyl.

[0141] A certain appeal, Z 1 is O; and each R c H is H.

[0142] In one embodiment, ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 5-10 membered bicycloheteroaryl.

[0143] In one embodiment, ring C is phenyl.

[0144] In one embodiment, ring C is pyridyl.

[0145] In one embodiment, b is 1 to 3.

[0146] In one embodiment, b is 2.

[0147] In one embodiment, ring C is phenyl; and b is 2.

[0148] In one embodiment, the above [ka] The part is, [ka] That is the case.

[0149] In one embodiment, ring C is pyridyl (e.g., 2-pyridyl); and b is 1.

[0150] In one embodiment, the above [ka] The part is, [ka] That is the case.

[0151] One reason, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN.

[0152] One reason, R b Each of them is independently a halogen or CN. For example, b is 2; R b One of them is a halogen (e.g., -F or -Cl); as well as a second R b is -CN. As another non-restrictive example, b is 2; and R b Each of them is an independently selected halogen (for example, each R b (These are independently -Cl or -F).

[0153] One reason, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0154] As a non-limiting example, the above [ka] The part is, [ka] It is possible.

[0155] In one embodiment, the compound of formula I is formula IA: [ka] Formula IA It is a compound of or a pharmaceutically acceptable salt or solvate thereof.

[0156] In one embodiment, the compound of formula I is formula IB: [ka] Formula IB It is a compound of or a pharmaceutically acceptable salt or solvate thereof.

[0157] In one embodiment of formula IA or IB, X 1 It is N.

[0158] In one embodiment of formula IA or IB, X 6 It is CH.

[0159] In one embodiment of formula IA or IB, X 1 is N; and X 6 It is CH.

[0160] In one embodiment of formula IA or IB, T 1 This is C(=O)OH.

[0161] In one embodiment of formula IA or IB, T 2 It is a (C1-C3) alkyl group substituted with a 3- to 6-membered heterocycloalkyl group.

[0162] In one embodiment of formula IA or IB, T 2 It is a (C1-C3) alkyl group substituted with oxetanyl.

[0163] In one embodiment of formula IA or IB, T 2 teeth, [ka] That is the case.

[0164] In one embodiment of formula IA or IB, T 2 is a (C1-C3) alkyl group substituted with a (C3-C6) cycloalkyl group, wherein the (C3-C6) cycloalkyl group may be appropriately substituted with CN (e.g., CN-substituted cyclopropyl; or unsubstituted cyclopropyl). For example, T 2 teeth, [ka] It is possible. As another non-restrictive example, T 2 teeth, [ka] It is possible.

[0165] In one embodiment of formula IA or IB, T 2 It is a (C1-C3) alkyl group substituted with (C1-C6) alkoxy groups.

[0166] One appeal, T 2 is a (C1-C3) alkyl group substituted with methoxy. For example, T 2 This could be -CH2CH2OCH3.

[0167] In one embodiment of formula IA or IB, T 2 is a (C1-C6) alkyl group substituted with CN. In one embodiment, T 2 This is a branched (C3-C6) alkyl group substituted with CN. For example, T 2 teeth, [ka] It is possible.

[0168] In one embodiment of formula IA or IB, T 2 This is a (C1-C3) alkyl group substituted with a (C2-C4) alkynyl group. For example, T 2 teeth, [ka] It is possible.

[0169] In some embodiments of formula IA or IB, ring B is [ka] (BI) That is the case.

[0170] In some embodiments of formula IA or IB, ring B is [ka] That is the case.

[0171] In some embodiments of formula IA or IB, ring B is [ka] Selected from the group consisting of . For example, ring B is, [ka] It is possible.

[0172] In some embodiments of formula IA or IB, ring B is [ka] (B-II) That is the case.

[0173] In some embodiments of formula IA or IB, ring B is [ka] That is the case.

[0174] In some embodiments of formula IA or IB, ring B is [ka] That is the case.

[0175] In some embodiments of formula IA or IB, ring B is [ka] (B-IV) That is the case.

[0176] In some embodiments of formula IA or IB, ring B is [ka] That is the case.

[0177] In embodiments of formula IA or IB, each R 1 These are independently either H or halogen.

[0178] In embodiments of formula IA or IB, each R 1 H is H.

[0179] In some embodiments of formula IA or IB, a is 0.

[0180] In one embodiment of formula IA or IB, Z 1 It is -O-.

[0181] In embodiments of formula IA or IB, each R c H is H.

[0182] In some embodiments of formula IA or IB, ring C is phenyl.

[0183] In an embodiment of formula IA or IB, b is 1 to 3.

[0184] In some embodiments of formula IA or IB, b is 2.

[0185] In some embodiments of formula IA or IB, ring C is phenyl; and b is 2.

[0186] In one embodiment of formula IA or IB, [ka] teeth, [ka] That is the case.

[0187] In some embodiments of formula IA or IB, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN.

[0188] In some embodiments of formula IA or IB, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0189] In one embodiment, the compound of formula I is selected from the group consisting of the compounds in Table C1 or their pharmaceutically acceptable salts or solvates. Table C1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0190] In one embodiment, the compound is selected from the group consisting of the compounds in Table C2 or pharmaceutically acceptable salts or solvates thereof. Table C2 [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0191] In another embodiment, Formula II: [ka] Formula II [In the formula, [ka] This indicates any single or double bond whose valence is acceptable; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 Each of them is independently selected from C, CH, and N, except X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 At least two of these, and four or fewer, is N; T 1 It is a C(=O)OH or carboxylic acid bioisoster; T 2(C1-C6) alkyl which may be appropriately substituted with (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl, and each of the (C3-C6) cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl has 1-4 R x It may be replaced as appropriate; Each R x These are independently selected from the group consisting of OH, SH, CN, NO2, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)cyanoalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C6)cycloalkyl, amino, (C1-C6)alkylamino, and di(C1-C6)alkylamino; L 1 This is 1 to 3 R L It is a (C1-C3) alkylene which may be appropriately substituted; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; Each R L These are independently selected from the group consisting of halogens, (C1-C3)alkyls, and (C1-C3)haloalkyls; or A pair of R on the same or adjacent carbon atoms L These atoms, together with the atoms to which they are bonded, form a (C3-C6) cycloalkyl ring; Ring A is, 1 to 4 R Y Phenylene may be substituted as appropriate; 1 to 3 R Y 5-6 member heteroarylenes which may be substituted as appropriate. Selected from the group consisting of; mm is L 2 The bond point to is shown, and nn indicates the bond point to ring B; and Each R YThese are independently selected from the group consisting of halogens, cyano, -OH, oxo, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, and (C1-C3)haloalkoxy; Ring B is, [ka] It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; B 1 B 2 , and B 3 Each of them is independent of CR 1 Selected from the group consisting of and N; B 4 and B 5 Each of these is independently N, NR 1 , C, CR 1 The group is selected from the group consisting of , O, and S, however, B 4 and B 5 The ring containing is a heteroaryl; R 1 It is selected from the group consisting of H, halogens, and (C1-C6)alkyl groups; Each R a These are independently (C1-C6)alkyl, (C1-C3)alkyl(C3-C6)cycloalkyl, (C1-C3)alkyl(3-5 member heterocycloalkyl), and -C(O)NR 2 R 3 Selected from the group consisting of (C1-C6) fluoroalkyl groups; Each R 2 and R 3 These are independently selected from the group consisting of H and (C1-C6) alkyl groups; a is an integer selected from 0 to 3; Z 1 is -O- or -NH-; Each R c These are independently selected from the group consisting of H, (C1-C6) alkyl, and (C1-C3) haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C3-C6) cycloalkyl, (C5-C 10 ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R b These are independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C3-C6)cycloalkyl, and CN; and b is an integer selected from 0 to 3. Compounds represented by are provided herein.

[0192] Embodiments of Formula II may include one or more of the features set forth below and / or in the claims.

[0193] For one reason, X 8 C is C; and X 5 It is C.

[0194] For one reason, X 3 It is C.

[0195] For one reason, X 2 It is N.

[0196] For one reason, X 4 It is N.

[0197] For one reason, X 3 C is X 2 is N; and X 4 It is N.

[0198] For one reason, X 7 It is CH.

[0199] For one reason, X 8 C is X 5 C is C; and X 7 It is CH.

[0200] For one reason, X 8 , X 5 , and X 3 C is X 2 and X 4 is N and X 7 CH is; and X 1 and X 6 It is independently CH or N. For example, X 1 and X 6 is CH. As another non-restrictive example, X 1 is N; and X 6 CH is. As yet another non-restrictive example, X 1 CH is; and X 6 It is N.

[0201] For one reason, X 8 , X 5 , and X 3 C is X 7 and X 6 CH is; X 1 is N; and X 2 and X 4 It is N.

[0202] For one reason, X 8 , X 5 , and X 3 C is X 7 , X 6 , and X 1 CH is; and X 2 and X 4 It is N.

[0203] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0204] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0205] In one embodiment, the above [ka] The part is formula: [ka] This is shown.

[0206] One appeal, T 1 This is C(=O)OH.

[0207] One appeal, T 1 It is a carboxylic acid bioisoster.

[0208] One example (T 1 However, if it is a carboxylic acid bioisoster, T 1 This is a five-membered heteroaryl compound comprising 2 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein the heteroaryl compound may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of hydroxyl, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen.

[0209] One appeal, T 1 This is a tetrazolyl which may be appropriately substituted with one or two substituents independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] It is selected from the group consisting of the following.

[0210] One appeal, T 1 This is a triazolyl or oxadiazolyl compound, which may be appropriately substituted with one or two substituents independently selected from (C1-C6) alkyl and hydroxyl compounds. For example, T 1 teeth, [ka] That is the case.

[0211] One appeal, T 1 This is a ring (e.g., a 4-6 membered ring, e.g., a 5-membered ring) containing 0-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the ring is substituted with 1-2 oxos and may be further substituted with 1-2 substituents independently selected from the group consisting of hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, and halogen. For example, T 1 teeth, [ka] That is the case.

[0212] One appeal, T 1 is a (C1-C6) alkyl group that is substituted with 1 to 3 hydroxyls and may be further substituted with 1 to 10 fluorols. In any of these embodiments, T 1 It is a (C1-C6) alkyl group that is substituted with 1 to 3 hydroxyls and further substituted with 1 to 10 fluorols. For example, T 1 teeth, [ka] That is the case.

[0213] One appeal, T 1 This is C(=O)NHS(O)2(C1-C4)alkyl. For example, T 1This is C(=O)NHS(O)2Me.

[0214] One appeal, T 1 The following: [ka] It is selected from the group consisting of the following.

[0215] One appeal, T 2 These are (C1-C3) alkyl groups substituted with (C3-C6) cycloalkyl groups, 3-6 member heterocycloalkyl groups, phenyl groups, or 5-6 member heteroaryl groups.

[0216] One appeal, T 2 This is a (C1-C3) alkyl group substituted with a (C3-C6) cycloalkyl group or a 3- to 6-membered heterocycloalkyl group.

[0217] One appeal, T 2 It is a (C1-C3) alkyl group substituted with a 3- to 6-membered heterocycloalkyl group.

[0218] One appeal, T 2 It is a (C1-C3) alkyl group substituted with a 4-6 member heterocycloalkyl group.

[0219] One appeal, T 2 It is a (C1-C3) alkyl group substituted with oxetanyl.

[0220] One appeal, T 2 teeth, [ka] In one example, T 2 teeth, [ka] and; as well as T 2The center of the solid has an (S)-configuration.

[0221] As a non-limiting example, the above [ka] The part is, [ka] It is possible.

[0222] As another non-limiting example, [ka] The part is, [ka] It is possible.

[0223] In one statement, L 2 It is a combination.

[0224] In one statement, L 2 It is -O-.

[0225] In one statement, L 1 This is 1 to 3 R L It is a (C1-C2) alkylene which may be appropriately substituted. In one embodiment, L 1 In one embodiment, L 1 In one embodiment, L 1 This is 1 to 3 R L It is a CH2CH2 that is substituted with L. In one embodiment, 1 This is two R's L CH2CH2 is substituted with a pair of R on adjacent carbon atoms. L These atoms, together with the atoms to which they are bonded, form a C3-C5 cycloalkyl ring.

[0226] In one statement, L2 is a combination; and L 1 This is 1 to 3 R L (C1-C3) (e.g., C1, C2, or C3) alkylene may be appropriately substituted. In one embodiment, L 2 is a combination; and L 1 In one embodiment, L 2 is a combination; and L 1 In one embodiment, L 2 is a combination; and L 1 teeth, [ka] That is the case.

[0227] In one statement, L 2 is -O-; and L 1 This is 1 to 3 R L It is a (C1-C2) alkylene which may be substituted as appropriate. As a non-restrictive example, L 2 is -O-; and L 1 This is CH2.

[0228] In one embodiment, mm is parametric with respect to nn. In another embodiment, mm is metametric with respect to nn.

[0229] In one statement, L 2 L is a combination; 1 is CH2; and mm is para with respect to nn.

[0230] In one statement, L 2 L is a combination; 1 is CH2CH2 or [ka] And; as well as mm is meta to nn.

[0231] In one statement, L2 is -O- and; L 1 is CH2; and mm is meta to nn.

[0232] In one embodiment, ring A has 1 to 4 R Y This is phenylene, which may be substituted as appropriate.

[0233] In one embodiment, ring A is composed of 1 to 2 R Y It is 1,4-phenylene or 1,3-phenylene, which may be substituted as appropriate.

[0234] In one embodiment, ring A is composed of 1 to 2 R Y This is 1,4-phenylene, which may be substituted as appropriate.

[0235] As a non-restrictive example, ring A is, [ka] It is possible.

[0236] In one embodiment, ring A has 1 to 3 R Y It is a 5-6 member heteroarylene which may be substituted as appropriate. In one embodiment, ring A has 1 to 3 R Y It is a 6-membered heteroarylene which may be substituted as appropriate.

[0237] In one embodiment, ring A is composed of 1 to 2 R Y It is 2,4-pyridinylene or 3,5-pyridinylene, which may be appropriately substituted with R. In one embodiment, ring A has 1 to 2 R Y It is 2,4-pyridinylene which may be substituted as appropriate. As a non-restrictive example, ring A is [ka] A selection can be made from the group consisting of the following:

[0238] In one embodiment, ring A has 1 to 3 RY A 6-membered heteroarylene substituted with R, however, Y At least one of them is an oxo. In one embodiment, ring A has 1-2 R Y The pyridnylene may be further substituted as appropriate. In one embodiment, ring A has 1-2 R Y It is a 1,4-pyridonylene which may be further substituted as appropriate. As a non-restrictive example, ring A is [ka] A selection can be made from the group consisting of the following:

[0239] In one embodiment, ring A is composed of 1 to 2 R Y It is a 5-membered heteroarylene which may be appropriately substituted with R. In one embodiment, ring A is 1-2 R Y It is a pyrazolylene which may be substituted as appropriate. In one embodiment, ring A is [ka] A selection from the group consisting of, each of which is one R Y It may be replaced as appropriate.

[0240] One way of doing this is for each R Y These are independently selected from the group consisting of halogens and (C1-C3)alkyl groups.

[0241] One appeal states that ring B is [ka] (BI) That is the case.

[0242] (BI) In one embodiment, B 2 It is N.

[0243] (BI) In one embodiment, B 1 and B 3CR is independent. 1 For example, B 2 It can be N, and also B 1 and B 3 The CR is selected independently. 1 It is possible.

[0244] (BI) In one embodiment, B 1 and B 3 One of them is N, and also B 1 and B 3 The other one is CR 1 In one embodiment of (BI), B 1 is N, and B 3 CR 1 In one embodiment of (BI), B 1 CR 1 B 3 It is N.

[0245] (BI) In one embodiment, B 2 N is B 1 is N, and B 3 CR 1 That is the case.

[0246] (BI) In one embodiment, B 2 N is B 1 CR 1 B 3 It is N.

[0247] (BI) In one embodiment, B 2 CR 1 That is the case.

[0248] (BI) In one embodiment, B 1 and B 3 CR is independent. 1 That is the case.

[0249] (BI) In one embodiment, B 2 CR 1B 1 and B 3 The CR is selected independently. 1 That is the case.

[0250] One appeal states that ring B is [ka] That is the case.

[0251] One appeal states that ring B is [ka] That is the case.

[0252] One appeal states that ring B is [ka] That is the case.

[0253] One appeal states that ring B is [ka] That is the case.

[0254] One appeal states that ring B is [ka] (B-II) That is the case.

[0255] In one embodiment (B-II), B 2 CR 1 That is the case.

[0256] In one embodiment (B-II), B 2 It is N.

[0257] In one embodiment (B-II), B 1 It is N.

[0258] In one embodiment (B-II), B 1 CR 1 That is the case.

[0259] In one embodiment (B-II), B 1 and B 2 It is N.

[0260] One appeal states that ring B is [ka] That is the case.

[0261] One appeal states that ring B is [ka] That is the case.

[0262] One way of doing this is for each R 1 These are independently either H or halogen.

[0263] One way of doing this is for each R 1 H is H.

[0264] In one example, a is 0.

[0265] A certain appeal, Z 1 It is -O-.

[0266] A certain appeal, Z 1 It is -NH-.

[0267] One way of doing this is for each R c H is H.

[0268] One way of doing this is for each R c This is an independently selected (C1-C6) alkyl or (C1-C3) haloalkyl.

[0269] A certain appeal, Z 1 is O, and each R c H is H.

[0270] In one embodiment, ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 5-10 membered bicycloheteroaryl.

[0271] In one embodiment, ring C is phenyl.

[0272] In one embodiment, b is 1 to 3. For example, b could be 2.

[0273] In one embodiment, b is 0.

[0274] In one embodiment, ring C is phenyl, and b is 2.

[0275] In one embodiment, the above [ka] The part is, [ka] That is the case.

[0276] In one embodiment, ring C is phenyl, and b is 0.

[0277] One reason, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN.

[0278] One reason, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0279] As a non-limiting example, the above [ka] The part is, [ka] It is possible.

[0280] In one embodiment, the compound of formula II is formula IIA: [ka] Formula IIA [In the formula, n1 is either 0 or 1] It is a compound of or a pharmaceutically acceptable salt or solvate thereof.

[0281] In one embodiment of equation IIA, n1 is 0.

[0282] In one embodiment of formula IIA, n1 is 1. For example, [ka] The part is, [ka] It is possible. As another non-limiting example, the above [ka] The part is, [ka] It is possible.

[0283] In one embodiment, the compound of formula II is formula IIB: [ka] Formula IIB [In the formula, n1 is either 0 or 1] It is a compound of or a pharmaceutically acceptable salt or solvate thereof.

[0284] In one embodiment of equation IIB, n1 is 0.

[0285] In one embodiment of equation IIB, n1 is 1.

[0286] In one embodiment, the compound of formula II is formula IIC: [ka] formula IIC [n1 is either 0 or 1] It is a compound of or a pharmaceutically acceptable salt or solvate thereof.

[0287] In one embodiment of formula IIC, L 1 CH2 is, and L 2 It is -O-.

[0288] In one embodiment of formula IIC, L 1 It is CH2CH2, and L 2 It is a combination.

[0289] In one embodiment of formula IIC, L 1 teeth, [ka] L 2 It is a combination.

[0290] In one embodiment of the formula IIC, n1 is 0.

[0291] In one embodiment of formula IIC, n1 is 1. For example, [ka] The part is, [ka] It is possible.

[0292] In some embodiments of formulas IIA, IIB, or IIC, X 1 It is N.

[0293] In some embodiments of formulas IIA, IIB, or IIC, X 1 It is CH.

[0294] In some embodiments of formulas IIA, IIB, or IIC, X 6 It is CH.

[0295] In some embodiments of formulas IIA, IIB, or IIC, X 1 is N; and X 6 It is CH.

[0296] In some embodiments of formulas IIA, IIB, or IIC, X 1 and X 6 CH is selected independently.

[0297] In some embodiments of formulas IIA, IIB, or IIC, T 1 This is C(=O)OH.

[0298] In some embodiments of formulas IIA, IIB, or IIC, T 2 is a (C1-C3) alkyl substituted with a 3- to 6-membered heterocycloalkyl group. In some embodiments of formula IIA, IIB, or IIC, T 2 is an oxetanyl-substituted (C1-C3) alkyl group. In some embodiments of formula IIA, IIB, or IIC, T 2 teeth, [ka] That is the case.

[0299] In some embodiments of formulas IIA, IIB, or IIC, R Y If present, these are independently selected from the group consisting of halogens and (C1-C3)alkyls.

[0300] In some embodiments of formulas IIA, IIB, or IIC, R Y If present, it is selected from the group consisting of -F and methyl.

[0301] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] (BI) That is the case.

[0302] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] That is the case.

[0303] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] It is selected from the group consisting of the following.

[0304] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] That is the case.

[0305] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] (B-II) That is the case.

[0306] In some embodiments of formulas IIA, IIB, or IIC, ring B is, [ka] That is the case.

[0307] In some embodiments of formulas IIA, IIB, or IIC, each R 1 These are independently either H or halogen.

[0308] In some embodiments of formulas IIA, IIB, or IIC, each R 1 H is H.

[0309] In some embodiments of formulas IIA, IIB, or IIC, a is 0.

[0310] In some embodiments of formulas IIA, IIB, or IIC, Z 1 It is -O-.

[0311] In some embodiments of formulas IIA, IIB, or IIC, each R c H is H.

[0312] In some embodiments of formula IIA, IIB, or IIC, ring C is phenyl.

[0313] In some embodiments of formulas IIA, IIB, or IIC, b is 1 to 3.

[0314] In some embodiments of formulas IIA, IIB, or IIC, b is 2.

[0315] In some embodiments of formulas IIA, IIB, or IIC, b is 0.

[0316] In some embodiments of formula IIA, IIB, or IIC, ring C is phenyl, and b is 2.

[0317] In some embodiments of formulas IIA, IIB, or IIC, [ka] teeth, [ka] That is the case.

[0318] In some embodiments of formula IIA, IIB, or IIC, ring C is phenyl, and b is 0.

[0319] In some embodiments of formulas IIA, IIB, or IIC, R b Each of these is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, halogen, and CN. In some embodiments of formula IIA, IIB, or IIC, R b Each of these is independently selected from the group consisting of -F, -Cl, and CN.

