Heterocyclic GLP-1 agonists

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application PCT / CN2022 / 086863, filed April 14, 2022, which is incorporated herein by reference in its entirety.

[0002] The present invention relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. [Background technology]

[0003] background Incretin metabolic hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important in controlling glucose homeostasis. Medications that target this family of gut peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0004] Diabetes mellitus is a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition that accounts for over 90% of diabetes cases. Onset typically occurs in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle modifications can be useful in managing the disorder, patients with T2DM may require the use of antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose ingestion. Although this incretin action is significantly reduced (if at all) in cases of T2DM, GLP-1 retains its insulinotropic properties even when the endocrine pancreatic response to GIP is effectively shut down. Thus, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in T2DM patients. Summary of the Invention [Problem to be solved by the invention]

[0006] overview The present invention describes heterocyclic GLP-1 agonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating GLP-1-related diseases, disorders, and conditions are also provided.

[0007] In some embodiments, provided is a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof.

[0008] Also provided herein is a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0009] 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 Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0010] 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 Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method for treating diabetes in a patient, comprising determining that the patient has type 2 diabetes and administering to the patient a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes comprises performing an assay to determine the level of an analyte in 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 some embodiments, the HbA1c level is about 6.5% or higher. In some embodiments, the fasting blood glucose level is about 126 mg / dL or higher. In some embodiments, the non-fasting blood glucose level is about 200 mg / dL or higher.

[0012] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of about 22 kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 That's all.

[0013] In certain embodiments, the method for treating type 2 diabetes comprises reducing fasting blood glucose levels, ie, reducing fasting blood glucose levels to about 100 mg / dL or less.

[0014] In certain embodiments, the method for treating type 2 diabetes comprises reducing HbA1c levels, hi certain embodiments, HbA1c levels are reduced to about 5.7% or less.

[0015] In certain embodiments, the method of treating type 2 diabetes comprises reducing glucagon levels.

[0016] In certain embodiments, the method of treating type 2 diabetes involves increasing insulin levels.

[0017] In certain embodiments, the method for treating type 2 diabetes includes reducing BMI. In certain embodiments, the BMI is about 25 kg / m 2 It decreases to the following:

[0018] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0019] In some embodiments, the method for treating type 2 diabetes further comprises administering an additional treatment or therapeutic agent to the patient.In some embodiments, the additional treatment or therapeutic agent is selected from the group consisting of antidiabetic agents, antiobesity agents, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatment agents, antiemetic agents, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.In some embodiments, the antidiabetic agent is selected from the group consisting of biguanides, sulfonylureas, glitazars, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-glucose transporter 2 (SGLT2) inhibitors, glitazones, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose transporter 1 (SGLT1) inhibitors, or any combination thereof.In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human pleurodipeptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a 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, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In some embodiments, the NASH treatment agent is selected from the group consisting of FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof. In some embodiments, the compound in Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered in separate preparations in any order.

[0020] Also provided herein is a method of modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation increases insulin levels.

[0021] Also provided herein is a method for modulating glucose levels in a patient in need of such modulation, comprising administering to the patient an effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation reduces glucose levels.

[0022] Also provided herein is a method of treating a GLP-1 associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), slow-onset autoimmune diabetes in adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, or renal disease. , adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial 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, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic The disease is selected from the group consisting of acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive dysfunction, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, Selected from the group consisting of insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0023] All publications, patents, and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated by reference herein. To the extent that the publications and patents or patent applications incorporated by reference contradict the disclosure herein, the present specification supersedes and / or takes precedence over such conflicting material. [Means for solving the problem]

[0024] Detailed Description Before the present