[0320] In one embodiment, the compound of formula II is selected from the group consisting of the compounds in Table C1-W or their pharmaceutically acceptable salts or solvates. Table C1-W [Table 12] [Table 13] [Table 14] [Table 15]

[0321] In one embodiment, the compound is selected from the group consisting of compounds in Table C2-W or pharmaceutically acceptable salts or solvates thereof. Table C2-W [Table 16] [Table 17] [Table 18] [Table 19]

[0322] Compounds of formula I or II include their pharmaceutically acceptable salts. Furthermore, compounds of formula I or II also include other salts of such compounds that are not necessarily pharmaceutically acceptable, and may be useful as intermediate compounds for preparing and / or purifying compounds of formula I or II, and / or separating enantiomers of compounds of formula I or II. Non-limiting examples of pharmaceutically acceptable salts of compounds of formula I include trifluoroacetate.

[0323] Furthermore, the compounds of formula I or II, or salts thereof, may be isolated in the form of solvates, and it is understood that any such solvates fall within the scope of the present invention. For example, the compounds of formula I or II and salts thereof may exist in an unsolvated form, as well as in a solvated form with a pharmaceutically acceptable solvent, such as water or ethanol.

[0324] Pharmaceutical composition and administration When used as a pharmaceutical, compounds of formula I or II (including their pharmaceutically acceptable salts or solvates) can be administered in the form of pharmaceutical compositions. These compositions can be prepared 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, epidermal, ocular, and mucosal delivery including intranasal, vaginal, and rectal), pulmonary (e.g., inhalation or inhalation of powders or aerosols (including nebulizers); intratracheal or intranasal), oral, or parenteral. Oral administration may include formulations prepared for once-daily or twice-daily (BID) administration. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracerebral, e.g., subarachnoid or intraventricular administration. Parenteral administration may be in the form of a single rapid dose, or, 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, fillers, etc., may be required or desired.

[0325] Pharmaceutical compositions comprising, as an active ingredient, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients (carriers) are also provided herein. For example, pharmaceutical compositions prepared using a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, such compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier, for example, in the form of a capsule, pouch, paper, or other container. When the excipient is provided as a diluent, it may be a solid, semi-solid, or liquid substance acting as a vehicle, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, pouches, cashews, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments (e.g., containing 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is a solid oral preparation. In one embodiment, the composition is formulated as a tablet or capsule.

[0326] Pharmaceutical compositions comprising a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable excipient are further provided herein. Pharmaceutical compositions comprising a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by closely mixing the compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can be in a wide range of forms depending on the desired route of administration (e.g., oral, parenteral). In one embodiment, the composition is a solid oral composition.

[0327] Appropriate pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain).

[0328] 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; 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; published by Marcel Dekker, Inc.

[0329] In some embodiments, the compound or pharmaceutical composition may be administered in combination with one or more conventional pharmaceutical excipients. Medicinally acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), e.g., d-α-tocopherol polyethylene glycol 1000 succinic acid, surfactants used in pharmaceutical formulations, e.g., Tween, poloxamer or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffering substances, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, 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 solubilized derivatives, can also be used to enhance the delivery of the compounds described herein. Formulations of compositions can be prepared that contain the chemicals described herein in a balanced manner, comprising non-toxic excipients in an amount ranging from 0.005% to 100%. The intended compositions may contain the compounds provided herein in amounts ranging from 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. Practical methods for preparing such formulations are known or obvious to those skilled in the art, e.g., Remington: The Science and Practice of Pharmacy, 22 nd See Edition (Pharmaceutical Press, London, UK. 2012).

[0330] In one embodiment, the compounds and pharmaceutical compositions described herein, or the pharmaceutical compositions thereof, may be administered to a patient in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, sinus, tracheal, intestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrasacral, intracerebral, cisterna magna, coronary, intradermal, intratubular, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intravascular, intramedullary, intrasynovial, intratesticular, subarachnoid, intratubular, intratumoral, intrauterine, intravascular, intravenous, transnasal (e.g., intranasal), transnasal-gastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0331] In some embodiments, the preferred route of administration is parenteral (e.g., intratumor). In some embodiments, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, can be formulated for parenteral administration and can be formulated for injection via, for example, intra-arterial, intrasternal, intracerebral, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such a composition can be prepared as either an injectable liquid solvent or suspension; a solid form suitable for use in preparing a solvent or suspension can also be prepared by adding liquid before injection; and the formulation may be emulsified. The preparation of such formulations is known to those skilled in the art with regard to this disclosure. In some embodiments, a device is used for parenteral administration. For example, such a device may include a needle injector, a microneedle injector, a needleless injector, and an injection technique.

[0332] In one embodiment, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersants; formulations (containing sesame oil, peanut oil, or propylene glycol solutions); and sterile powders for the immediate preparation of sterile injection solvents or dispersants. In one embodiment, the forms need to be sterile and fluid enough to be easily injected. In one embodiment, the forms need to be stable under manufacturing and storage conditions and must be resistant to contamination by microorganisms, such as bacteria and fungi.

[0333] In one embodiment, the carrier may also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one embodiment, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the particle size required during dispersion, and by the use of a surfactant. In one embodiment, microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In one embodiment, an isotonic agent, such as sugar or sodium chloride, may be included. In one embodiment, sustained absorption of the injectable composition can be achieved by the use of absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0334] In one embodiment, a sterile injection solution is prepared by incorporating a required amount of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) in a suitable solvent into various other components listed above, and subsequently by sterile filtration as necessary. In one embodiment, a dispersant is prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In one embodiment, a sterile powder is used for the preparation of a sterile injection solution. In one embodiment, the preparation method is a vacuum drying and freeze-drying technique for obtaining a powder of the active ingredient and any further desired components from the previously sterile-filtered solution.

[0335] In some embodiments, pharmacoagulably acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers, e.g., polyvinylpyrrolidone, PEG (e.g., PEG ointments), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamer, polyethylene glycol and mixtures of fatty acid esters of polyethylene glycol of various molecular weights, Vaseline, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide SBN, vanilla essential oil), aerosols, parabens in phenoxyethanol, sodium methyl p-oxobenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, Carbopol, methyl oxybenzoate, macrogol cetostearyl ether, and cocoyl phosphate. Caprylica plate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-methabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins, such as vitamins A and E, and potassium acetate, one or more of these.

[0336] In one embodiment, a suppository can be prepared by mixing a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition with a suitable non-irritating excipient or carrier that is solid at ambient temperature but liquid at body temperature, and therefore melts rectally to release the active compound, such as cocoa butter, polyethylene glycol, or suppository wax. In one embodiment, the composition for rectal administration is in the form of an enema.

[0337] In one embodiment, a compound of formula I or II described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) or a pharmaceutical composition thereof is formulated for topical delivery to the gastrointestinal tract or GI tract by oral administration (e.g., solid or liquid formulations). In one embodiment, solid formulations for oral administration include capsules, tablets, pills, powders, and granules.

[0338] In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof) is mixed with one or more pharmaceutically acceptable excipients, 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, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarding agents. f) an agent, e.g., paraffin; g) an absorption enhancer, e.g., a quaternary ammonium compound; h) a wetting agent, e.g., cetyl alcohol and glycerol monostearate; i) 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 formulation may also contain a buffer. In some embodiments, similar types of solid compositions may be used in soft and hard gelatin capsules as fillers, e.g., excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0339] In one embodiment, the pharmaceutical composition is in the form of a unit formulation such as a pill or tablet, and therefore the composition may contain, together with a compound of formula I or II provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof), a diluent, such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant, such as magnesium stearate, etc.; and a binder, such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In one embodiment, another solid formulation, powder, pill (marume), solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulosic capsule). In some embodiments, unit formulations in which one or more of the compounds and pharmaceutical compositions or further active agents provided herein are physically separated, such as granular capsules and granular (or tablet in capsule) formulations; double-layer tablets; two-compartment gel capsules, etc. In some embodiments, enteric-coated or sustained-release oral formulations are also included.

[0340] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, a variety of preservatives are well known, including, for instance, phenol and ascorbic acid.

[0341] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments for various oral formulation excipients, such as tablets and capsules, sterilization is not required. For example, the United States Pharmacopeia / National Standard (USP / NF) standard may suffice.

[0342] In some embodiments, the compounds of formula I or II described herein or their pharmaceutically acceptable salts or solvates (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or their pharmaceutically acceptable salts or solvates), or the pharmaceutical compositions thereof, are formulated for ophthalmic use. In some embodiments, the ophthalmic composition may include, 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); and preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxyloro complex; Allergan, Inc.)).

[0343] Sa In some embodiments, the compounds of formula I or II described herein, or their pharmaceutically acceptable salts or solvates (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or their pharmaceutically acceptable salts or solvates), or the pharmaceutical compositions thereof, are formulated for topical administration to the skin or mucous membranes (e.g., skin or transdermally). In some embodiments, the topical compositions may include ointments and creams. In some embodiments, the ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, the creams containing the selected active agent are typically viscous liquids or semi-solid emulsions, and are often either oil-in-water or water-in-oil. For example, the cream base is typically water-washable and comprises an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase is also called the “internal” phase and generally consists of petrolatum and fatty alcohols, such as cetyl or stearyl alcohol, and the aqueous phase is usually not necessary but is generally present in greater volume than the oil phase and generally contains a wetting agent. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, needs to be inert, stable, non-irritating, and non-sensitizing.

[0344] In any of the embodiments described herein, the pharmaceutical composition may comprise one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic acid-coglycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and a nanoporous particle-supporting lipid bilayer.

[0345] In some embodiments, the dose for a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is determined based on many 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 a pharmaceutically acceptable salt or solvate thereof. In some embodiments, an appropriate dose for a particular situation can be determined by a person skilled in the pharmaceutical art. In some embodiments, the total daily dose may be divided and administered in portions throughout the day, or administered by means of continuous delivery.

[0346] In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered in doses ranging from about 0.01 to about 1000 mg. For example, doses ranging from about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In one embodiment, the dose is a therapeutically effective dose.

[0347] In one embodiment, a compound of formula I or II described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., any one of formulas IA and IB or any one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) may be present in amounts of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; Approx. 0.0002mg / Kg~Approx. 25mg / Kg;Approx. 0.0002mg / Kg~Approx. 10mg / Kg;Approx. 0.0002mg / Kg~Approx. 5mg / Kg;Approx. 0.0002mg / Kg~Approx. 1mg / Kg;Approx. 0.0 002mg / Kg ~ approx. 0.5mg / Kg; approx. 0.0002mg / Kg ~ approx. 0.1mg / Kg; approx. 0.001mg / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001m g / Kg~about 10mg / Kg;about 0.001mg / Kg~about 5mg / Kg;about 0.001mg / Kg~about 1mg / Kg;about 0.001mg / Kg~about 0.5mg / Kg;about 0.001mg / Kg~about 0 .1mg / Kg; about 0.01mg / Kg to about 50mg / Kg; about 0.01mg / Kg to about 25mg / Kg; about 0.01mg / Kg to about 10mg / Kg; about 0.01mg / Kg to about 5mg / Kg; about 0. It is administered in doses of approximately 0.1 mg / kg to 1 mg / kg; approximately 0.01 mg / kg to 0.5 mg / kg; approximately 0.01 mg / kg to 0.1 mg / kg; approximately 0.1 mg / kg to 50 mg / kg; approximately 0.1 mg / kg to 25 mg / kg; approximately 0.1 mg / kg to 10 mg / kg; approximately 0.1 mg / kg to 5 mg / kg; approximately 0.1 mg / kg to 1 mg / kg; approximately 0.1 mg / kg to 0.5 mg / kg). In one embodiment, a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered in a dose of approximately 100 mg / kg.

[0348] In one embodiment, the dose of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) may be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or not on a daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0349] In one embodiment, the duration of administration of a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate 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, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient for a certain period, followed by a separation period during which administration of the compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is discontinued.In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered for a first period, followed by a second period after the first period, during which administration is discontinued, then a third period in which administration of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is initiated, followed by a fourth period after the third period in which administration is discontinued. For example, the period of administration of a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof), followed by a period of discontinuation thereof, is repeated for a predetermined or unspecified period. In one embodiment, 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 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.

[0350] In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered orally to the patient once or more daily (e.g., once daily, twice daily, three times daily, four times daily, or once daily). In another embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to the patient once or more daily (e.g., 1 to 4 times daily, twice daily, three times daily, four times daily, or once daily).

[0351] In one embodiment, a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof) is administered parenterally to the patient once a week.

[0352] Treatment method In some embodiments, the Disclosure features a method for treating a patient (e.g., a human) suffering from a disease, disorder, or illness in which the modulation of GLP-1R (e.g., inhibited or impaired, and / or increased or undesired GLP-1R) is beneficial in treating the disease, disorder, or the underlying pathology and / or symptoms and / or progression of the disease. In some embodiments, the methods described herein may include, or further include, one or more diseases related to, coexisting with, or secondary to one or more of the diseases described herein.

[0353] This specification provides a method for treating a GLP-1 related disorder, disorder, or illness, comprising administering an effective amount of a compound of formula I or II disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, to a patient in need thereof.

[0354] In one embodiment, the diseases, disorders, or illnesses include, but are not limited to, type 1 diabetes, type 2 diabetes, juvenile-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 (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram syndrome, Gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, 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, blood Embolism, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake 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, joints This includes inflammation, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic 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).

[0355] In one embodiment, the diseases, disorders, or illnesses include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular diseases, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, and hyper This includes blood glucose, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake disorders, 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 ulcers, psoriasis, psychogenic 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.

[0356] In some embodiments, the diseases, disorders, or illnesses include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram syndrome, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, 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 ulcers, or any combination thereof.

[0357] In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, produce one or more of the following: a decrease in blood glucose levels (e.g., a decrease in blood glucose levels), a decrease in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, activation of insulin secretion, an increase in the population of β-cells, regulation of gastric acid secretion, 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, as well as methods for treating a patient, can produce a decrease in blood glucose levels, a decrease in blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, activation of insulin secretion, an increase in the population of β-cells, regulation of gastric acid secretion, regulation of gastric emptying, a decrease in body mass index (BMI), a decrease in glucagon production (e.g., levels), and any combination thereof. In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided is a method for regulating glucose or insulin levels in a patient requiring adjustment, comprising administering to the patient an effective amount of a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof.

[0358] In one embodiment, a method is provided herein for reducing the risk of major cardiovascular events (MACE) in a patient requiring reduction (e.g., by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%), comprising administering to the patient an effective amount of a compound of formula I or II described herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition. In any 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 type 2 diabetes mellitus (T2D) and heart disease. In one embodiment, 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 suffers from type 2 diabetes (T2D) and heart disease.

[0359] Indications Obesity In some embodiments, the disease, disorder, or condition is a disease, disorder, or condition 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 fat accumulation). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, reproductive dysfunction), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence Moon-Beadle syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea, or beta-blocker-induced obesity).

[0360] In some embodiments, the disease, disorder, or condition is related to obesity. Examples of such diseases, disorders, or conditions include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obesity 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, spondylitis degeneratively, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick's syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual bleeding and cycle abnormalities, amenorrhea, abnormal circadian rhythms), visceral obesity syndrome, urinary incontinence, and metabolic syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting symptoms of both obesity and insulin deficiency.

[0361] diabetes In one embodiment, the disease, disorder, or disorder is diabetes mellitus. Non-limiting examples of diabetes mellitus include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-dependent type 2 diabetes mellitus, sulfonylurea-dependent type 2 diabetes mellitus, more advanced stage type 2 diabetes mellitus, long-term insulin-dependent 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 disease, disorder, or disorder is type 2 diabetes mellitus (e.g., diet-dependent type 2 diabetes mellitus, sulfonylurea-dependent type 2 diabetes mellitus, more advanced stage type 2 diabetes mellitus, long-term insulin-dependent type 2 diabetes mellitus).

[0362] A method for treating diabetes in a patient is provided herein, comprising (a) determining that the patient has type 2 diabetes, and then (b) administering to the patient a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., one of formulas IA and IB or one of formulas IIA, IIB and IIC, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition.

[0363] A method for treating type 2 diabetes in a patient is provided herein, comprising administering a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt or solvate thereof (for example, one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition, to a patient identified or diagnosed with type 2 diabetes.

[0364] Also provided is a method for treating type 2 diabetes in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula I or II disclosed herein or a pharmaceutically acceptable salt or solvate thereof (for example, one of formulas IA and IB or one of formulas IIA, IIB, and IIC, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof.

[0365] In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce fasting blood glucose levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce non-fasting blood glucose levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce HbA1c levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce glucagon levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) increase insulin levels. In one embodiment, compounds, pharmaceutical compositions, and methods for treating patients with the disease, illness, or disorder described herein (e.g., type 2 diabetes) reduce BMI.

[0366] In one embodiment, a reduction in fasting blood glucose levels of approximately 5% to approximately 95% is demonstrated by the treatment of type 2 diabetes. A reduction in fasting blood glucose levels of approximately 15% to approximately 80% is demonstrated by the treatment of type 2 diabetes. A reduction in fasting blood glucose levels of approximately 25% to approximately 60% is demonstrated by the treatment of type 2 diabetes. In one embodiment, a reduction in fasting blood glucose levels to approximately 126 mg / dL or less, approximately 110 mg / dL or less, or approximately 90 mg / dL or less is demonstrated by the treatment of type 2 diabetes.

[0367] In one embodiment, a reduction of approximately 5% to approximately 95% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. A reduction of approximately 15% to approximately 80% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. A reduction of approximately 25% to approximately 60% in non-fasting blood glucose levels is demonstrated by the treatment of type 2 diabetes. In one embodiment, a reduction of non-fasting blood glucose levels to approximately 200 mg / dL or less, approximately 150 mg / dL or less, or approximately 130 mg / dL or less is demonstrated by the treatment of type 2 diabetes.

[0368] In one embodiment, a reduction in HbA1c levels of approximately 5% to approximately 95% is shown by treatment of type 2 diabetes. A reduction in HbA1c levels of approximately 15% to approximately 80% is shown by treatment of type 2 diabetes. A reduction in HbA1c levels of approximately 25% to approximately 60% is shown by treatment of type 2 diabetes. In one embodiment, a reduction in HbA1c levels of approximately 6.5% or less, approximately 6.0% or less, or approximately 5.0% or less is shown by treatment of type 2 diabetes.

[0369] In one embodiment, a decrease in glucagon levels of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. A decrease in glucagon levels of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. A decrease in glucagon levels of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. An increase in insulin levels of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes.

[0370] In one embodiment, a BMI reduction of approximately 5% to approximately 95% is shown by the treatment of type 2 diabetes. A BMI reduction of approximately 15% to approximately 80% is shown by the treatment of type 2 diabetes. A BMI reduction of approximately 25% to approximately 60% is shown by the treatment of type 2 diabetes. In one embodiment, a BMI reduction of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% is shown by the treatment of type 2 diabetes. In one embodiment, a BMI reduction of approximately 40 or less, approximately 30 or less, or approximately 20 or less is shown by the treatment of type 2 diabetes.

[0371] In one embodiment, the disease, disorder, or impairment is related to diabetes (e.g., complications of diabetes). Non-limiting examples of disorders related to diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, renal impairment (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disorders, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing impairment, 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.

[0372] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-LDL cholesterolemia, postprandial dyslipidemia), 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.

[0373] In one embodiment, the disease, disorder, or condition is diabetes and obesity. In one embodiment, the compounds described herein are useful for improving the therapeutic efficacy of metformin.

[0374] Damage to metabolically important tissues In one embodiment, the disease, disorder, or impairment is a disorder of metabolically important tissues. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0375] In one embodiment, the disease, disorder, or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wollman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0376] Non-alcoholic fatty liver disease (NAFLD) is a set of disorders that occur in the absence of alcohol abuse and are typically characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various diseases, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and can eventually lead 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, mostly isolated macrodrip fatty liver (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0377] Other non-limiting examples of disorders of metabolically important tissues include arthropathy (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., liver); fibrosis (e.g., liver); cirrhosis (e.g., liver); gallstones; gallbladder disease; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by changes in bone metabolism, e.g., osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection from fractures, and malnutrition; 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 resulting from surgical trauma.

[0378] Cardiovascular and vascular diseases In one embodiment, the disease, disorder, or condition 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, elevated blood pressure (e.g., 130 / 85 mmHg or higher), and pro-thrombus formation conditions (e.g., high levels of fibrinogen or plasminogen activator inhibitors in the blood).

[0379] In one embodiment, the disease, disorder, or disability is related to a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, megavascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, renal impairment, and neurological disorders.

[0380] Neurological diseases In one embodiment, the disease, disorder, or disability is a neurological disorder (e.g., a neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), 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, hyperkinesia, mania, Morbus Parkinson's disease, Steel-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, traumatic brain injury, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, 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 syndrome). For example, see U.S. Publication No. 20060275288A1.

[0381] In one embodiment, the disease, disorder, or disorder is idiopathic hypertension. Idiopathic hypertension is characterized by increased intracranial pressure and papilledema. See, for example, Virdee et al. Ophthalmol Ther. 2020; 9(4):767-781. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic hypertension. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic hypertension. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms in patients with idiopathic hypertension. Symptoms of idiopathic hypertension may include severe headache and visual impairment. In one embodiment, the patient with idiopathic hypertension is female. In one embodiment, the patient with idiopathic intracranial hypertension is approximately 20 to 30 years old. In another embodiment, the patient with idiopathic intracranial hypertension is obese.

[0382] In one embodiment, the disease, disorder, or disability is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may present first as diabetes, followed by symptoms of optic nerve atrophy, hearing loss, and neurodegeneration. Patients with Wolfram syndrome may exhibit symptoms of ataxia due to brainstem atrophy, sleep apnea, dysphagia, hearing loss, and loss of taste. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In one embodiment, the neuroinflammation is reduced in the lower olivary gland of the patient. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In one embodiment, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in patients with Wolfram syndrome.

[0383] Non-limiting examples of mental disorders include drug addiction / indulgence (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 drug dependence, preventing relapse of substance abuse, and alleviating anxiety caused by the absence of certain addictive substances. See, for example, U.S. Publication No. 20120021979A1.

[0384] In one embodiment, the compounds and pharmaceutical compositions described herein are useful for improving learning and memory by enhancing neuroplasticity and cell differentiation, and for maintaining dopamine neurons and motor function in Morbus Parkinson's disease.

[0385] Insulin-related In one embodiment, the disease, disorder, or impairment is poor fasting blood glucose (IFG), fasting hyperglycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic state, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides, and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant comatose endpoint.

[0386] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or delay the progression of pre-diabetes with poor fasting blood glucose levels or hyperglycemia.

[0387] autoimmune disease In some embodiments, the disease, disorder, or condition is an autoimmune disease. Non-limiting examples of autoimmune diseases include multiple sclerosis and experimental autoimmune encephalomyelitis, and autoimmune diseases may be 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, U.S. Publication No. 20120148586A1.

[0388] Gastrointestinal disorders In some embodiments, the disease, disorder, or disorder is a disorder relating to the stomach or intestines. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcer, Zollinger-Ellison syndrome, drug-induced ulcer, infection or other pathogen-related ulcer), gastrointestinal disorders, malabsorption, short bowel syndrome, duct-blind syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., aspirin-induced gastric mucosal injury), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with hematological disorders, cachexia associated with endocrine disorders, cachexia associated with infections, and cachexia caused by acquired immunodeficiency syndrome).

[0389] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used in patients (e.g., patients in need) to reduce body weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, the patient's weight gain may be due to excessive food intake or an unbalanced diet, or it may be due to concomitant medications (e.g., insulin sensitivity improving agents having PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, siglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be weight gain before becoming obese, or it may be weight gain in obese patients. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain after quitting smoking. In some embodiments, the weight gain may be caused by the use of steroids or antipsychotics.

[0390] In one embodiment, the disease, disorder, or disorder is an eating disorder, such as binge eating, overeating, bulimia, forced eating, or symptomatic obesity, such as Prader-Willi syndrome and Valde-Biedl syndrome.

[0391] Inflammatory diseases In one embodiment, the disease, disorder, or condition is an inflammatory disease. Non-limiting examples of inflammatory diseases include rheumatoid arthritis, spondylitis degenerative, osteoarthritis, lumbago, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, 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 markers such as C-reactive proteins in the blood).

[0392] cancer In one embodiment, the disease, disorder, 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 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 tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary liver cancer) Cancer (extrahepatic cholangiocarcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor with low malignancy), bladder cancer, urethral cancer, skin cancer (e.g., intraocular melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), This includes parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, pediatric solid tumors (e.g., Wilms' tumor, pediatric renal tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0393] Hypothalamic-pituitary dysfunction In one embodiment, the disease, disorder, or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the disease, disorder, or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the disease, disorder, or disorder is related to the hypothalamic-pituitary-testicular axis. Disorders of the hypothalamic-pituitary-gonadal axis include, but are not limited to, reproductive dysfunction, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0394] In one embodiment, a disease, disorder, or condition related to diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0395] Lung disease In one embodiment, the disease, disorder, or impairment is related to a lung disease. Lung diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0396] In one embodiment, a disease, disorder, or condition associated with diabetes is a lung disease.

[0397] Combination therapy In some embodiments, this disclosure includes both monotherapy regimens and combination therapy regimens.

[0398] In one embodiment, the method described herein may further include administering one or more additional therapies (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.

[0399] In one embodiment, the methods described herein include administering the compounds described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modifications.

[0400] In one embodiment, a compound of formula I or II described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, may be administered in combination with one or more further therapeutic agents.

[0401] Representative additional treatments include, but are not limited to, anti-obesity drugs, drugs for diabetes, drugs for diabetic complications, drugs for hyperlipidemia, antihypertensives, diuretics, chemotherapeutic drugs, immunotherapeutic drugs, anti-inflammatory drugs, antithrombotic drugs, antioxidants, drugs for osteoporosis, vitamins, drugs for dementia, drugs for erectile dysfunction, drugs for frequent urination or urinary incontinence, drugs for NAFLD, drugs for NASH, and drugs for voiding disorders.

[0402] In one embodiment, the 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 modifiers, GABA modifiers (e.g., topiramates) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., berneperito), peptide YY or its analogues. Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylates inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., compounds described in WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearate-CoA desaturate inhibitors, microsomal triglyceride transport protein inhibitors (e.g., R-256918), sodium glucose transporter 2 (SGL) T-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, or erzgliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists,Appetite suppressants (e.g., bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogues, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, fenofibrate, paraglitazone, siglitazone, dalglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2) 433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemin), GPR119 agonists (e.g., compounds listed in PSN-821, MBX-2982, APD597, WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., pyragliatin, Compounds listed in AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 and WO2008 / 156757), rep Tin, leptin derivatives (e.g., metreleptin), leptin resistance improvers, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., plumlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335), oxintomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g.,Animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptide (HIP), melanocortin receptor 4 agonists (e.g., cetomelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, silofexol, LY2562175, Met409, TERN-101, EDP305, compounds described in WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, nor Examples include epinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modifiers, biotin, MAS receptor modifiers, glucagon receptor agonists, CCKa agonists (e.g., compounds listed in WO2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0403] In one embodiment, the one or more further therapeutic agents include, for example, agents 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 sensitivity enhancers (e.g., pioglitazone or its salts), biguanides (e.g., metformin, buformin or its salts (e.g., hydrochloride)). (Fumarate, succinate), glucagon analogs (e.g., any of the glucagon analogs listed in WO2010 / 011439), drugs that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea drugs (e.g., chloropropamide, trazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glibzol, glibrid, glipizide), thiazolidinedione drugs (e.g., rosiglitazone, robeglitazone, troglitazone) (e.g., paraglitazone, riboglitazone, lobeglitazone or pioglitazone), glitazar (e.g., alleglitazar, chiglitazar, saroglitazal, mulaglitazal, tesaglitazal), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin) , canagliflozin, ipragliflozin, tofogliflozin, cergliflozin etabonate, remogliflozin etabonate, erzgliflozin (compounds listed in WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposin, camiglibose, pradymycin-Q, salvostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g.,Dietary glucose regulators (sometimes called "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, GLP-1 / GIP receptor dual agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4) Examples include P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omaligliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0404] In one embodiment, the one or more additional therapeutic agents include, for example, drugs useful for treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., ellafibrano), synthetic fatty acid bile conjugates (e.g., aramchol), anti-lysyl oxidase analog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD). -02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipercast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI010976, as well as compounds described in WO2009 / 144554, WO2003 / 072197, WO2009 / 144555, and WO2008 / 065508), ketohexokinase (KHK) Inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, chemokine receptor 2 (CCR2) and CCR5 dual antagonists (e.g., senicliviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Schisandra genus, ascorbic acid, glycyrrhizin Examples include glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complexes, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, paraglitazone, riboglitazone, robeglitazone), metformin, cysteamine, sulfonylurea, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipustatin, milk thistle protein, antiviral agents, and antioxidants.

[0405] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., torrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), their neurotrophic factors and growth factors (e.g., NGF, NT-3, BDNF, neurotrophic synthesis / secretion-promoting agents 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., rubo Examples include xystaurine mesylate, 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.

[0406] In one embodiment, the one or more further therapeutic agents include, for example, drugs 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 salts, calcium salts)), 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]acetyl Examples include piperidine-4-acetic acid, fibrate compounds (e.g., bezafibrate, clofibrate, cinfibrate, 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 omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90).

[0407] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, hosinopril, enalapril, ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), and angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, val These include sartans (e.g., telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol). Further non-exclusive examples of antihypertensive drugs include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrine, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, musolimine, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium thi These include channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., citaxsentan, atrasentan, compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), ET / AII dual antagonists (e.g., compounds disclosed in WO2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blockers (IV channel blockers) such as ivabradine, and vasopeptidase inhibitors (NEP-ACE dual inhibitors) (e.g., gemopatrilate and nitrates).

[0408] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium salicylate theobromine, calcium salicylate theobromine), thiazide drugs (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, meticlothiazide), anti-aldosterone drugs (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide drugs (e.g., chlorthalidone, mefluside, indapamide).

[0409] In one embodiment, the one or more further therapeutic agents include, for example, drugs useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides having immunosuppressive activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic manipulation (e.g., interferons, interleukins (IL), e.g., IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0410] In one embodiment, the one or more further therapeutic agents include, for example, drugs 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, boroarginine derivatives, boropeptides, heparin, hirudin, and melagan); FXa inhibitors (e.g., Rivaroxaban, apixaban, edoxaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504), thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tysokinase, alteplase, nateplase, mo These include steroids (e.g., plasminogen streptokinase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, alpha-2 plasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0411] In one embodiment, the one or more further therapeutic agents include, for example, drugs 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 drugs for treating erectile dysfunction include apomorphine and sildenafil citrate. Suitable examples of drugs for treating frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of drugs for treating urinary disorders include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0412] Other exemplary 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 persistent hyperglycemia (e.g., aldose reductase inhibitors, epalrestat and ranirestat), drugs used to treat complications associated with microvascular complications, and drugs for treating dyslipidemia (e.g., HMG-COA reductase inhibitors, statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin). Simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering drugs, bile acid scavengers (e.g., cholestyramine, questran, colestipol, and coleseveram), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., compounds described in AZD7687, LCQ908, WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modifiers (e.g., the compounds listed), GPBAR1 receptor modifiers, GPR120 modifiers, high-affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modifiers, GPR39 modifiers, GPR43 modifiers, GPR41 modifiers, GPR105 modifiers, Kv1.3 modifiers, retinol-binding protein 4 modifiers, somatostatin receptor modifiers, PDHK2 modifiers, PDHK4 modifiers, MAP4K4 inhibitors,IL1 family modifiers (e.g., ILI beta modifier), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modifiers (e.g., alirocumab and evolocumab), RXR alpha modifier, cysteamine, cystamine, RNA antisense constructs for inhibiting protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodasquemin, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezitimbe, betaine, pentoxifylline, alpha delta-9 desaturase Desaturase), BCKDK inhibitors, branched-chain alpha-keto acid dehydrogenase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensives, e.g., adrenergic receptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers (e.g., labetalol), adrenergic receptor agonists, e.g., alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (AC) E) Inhibitors (e.g., lisinopril), calcium channel blockers (e.g., dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs (e.g., centrally acting alpha agonists (e.g., clonidine)), diuretics (e.g., furosemide, torsemide, bumetanide, ethacrine), thiazide diuretics (e.g., chlorothiazide),Hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, meticlothiazide, polythiazide, trichlormethiazide, indapamide), phthalomidine diuretics (e.g., chlorthalidone, metrazone), quinazoline diuretics (e.g., quinazoline), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds listed in WO2020 / 117987), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activator)), thrombin antagonists, VI Factor Ia inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2 receptor antagonists (e.g., ifetroban), thromboxane-A2 synthase inhibitors, PDE inhibitors (e.g., pletar, dipyridamole)), purine receptor antagonists (e.g., For example, P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tyrofiban, eptifivatide, and absiximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agonists (e.g., phentermine), serotonergic agonists (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior enhancers, pi Rubinate dehydrogenase kinase (PDK) modifiers, serotonin receptor modifiers, monoamine transport modifiers, e.g., selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., troxatone and amyflamin), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794,GPR40 agonists (e.g., faciglifam or its hydrate, compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT-1 inhibitors, adiponectin or its agonists, IKK inhibitors Harmful agents (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-improving agents (e.g., cyclooxygenase inhibitors, e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, drugs to improve lipid metabolism (e.g., eicosapentaenoic acid), growth hormones Antibodies against Lumont, IGF-1, cachexia inducers TNF-α, LIF, IL-6, and oncostatin M, metabolic-improving proteins or peptides, e.g., 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 promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trireptal, Keppra, Zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +Channel openers (mexiletine, propafenone, metoprolol, atenolol, carvadiol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., Clonidine), local anesthetics (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 therapy drugs (e.g., anti-CD20 antibodies (e.g., rituximab), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin alpha-4 / beta-1 antibodies (e.g., taisotherapy) Drugs acting 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., mycophenolic acid), metaglidacen, AMG-131, paraglitazone, MBX-2044, riboglitazone, alleglitazar, tiglitazar, Examples include saroglitazal, mulaglitazal, tesaglitazal, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentate, clonidine, azosemide, isosorbide, ethacrine, pyretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrate esters), and NO promoters (e.g., phosphodiesterase inhibitors).

[0413] In one embodiment, the further therapeutic agent or regimen is administered to the patient before contact with or administration of the compound and pharmaceutical composition (for example, about 1 hour, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 1 week, or about 1 month prior).

[0414] In one embodiment, the further therapeutic agent or regimen is administered to the patient almost simultaneously with the contact or administration of the compound and pharmaceutical composition. As an example, the further therapeutic agent or regimen, as well as the compound and pharmaceutical composition, are administered to the patient simultaneously in the same formulation. As another example, the further therapeutic agent or regimen, as well as the compound and pharmaceutical composition, are administered to the patient simultaneously in separate formulations.

[0415] In one embodiment, the method described herein further includes the step of identifying patients (e.g., subjects) who require such treatment (e.g., by a blood assay, a body mass index, or other conventional method known in the art).

[0416] In one embodiment, the method described herein further includes the step of identifying a patient (e.g., a patient) suffering from one of the diseases, disorders, or illnesses provided herein (e.g., GLP-1 related disease, disorder, or illness).

[0417] 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, determining a patient who has type 2 diabetes includes performing assays to determine hemoglobin A1c (HbA1c) levels, fasting blood glucose, non-fasting blood 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 approximately 18.0% or higher. In another embodiment, the HbA1c level is approximately 20.0% or higher. In yet another embodiment, the HbA1c level is approximately 22.0% or higher. In yet another embodiment, the HbA1c level is approximately 24.0% or higher.

[0418] In one embodiment, the fasting blood glucose level is approximately 120 mg / dL or higher to approximately 750 mg / dL or higher. In another embodiment, the fasting blood glucose level is approximately 200 mg / dL or higher to approximately 500 mg / dL or higher. In yet another embodiment, the fasting blood glucose level is approximately 300 mg / dL or higher to approximately 700 mg / dL or higher.

[0419] In one embodiment, the non-fasting blood glucose level is approximately 190 mg / dL or higher to approximately 750 mg / dL or higher. In another embodiment, the non-fasting blood glucose level is approximately 250 mg / dL or higher to approximately 450 mg / dL or higher. In yet another embodiment, the non-fasting blood glucose level is approximately 400 mg / dL or higher to approximately 700 mg / dL or higher.

[0420] In one embodiment, determining whether 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 Or more, up to approximately 100 kg / m 2 or greater. In one embodiment, the patient's BMI is approximately 30 kg / m². 2 Or more, up to approximately 90 kg / m³ 2 or greater. In one embodiment, the patient's BMI is approximately 40 kg / m². 2 Or more, up to approximately 80 kg / m³ 2 or greater. In one embodiment, the patient's BMI is approximately 50 kg / m². 2 Or more, up to approximately 70 kg / m³ 2 Or more.

[0421] 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 about 10 years or older. In one embodiment, the patient's age is about 15 years or older. In one embodiment, the patient's age is about 20 years or older. In one embodiment, the patient's age is about 25 years or older. In one embodiment, the patient's age is about 30 years or older. In one embodiment, the patient's age is about 35 years or older. In one embodiment, the patient's age is about 40 years or older. In one embodiment, the patient's age is about 42 years or older. In one embodiment, the patient's age is about 44 years or older. In one embodiment, the patient's age is about 46 years or older. In one embodiment, the patient's age is about 48 years or older. In one embodiment, the patient's age is about 50 years or older. In one embodiment, the patient's age is about 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 embodiment, the patient's age is approximately 60 years or older. In one embodiment, the patient's age is approximately 62 years or older. In one embodiment, the patient's age is approximately 64 years or older. In one embodiment, the patient's age is approximately 66 years or older. In one embodiment, the patient's age is approximately 68 years or older. In one embodiment, the patient's age is approximately 70 years or older. In one embodiment, the patient's age is approximately 72 years or older. In one embodiment, the patient's age is approximately 74 years or older. In one embodiment, the patient's age is approximately 76 years or older. In one embodiment, the patient's age is approximately 78 years or older.In one embodiment, the patient's age is approximately 80 years or older. In one embodiment, the patient's age is approximately 85 years or older. In one embodiment, the patient's age is approximately 90 years or older. In one embodiment, 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, Hispanic or Latino American, or Native Hawaiian or Pacific Islander.

[0422] In one embodiment, the patient is a pediatric patient. As used herein, the term “pediatric patient” means a patient who is 21 years of age or younger at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including neonates (from birth to 1 month of age); infants (1 month to 2 years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age, including but not limited to 22 years of age) (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, a pediatric patient is from birth to 28 days old, from 29 days old to 2 years old, from 2 years old to 12 years old, or from 12 years old to 21 years old (including but not limited to 22 years old). In another embodiment, a pediatric patient is from birth to 28 days old, from 29 days old to 1 year old, from 1 month old to 4 months old, from 3 months old to 7 months old, from 6 months old to 1 year old, from 1 year old to 2 years old, from 2 years old to 3 years old, from 2 years old to 7 years old, from 3 years old to 5 years old, from 5 years old to 10 years old, from 6 years old to 13 years old, from 10 years old to 15 years old, or from 15 years old to 22 years old. In another embodiment, the patient is an adult patient. [Examples]

[0423] The present invention is further described in the following embodiments and is not limited to the scope of the invention as described in the claims.

[0424] General information:All evaporation was performed using a rotary evaporator under reduced pressure. Analytical samples were dried at room temperature under reduced pressure (1–5 mmHg). 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 (200–400 mesh). Solvent systems were reported as mixtures (by volume). All NMR spectra were recorded using a Bruker 400 or VARIAN (400 MHz) spectrometer. 1H chemical shifts were reported as δ values ​​(ppm) using deuterated solvent as an internal standard. Data were reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broadband signal, m=multilet), coupling constant (Hz), and integration. LCMS spectra were acquired using an Agilent 1200 series 6110 or 6120 mass spectrometer by electrospray ionization. Unless otherwise specified, general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm*4.6 mm*3.5 μm), flow rate: 2.0 mL / min, column temperature: 40 °C.

[0425] Example 1: 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 102a) [ka] [ka] Step A: Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine To a suspension of NaH (4.2 g, 108 mmol) in dry THF (200 mL), (4-chloro-2-fluorophenyl)methanol (17.2 g, 108 mmol) was added under N2 at 0°C. The mixture was stirred at room temperature for 30 minutes. Then, 2,6-dibromopyridine (21.2 g, 90 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (50 mL x 3), washed with saline solution (50 mL x 3), dried over sodium sulfate, filtered, concentrated under vacuum, and the residue purified by column chromatography to obtain 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine as a white solid (27 g, yield: 94%). MS theoretical value: 314.9; MS measured value: 316.0 [M+H] + .

[0426] Step B: Synthesis of ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate A mixture of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (400 mg, 1.26 mmol), Pd(PPh3)4 (15 mg, 0.12 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl)acetate (483 mg, 1.64 mmol), and potassium carbonate (349 mg, 2.53 mmol) in dioxane (5 ml) and water (1 ml) was stirred at 100°C for 12 hours under a nitrogen atmosphere. The mixture was poured into cold water and extracted with butyl (3 x 15 ml). The organic layers were combined, washed with water (30 ml), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate as a yellow oil (490 mg, yield: 82%). MS theoretical value: 403.1; MS measured value: 404.2 [M+H] + .

[0427] Step C: Synthesis of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol LiAlH4 (188 mg, 4.95 mmol) was added to a two-port RBF under N2 conditions. Then, a solution of ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl) acetate (500 mg, 1.24 mmol) in THF (5 ml) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction product was quenched with H2O:NaOH (aqueous solution, 15%):H2O = 1:3:1. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate (15 mL x 3). The ethyl acetate layers were combined, washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica gel to obtain 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3--en-1-yl)ethane-1-ol as a yellow oily substance (170 mg, yield: 40%). MS theoretical value: 361.1; MS measured value: 362.0 [M+H] + .

[0428] Step D: Synthesis of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde A mixture of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (170 mg, 0.46 mmol) and IBX (263 mg, 0.94 mmol) was mixed in ELISA (5 ml). The mixture was stirred at 80°C for 30 hours. The remaining IBX was removed by filtration. The solvent was removed from the filtrate to obtain the crude product 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde as a yellow oil (200 mg, yield: 63%). MS theoretical value: 359.1; MS measured value: 360.1 [M+H] + .

[0429] Step E: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (200 mg, 0.58 mmol) and methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (138 mg, 0.58 mmol) was mixed in toluene (5 ml). The mixture was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow oil (150 mg, yield: 45%). MS theoretical value: 576.2; MS measured value: 577.2 [M+H] + .

[0430] Step F: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg, 0.26 mmol) and lithium hydroxide (12 mg, 0.52 mmol) in methanol (3 ml) and water (0.5 ml) was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (49.2 mg, yield: 34%). MS theoretical value: 562.2; MS measured value: 563.1 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 14.2, 4.8 Hz, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.27 (d, J = 7.0 Hz, 1H), 4.71 (ddd, J = 47.7, 25.0, 7.8 Hz, 3H), 4.47 - 4.38 (m, 1H), 3.18 (dd, J = 15.6, 8.6 Hz, 2H), 2.83 - 2.66 (m, 2H), 2.57 - 2.41 (m, 4H), 2.11 (m, 2H), 1.61 (d, J = 6.7 Hz, 1H).

[0431] Example 2: 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid diastereomer-1 (compound 102b) Example 3: 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid diastereomer-2 (compound 102c) Compound 102a (400 mg) was split into its constituent diastereomers as cyclohexane using supercritical fluid chromatography [apparatus: Gilson-281, column: IG20*250, 10 μm, mobile phase: n-hexane (0.1% FA): EtOH (0.1% FA) = 7:3]. The first diastereomer to elute was named compound 102b. This was further purified by reverse-phase HPLC [column: SunFire C18, 10 μm, mobile phase A: 0.05% ammonium bicarbonate, mobile phase B: acetonitrile, 20-70% B for 8 minutes, stopped at 16 minutes] (yield: 80 mg, 20%). LCMS: m / z 563.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.08 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.29 - 7.15 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.77 (s, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.35 - 5.23 (m, 1H), 4.81 - 4.67 (m, 2H), 4.64 - 4.55 (m, 1H), 4.49 - 4.36 (m, 1H), 3.17 (d, J = 6.9 Hz, 2H), 2.86 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.60 - 2.38 (m, 4H), 2.23 - 2.00 (m, 2H), 1.68 - 1.52 (m, 1H).

[0432] Next, the eluted diastereomer was named compound 102c. This was further purified by reverse-phase HPLC [column: SunFire C18, 10 μm, mobile phase A: 0.05% ammonium bicarbonate, mobile phase B: acetonitrile, 20-70% B for 8 minutes, stopped at 16 minutes] (yield: 53 mg, 13%). LCMS: m / z 563.1 [M+H]+ . 1 H NMR (400 MHz, CD3OD) δ 8.16 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.67 - 7.55 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.29 - 7.15 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.78 (s, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.31 - 5.19 (m, 1H), 4.85 - 4.68 (m, 2H), 4.65 - 4.53 (m, 1H), 4.41 (dt, J = 9.1, 6.0 Hz, 1H), 3.28 - 3.10 (m, 2H), 2.85 - 2.75 (m, 1H), 2.74 - 2.62 (m, 1H), 2.60 - 2.43 (m, 4H), 2.23 - 1.99 (m, 2H), 1.67 - 1.55 (m, 1H).

[0433] Example 4: 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 101a) [ka] [ka] Step A: Synthesis of ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3--en-1-yl)acetate A mixture of 4-(((6-bromopyridine-2-yl)oxy)methyl)-3-fluorobenzonitrile (1.2 g, 4 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl) acetate (1.2 g, 4 mmol), and K2CO3 (1.1 g, 8 mmol) in dioxane (5 mL) and water (1 mL) was degassed with N2 for 10 minutes. Then, Pd(dppf)Cl2 (330 mg, 0.4 mmol) was added. The mixture was stirred at 85°C for 15 hours, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate (1.4 g, yield: 86.5%) as a colorless oil. MS theoretical value: 394.2; MS measured value: 395.1 [M+H] + .

[0434] Step B: Synthesis of 3-fluoro-4-(((6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile A mixture of ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate (1.1 g, 2.79 mmol) in THF (15 mL) was mixed with DIBAL-H (9.78 mmol) at -78 °C. The mixture was stirred at -78 °C for 4 hours, and the reaction was quenched by adding saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ELISA (3 x 15 mL). The organic layers were washed with water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the desired product, 3-fluoro-4-(((6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile as a white solid (0.5 g, yield: 50%). MS theoretical value: 352.2; MS measured value: 353.0 [M+H] + .

[0435] Step C: Synthesis of 3-fluoro-4-(((6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile To a solution of 3-fluoro-4-(((6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile (500 mg, 1.42 mmol) in siRNA (20 mL), IBX (1100 mg, 3.46 mmol) was slowly added. The mixture was stirred at 80°C for 15 hours. The mixture was filtered, and the filtrate was concentrated to obtain the crude product 3-fluoro-4-(((6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile as a white solid (400 mg, yield: 80%). MS theoretical value: 350.1; MS measured value: 351.0 [M+H] +

[0436] Step D: Synthesis of ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 3-fluoro-4-(((6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile (0.6 g, 1.71 mmol) and methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (0.4 g, 1.71 mmol) in toluene (20 mL) was stirred at 80°C for 48 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica, DCM / MeOH = 20 / 1) to obtain the desired product, ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate, as a brown solid (460 mg, yield: 46%). MS theoretical value: 581.2; MS measured value: 582.2 [M+H] + .

[0437] Step E: Synthesis of 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A solution of ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (270 mg, 0.47 mmol) and lithium hydroxide (78 mg, 1.86 mmol) in THF (2 mL) and water (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was purified by preparative HPLC to obtain the desired product, 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, as a white solid (120 mg, yield: 47%). MS theoretical value: 553.2; MS measured value: 554.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 8.4 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1H), 7.71-7.55 (m, 4 H), 7.07 (d, J = 8.4 Hz, 1H), 6.74-6.70 (m, 2 H), 5.55 (s, 2 H), 5.27-5.25 (m, 1 H), 4.83-4.77 (m, 1H), 4.72-4.68 (m, 1 H), 4.62-4.60 (m, 1 H), 4.46-4.39 (m, 1 H), 3.25-3.12 (m, 2 H), 2.83-2.78 (m, 1 H), 2.68-2.63 (m, 1H), 2.54-2.47 (m, 4H), 2.15- 2.05 (m, 2H), 1.63-1.56 (m, 1H).

[0438] Example 5: 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid diastereomer-1 Example 6: 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid diastereomer-2 Compound 101a (300 mg) was divided into its constituent diastereomers as cyclohexene by supercritical fluid chromatography [apparatus: Gilson-281, column: IG20*250, 10 μm, mobile phase: n-hexane (0.1% FA): EtOH (0.1% FA) = 7:3].

[0439] The first diastereomer to elute was named compound 101b. This was further purified using reverse-phase HPLC [column: SunFire C18, 10 μm, mobile phase A: 0.05% ammonium bicarbonate, mobile phase B: acetonitrile, 20-70% B for 8 minutes, stopped at 16 minutes] (yield: 50 mg, 17%). LCMS: m / z 554.0 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.72 - 7.50 (m, 4H), 7.05 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 2H), 5.54 (s, 2H), 5.34 - 5.20 (m, 1H), 4.83 - 4.74 (m, 1H), 4.74 - 4.65 (m, 1H), 4.65 - 4.55 (m, 1H), 4.48 - 4.36 (m, 1H), 3.17 (d, J = 6.9 Hz, 2H), 2.86 - 2.74 (m, 1H), 2.69 - 2.60 (m, 1H), 2.57 - 2.36 (m, 4H), 2.18 - 1.99 (m, 2H), 1.68 - 1.50 (m, 1H).

[0440] Next, the eluted diastereomer was named compound 101c. This was further purified using reverse-phase HPLC [column: SunFire C18, 10 μm, mobile phase A: 0.05% ammonium bicarbonate, mobile phase B: acetonitrile, 20-70% B for 8 minutes, stopped at 16 minutes] (yield: 50 mg, 17%). LCMS: m / z 554.0 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.15 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.75 - 7.50 (m, 4H), 7.07 (d, J = 7.5 Hz, 1H), 6.80 - 6.62 (m, 2H), 5.55 (s, 2H), 5.27 (d, J = 4.5 Hz, 1H), 4.79 (dd, J = 15.0, 6.8 Hz, 1H), 4.70 (dd, J = 14.9, 3.0 Hz, 1H), 4.60 (dd, J = 13.8, 7.8 Hz, 1H), 4.41 (dt, J = 9.0, 5.9 Hz, 1H), 3.18 (qd, J = 15.5, 7.0 Hz, 2H), 2.90 - 2.74 (m, 1H), 2.65 (d, J = 16.9 Hz, 1H), 2.48 (d, J = 13.2 Hz, 4H), 2.24 - 1.97 (m, 2H), 1.59 (d, J = 7.0 Hz, 1H).

[0441] Example 7: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 103a) [ka] [ka] Step A: Synthesis of 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine To a solution of compound 2,4-dichloropyrimidine (5.0 g, 33.5 mmol) and 4-chloro-2-fluorobenzyl alcohol (5.1 g, 31.8 mmol) in CH3CN (50 mL), Cs2CO3 (16.3 g, 50.3 mmol) was gradually added over 10 minutes while cooling with ice water. The mixture was stirred at 30°C for 16 hours. The mixture was diluted with ELISA (50 mL) and stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated until dry. The residue was diluted with a mixture of PE / ELISA (12 mL / 1 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and the filter cake was washed with PE (8 mL). The solid was then diluted with PE (8 mL) and stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to obtain the desired product, 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine, as a gray solid (4.6 g, yield: 54%). MS theoretical value: 272.0; MS measured value: 273.0 [M+H] + .

[0442] Step B: Synthesis of ethyl 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate A mixture of 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine (400 mg, 1.46 mmol), Pd(dppf)Cl2 (15 mg, 0.12 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl)acetate (560 mg, 1.9 mmol), and potassium carbonate (404 mg, 2.93 mmol) in dioxane (3 mL) and water (1 mL) was stirred at 85°C for 12 hours under a nitrogen atmosphere. The mixture was poured into cold water and extracted with ethyl acetate (3 x 15 mL). The organic layers were washed with water (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain ethyl 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate as a yellow oily substance (400 mg, yield: 67%). MS theoretical value: 404.1; MS measured value: 405.1 [M+H] + .

[0443] Step C: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol LiAlH4 (187 mg, 4.94 mmol) was allowed to stand in a two-bottomed container under N2. Then, ethyl 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate (400 mg, 0.98 mmol) in THF (5 mL) was added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction product was quenched with H2O:NaOH (aqueous solution, 15%):H2O = 1:3:1. The resulting mixture was extracted with ELISA (15 mL x 3), washed with saline solution (10 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica gel to obtain the desired product 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol as a yellow oily substance (240 mg, yield: 67%). MS theoretical value: 362.1; MS measured value: 363.1 [M+H] + .

[0444] Step D: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde A mixture of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (240 mg, 0.6 mmol) and IBX (370 mg, 1.3 mmol) was mixed in ELISA (5 mL). The mixture was stirred at 80°C for 30 hours. The remaining IBX was removed by filtration. The filtrate was concentrated to obtain the crude product 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde as a yellow oil (330 mg, yield: 95%). MS theoretical value: 360.1; MS measured value: 361.1 [M+H] + .

[0445] Step E: Synthesis of ethyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (330 mg, 0.9 mmol) and ethyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (230 mg, 0.9 mmol) was mixed in toluene (6 mL). The mixture was stirred at 80°C for 16 hours and concentrated under reduced pressure. The resulting residue was purified with silica gel to obtain ethyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow oil (80 mg, yield: 15%). MS theoretical value: 591.2; MS measured value: 591.9 [M+H] + .

[0446] Step F: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of ethyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (80 mg, 0.13 mmol) and lithium hydroxide (10 mg, 0.30 mmol) in methanol (3 mL) and water (0.5 mL) was stirred at room temperature for 3 hours. The reaction mixture was purified by preparative HPLC to obtain the desired product 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (22.5 mg, yield: 30%). MS theoretical value: 563.1; MS measured value: 564.1 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 5.8 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.25 (t, J = 9.7 Hz, 3H), 6.72 (d, J = 5.8 Hz, 1H), 5.53 (s, 2H), 5.28 (d, J = 4.0 Hz, 1H), 4.77 (dt, J = 29.5, 9.7 Hz, 2H), 4.60 (dd, J = 14.5, 7.3 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.26 - 3.12 (m, 2H), 2.81 (d, J = 11.4 Hz, 2H), 2.52 (d, J = 7.7 Hz, 4H), 2.18 (s, 1H), 2.07 (s, 1H), 1.61 (s, 1H).

[0447] Example 8: 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104a) [ka] [ka] Step A: Synthesis of ethyl 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetate Pd(dppf)Cl2 (1.23g, 1.67mmol) was added to a mixture of 2,4-dichloropyrimidine (5g, 33.5mL), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-enyl) acetate (9.87g, 33.5mmol), and K2CO3 (9.26g, 67.1mmol) in 1,4-dioxane (70mL) and H2O (15mL). The mixture was stirred at 80°C for 16 hours under N2. The mixture was cooled to room temperature and diluted with saline solution (40mL). This was extracted with ELISA (35mL x 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluted with PE / siRNA(12 / 1~8 / 1)) to obtain ethyl 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetate as a pale yellow oily substance (6.3 g, yield: 67.1%). MS theoretical value: 280.1; MS measured value: 281.1 [M+H] + .

[0448] Step B: Synthesis of 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)ethane-1-ol A solution of ethyl 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetate (4.0 g, 14.3 mmol) in THF (100 mL) was to be added dropwise with DIBAl-H (42.9 mL, 42.9 mmol) at -78 °C. The mixture was then warmed to -40 °C and stirred for 1 hour. This was quenched with saturated NH4Cl (20 mL) and stirred at 0 °C for 15 minutes. This was filtered, and the filtrate was diluted with ELISA (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)ethane-1-ol as a colorless oil (3.2 g, yield: 94.1%). MS theoretical value: 238.1; MS measured value: 239.1 [M+H] + .

[0449] Step C: Synthesis of 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetaldehyde A mixture of 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)ethane-1-ol (3.2 g, 13.4 mmol), TEMPO (21 mg, 0.13 mmol), NaHCO3 (1.13 g, 13.4 mmol), NaCl (780 mg, 13.4 mmol), and KBr (160 mg, 1.34 mmol) in DCM (15 mL) and H2O (15 mL) was to be added dropwise with NaClO (13.9 mL, 14.1 mmol) over 30 minutes at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The aqueous layer was separated and extracted with DCM (15 mL x 3). The organic layers were combined and washed with saturated Na2S2O3 (25 mL), saturated NaHCO3 (25 mL), and saline solution (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluted with PE / siRNA (10 / 1~6 / 1)) to obtain 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetaldehyde as a pale yellow oil (2 g, yield: 63.0%). MS theoretical value: 236.1; MS measured value: 236.9 [M+H] + .

[0450] Step D: Synthesis of ethyl 2-((4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a solution of 2-(4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)acetaldehyde (2 g, 8.47 mmol) in toluene (20 mL), (S)-ethyl 5-amino-6-(oxetan-2-ylmethylamino)picolinate (2.13 g, 8.47 mmol) and molecular sieves (2.13 g) were added. The mixture was stirred at 80°C for 40 hours under an O2 atmosphere. It was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography (eluted with DCM / MeOH (80 / 1~60 / 1)) to obtain ethyl 2-((4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow solid (3.2 g, yield: 80.8%). MS theoretical value: 467.2; MS measured value: 468.0 [M+H] + .

[0451] Step E: Synthesis of 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of ethyl 2-((4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (500 mg, 1.07 mmol) in CH3CN (15 mL), (4-chloro-2-fluorophenyl)methanol (214 mg, 1.34 mmol) and Cs2CO3 (696 mg, 2.14 mmol) were added. The mixture was stirred at 80°C for 16 hours. Subsequently, it was cooled to room temperature and filtered. The filtrate was concentrated. This was diluted with H2O (5 mL) and acidified to pH=5 with AcOH solution (10%). Next, this was extracted with DCM (50 mL x 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (high pH) to obtain 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a pale yellow solid (13.5 mg, yield: 2.2%). MS Calcd.: 563.2; MS Found: 564.0 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.27-7.21 (m, 3H), 7.10 (s, 1H), 5.50 (s, 2H), 5.27-5.25 (m, 1H), 4.82-4.77 (m, 1H), 4.72-4.68 (m, 1H), 4.63-4.58 (m, 1H), 4.44-4.40 (m, 1H), 3.22-3.17 (m, 2H), 2.82-2.77 (m, 1H), 2.72-2.67 (m, 1H), 2.57-2.46 (m, 4H), 2.21-2.06 (m, 2H), 1.63-1.59 (m, 1H).

[0452] Example 9: (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 110a) [ka] Step A: Synthesis of tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate A mixture of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (500 mg, 1.58 mmol), Pd(dppf)Cl2 (15 mg, 0.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (732 mg, 2.37 mmol), and potassium carbonate (654 mg, 4.74 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 85°C for 12 hours under a nitrogen atmosphere. The mixture was poured into cold water and extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, washed with water (30 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate as a yellow oil (800 mg, yield: 96%). MS theoretical value: 418.1; MS measured value: 419.1 [M+H] + .

[0453] Step B: Synthesis of 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine A solution of tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (800 mg, 1.96 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine as a chestnut-colored oil (800 mg, yield: 99%), which was used directly in the next step. MS theoretical value: 318.1; MS measured value: 319.0 [M+H] + .

[0454] Step C: Synthesis of ethyl (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (500 mg, 1.5 mmol), ethyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (630 mg, 2.0 mmol), and cesium carbonate (1.5 g, 4.7 mmol) in DMF (6 mL) was stirred at room temperature for 5 hours. The reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saline solution (10 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica gel to obtain ethyl (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow oil (260 mg, yield: 32%). MS theoretical value: 591.2; MS measured value: 591.9 [M+H] + .

[0455] Step D: Synthesis of (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of ethyl (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (260 mg, 0.5 mmol) and lithium hydroxide (25 mg, 1.0 mmol) in methanol (3 mL) and water (0.5 mL) was stirred at room temperature for 4 hours. The reaction mixture was directly purified by preparative HPLC to obtain (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (39.9 mg, yield: 14%). MS theoretical value: 563.1; MS measured value: 564.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.21 - 8.06 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.22 (t, J = 9.4 Hz, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.79 - 6.63 (m, 2H), 5.45 (s, 2H), 5.35 - 5.26 (m, 1H), 5.04 (dd, J = 14.9, 6.8 Hz, 1H), 4.88 (dd, J = 14.9, 3.0 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.49 - 4.40 (m, 1H), 4.32 (d, J = 14.1 Hz, 1H), 4.21 (d, J = 14.0 Hz, 1H), 3.42 (s, 2H), 2.96 (t, J = 5.5 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.70 (s, 2H), 2.59 - 2.49 (m, 1H).

[0456] Example 10: (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thiazole-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 112a) [ka] [ka] Step A: Synthesis of 4-((4-bromothiazole-2-yloxy)methyl)-3-fluorobenzonitrile A solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (1.51 g, 10 mmol) in dry THF (20 mL) was added to a solution of NaH (600 mg, 15 mmol) in dry THF (15 mL) at 0°C. The mixture was stirred at 0°C for 0.5 hours. 2,4-dibromothiazole (2.42 g, 10 mmol) was added, and the mixture was stirred at 25°C for 6 hours. The reaction product was diluted with water (20 mL) and extracted with ethyl acetate (45 mL x 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4-((4-bromothiazole-2-yloxy)methyl)-3-fluorobenzonitrile as a white solid (1.9 g, yield: 61%). MS theoretical value: 311.9; MS measured value: 312.8 [M+H] + .

[0457] Step B: Synthesis of tert-butyl 4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate To a solution of 4-((4-bromothiazole-2-yloxy)methyl)-3-fluorobenzonitrile (1.8 g, 5.77 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.67 g, 8.66 mmol), and Na2CO3 (1.22 g, 11.54 mmol) in Dox / H2O (20 mL / 4 mL), Pd(dppf)Cl2 (230 mg, 0.31 mmol) was added at room temperature. The mixture was stirred overnight at 85°C under an N2 atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl 4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a white solid (1.1 g, yield: 50%). MS theoretical value: 415.1; MS measured value: 438.0 [M+Na] + .

[0458] Step C: 3-Fluoro-4-((4-(1,2,3,6-tetrahydropyridine-4-yl)thiazole-2-yloxy)methyl)benzonitrile A solution of tert-butyl 4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.72 mmol) in HFIP (2 mL). The mixture was stirred under microwave at 140°C for 4 hours. The reaction mixture was concentrated to obtain the crude product 3-fluoro-4-((4-(1,2,3,6-tetrahydropyridine-4-yl)thiazole-2-yloxy)methyl)benzonitrile as a white solid (210 mg, crude product), which was used directly in the next step. MS theoretical value: 315.1; MS measured value: 316.0 [M+H] + .

[0459] Step D: Synthesis of (S)-ethyl 2-((4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a solution of (S)-ethyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (185 mg, 0.6 mmol) in dry DMF (5 mL), 3-fluoro-4-((4-(1,2,3,6-tetrahydropyridine-4-yl)thiazole-2-yloxy)methyl)benzonitrile (210 mg, crude product) and K2CO3 (696 mg, 2.14 mmol) were added. The mixture was stirred at 25°C for 2 hours. The mixture was then filtered. The filtrate was concentrated, and the resulting residue was purified by preparative HPLC (high pH) to obtain (S)-ethyl 2-((4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a white solid (80 mg). MS theoretical value: 588.2; MS measured value: 589.1 [M+H] + .

[0460] Step E: Synthesis of (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thiazole-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of (S)-ethyl 2-((4-(2-(4-cyano-2-fluorobenzyloxy)thiazole-4-yl)-5,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (80 mg, 0.14 mmol) and lithium hydroxide (29.4 mg, 0.7 mmol) in THF (3 mL) and water (1 mL) was stirred at room temperature for 6 hours. The reaction mixture was directly purified by preparative HPLC to obtain (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thiazole-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (25 mg, yield: 32%). MS theoretical value: 560.2; MS measured value: 561.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.11-8.05 (m, 2H), 7.76 (t, J = 6.0 Hz, 1H), 7.62 (t, J = 6.0 Hz, 2H), 6.69 (s, 1H), 6.52(s, 1H), 5.61 (s, 2H), 5.32-5.30 (m,1H), 5.06-5.01 (m, 1H), 4.64-4.60 (m, 2H), 4.46-4.42 (m, 1H), 4.23 (d, J = 11.2 Hz, 1H), 4.11 (d, J = 10.8 Hz, 1H), 3.33 - 3.29 (m, 2H), 2.85-2.76 (m, 3H), 2.56-2.51 (m, 3H).

[0461] Example 11: 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 105a) [ka] Step A: Synthesis of ethyl 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a solution of ethyl 2-((4-(2-chloropyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (700 mg, 1.50 mmol) in CH3CN (20 mL), 3-fluoro-4-(hydroxymethyl)benzonitrile (283 mg, 1.87 mmol) and Cs2CO3 (974 mg, 3.0 mmol) were added. The mixture was stirred at 80°C for 3 hours. Subsequently, it was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC (high pH) to obtain ethyl 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow solid (320 mg, yield: 36.7%). MS theoretical value: 582.2; MS measured value: 582.9 [M+H] + .

[0462] Step B: Synthesis of 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of ethyl 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (320 mg, 0.55 mmol) in CH3OH (9 mL) and H2O (3 mL), LiOH·H2O (69 mg, 1.65 mmol) was added. The mixture was stirred at room temperature for 2 hours. This was acidified to pH=5 with AcOH (10%) and extracted with DCM (15 mL x 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to obtain 2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidine-4-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (182.5 mg, yield: 59.9%). MS theoretical value: 554.2; MS measured value: 555.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 4.4 Hz, 1H), 8.13 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.75 (t, J = 6.0 Hz, 1H), 7.63~7.58 (m, 2H), 7.22 (d, J = 4.4 Hz, 1H), 7.09 (s, 1H), 5.61 (s, 2H), 5.29~5.25 (m, 1H), 4.81~4.76 (m, 1H), 4.72~4.68 (m, 1H), 4.63~4.58 (m, 1H), 4.44~4.38 (m, 1H), 3.24~3.15 (m, 2H), 2.81~2.78 (m, 1H), 2.69~2.62 (m, 1H), 2.57~2.48 (m, 4H), 2.23~2.07 (m, 2H), 1.65~1.58 (m, 1H).

[0463] Example 12: Synthesis scheme of 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 113a) [ka] Step A: Synthesis of 6-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine A solution of 2,6-dichloro-3-fluoropyridine (3.2 g, 20 mmol) and (4-chloro-2-fluorophenyl)methanol (3.3 g, 20 mmol) in CH3CN (60 mL) was mixed with K2CO3 (5.5 g, 40 mmol) and stirred at 80 °C for 13 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with H2O (100 mL) and extracted twice with ELISA (100 mL). The organic layer was washed with saline solution (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by Combi-flush (eluted with silica gel, ethyl / petroleum (0% to 25%)) to obtain 6-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine as a white solid (0.9 g, 5 mmol, yield 25%). LCMS: m / z 290.0 [M+H] + .

[0464] Step B: Synthesis of ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetate To a suspension of 6-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (0.9 g, 3.1 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl) acetate (1 g, 3.4 mmol) in dioxane (20 mL) and H2O (7 mL), K2CO3 (0.9 g, 6 mmol) and Pd(dppf)Cl2 (245 mg, 0.3 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 16 hours under an N2 atmosphere. The mixture was diluted with H2O (50 mL) and extracted twice with ELISA (80 mL). The organic layer was washed with saline solution (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product as a brown oily substance. The crude product was purified by Combi-flush (eluted with silica gel, ethyl / petroleum (5 to 25%)) to obtain ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetate (0.6 g, 1.5 mmol, yield 50%). LCMS: m / z 422.1 [M+H] +

[0465] Step C: Synthesis of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol A mixture of LiAlH4 (182 mg, 4.8 mmol) in dry THF (10 mL) was added dropwise to a solution of ethyl 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl) acetate (340 mg, 0.81 mmol) in dry THF (2 mL) at -20°C. The mixture was stirred at -20°C for 1 hour and then cooled to -78°C. The reaction was quenched by adding H2O (0.206 mL) dropwise. Aqueous NaOH solution (15%, 0.206 mL) was added, followed by H2O (0.618 mL). The mixture was warmed to 0°C and stirred for 30 minutes. The resulting white suspension was filtered, and the filtrate was dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol as an orange oily substance (0.4g, 70%). LCMS: m / z 380.1 [M+H] +

[0466] Step D: Synthesis of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (300 mg, 0.79 mmol) and IBX (665 mg, 2.37 mmol) were dissolved in ELISA (20 ml). The mixture was stirred at 80°C for 15 hours. The mixture was filtered, and the filtrate was concentrated to obtain 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde as a white solid (crude product) (300 mg). MS measured value: 378.1 [M+H] + .

[0467] Step E: Synthesis of ethyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (130 mg) and ethyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (86 mg, 0.34 mmol) was mixed in toluene (20 ml). The mixture was stirred at 80°C for 48 hours. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain ethyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a brown oil (140 mg, yield: 60%). LCMS: m / z609.2 [M+H]

[0468] Step F: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A solution of ethyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (140 mg, 0.25 mmol) and lithium hydroxide (42 mg, 1 mmol) in THF (2 ml) and water (1 ml) was stirred at room temperature for 10 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (66 mg, yield: 46%). LCMS: m / z 581.2 [M+H] + 1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.26-7.22 (m, 2 H), 7.06-7.03 (m, 1H), 6.75-6.68 (m, 1 H), 5.52 (s, 2 H), 5.30-5.25(m, 1 H), 4.83-4.77 (m, 1H), 4.72-4.68 (m, 1 H), 4.62-4.58 (m, 1 H),4.46-4.39 (m, 1 H), 3.19-3.12 (m, 2H), 2.83-2.78 (m, 1H), 2.68-2.63 (m, 1H), 2.54-2.47 (m, 4H), 2.13- 2.05 (m, 2H), 1.62-1.55 (m, 1H).

[0469] Example 13: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 114a) [ka] Step A: Synthesis of 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine To a solution of 2,4-dichloro-5-fluoropyrimidine (6.0 g, 35.9 mmol) and (4-chloro-2-fluorophenyl)methanol (5.65 g, 35.21 mmol) in CH3CN (50 mL), K2CO3 (6.4 g, 46.67 mmol) was added. The mixture was stirred at 80°C for 16 hours. LC-MS showed that 2,4-dichloro-5-fluoropyrimidine was completely consumed and the desired product was formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine, as a white solid (9 g, crude product), which was used directly in the next step. MS theoretical value: 290.0; MS measured value: 291.0 [M+H] + .

[0470] Step B: Synthesis of ethyl-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate 5.5 g of 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine, 5.55 g of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, and 5.2 g of K2CO3 (37.78 mmol) were dissolved in dioxane / H2O (85 mL / 17 mL). Pd(dppf)Cl2 (691 mg, 0.94 mmol) was added at room temperature. The mixture was stirred overnight at 85 °C under an N2 atmosphere. LC-MS showed that 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine was completely consumed and the desired product was formed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate as a white solid (5g, yield: 63%). MS theoretical value: 422.1; MS measured value: 422.9 [M+1] + .

[0471] Step C: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol To a solution of ethyl-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate (2.5 g, 5.9 mmol) in dry THF (50 mL), LAH (448.7 mg, 11.8 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. LC-MS showed that 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine was completely consumed and the desired product was formed. The reaction product was quenched by adding 448 mg of H2O and 448 mg of NaOH (15% aqueous solution). The resulting suspension was then filtered, washed with EA (10 mL), and the filtrate was extracted with EA (20 mL x 3). The EA layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol as a colorless oil (1.6 g, crude product). MS theoretical value: 380.1; MS measured value: 380.9 [M+H] + .

[0472] Step D: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde To a solution of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (1 g, 2.62 mmol), TEMPO (4 mg, 0.026 mmol), NaCl (153.1 mg, 2.62 mmol), NaHCO3 (220.6 mg, 2.62 mmol), and KBr (31 mg, 0.262 mmol), an aqueous solution of NaClO (7.5%, 2.6 mL) was added dropwise over 20 minutes at 0°C. LC-MS demonstrated that 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol was completely consumed and the desired product was formed. The reaction mixture was extracted with dichloromethane (30 mL x 2) and washed with saturated Na2S2O3 aqueous solution (25 mL), saturated NaHCO3 aqueous solution (30 mL), and saline solution (30 mL). The resulting DCM solution was concentrated and purified on silica gel (0-3% methanol in dichloromethane) to obtain the title product 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (750 mg, 1.98 mmol). MS theoretical value: 378.1; MS measured value: 378.9 [M+H] + .

[0473] Step E: Synthesis of ethyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (210 mg, 0.57 mmol) and (S)-ethyl 5-amino-6-(oxetane-2-ylmethylamino)picolinate (171.4 mg, 0.68 mmol) were mixed in dry toluene (5 mL), to which 4A molecular sieves (130 mg) was added. The mixture was stirred at 100 °C for 40 hours under an O2 atmosphere. LC-MS showed that the starting material 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde was completely consumed and the desired product was produced. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=20\1, UV254nm) to obtain the title product as a brown solid (210 mg, 0.34 mmol). MS theoretical value: 609.2; MS measured value: 609.9 [M+H] + .

[0474] Step F: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of ethyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg, 0.24 mmol) in THF (4 mL) and H2O (2 mL), LiOH·H2O (125.88 mg, 0.5 M) was added. The mixture was stirred at 20°C for 4 hours. LC-MS showed that the starting material was completely consumed and the desired product was produced. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (69 mg, 0.011 mmol). MS theoretical value: 581.2; MS measured value: 582.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.53 (dd, J = 9.9, 1.8 Hz, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.16 (s, 1H), 5.58 (s, 2H), 5.17 - 5.04 (m, 1H), 4.70 - 4.58 (m, 1H), 4.56 - 4.40 (m, 2H), 4.35 - 4.24 (m, 1H), 3.23 - 2.95 (m, 2H), 2.77 - 2.61 (m, 2H), 2.45 - 2.29 (m, 4H), 2.19 - 2.04 (m, 1H), 2.04 - 1.93 (m, 1H), 1.55 - 1.41 (m, 1H).

[0475] [ka] Compound 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 114a) was purified by SFC (column: IH, eluent: 30% MeOH [0.2% methanol ammonia]; flow rate: 4 ml / min; temperature: 40℃; PB: 120 bar) to obtain diastereomer 1 (2.38 g, 4.01 mmol) and diastereomer 2 (2.68 g, 4.6 mmol). Diastereomer 1 (Compound 114b) MS theoretical value: 581.2; MS measured value: 582.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.53 (dd, J = 10.0, 1.9 Hz, 1H), 7.35 (d, J = 8.2, 1.8 Hz, 1H), 7.16 (s, 1H), 5.58 (s, 2H), 5.10-5.04 (m, 1H), 4.70 - 4.58 (m, 1H), 4.56 - 4.40 (m, 2H), 4.35 - 4.24 (m, 1H), 3.23 - 2.95 (m, 2H), 2.77 - 2.61 (m, 2H), 2.45 - 2.29 (m, 4H), 2.19 - 2.04 (m, 1H), 2.04 - 1.93 (m, 1H), 1.55 - 1.41 (m, 1H). ジアステレオマー2 (Compound 114c) MS theoretical value: 581.2; MS experimental value: 582.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.52 (dd, J = 9.9, 1.8 Hz, 1H), 7.35 (d, J = 8.2, 1.6 Hz, 1H), 7.16 (s, 1H), 5.57 (s, 2H), 5.20 - 4.95 (m, 1H), 4.74 - 4.49 (m, 2H), 4.42 - 4.32 (m, 1H), 4.29-4.17 (m, 1H), 3.20-2.92 (m, 2H), 2.82-2.69 (m, 1H), 2.62 - 2.53 (m, 2H), 2.45 - 2.29 (m, 3H), 2.19 - 2.04 (m, 1H), 2.04 - 1.93 (m, 1H), 1.55 - 1.41 (m, 1H).

[0476] Example 14: 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 115a) [ka] Step A: Synthesis of 4-(((6-chloro-3-fluoropyridine-2-yl)oxy)methyl)-3-fluorobenzonitrile To a solution of 2,6-dichloro-3-fluoropyridine (1.1 g, 6.7 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (1.0 g, 6.71 mmol) in CH3CN (60 mL), Cs2CO3 (4.4 g, 14 mmol) was added all at once. The mixture was stirred at 80 °C for 13 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with H2O (100 mL) and extracted twice with ELISA (100 mL). The organic layers were combined, washed with saline solution (50 mL), and dried over anhydrous Na2SO4. The mixture was filtered, the filtrate was concentrated, and purified by flash (elution with silica gel, ethyl acetate / petroleum ether = 1 / 5, UV 254 nm) to obtain 4-(((6-chloro-3-fluoropyridine-2-yl)oxy)methyl)-3-fluorobenzonitrile as a white solid (0.7 g, 2.5 mmol, yield 38%). LCMS: m / z 280.9 [M+H]+.

[0477] Step B: Synthesis of ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetate To a suspension of 4-(((6-chloro-3-fluoropyridine-2-yl)oxy)methyl-3-fluorobenzonitrile (0.6 g, 2 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl)acetate (0.6 g, 2 mmol) in dioxane (20 mL) and H2O (7 mL), K2CO3 (0.9 g, 6 mmol) and Pd(dppf)Cl2 (165 mg, 0.2 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. TLC (petroleum ether:ethyl acetate = 5:1, UV 254 nm) showed that the starting materials had been consumed. The mixture was diluted with H2O (50 mL) and extracted twice with ELISA (80 mL). The organic layers were combined, washed with saline solution (100 mL), and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated to obtain the crude product as a brown oily substance. This crude product was purified by Combi-flush (eluted with silica gel, ethyl acetate / petroleum ether = 1 / 5) to obtain ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetate (0.5 g, 1.2 mmol, yield 60%). LCMS: m / z 413.1 [M+H] +

[0478] Step C: Synthesis of 3-fluoro-4-(((3-fluoro-6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile To a solution of DIBAL-H (4 mmol, 1 M solution in toluene, 4 mL), a solution of ethyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)acetate (320 mg, 0.78 mmol) in anhydrous THF (2 mL) was added dropwise at -50°C. The mixture was stirred at -50°C for 1 hour and then cooled to -78°C. Water (0.206 mL) was added dropwise to quench the reaction at -78°C. The resulting white suspension was filtered, and the filtrate was dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain 3-fluoro-4-(((3-fluoro-6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile as an orange oily substance (0.2 g, 70%). LCMS: m / z 371.0 [M+H] +

[0479] Step D: Synthesis of 3-fluoro-4-(((3-fluoro-6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile To a mixture of 3-fluoro-4-(((3-fluoro-6-(4-(2-hydroxyethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile (300 mg) in ethyl phosphate (20 mL), IBX (665 mg, 2.37 mmol) was added gradually. The resulting mixture was stirred at 80°C for 15 hours. The mixture was cooled to room temperature and filtered. The resulting filtrate was concentrated to obtain the crude product 3-fluoro-4-(((3-fluoro-6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile as a white solid (300 mg, yield: 80%). LCMS: m / z 369.0 [M+H] + .

[0480] Step E: Synthesis of ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of 3-fluoro-4-(((3-fluoro-6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile (130 mg) and ethyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (86 mg, 0.34 mmol) in anhydrous toluene (10 mL) was stirred at 80°C for 48 hours. The mixture was concentrated under vacuum, and the crude product was purified by column chromatography to obtain ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a brown oil (130 mg, yield: 60%). LCMS: m / z 600.2 [M+H] + .

[0481] Step F: Synthesis of 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of ethyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg, 0.25 mmol) in THF (2 mL), lithium hydroxide (42 mg, 1 mmol) and water (1 mL) were added. The mixture was stirred at room temperature for 10 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (30 mg, yield: 46%). LCMS: m / z 571.9 [M+H] + 1H NMR (400 MHz, MeOD) δ 8.13 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.46-7.41 (m, 1 H), 7.07-7.04 (m, 1H), 6.67-6.66 (m, 1 H), 5.61 (s, 2 H), 5.28-5.27(m, 1 H), 4.77-4.60 (m, 2H), 4.61-4.59 (m, 1 H), 4.43-4.39 (m, 1 H), 3.19-3.14 (m, 2 H), 2.83-2.78 (m, 1H), 2.68-2.58 (m, 1H), 2.54-2.37 (m, 4H), 2.13- 2.05 (m, 2H), 1.62-1.60 (m, 1H),

[0482] Example 15: 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (compound 116a) [ka] Step A: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate A solution of 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (180 mg, 0.5 mmol) in EtOH (1.5 mL) was added to a solution of sodium metabisulfite (48 mg, 0.25 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for 3 hours and then diluted with EtOH (2 mL). The resulting suspension was stored in a refrigerator for 12 hours. The suspension was filtered. The precipitate was collected and dried. This precipitate was added to a solution of methyl(S)-5-amino-4-((oxetan-2-ylmethyl)amino)picolinate (120 mg, 0.5 mmol) in DMF (5 mL). The mixture was stirred at 110 °C for 3 hours. Subsequently, the reaction mixture was cooled and poured into water (20 mL). The resulting suspension was extracted twice with ELISA (100 mL). The organic layers were washed together with saline solution (10 mL) and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by Combi-flush (eluted with silica gel, ethyl acetate / petroleum ether (0% to 50%)) to obtain methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate as a brown oily substance (0.2 g, yield 56%). LCMS: m / z 577.1 [M+H] + .

[0483] Step B: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid A mixture of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate (90 mg, 0.25 mmol) and lithium hydroxide (42 mg, 1 mmol) in THF (2 mL) and water (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid as a white solid (40 mg, yield: 46%). LCMS: m / z 563.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 8.97(s, 1 H),8.42 (s, 1 H), 7.68 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.48 (dd, J1= 2 Hz, J2= 10 Hz ,1 H), 7.30(dd, J1= 2 Hz, J2= 8 Hz ,1 H), 7.08 (d, J = 8 Hz, 1 H),6.82-6.76 (m, 1 H), 6.72-6.70 (m, 1H), 5.40 (s, 2 H), 5.04-5.02(m, 1 H), 4.77-4.72 (m, 1H), 4.61-4.59 (m, 1 H), 4.43-4.39 (m, 1 H), 4.35-4.29 (m, 1 H), 3.14-3.02(m, 2 H), 2.72-2.58 (m, 2 H), 2.42-2.33 (m, 4 H), 2.13- 2.05 (m, 2H), 1.60-1.42 (m, 1H),

[0484] Example 16: 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (compound 117a) [ka] Step A: Synthesis of methyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate A solution of 3-fluoro-4-(((6-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyridine-2-yl)oxy)methyl)benzonitrile (330 mg, 0.94 mmol) in EtOH (1.5 mL) was mixed with a solution of sodium metabisulfite (48 mg, 0.25 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for 3 hours and then diluted with EtOH (2 mL). The resulting suspension was kept in the refrigerator for 12 hours. The suspension was filtered. The precipitate was collected and dried. The resulting precipitate was added to a solution of methyl (S)-5-amino-4-((oxetan-2-ylmethyl)amino)picolinate (120 mg, 0.5 mmol) in DMF (5 mL). The mixture was stirred at 110 °C for 3 hours. The reaction mixture was then cooled and poured into water (20 mL). The resulting suspension was extracted twice with ELISA (100 mL). The organic layers were combined, washed with saline solution (10 mL), and dried over anhydrous sodium 2SO4. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by Combi-flush (eluted with silica gel, ethyl acetate / petroleum ether (0% to 50%)) to obtain methyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate as a brown oily substance (0.2 g, yield 35%). LCMS: m / z 568.0 [M+H] + .

[0485] Step B: Synthesis of 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid A mixture of methyl 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylate (100 mg, 0.25 mmol) and lithium hydroxide (42 mg, 1 mmol) in THF (2 mL) and water (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid as a white solid (60 mg, yield: 60%). LCMS: m / z 554.1 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 8.97(s, 1 H),8.44 (s, 1 H), 7.92 (d, J = 10 Hz, 1 H),7.73-7.67 (m, 3 H), 7.10(d, J = 8.0 Hz, 1H), 6.75 (m ,2 H), 5.50 (s, 2 H), 5.04-5.02(m, 1 H), 4.77-4.72 (m, 1H), 4.63-4.57 (m, 1 H), 4.43-4.39 (m, 1 H), 4.30-4.25 (m, 1 H), 3.20-3.00(m, 2) H), 2.75-2.50 (m, 2 H), 2.42-2.33 (m, 4H), 2.13- 1.90 (m, 2H), 1.62-1.40 (m, 1H),

[0486] Example 17: 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (compound 118a) [ka] Step A: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate A solution of compound 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (90 mg, 0.25 mmol) in EtOH (1.5 mL) was added to a solution of sodium metabisulfite (25 mg, 0.13 mmol) in H2O (1.5 mL). The mixture was stirred at room temperature for 3 hours and then diluted with EtOH (2 mL). The resulting suspension was kept warm in a refrigerator for 12 hours. The suspension was filtered. The precipitate was collected and dried. This precipitate was added to a solution of methyl (S)-6-amino-5-((oxetan-2-ylmethyl)amino)nicotinate (60 mg, 0.25 mmol) in DMF (5 mL). The mixture was stirred at 110 °C for 3 hours. The reaction mixture was then cooled and poured into water (20 mL). The resulting suspension was extracted twice with ELISA (100 mL). The organic layers were combined, washed with saline solution (10 mL), and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by Combi-flush (eluted with silica gel, ethyl acetate / petroleum ether (0% to 50%)) to obtain the compound methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate as a brown oily substance (0.06 g, yield 42%). LCMS: m / z 577.2 [M+H] + .

[0487] Step B: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid A mixture of methyl 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate (60 mg, 0.10 mmol) and lithium hydroxide (21 mg, 0.5 mmol) in THF (2 mL) and water (1 mL) was stirred at room temperature for 10 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid as a white solid (30 mg, yield: 53%). LCMS: m / z 563.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1 H),8.50 (s, 1 H), 7.48 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.20-7.08 (m, 2 H), 6.92 (d, J = 8 Hz, 1 H), 6.70 - 6.60 (m, 1 H), 6.54 (d, = 8 Hz, 1H), 5.32 (s, 2 H), 5.14-5.02 (m, 1 H), 4.70-4.58 (m, 1H), 4.58-4.40 (m, 2H), 4.38-4.20 (m, 1H), 3.10-2.90 (m, 2H), 2.75-2.65 (m, 1H), 2.60 - 2.50 (m, 1H), 2.45-2.29 (m, 4H), 2.10- 1.93 (m, 2H), 1.54-1.47 (m, 1H).

[0488] Example 18: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (compound 119a) [ka] Step A: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate A mixture of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (120 mg, 0.3 mmol) in EtOH (3 mL) was to be mixed with Na2S2O5 (31 mg, 0.1 mmol) all at once. The mixture was stirred at room temperature for 6 hours. The resulting suspension was filtered. The mixture was collected, dried, and added to a solution of methyl (S)-6-amino-5-((oxetan-2-ylmethyl)amino)nicotinate (63 mg, 0.2 mmol) in DMF (3 mL). The mixture was stirred at 110 °C for 6 hours. The mixture was cooled, diluted with water (10 mL), and extracted with ELISA (15 mL x 3). The organic layers were combined, washed with saline solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with silica gel to obtain methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate as a yellow oil (41 mg, yield: 21%). MS theoretical value: 577.2; MS measured value: 578.2 [M+H] + .

[0489] Step B: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid A mixture of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate (41 mg, 0.07 mmol) and lithium hydroxide (10 mg, 0.30 mmol) in THF (3 ml) and water (0.5 ml) was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)pyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid as a white solid (10 mg, yield: 25%). MS theoretical value: 563.1; MS measured value: 564.2 [M+H] + . 1 H NMR (500 MHz, MeOD) δ 9.06 (d, J = 1.4 Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 5.8 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.30 - 7.20 (m, 3H), 6.71 (d, J = 5.8 Hz, 1H), 5.52 (s, 2H), 5.25 - 5.18 (t, 1H), 4.78 - 4.70 (m, 1H), 4.65 - 4.58 (m, 2H), 4.42 - 4.39 (m, 1H), 3.20 - 3.15 (m, 2H), 2.84 - 2.72 (m, 2H), 2.60 - 2.42 (m, 4H), 2.21 - 2.10 (m, 1H), 2.10 - 2.02 (m, 1H), 1.65 - 1.55 (m, 1H).

[0490] Example 19: 2-((4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 120a) [ka] Step A: Synthesis of 2-chloro-4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine To a solution of 2,4-dichloro-5-fluoropyrimidine (1.8 g, 10.78 mmol) and (5-chloropyridine-2-yl)methanol (1.5 g, 10.56 mmol) in CH3CN (50 mL), Cs2CO3 (7.02 g, 21.56 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, 2-chloro-4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine, as a white solid (2.5 g, crude product, yield 85%), which was used directly in the next step. MS theoretical value: 273.0; MS measured value: 274.0 [M+H] + .

[0491] Step B: Synthesis of ethyl 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate To a solution of 2-chloro-4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine (1 g, 3.65 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.07 g, 3.65 mmol), and K2CO3 (1 g, 7.3 mmol) in dioxane (32 mL) and H2O (6 mL), Pd(dppf)Cl2 (133 mg, 0.18 mmol) was added at room temperature. The mixture was stirred overnight at 85°C under an N2 atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate as a white solid (1 g, 2.46 mmol, yield 67%). MS theoretical value: 405.1; MS measured value: 406.1 [M+1] + .

[0492] Step C: Synthesis of 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol To a solution of ethyl 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetate (1 g, 2.46 mmol) in dry THF (30 mL), LAH (187 mg, 4.92 mmol) was added at -20°C. The mixture was stirred at 0°C for 2 hours. The reaction product was quenched by adding water (0.4 mL) and aqueous sodium hydroxide solution (0.6 mL). The resulting suspension was filtered, and the filtrate cake was washed with ethyl acetate (30 mL). The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain the title compound as a colorless oil (600 mg, yield 67%). MS theoretical value: 363.1; MS measured value: 364.1 [M+H] + .

[0493] Step D: Synthesis of 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde To a solution of 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (300 mg, 0.82 mmol), TEMPO (1.2 mg, 0.08 mmol), NaCl (61.3 mg, 0.82 mmol), NaHCO3 (47.9 mg, 0.82 mmol), and KBr (9.5 mg, 0.08 mmol) in a dichloromethane / water mixture (20 mL / 20 mL), an aqueous solution of NaClO (0.98 mL, 7%, 0.82 mmol) was added dropwise over 20 minutes at 0°C. The mixture was stirred at the same temperature for 15 minutes. The mixture was then diluted with an aqueous solution of Na2S2O3 (10 mL) and a saturated aqueous solution of NaHCO3 (30 mL). The resulting mixture was extracted with dichloromethane (60 mL x 3). The organic layers were combined and washed with saline solution (50 mL x 2), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified on silica gel (0-3% methanol in dichloromethane) to obtain the title product (280 mg, 0.77 mmol, yield 93%). MS theoretical value: 361.0; MS measured value: 362.1 [M+H] + .

[0494] Step E: Synthesis of methyl 2-((4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 2-(4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (280 mg, 0.77 mmol) and methyl (S)-5-amino-6-((oxetane-2-ylmethyl)amino)picolinate (182.8 mg, 0.77 mmol) were mixed in dry toluene (5 mL), to which 4A molecular sieves (150 mg) was added. The mixture was stirred at 100 °C for 40 hours under an O2 atmosphere. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=20\1, UV254 nm) to obtain the title product as a brown solid (400 mg, 0.69 mmol, yield 89%). MS theoretical value: 578.2; MS measured value: 579.0 [M+H] + .

[0495] Step F: Synthesis of 2-((4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of methyl 2-((4-(4-((5-chloropyridine-2-yl)methoxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg, 0.69 mmol) in THF (8 mL) and H2O (4 mL), LiOH·H2O (252 mg, 0.5 M) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was directly purified by preparative HPLC (high pH method) to obtain the desired product (350 mg, 0.62 mmol, yield 89%). MS theoretical value: 564.1; MS measured value: 565.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.6 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H), 8.01 - 7.90 (m, 3H), 7.57 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 5.61 (s, 2H), 5.25 - 5.15 (m, 1H), 4.68 - 4.58 (m, 1H), 4.56 - 4.39 (m, 2H), 4.38 - 4.20 (m, 1H), 3.18 - 2.91 (m, 2H), 2.74 - 2.57 (m, 2H), 2.47 - 2.22 (m, 4H), 2.15 - 2.00(m, 1H), 2.10 - 1.90 (m, 1H), 1.57 - 1.34 (m, 1H).

[0496] Example 20: 2-((4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 121a) [ka] Step A: Synthesis of 5-chloro-2-(((6-chloropyridine-2-yl)oxy)methyl)pyridine To a solution of 2,6-dichloropyridine (1 g, 6.24 mmol) and (5-chloropyridine-2-yl)methanol (865.05 mg, 6.24 mmol) in THF (50 mL), NaH (449 mg) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ice water (100 mL). The resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic layers were combined, washed with brine (80 mL x 2), and dried over Na₂SO₄. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain the title product as a white solid (500 mg, 1.96 mmol, yield 31%). MS theoretical value: 254.0; MS measured value: 255.0 [M+H] + .

[0497] Step B: Synthesis of ethyl 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate To a solution of 5-chloro-2-(((6-chloropyridine-2-yl)oxy)methyl)pyridine (450 mg, 1.76 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (519 mg, 1.76 mmol), and K2CO3 (486.5 mg, 3.52 mmol) in dioxane (32 mL) and H2O (6 mL), Pd(dppf)Cl2 (64.38 mg, 0.09 mmol) was added at room temperature. The mixture was stirred overnight at 85°C under an N2 atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate as a white solid (500 mg, 1.29 mmol, yield 73%). MS theoretical value: 386.1; MS measured value: 387.0 [M+1] + .

[0498] Step C: Synthesis of 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol A solution of ethyl 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetate (500 mg, 1.29 mmol) in anhydrous THF (30 mL) was mixed with LAH (98 mg, 2.58 mmol) at -20°C. The mixture was stirred at 0°C for 2 hours. The mixture was quenched by adding water (0.4 mL) and aqueous sodium hydroxide solution (0.6 mL). The resulting suspension was filtered, and the filtered cake was washed with ethyl acetate (50 mL). The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to obtain 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol as a colorless oil (400 mg, 1.1 mmol, yield 89%). MS theoretical value: 344.1; MS measured value: 344.9 [M+H] + .

[0499] Step D: Synthesis of 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde A solution of 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)ethane-1-ol (450 mg, 1.31 mmol), TEMPO (1.5 mg, 0.01 mmol), NaCl (76.5 mg, 1.31 mmol), NaHCO3 (110 mg, 1.31 mmol), and KBr (15.4 mg, 0.13 mmol) was added dropwise to a solution of NaClO aqueous solution (1.4 mL, 7%, 1.31 mmol) at 0°C over 20 minutes. The mixture was diluted with saturated Na2S2O3 aqueous solution (10 mL) and saturated NaHCO3 aqueous solution (30 mL). The resulting mixture was extracted with dichloromethane (60 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. This crude product was then purified on silica gel (with 0-3% methanol in dichloromethane) to obtain the title product (350 mg, 1.02 mmol, yield 78%). MS theoretical value: 342.1; MS measured value: 343.1 [M+H] + .

[0500] Step E: Synthesis of methyl 2-((4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 350 mg, 1.02 mmol of 2-(4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde and 241.2 mg, 1.02 mmol of methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate were added to a mixture of 4A molecular sieves (150 mg) in dry toluene (10 mL). The mixture was stirred at 80°C for 40 hours under an O2 atmosphere. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=20\1, UV254 nm) to obtain the title product as a brown solid (500 mg, 0.89 mmol, yield 87%). MS theoretical value: 559.2; MS measured value: 560.2 [M+H] + .

[0501] Step F: Synthesis of 2-((4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of methyl 2-((4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (500 mg, 0.89 mmol) in THF (8 mL) and H2O (4 mL), LiOH·H2O (252 mg, 0.5 M) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was directly purified by preparative HPLC (high pH method) to obtain 2-((4-(6-((5-chloropyridine-2-yl)methoxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (210 mg, 0.38 mmol, yield 43%). MS theoretical value: 545.2; MS measured value: 546.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.01 - 7.87 (m, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.71 (br.s, 1H), 5.46 (d, J = 12.5 Hz, 2H), 5.20 - 5.12 (br.s, 1H), 4.70 - 4.60 (m, 1H), 4.60 - 4.40 (m, 2H), 4.35 - 4.23 (m, 1H), 3.17 - 2.94 (m, 2H), 2.76 - 2.60 (m, 1H), 2.47 - 2.21 (m, 5H), 2.11 - 1.91 (m, 2H), 1.57 - 1.34 (m, 1H).

[0502] Example 21: 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 122) [ka] Step A: Synthesis of methyl 6-((cyclopropylmethyl)amino)-5-nitropicolinate To a solution of methyl 6-chloro-5-nitropicolinate (1.0 g, 4.6 mmol) in acetonitrile (5 mL), K2CO3 (1.28 g, 9.25 mmol) and cyclopropylmethaneamine (0.4 mg, 5.1 mmol) were added, and the mixture was stirred at 30°C for 24 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL) and saline solution (10 mL). The organic layer was concentrated and purified on silica gel (0-35% (ethyl acetate in petroleum ether)) to obtain methyl 6-((cyclopropylmethyl)amino)-5-nitropicolinate (0.8 g, 3.19 mmol). MS theoretical value: 251.1; MS measured value: 252.0 [M+H] + .

[0503] Step B: Synthesis of methyl 5-amino-6-((cyclopropylmethyl)amino)picolinate To a solution of methyl 6-((cyclopropylmethyl)amino)-5-nitropicolinate (200 mg, 0.797 mmol) in MeOH (10 mL), Pd / C (10%, 20 mg) was added at room temperature. The mixture was stirred at room temperature under an H2 atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 5-amino-6-((cyclopropylmethyl)amino)picolinate as a white solid (120 mg, 92% yield), which was used directly in the next step. MS theoretical value: 221.0; MS measured value: 222.1 [M+H] + .

[0504] Step C: Synthesis of methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 120 mg of methyl 5-amino-6-((cyclopropylmethyl)amino)picolinate and 182 mg (0.494 mmol) of 3-fluoro-4-(((5-fluoro-2-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyrimidine-4-yl)oxy)methyl)benzonitrile were added to a suspension in 5 mL of dry toluene, to which 364 mg of 4A molecular sieves was added. The mixture was stirred at 80°C for 40 hours under an O2 atmosphere. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=10\1, UV254nm) to obtain methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a brown solid (150 mg, 0.263 mmol). MS theoretical value: 570.0; MS measured value: 571.0 [M+H] + .

[0505] Step D: Synthesis of 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg, 0.263 mmol) in THF (4 mL) and H2O (2 mL), LiOH·H2O (22 mg, 0.526 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was directly purified by preparative HPLC (high pH method) to obtain 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (64 mg, 0.11 mmol). MS theoretical value: 556.2; MS measured value: 557.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.38 (d, J = 2.9 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.75 (t, J = 7.4 Hz, 1H), 7.69 - 7.56 (m, 2H), 7.17 (br.s, 1H), 5.69 (s, 2H), 4.38 (d, J = 7.1 Hz, 2H), 3.09 (t, J = 11.3 Hz, 2H), 2.78 (d, J = 17.0 Hz, 1H), 2.60 - 2.40 (m, 3H), 2.21 - 2.01 (m, 2H), 1.65 - 1.52 (m, 1H), 1.44 - 1.24 (m, 1H), 0.66 - 0.50 (m, 4H).

[0506] Example 22: 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 123) [ka] Step A: Synthesis of methyl 6-(((1-cyanocyclopropyl)methyl)amino)-5-nitropicolinate To a solution of 1-(aminomethyl)cyclopropane-1-carbonitrile (300 mg, 3.1 mmol) and K2CO3 (850 mg, 6.2 mmol) in ACN (10 mL), ethyl 6-chloro-5-nitropicolinate (700 mg, 3.1 mmol) was added at room temperature. The mixture was stirred overnight at 30°C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EA = 10 / 1) to obtain ethyl 6-(((1-cyanocyclopropyl)methyl)amino)-5-nitropicolinate as a yellow oil (100 mg, yield: 10%). MS theoretical value: 290.1; MS measured value: 291.0 [M+H] + .

[0507] Step B: Synthesis of ethyl 5-amino-6-(((1-cyanocyclopropyl)methyl)amino)picolinate To a solution of ethyl 6-(((1-cyanocyclopropyl)methyl)amino)-5-nitropicolinate (100 mg, 0.34 mmol) in MeOH (5 mL), Pd / C (10%, 60 mg) was added at room temperature. The mixture was stirred under H2 at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain ethyl 5-amino-6-(((1-cyanocyclopropyl)methyl)amino)picolinate as a yellow solid (64 mg, yield: 82%). MS theoretical value: 260.1; MS measured value: 261.1 [M+H] + .

[0508] Step C: Synthesis of ethyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of methyl 5-amino-6-(((1-cyanocyclopropyl)methyl)amino)picolinate (64 mg, 0.26 mmol), 3-fluoro-4-(((5-fluoro-2-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyrimidine-4-yl)oxy)methyl)benzonitrile (121 mg, 0.33 mmol), and molecular sieves (250 mg) in toluene (5 mL) was stirred at 80°C for 3 days under O2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica column chromatography (eluent = 5% to 80% EA in PE) to obtain ethyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow solid (80 mg, yield: 45%). MS theoretical value: 609.2; MS measured value: 610 [M+H] + .

[0509] Step D: Synthesis of 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of ethyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (80 mg, 0.13 mmol) and lithium hydroxide (40 mg, 1 mmol) in methanol (3 mL) and water (0.5 mL) was stirred at room temperature for 5 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a yellow solid (6 mg, yield: 8%). MS theoretical value: 581.2; MS measured value: 582.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.37 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8 Hz, 1H), 7.75 (t, J = 7.6 Hz,1H), 7.68 - 7.60 (m, 2H), 7.18 (br.s, 1H), 5.73 (s, 2H), 4.66 (d, J = 2 Hz, 2H), 3.25 (d, J = 6.8 Hz, 2H), 2.78 (d, J = 12 Hz, 1H), 2.60 - 2.40 (m, 3H), 2.22-2.17 (m, 1H), 2.17-2.05 (m, 1H), 1.74-1.68 (m, 2H), 1.64-1.45 (m, 1H), 1.39-1.30 (m, 2H).

[0510] Example 23: 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 124) [ka] Step A: Synthesis of 3-amino-2,2-dimethylpropanenitrile To a solution of 3-amino-2,2-dimethylpropanamide (1.0 g, 8.62 mmol) in DCE (10 mL), SOCl2 (2.0 g, 17.24 mmol) was added and the mixture was stirred at 90°C for 5 hours under a nitrogen atmosphere. The mixture was diluted with DCM (20 mL) and washed with water (20 mL) and saline solution (10 mL). The organic layer was separated, concentrated, and purified on silica gel (0-35%, ethyl acetate in petroleum ether) to obtain 3-amino-2,2-dimethylpropanenitrile (0.5 g, 5.10 mmol). MS theoretical value: 98.1; MS measured value: 99.1 (M+H).

[0511] Step B: Synthesis of methyl 6-((2-cyano-2-methylpropyl)amino)-5-nitropicolinate To a solution of 3-amino-2,2-dimethylpropanenitrile (500 mg, 5.05 mmol) and methyl 6-chloro-5-nitropicolinate (1.09 g, 5.05 mmol) in CH3CN (30 mL), K2CO3 (1.394 g, 10.1 mmol) was added all at once. The reaction mixture was stirred at 30 °C for 13 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with H2O (100 mL) and extracted twice with  (100 mL). The organic layers were washed together with saline solution (50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated and purified by Combi-flush (eluting with silica gel, ethyl acetate / petroleum ether (0% to 25%), UV 254nm) to obtain methyl 6-((2-cyano-2-methylpropyl)amino)-5-nitropicolinate as a white solid (300 mg, 1.08 mmol, yield 21%). MS theoretical value: 278.1; MS measured value: 279.1 (M+H)

[0512] Step C: Synthesis of methyl 5-amino-6-((2-cyano-2-methylpropyl)amino)picolinate To a solution of methyl 6-((2-cyano-2-methylpropyl)amino)-5-nitropicolinate (300 mg, 1.08 mmol) in methanol (5 mL), Pd / C (10%, 100 mg) was added. The mixture was stirred at room temperature under an H2 atmosphere for 16 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica, UV 254 nm, PE / EA = 10 / 1) to obtain methyl 5-amino-6-((2-cyano-2-methylpropyl)amino)picolinate as a yellow oil (260 mg, yield: 97%). MS theoretical value: 248.1; MS measured value: 249.1 [M+H] + .

[0513] Step D: Synthesis of methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 100 mg, 0.40 mmol of methyl 5-amino-6-((2-cyano-2-methylpropyl)amino)picolinate and 149 mg, 0.40 mmol of 3-fluoro-4-(((5-fluoro-2-(4-(2-oxoethyl)cyclohexa-1-en-1-yl)pyrimidine-4-yl)oxy)methyl)benzonitrile) in 5 mL of anhydrous toluene were mixed with 200 mg of 4A molecular sieves. The mixture was stirred at 80°C for 40 hours under an O2 atmosphere. LC-MS showed that the starting materials were completely consumed and the desired product was found as the main peak. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=10\1, UV254nm) to obtain methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a brown solid (120 mg, 0.201 mmol). MS theoretical value: 597.2; MS measured value: 597.9 [M+H] + .

[0514] Step E: Synthesis of 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of methyl 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (120 mg, 0.201 mmol) in THF (4 mL) and H2O (2 mL), LiOH·H2O (34 mg, 0.804 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was directly purified by preparative HPLC (high pH method) to obtain 2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (10.3 mg, 0.02 mmol). MS theoretical value: 583.2; MS measured value: 583.9 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.38 (d, J = 2.9 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.17 (br.s, 1H), 5.70 (s, 2H), 4.73 (s, 2H), 3.26 (d, J = 6.8 Hz, 2H), 2.78 (d, J = 15.9 Hz, 1H), 2.60 - 2.40 (m, 3H), 2.25 - 2.10 (m, 1H), 2.10 -2.00 (m, 1H), 1.65 - 1.50 (m, 1H), 1.52 (s, 6H).

[0515] Example 24: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 125) [ka] Step A: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A mixture of methyl 5-amino-6-(((1-cyanocyclopropyl)methyl)amino)picolinate (100 mg, 0.4 mmol), 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (181 mg, 0.48 mmol), and molecular sieves (4A, 360 mg) in toluene (10 mL) was stirred at 80°C for 40 hours under O2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica column chromatography (eluent = 5% to 80% EA in PE) to obtain methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow solid (140 mg, yield: 58%). MS theoretical value: 604.2; MS measured value: 604.9 [M+H] + .

[0516] Step B: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid A mixture of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (140 mg, 0.23 mmol) and lithium hydroxide (84 mg, 2.0 mmol) in methanol (4 mL) and water (0.8 mL) was stirred at room temperature for 3 hours. The reaction mixture was directly purified by preparative HPLC to obtain 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-((1-cyanocyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a yellow solid (19 mg, yield: 14%). MS theoretical value: 590.2; MS measured value: 591.0 [M+H] + . 1 H NMR (500 MHz, CD3OD) δ 8.34-8.34 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 8 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 7.55 (t, J = 8.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.20 (br.s, 1H), 5.60 (s, 2H), 4.66-4.66 (d, J = 3 Hz, 2H), 3.26 (d, J = 7 Hz, 2H), 2.82 (d, J = 17.5 Hz, 1H), 2.60 - 2.45 (m, 3H), 2.25-2.05 (m, 2H), 1.70-1.68 (m, 2H), 1.68 -1.55 (m, 1H), 1.40-1.32 (m, 2H).

[0517] Example 25: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 126) [ka] Step A: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 4A molecular sieves (200 mg) were added to a mixture of methyl 5-amino-6-((2-cyano-2-methylpropyl)amino)picolinate (100 mg, 0.40 mmol) and 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (152 mg, 0.40 mmol) in anhydrous toluene (5 mL). The mixture was stirred at 80°C for 40 hours under an O2 atmosphere. The reaction mixture was concentrated and purified on silica gel (DCM\MeOH=10¹, UV254nm) to obtain methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a brown solid (74 mg, 0.122 mmol). MS theoretical value: 606.2; MS measured value: 607.2 [M+H] + .

[0518] Step B: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg, 0.122 mmol) in THF (4 mL) and H2O (2 mL), LiOH·H2O (21 mg, 0.488 mmol) was added. The mixture was stirred at 20°C for 4 hours. The reaction mixture was directly purified by preparative HPLC to obtain the desired target product, 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-cyano-2-methylpropyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (21.6 mg, 0.04 mmol). MS theoretical value: 592.2; MS measured value: 592.9 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.35 (d, J = 2.9 Hz, 1H), 8.17 (dd J = 8.3 Hz, 1H), 8.11 (dd J = 8.3 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.35 - 7.10 (m, 3H), 5.60 (s, 2H), 4.73 (s, 2H), 3.27 (d, J = 6.7 Hz, 2H), 2.90 - 2.69 (m, 1H), 2.60 - 2.40 (m, 3H), 2.25 - 2.09 (m, 1H), 2.00 - 2.00 (m, 1H), 1.70 - 1.58 (m, 1H) 1.52 (s, 6H).

[0519] Example 26: 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 127) [ka] Step A: Synthesis of methyl 6-((2-methoxyethyl)amino)-5-nitropicolinate To a solution of 2-methoxyethane-1-amine (210 mg, 2.8 mmol) in ACN (10 mL), methyl 6-chloro-5-nitropicolinate (600 mg, 2.8 mmol) and K2CO3 (1.2 g, 8.4 mmol) were added. The mixture was stirred overnight at room temperature under N2 protection. The mixture was then diluted with water (20 mL) and extracted with EA (30 mL x 3). The organic layer was concentrated under reduced pressure, and the residue was purified by flash column (silica, UV 254 nm, PE / EA = 3 / 1) to obtain methyl 6-((2-methoxyethyl)amino)-5-nitropicolinate as a yellow oil (600 mg, yield: 80%). MS theoretical value: 255.1; MS measured value: 256.1 [M+H] + .

[0520] Step B: Synthesis of methyl 5-amino-6-((2-methoxyethyl)amino)picolinate To a solution of methyl 6-((2-methoxyethyl)amino)-5-nitropicolinate (600 mg, 2.35 mmol) in methanol (20 mL), Pd / C (10%, 95 mg) was added. The mixture was stirred at room temperature under H2 for 4 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain the desired product, methyl 5-amino-6-((2-methoxyethyl)amino)picolinate, as a brown solid (500 mg, yield: 92%). MS theoretical value: 225.1; MS measured value: 226.1 [M+H] + .

[0521] Step C: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a suspension of methyl 5-amino-6-((2-methoxyethyl)amino)picolinate (140 mg) in dry toluene (2 mL), 2-(4-(4-((4-chloro-2-fluorobenzyl)fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (208 mg, 0.55 mmol) and molecular sieves (416 mg) were added. The mixture was stirred at 80°C for 48 hours under an O2 atmosphere. The mixture was then filtered through a Celite pad, the solid was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (silica, UV254nm, DCM / MEOH=30 / 1) to obtain the desired product, methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate, as a yellow oil (160 mg, yield: 50%). MS theoretical value: 583.2; MS measured value: 583.9 [M+H] + .

[0522] Step D: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid LiOH (24 mg, 1.0 mmol) was added to a solution of methyl 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (160 mg, 0.27 mmol) in MeOH (3 mL) and water (0.3 mL). The mixture was stirred at room temperature for 4 hours. Next, the mixture was filtered, and the filtrate was purified by preparative HPLC (high pH method) to obtain 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidine-2-yl)cyclohexa-3-en-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (50 mg, yield: 33%). MS theoretical value: 569.2; MS measured value: 570.0 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.34 (d, J = 3.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.32-7.20 (m, 2H), 7.19 (br. s, 1H), 5.59 (s, 2H), 4.64 (t, J = 5.0 Hz, 2H), 3.82 (t, J = 5.0 Hz, 2H), 3.27 (s, 3H), 3.11 (d, J = 6.9 Hz, 2H), 2.85-2.73 (m, 1H), 2.57 - 2.36 (m, 3H), 2.20 - 1.95 (m, 2H), 1.65-1.50 (m, 1H).

[0523] Example 27: 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 128) [ka] Step A: Synthesis of 6-chloro-5-nitropicolinic acid To a solution of 6-chloro-5-nitropicolinic acid (2.0 g, 10 mmol) in THF (10 mL), NH3·H2O (10 mL) was added. The mixture was stirred overnight at 50°C. The mixture was concentrated under vacuum to obtain the crude product 6-amino-5-nitropicolinic acid as a yellow solid (1.9 g), which was used directly in the next step. MS theoretical value: 183.0; MS measured value: 184.0 [M+H] + .

[0524] Step B: Synthesis of methyl 6-amino-5-nitropicolinate A solution of 6-amino-5-nitropicolinic acid (1.85 g, 10 mmol) in anhydrous methanol (20 mL) was mixed with concentrated sulfuric acid (1 mL). The mixture was stirred under reflux for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with saturated sodium bicarbonate aqueous solution (15 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 6-amino-5-nitropicolinate as a yellow solid (1.56 g, 78%). MS theoretical value: 197.0; MS measured value: 197.9 [M+1] + .

[0525] Step C: Synthesis of methyl 6-(buta-2-in-1-ylamino)-5-nitropicolinate A mixture of methyl 6-amino-5-nitropicolinate (200 mg, 1 mmol), 1-bromobuta-2-yin (132 mg, 1 mmol), and Cs2CO3 (650 mg, 2 mmol) in CH3CN (10 mL) was stirred overnight at 65°C under an N2 atmosphere. The mixture was filtered through a silica pad (eluted with EA (50 mL)), and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica column chromatography (eluent = 1%~10% MeOH in CH2Cl2) to obtain methyl 6-(buta-2-yin-1-ylamino)-5-nitropicolinate as a yellow solid (90 mg, yield 37%). Theoretical Ms value: 249.1; Measured MS value: 250.1 [M+H] + .

[0526] Step D: Synthesis of methyl 5-amino-6-(buta-2-in-1-ylamino)picolinate A suspension of methyl 6-(buta-2-in-1-ylamino)-5-nitropicolinate (320 mg, 1.28 mmol) and SnCl2 (1.2 g, 6.4 mmol) in MeOH (10 mL) was stirred overnight under reflux. The mixture was cooled and diluted with saturated NaHCO3 solution (20 mL). The resulting mixed aqueous solution was extracted with ethyl acetate (30 mL x 3). The extracts were combined, washed with saline solution (50 mL), dried, and concentrated under reduced pressure. The crude product was purified by flash silica column chromatography (eluent = 10%~30% EA in PE) to obtain methyl 5-amino-6-(buta-2-in-1-ylamino)picolinate as a yellow oil (230 mg, yield 82%). MS theoretical value: 219.1; MS measured value: 220 [M+H] + .

[0527] Step E: Synthesis of methyl 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A suspension of methyl 5-amino-6-(buta-2-in-1-ylamino)picolinate (88 mg, 0.4 mmol) and 2-(4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)acetaldehyde (72 mg, 0.2 mmol) in toluene (20 mL) was stirred at 110 °C for 72 hours. The mixture was filtered, and the filtered cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product methyl 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow oil (200 mg, yield: 66%). MS theoretical value: 558.2; MS measured value: 559.0 [M+H] + .

[0528] Step F: Synthesis of 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a solution of the crude product methyl 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.30 mmol) in MeOH (3 mL) and water (0.3 mL), LiOH·H2O (48 mg, 1.2 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was directly purified by preparative HPLC (high pH) to obtain 3-(buta-2-in-1-yl)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridine-2-yl)cyclohexa-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a white solid (55 mg, yield: 33%). MS theoretical value: 544.2; MS measured value: 545.1 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ 8.07 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.30-7.16 (m, 2H), 7.05 (d, J=7.6 Hz, 1H), 6.78 (br.s, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.45 (s, 2H), 5.27 (d, J=2.4 Hz, 2H), 3.18-3.11 (m, 2H), 2.75-2.65 (m, 1H), 2.60-2.40 (m, 3H), 2.25-2.05 (m, 2H), 1.76 - 1.70 (m, 3H), 1.65-1.61 (m, 1H).

[0529] Example 1W: (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 103aw) [ka] [ka] [ka] Step A: Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine To a solution of (4-chloro-2-fluorophenyl)methanol (2.00 g, 12.46 mmol) in DMF (25 mL), Cs2CO3 (12.17 g, 37.37 mmol) and 2-bromo-6-fluoropyridine (2.19 g, 12.46 mmol) were added. The suspension was stirred at 25°C for 16 hours. The yellow suspension was diluted with water (50 mL) and extracted twice with ethyl acetate (35 mL). The organic layer was washed with water (50 mL) and saline solution (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product as a yellow oily substance (3.78 g). The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether (0-10%)) to obtain 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine as a white solid (3.18 g, yield 80.6%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.41 - 7.50 (m, 2 H) 7.08 - 7.18 (m, 3 H) 6.74 (d, J=8.27 Hz, 1 H) 5.39 (s, 2 H)

[0530] Step B: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one To a solution of 4-bromopyridine-2(1H)-one (400.0 mg, 2.30 mmol) in dioxane (5 mL), Pin2B2 (613.0 mg, 2.41 mmol), Pd(dppf)Cl2 (168.2 mg, 229.87 μmol), and KOAc (676.9 mg, 6.90 mmol) were added. The suspension was stirred at 80°C for 3 hours under N2. The yellow solution was filtered, and the filtrate was used in the next step without further purification.

[0531] Step C: Preparation of 6-((4-chloro-2-fluorobenzyl)oxy)-[2,4'-bipyridine]-2'(1'H)-one To a solution of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (350 mg, 1.11 mmol) in dioxane (2 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (508.44 mg, 2.30 mmol), Pd(dppf)Cl2 (80.90 mg, 110.57 μmol), K2CO3 (458.43 mg, 3.32 mmol), and H2O (2 mL) were added. The suspension was stirred at 80°C for 1.5 hours under N2. The dark mixture was diluted with water (5 mL) and extracted twice with ethyl acetate (5 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the crude product as a dark, gum-like substance (863 mg). The crude product was purified by Combi-flush (silica gel, ethyl acetate in petroleum (50-100%)) to obtain 6-((4-chloro-2-fluorobenzyl)oxy)-[2,4'-bipyridine]-2'(1'H)-one as a yellow solid (316.5 mg, yield 86.5%) (the yield was obtained from two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (br s, 1 H) 7.85 (t, J=7.44 Hz, 1 H) 7.64 (d, J=7.15 Hz, 1 H) 7.60 (t, J=7.96 Hz, 1 H) 7.42 - 7.55 (m, 2 H) 7.32 (dd, J=8.19, 1.71 Hz, 1 H) 7.02 (s, 1 H) 6.96 (d, J=8.38 Hz, 1 H) 6.84 (d, J=6.72 Hz, 1 H) 5.49 (s, 2 H); LCMS: m / z 330.9[M+H] + .

[0532] Step D: Preparation of (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate A solution of methyl (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino) picolinate (intermediate 2,600.0 mg, 2.53 mmol) in THF (5 mL) was added dropwise to a solution of 2-chloroacetic anhydride (475.6 mg, 2.78 mmol) in THF (2 mL). The solution was stirred at 25°C for 2 hours under N2. Then, the solution was stirred at 60°C for 12 hours. The deep yellow solution was diluted with water (6 mL) and extracted twice with ethyl acetate (5 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the crude product as a yellow gum-like substance. The crude product was purified by Combi-flush (silica gel, ethyl acetate in petroleum ether (10-60%)) to obtain (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a white solid (330.5 mg, yield 44.2%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.11-8.18 (m, 2 H) 5.19 - 5.27 (m, 1 H) 5.09 (q, J=7.13 Hz, 2 H) 4.71 - 4.85 (m, 2 H) 4.57 - 4.64 (m, 1 H) 4.27-4.36 (m, 1 H) 4.02 (s, 3 H) 2.73-2.84 (m, 1 H) 2.38-2.50 (m, 1 H)

[0533] Step E: Preparation of (S)-methyl 2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a solution of 6-((4-chloro-2-fluorobenzyl)oxy)-[2,4'-bipyridine]-2'(1'H)-one (150.0 mg, 453.53 μmol) and (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (134.1 mg, 453.47 μmol) in DMF (2 mL), Cs2CO3 (443.30 mg, 1.36 mmol) was added. The yellow suspension was stirred at 70°C for 0.5 hours under N2. The deep yellow suspension was diluted with water (5 mL) and extracted twice with ethyl acetate (5 mL). The organic layer was washed with water (8 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to obtain a crude product, which was a yellow gum-like substance. The crude product was purified by Combi-Flash (MeOH in silica gel, DCM (0-15%)) to obtain (S)-methyl 2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate as a yellow gum-like substance (156.3 mg, yield 58.4%). 1H NMR (400 MHz, CD3OD) δ ppm 8.01-8.09 (m, 2 H) 7.96 (s, 1 H) 7.90 (d, J=7.09 Hz, 1 H) 7.76 (t, J=7.18 Hz, 1 H) 7.45 - 7.54 (m, 2 H) 7.14 - 7.24 (m, 3 H) 7.05 (dd, J=7.20, 2.00 Hz, 1 H) 6.88 (d, J=7.80 Hz, 1 H) 5.75 (d, J=16.14 Hz, 1 H) 5.54 (d, J=16.14 Hz, 1 H) 5.47 (s, 2 H) 5.18 - 5.28 (m, 1H) 4.90 - 5.01 (m, 1 H) 4.78 - 4.85 (m, 1 H) 4.56 - 4.65 (m, 1 H) 4.37-4.46 (m, 1 H) 3.97 (s, 3 H) 2.74 - 2.82 (m, 1 H) 2.40 - 2.50 (m, 1 H)

[0534] Step F: Preparation of (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid To a suspension of (S)-methyl 2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (126.0 mg, 213.56 μmol) in MeOH (2 mL) and THF (1 mL), LiOH (2 M, 427.12 μL) was added. The yellow suspension was stirred at 25°C for 2 hours. The pH of the yellow solution was adjusted to 8-9 by adding 1N HCl. The mixture was concentrated to obtain the crude product as a yellow gum-like substance (209.5 mg). The crude product was purified by preparative HPLC to obtain (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid as a yellow solid (31.66 mg, yield 25.7%, purity 100%). 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=7.96 Hz, 1 H) 8.03 (d, J=8.45 Hz, 1 H) 7.91 (d, J=7.13 Hz, 1 H) 7.80 (t, J=7.81 Hz, 1 H) 7.57 (d, J=7.26 Hz, 1 H) 7.52 (t, J=8.01 Hz, 1 H) 7.16-7.27 (m, 3 H) 7.13 (dd, J=7.20, 2.00 Hz, 2 H) 6.91 (d, J=8.25 Hz, 1 H) 5.77 (d, J=16.13 Hz, 1 H) 5.55 (d, J= 16.13 Hz, 1 H) 5.51 (s, 2 H) 5.22-5.30 (m, 1 H) 4.92 - 5.03 (m, 1 H) 4.73 - 4.84 (m, 1 H) 4.59 - 4.65 (m, 1 H) 4.40 - 4.47 (m, 1 H) 2.74 - 2.85 (m, 1 H) 2.43 - 2.53 (m, 1 H).

[0535] Example 2W: (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-5'-methyl-2'-oxo-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 104aw) [ka] [ka] [ka] Step A: Preparation of 4-bromo-5-methylpyridine-2(1H)-one To a solution of 4-bromo-2-chloro-5-methylpyridine (2.0 g, 9.69 mmol) in t-BuOH (25 mL), KOH (1.63 g, 29.06 mmol) was added. The mixture was stirred at 110°C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with siRNA (60 mL x 2). The organic layers were combined, collected, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with a solution of DMF (3 mL) and MeOH (2 mL). The solid was filtered, collected, and dried under reduced pressure. 4-bromo-5-methyl-1H-pyridine-2-one was obtained as a white solid (796 mg, yield: 39.7%). LCMS: m / z 187.8 [M+H] +

[0536] Step B: Preparation of (S)-methyl 2-((4-bromo-5-methyl-2-oxopyridine-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate To a solution of 4-bromo-5-methyl-1H-pyridine-2-one (385 mg, 2.05 mmol) in CH3CN (5 mL), methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (606 mg, 2.05 mmol) and K2CO3 (850 mg, 6.15 mmol) were added. The mixture was then stirred at 50°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with  (30 mL x 3). The organic layers were combined, collected, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, ethyl acetate / MeOH = 1 / 0~15 / 1). Methyl 2-[(4-bromo-5-methyl-2-oxo-1-pyridyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate was obtained as a pale yellow solid (660 mg, yield: 66.7%). LCMS: m / z 446.8 [M+H] + .

[0537] Step C: Preparation of (S)-(1-((5-(methoxycarbonyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-yl)methyl)-5-methyl-2-oxo-1,2-dihydropyridine-4-yl)boronic acid To a solution of methyl 2-[(4-bromo-5-methyl-2-oxo-1-pyridyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]imidazo[4,5-b]pyridine-5-carboxylate (563 mg, 1.26 mmol) in dioxane (5 mL), Pin2B2 (320 mg, 1.26 mmol), KOAc (371 mg, 3.78 mmol), and Pd(dppf...

Claims

1. Formula I: 【Chemistry 1】 Equation I [In the formula, 【Chemistry 2】 This indicates any single or double bond whose valence is acceptable; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ each of which is independently selected from C, CH, and N, provided that at least two of X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ are N, and no more than four are N; T １ It is a C(=O)OH or carboxylic acid bioisoster; T ２ is, (C ３ -C ６ ) Cycloalkyl, 3-6 member heterocycloalkyl, phenyl, 5-6 member heteroaryl, (C １ -C ６ ) Alkoxy, CN, or (C ２ -C ４ ) May be appropriately substituted with alkynyl (C １ -C ６ ) alkyl, and the (C ３ -C ６ Each of the cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl groups contains 1-4 R ｘ It may be replaced as appropriate; Each R ｘ These are independently OH, SH, CN, NO ２ , halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) cyanoalkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) Cycloalkyl, amino, (C １ -C ６ ) alkylamino and di(C １ -C ６ ) Selected from the group consisting of alkylaminos; L １ This is 1 to 3 R Ｌ It may be replaced as appropriate (C １ -C ３ ) is alkylene; L ２ is a bond, -O-, -S(O) ０－２ -, or -NH-; Each R Ｌ These are, independently, halogen, (C １ -C ３ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl groups; or A pair of R on the same or adjacent carbon atoms Ｌ Each atom, together with the atom it is bonded to, (C ３ -C ６ ) forming a cycloalkyl ring; Ring A is, Halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) A partially unsaturated monocyclic (C) which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. ５ -C ８ ) Cycloalkylene; Furthermore Halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) Selected from the group consisting of partially unsaturated monocyclic 5-8 membered heterocycloalkylenes, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys; mm is L ２ The bond point to ring B is shown, and nn is the bond point to ring B; Ring B is, 【Transformation 3】 It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; B １ 、 B ２ 、 and B ３ each of which is independently selected from CR １ and N; B ４ and B ５ Each of these is independently N, NR １ , C, CR １ The group is selected from the group consisting of , O, and S, however, B ４ and B ５ The ring containing is a heteroaryl; R １ is selected from the group consisting of H, halogen, and (C １ -C ６ )alkyl; Each R ａ (C １ -C ６ ) alkyl, (C １ -C ３ ) Alkyl (C ３ -C ６ ) Cycloalkyl, (C １ -C ３ ) Alkyl (3-5 member heterocycloalkyl), -C(O)NR ２ R ３ , and (C １ -C ６ ) Selected from the group consisting of fluoroalkyl; Each R ２ and R ３ H and (C １ -C ６ ) Selected from the group consisting of alkyl groups; a is an integer selected from 0 to 3; Z １ is -O- or -NH-; Each R ｃ H, (C １ -C ６ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C ３ -C ６ ) Cycloalkyl, (C ５ -C １０ ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R ｂ (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkyl, halogen, (C ３ -C ６ ) Selected from the group consisting of cycloalkyl and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.

2. Formula II: 【Chemistry 4】 Formula II [In the formula, 【Transformation 5】 This indicates any single or double bond whose valence is acceptable; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ Each of them is independently selected from C, CH, and N, except X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , and X ８ At least two of these, and four or fewer, is N; T １ It is a C(=O)OH or carboxylic acid bioisoster; T ２ is, (C ３ -C ６ ) They may be appropriately substituted with cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl (C １ -C ６ ) alkyl, and the (C ３ -C ６ Each of the cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl groups contains 1-4 R ｘ It may be replaced as appropriate; Each R ｘ These are independently OH, SH, CN, NO ２ , halogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) cyanoalkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ３ -C ６ ) Cycloalkyl, amino, (C １ -C ６ ) alkylamino and di(C １ -C ６ ) Selected from the group consisting of alkylaminos; L １ This is 1 to 3 R Ｌ It may be replaced as appropriate (C １ -C ３ ) is alkylene; L ２ is a bond, -O-, -S(O) ０－２ -, or -NH-; Each R Ｌ These are, independently, halogen, (C １ -C ３ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl groups; or A pair of R on the same or adjacent carbon atoms Ｌ Each atom, together with the atom it is bonded to, (C ３ -C ６ ) forming a cycloalkyl ring; Ring A is, 1 to 4 R Ｙ Phenylene may be substituted as appropriate; 1 to 3 R Ｙ Five- to six-membered heteroarylenes which may be substituted as appropriate. Selected from the group consisting of; mm is L ２ The bond point to is shown, and nn indicates the bond point to ring B; and Each R Ｙ These are, independently, halogen, cyano, -OH, oxo, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) Selected from the group consisting of haloalkoxys; Ring B is, 【Transformation 6】 It is selected from the group consisting of, in the formula, aa indicates a bonding point to ring A; B １ , B ２ , and B ３ Each of them independently, CR １ Selected from the group consisting of and N; B ４ and B ５ Each of these is independently N, NR １ , C, CR １ The group is selected from the group consisting of , O, and S, however, B ４ and B ５ The ring containing is a heteroaryl; R １ H, halogen, and (C １ -C ６ ) Selected from the group consisting of alkyl groups; Each R ａ (C １ -C ６ ) alkyl, (C １ -C ３ ) Alkyl (C ３ -C ６ ) Cycloalkyl, (C １ -C ３ ) Alkyl (3-5 member heterocycloalkyl), -C(O)NR ２ R ３ , and (C １ -C ６ ) Selected from the group consisting of fluoroalkyl; Each R ２ and R ３ H and (C １ -C ６ ) Selected from the group consisting of alkyl groups; a is an integer selected from 0 to 3; Z １ is -O- or -NH-; Each R ｃ H, (C １ -C ６ ) alkyl, and (C １ -C ３ ) Selected from the group consisting of haloalkyl; Ring C is phenyl, 5-6 member heteroaryl, (C ３ -C ６ ) Cycloalkyl, (C ５ -C １０ ) Selected from the group consisting of bicycloalkyl, 5-10 membered bicycloheteroaryl, and 3-6 membered heterocycloalkyl; Each R ｂ (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkyl, halogen, (C ３ -C ６ ) Selected from the group consisting of cycloalkyl and CN; and b is an integer selected from 0 to 3. The compound indicated by or its pharmaceutically acceptable salt or solvate.

3. X ８ However, C is also X ５ The compound according to claim 1 or 2, wherein C is present.

4. X ３ The compound according to any one of claims 1 to 3, wherein C is present.

5. X ２ The compound according to any one of claims 1 to 4, wherein N is present.

6. X ４ The compound according to any one of claims 1 to 5, wherein N is present.

7. X ７ The compound according to any one of claims 1 to 6, wherein the compound is CH.

8. Each X ８ , X ５ , and X ３ However, C is X ２ and X ４ However, N is X ７ However, CH is, and X １ and X ６ The compound according to any one of claims 1 to 7, wherein the compound is independently CH or N.

9. X １ and X ６ The compound according to claim 8, wherein the compound is CH.

10. X １ However, N is, and X ６ The compound according to claim 8, wherein the compound is CH.

11. X １ However, CH is, and X ６ The compound according to claim 8, wherein N is present.

12. T １ The compound according to any one of claims 1 to 11, wherein the compound is C(=O)OH.

13. T ２ However, (C ３ -C ６ ) Substituted with cycloalkyl, 3-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl (C １ -C ３ The compound according to any one of claims 1 to 12, wherein it is alkyl.

14. T ２ However, (C ３ -C ６ ) Substituted with cycloalkyl or 3-6 member heterocycloalkyl (C １ -C ３ The compound according to any one of claims 1 to 13, wherein it is alkyl.

15. T ２ However, it is substituted with a 3-6 member heterocycloalkyl group (C １ -C ３ The compound according to any one of claims 1 to 14, wherein it is alkyl.

16. T ２ However, it is substituted with a 4-6 member heterocycloalkyl group (C １ -C ３ The compound according to any one of claims 1 to 15, wherein it is alkyl.

17. T ２ However, it is substituted with oxetanyl (C １ -C ３ The compound according to any one of claims 1 to 16, wherein it is alkyl.

18. T ２ but, 【Transformation 7】 The compound according to any one of claims 1 to 17.

19. L ２ The compound according to any one of claims 1 to 18, wherein the bond is a combination.

20. L ２ The compound according to any one of claims 1 to 18, wherein the compound is -O-.

21. L １ However, 1 to 3 R Ｌ C may be replaced as appropriate. １－２ The compound according to any one of claims 1 to 20, which is an alkylene.

22. L １ However, CH ２ The compound according to any one of claims 1 to 21.

23. L １ However, CH ２ CH ２ The compound according to any one of claims 1 to 21.

24. L １ However, 1 to 3 R Ｌ CH is appropriately substituted ２ CH ２ The compound according to any one of claims 1 to 21.

25. L １ However, R Ｌ CH is replaced by ２ CH ２ and a pair of adjacent R on a carbon atom Ｌ However, together with the atoms to which each is bonded, C ３ -C ５ A compound according to any one of claims 1 to 21, which forms a cycloalkyl ring.

26. L ２ However, it is a bond, and L １ However, CH ２ The compound according to any one of claims 1 to 18.

27. L ２ However, it is a bond, and L １ However, CH ２ CH ２ or 【Transformation 8】 The compound according to any one of claims 1 to 18.

28. L ２ However, it is -O- and L １ However, 1 to 3 R Ｌ C may be replaced as appropriate. １－２ The compound according to any one of claims 1 to 18, wherein it is an alkylene.

29. L １ However, CH ２ The compound according to claim 28.

30. (i) mm is parallel with respect to nn; (ii) mm is meta to nn; (iii) L ２ However, it is a bond, L １ However, CH ２ And mm is parallel to nn; (iv) L ２ However, it is a bond, L １ However, CH ２ CH ２ or 【Chemistry 9】 And mm is meta to nn; or (v) L ２ However, it is -O- and L １ However, CH ２ The compound according to any one of claims 1 to 29, wherein mm is meta with respect to nn.

31. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) A partially unsaturated monocycle (C) which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. ５ -C ８ The compound according to any one of claims 1 or 3 to 30, wherein it is a cycloalkylene.

32. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ ) A partially unsaturated monocyclic C, which may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. ６ A compound according to any one of claims 1 or 3 to 31, wherein the compound is a cycloalkylene.

33. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ The compound according to claim 1 or any one of claims 3 to 32, which is a cyclohexenylene that may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys.

34. The compound according to any one of claims 1 or 3 to 33, wherein ring A is an unsubstituted cyclohexenylene.

35. Ring A is 【Chemistry 10】 The compound according to any one of claims 1 or 3 to 34.

36. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ The compound according to any one of claims 1 or 3 to 30, which is a partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene that may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys.

37. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ The compound according to any one of claims 1, 3 to 30, or 36, which is a partially unsaturated monocyclic 5-6 membered heterocycloalkylene that may be appropriately substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys.

38. Ring A is halogen, (C １ -C ３ ) alkyl, (C １ -C ３ ) Haloalkyl, (C １ -C ３ )alkoxy, and (C １ -C ３ The compound according to any one of claims 1, 3 to 30, or 36 to 37, which is a tetrahydropyridinylene that may be appropriately substituted with one to four substituents independently selected from the group consisting of haloalkoxys.

39. The compound according to any one of claims 1, 3 to 30, or 36 to 38, wherein ring A is an unsubstituted tetrahydropyridinylene.

40. Ring A is 【Chemistry 11】 The compound according to any one of claims 1, 3 to 30, or 36 to 39.

41. Ring A has 1 to 4 R Ｙ The compound according to any one of claims 2 to 30, wherein phenylene may be appropriately substituted with phenylene.

42. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30, which is 1,4-phenylene or 1,3-phenylene, which may be appropriately substituted with phenylene.

43. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30 or 42, wherein 1,4-phenylene may be appropriately substituted with phenylene.

44. Ring A is 【Chemistry 12】 The compound according to any one of claims 2 to 30 or 42 to 43.

45. Ring A has 1 to 3 R Ｙ The compound according to any one of claims 2 to 30, which is a 5-6 member heteroarylene that may be appropriately substituted with the other members.

46. Ring A has 1 to 3 R Ｙ The compound according to any one of claims 2 to 30 or 45, which is a six-membered heteroarylene that may be appropriately substituted with the other.

47. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30 or 45 to 46, which is 2,4-pyridinylene or 3,5-pyridinylene, which may be appropriately substituted with the compound.

48. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30 or 45 to 47, wherein 2,4-pyridinylene may be appropriately substituted with the compound according to claim 2 to 30 or 45 to 47.

49. Ring A is 【Chemistry 13】 A compound according to any one of claims 2 to 30 or 45 to 48, selected from the group consisting of the above.

50. Ring A has 1 to 3 R Ｙ A six-membered heteroarylene substituted with R, however, Ｙ The compound according to any one of claims 2 to 30 or 45 to 46, wherein at least one of the compounds is an oxo.

51. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30, 45 to 46, or 50, wherein the pyridnylene is further optionally substituted.

52. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30, 45 to 46, or 50 to 51, wherein the compound is 1,4-pyridonylene which may be further appropriately substituted.

53. Ring A is 【Chemistry 14】 A compound according to any one of claims 2 to 30, 45 to 46, or 50 to 52, selected from the group consisting of the above.

54. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30 or 45 to 46, which is a five-membered heteroarylene that may be appropriately substituted with the other.

55. Ring A has 1 to 2 R Ｙ The compound according to any one of claims 2 to 30, 45 to 46, or 54, which is a pyrazolylene that may be appropriately substituted with a pyrazolylene.

56. Ring A is 【Chemistry 15】 A group consisting of is selected, and each of these is one R Ｙ The compound according to any one of claims 2 to 30, 45 to 46, or 54 to 55, which may be appropriately substituted with.

57. Each R Ｙ However, independently, halogen and (C １ -C ３ A compound according to any one of claims 1 to 56, selected from the group consisting of alkyl groups.

58. Ring B is 【Chemistry 16】 (B-I) The compound according to any one of claims 1 to 57.

59. B ２ The compound according to claim 58, wherein N is present.

60. B １ and B ３ However, CR became independent. １ The compound according to claim 58 or 59.

61. B １ and B ３ One of them is N, and B １ and B ３ The other one is CR １ The compound according to claim 58 or 59.

62. B １ However, N is, and B ３ However, CR １ The compound according to claim 58 or 59.

63. B １ However, CR １ B ３ The compound according to claim 58 or 59, wherein N is present.

64. B ２ However, CR １ The compound according to claim 58.

65. B １ and B ３ However, CR became independent. １ The compound according to claim 58 or 64.

66. Ring B is 【Chemistry 17】 The compound according to any one of claims 1 to 58.

67. Ring B is [Chemistry 18] The compound according to any one of claims 1 to 58.

68. Ring B is 【Chemistry 19】 The compound according to any one of claims 1 to 58.

69. Ring B is 【Chemistry 20】 The compound according to any one of claims 1 to 58.

70. Ring B is 【Chemistry 21】 (B-II) The compound according to any one of claims 1 to 57.

71. B ２ However, it is either N or B ２ However, CR １ The compound according to claim 70.

72. B １ However, CR １ The compound according to claim 70 or 71.

73. B １ The compound according to claim 70 or 71, wherein N is present.

74. Ring B is 【Chemistry 22】 The compound according to any one of claims 1 to 57 or 70.

75. Ring B is 【Chemistry 23】 The compound according to any one of claims 1 to 57 or 70.

76. Ring B is 【Chemistry 24】 (B-IV) The compound according to any one of claims 1 to 57.

77. B ５ The compound according to claim 76, wherein N is present.

78. B ４ However, NR １ A compound according to any one of claims 76 to 77, selected from the group consisting of , S, and O.

79. B ４ The compound according to claim 78, wherein S is present.

80. Ring B is 【Chemistry 25】 The compound according to any one of claims 1 to 57 or 76.

81. Each R １ The compound according to any one of claims 1 to 80, wherein the compound is independently H or a halogen.

82. Each R １ The compound according to any one of claims 1 to 81, wherein H is present.

83. The compound according to any one of claims 1 to 82, wherein a is 0.

84. Z １ The compound according to any one of claims 1 to 83, wherein the compound is -O-.

85. Each R ｃ The compound according to any one of claims 1 to 84, wherein H is present.

86. The compound according to any one of claims 1 to 85, wherein ring C is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 5-10 membered bicycloheteraryl.

87. The compound according to any one of claims 1 to 86, wherein ring C is phenyl.

88. The compound according to any one of claims 1 to 87, wherein b is 1 to 3.

89. The compound according to any one of claims 1 to 88, wherein b is 2.

90. The compound according to any one of claims 1 to 85, wherein ring C is phenyl and b is 2. 【Request Item 91】 【Chemistry 26】 but, 【Chemistry 27】 The compound according to claim 90.

92. R ｂ Each of them independently, (C １ -C ６ ) alkyl, (C １ -C ６ ) A compound according to any one of claims 1 to 91, selected from the group consisting of alkoxys, halogens, and CNs.

93. R ｂ The compound according to any one of claims 1 to 92, wherein each of is independently selected from the group consisting of -F, -Cl, and CN.

94. The compound of formula I is, formula IA: 【Chemistry 28】 Formula IA A compound of the compound described in claim 1 or a pharmaceutically acceptable salt or solvate thereof.

95. The compound of formula I is, formula IB: 【Chemistry 29】 Formula IB A compound of the compound described in claim 1 or a pharmaceutically acceptable salt or solvate thereof.

96. X １ The compound according to claim 94 or 95, wherein N is present.

97. X ６ The compound according to any one of claims 94 to 96, wherein the compound is CH.

98. X １ However, N is, and X ６ The compound according to claim 94 or 95, wherein the compound is CH.

99. T １ The compound according to any one of claims 94 to 98, wherein the compound is C(=O)OH.

100. T ２ However, it is substituted with a 3-6 member heterocycloalkyl group (C １ -C ３ The compound according to any one of claims 94 to 99, wherein it is an alkyl group.

101. T ２ However, it is substituted with oxetanyl (C １ -C ３ The compound according to any one of claims 94 to 100, wherein it is alkyl.

102. T ２ but, 【Transformation 30】 The compound according to any one of claims 74 to 101.

103. Ring B is 【Chemistry 31】 (B-I) The compound according to any one of claims 94 to 102.

104. Ring B is 【Chemistry 32】 The compound according to any one of claims 94 to 103.

105. Ring B is 【Transformation 33】 A compound according to any one of claims 94 to 103, selected from the group consisting of the following.

106. Ring B is 【Transformation 34】 (B-II) The compound according to any one of claims 94 to 102.

107. Ring B is 【Chemistry 35】 The compound according to any one of claims 94 to 102 or 106.

108. Ring B is 【Transformation 36】 The compound according to any one of claims 94 to 102 or 106.

109. Ring B is 【Chemistry 37】 (B-IV) The compound according to any one of claims 94 to 102.

110. Ring B is 【Transformation 38】 The compound according to any one of claims 94 to 102 or 109.

111. Each R １ The compound according to any one of claims 94 to 110, wherein the compound is independently H or a halogen.

112. Each R １ The compound according to any one of claims 94 to 111, wherein H is present.

113. The compound according to any one of claims 94 to 112, wherein a is 0.

114. Z １ The compound according to any one of claims 94 to 113, wherein the compound is -O-.

115. Each R ｃ The compound according to any one of claims 94 to 114, wherein H is present.

116. The compound according to any one of claims 94 to 115, wherein ring C is phenyl.

117. The compound according to any one of claims 94 to 116, wherein b is 1 to 3.

118. The compound according to any one of claims 94 to 117, wherein b is 2.

119. The compound according to any one of claims 94 to 118, wherein ring C is phenyl and b is 2. [Request Item 120] [Chemistry 39] but, 【Chemistry 40】 The compound according to any one of claims 94 to 119.

121. R ｂ Each of them independently, (C １ -C ６ ) alkyl, (C １ -C ６ ) A compound according to any one of claims 94 to 120, selected from the group consisting of alkoxy, halogen, and CN.

122. R ｂ The compound according to any one of claims 94 to 121, wherein each of is independently selected from the group consisting of -F, -Cl, and CN.

123. The compound according to any one of claims 1 or 3 to 122, wherein the compound of formula I is selected from the group consisting of the compounds in Table C1, or a pharmaceutically acceptable salt or solvate thereof.

124. The compound according to any one of claims 1 or 3 to 123, wherein the compound of formula I is selected from the group consisting of the compounds in Table C2, or a pharmaceutically acceptable salt or solvate thereof.

125. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or solvate according to any one of claims 1 to 124, and a pharmaceutically acceptable excipient.

126. The compound of formula II is, formula IIA: 【Chemistry 41】 Formula IIA [In the formula, n1 is either 0 or 1] A compound of the compound described in claim 2, or a pharmaceutically acceptable salt or solvate thereof.

127. The compound of formula II is formula IIB: 【Chemistry 42】 Formula IIB [In the formula, n1 is either 0 or 1] A compound of the compound described in claim 2, or a pharmaceutically acceptable salt or solvate thereof.

128. The compound of formula II is formula IIC: 【Chemistry 43】 Formula IIC [In the formula, n1 is either 0 or 1] A compound of the compound described in claim 2, or a pharmaceutically acceptable salt or solvate thereof.

129. L １ However, CH ２ L ２ The compound according to claim 128, wherein the compound is -O-.

130. L １ However, CH ２ CH ２ L ２ The compound according to claim 128, wherein the bond is a combination.

131. L １ but, 【Chemistry 44】 L ２ The compound according to claim 128, wherein the bond is a combination.

132. X １ The compound according to any one of claims 126 to 128, wherein N is present.

133. X １ The compound according to any one of claims 126 to 128, wherein the compound is CH.

134. X ６ The compound according to any one of claims 126 to 133, wherein the compound is CH.

135. X １ However, N is, and X ６ The compound according to any one of claims 126 to 128, wherein the compound is CH.

136. X １ and X ６ The compound according to any one of claims 126 to 128, wherein each is CH.

137. T １ The compound according to any one of claims 126 to 136, wherein the compound is C(=O)OH.

138. T ２ However, it is substituted with a 3-6 member heterocycloalkyl group (C １ -C ３ The compound according to any one of claims 126 to 137, wherein it is alkyl.

139. T ２ However, it is substituted with oxetanyl (C １ -C ３ The compound according to any one of claims 126 to 138, wherein it is alkyl.

140. T ２ but, 【Chemistry 45】 The compound according to any one of claims 126 to 139.

141. The compound according to any one of claims 126 to 140, wherein n1 is 0.

142. The compound according to any one of claims 126 to 140, wherein n1 is 1.

143. R Ｙ However, independently, halogen and (C １ -C ３ The compound according to claim 142, selected from the group consisting of alkyl groups.

144. R Ｙ The compound according to claim 143, wherein the compound is selected from the group consisting of -F and methyl.

145. Ring B is 【Chemistry 46】 (B-I) The compound according to any one of claims 126 to 144.

146. Ring B is 【Chemistry 47】 The compound according to any one of claims 126 to 145.

147. Ring B is 【Chemistry 48】 A compound according to any one of claims 126 to 145, selected from the group consisting of the following.

148. Ring B is 【Chemistry 49】 The compound according to any one of claims 126 to 145.

149. Ring B is [Transformation 50] (B-II) The compound according to any one of claims 126 to 144.

150. Ring B is 【Chemistry 51】 The compound according to any one of claims 126 to 144 or 149.

151. Each R １ The compound according to any one of claims 126 to 150, wherein the compound is independently H or a halogen.

152. Each R １ The compound according to any one of claims 126 to 151, wherein H is present.

153. The compound according to any one of claims 126 to 152, wherein a is 0.

154. Z １ The compound according to any one of claims 126 to 153, wherein the compound is -O-.

155. Each R ｃ The compound according to any one of claims 126 to 154, wherein H is present.

156. The compound according to any one of claims 126 to 155, wherein ring C is phenyl.

157. The compound according to any one of claims 126 to 156, wherein b is 1 to 3.

158. The compound according to any one of claims 126 to 157, wherein b is 2.

159. The compound according to any one of claims 126 to 156, wherein b is 0.

160. The compound according to any one of claims 126 to 158, wherein ring C is phenyl and b is 2. 【Request Item 161】 【Chemistry 52】 but, 【Chemistry 53】 The compound according to claim 160.

162. The compound according to any one of claims 126 to 155, wherein ring C is phenyl and b is 0.

163. R ｂ Each of them independently, (C １ -C ６ ) alkyl, (C １ -C ６ ) A compound according to any one of claims 126 to 161, selected from the group consisting of alkoxy, halogen, and CN.

164. R ｂ The compound according to any one of claims 126 to 161 or 163, wherein each of is independently selected from the group consisting of -F, -Cl, and CN.

165. A compound according to any one of claims 2 to 93 or 126 to 164, wherein the compound of formula II is selected from the group consisting of compounds in Tables C1-W and C2-W, or a pharmaceutically acceptable salt or solvate thereof.

166. A pharmaceutical composition comprising a compound according to any one of claims 2 to 93 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

167. A method for treating type 2 diabetes in a patient requiring treatment, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166.

168. A method for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed with type 2 diabetes in a therapeutically effective amount of a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166.

169. A method for treating diabetes in patients, a) Determine that the patient has type 2 diabetes; then b) A method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166.

170. The method according to any one of claims 167 to 169, wherein the step of determining that the patient has type 2 diabetes includes performing an assay to determine the level of an analyte in a sample from a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof.

171. The method according to claim 170, wherein the HbA1c level is approximately 6.5% or higher.

172. The method according to any one of claims 170 to 171, wherein the fasting blood glucose level is approximately 126 mg / dL or higher.

173. The method according to any one of claims 170 to 171, wherein the non-fasting blood glucose level is about 200 mg / dL or higher.

174. The method according to any one of claims 167 to 173, further comprising obtaining a sample from the patient.

175. The method according to claim 174, wherein the sample is a bodily fluid sample.

176. The method according to any one of claims 167 to 175, wherein the patient is approximately 40 to approximately 70 years old and is overweight or obese.

177. The aforementioned patient weighed approximately 22 kg / m². ２ The method according to any one of claims 167 to 176, wherein the body mass index (BMI) is or higher.

178. The aforementioned patient weighed approximately 30 kg / m². ２ The method according to any one of claims 167 to 177, wherein the BMI is or greater.

179. The method according to any one of claims 167 to 178, wherein the treatment of type 2 diabetes includes reducing fasting blood glucose levels.

180. The method according to claim 179, wherein the fasting blood glucose level is reduced to about 100 mg / dL or less.

181. The method according to any one of claims 167 to 180, wherein the treatment of type 2 diabetes includes a reduction in HbA1c levels.

182. The method according to claim 181, wherein the HbA1c level is reduced to approximately 5.7% or less.

183. The method according to any one of claims 167 to 182, wherein the treatment of type 2 diabetes includes reducing glucagon levels.

184. The method according to any one of claims 167 to 182, wherein the treatment of type 2 diabetes includes increasing insulin levels.

185. The method according to any one of claims 167 to 182, wherein the treatment of type 2 diabetes includes a reduction in BMI.

186. The aforementioned BMI is approximately 25 kg / m². ２ The method according to claim 185, which reduces the amount to or less than that.

187. The method according to any one of claims 167 to 186, wherein the compound according to any one of claims 1 to 165 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 125 or 166, is administered orally.

188. The method according to any one of claims 167 to 187, further comprising administering a further therapy or therapeutic agent to the patient.

189. The method according to claim 188, wherein the further therapy or therapeutic agent is selected from the group consisting of antidiabetic drugs, anti-obesity drugs, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatments, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.

190. The method according to claim 189, wherein the antidiabetic drug is selected from the group consisting of biguanides, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-dependent glucose transporter 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic polypeptides (GIPs), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-dependent glucose transporter 1 (SGLT1) inhibitors, or any combination thereof.

191. The method according to claim 190, wherein the biguanide is metformin.

192. The aforementioned anti-obesity drug is a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, or a human proislet peptide. The method according to claim 189, comprising a peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, fendimethrazine, benzfetamine, a fibroblast growth factor receptor (FGFR) modifier, an AMP-activated protein kinase (AMPK) activator, a sodium-glucose transporter 1 (SGLT-1) inhibitor, or any combination thereof, selected from the group.

193. The method according to claim 189, wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.

194. The method according to claim 189, wherein the NASH therapeutic agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase analog 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-regulated kinase 1 (ASK1) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, diacylglycerol acyltransferase 2 (DGAT2) inhibitors, or any combination thereof.

195. The method according to any one of claims 188 to 194, wherein a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166, and a further therapeutic agent are administered sequentially as separate formulations in any order.

196. A method for regulating insulin levels in a patient requiring adjustment, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166.

197. The method according to claim 196, wherein the adjustment results in an increase in insulin levels.

198. A method for regulating glucose levels in a patient requiring regulation, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166.

199. The method according to claim 198, wherein the adjustment results in a decrease in glucose levels.

200. A method for treating a GLP-1 related disease, disorder, or illness, comprising administering an effective amount of a compound according to any one of claims 1 to 124 or 126 to 165 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 125 or 166, to a patient in need thereof.

201. The aforementioned diseases, disorders, or illnesses include type 1 diabetes, type 2 diabetes, juvenile-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 intake, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, and gestational diabetes. Kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, 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, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial hyperlipidemia The method according to claim 200, selected from the group consisting of: disease, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol intake 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, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, psychogenic 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.

202. The aforementioned diseases, disorders, or illnesses include type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular diseases, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, and The method according to claim 201, selected from the group consisting of: impaired blood sugar intake, 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 ulcers, psoriasis, psychogenic polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

203. The method according to claim 202, wherein the disease, disorder, or illness includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other drugs, gout, excessive sugar intake, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, 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 ulcers, idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.

Images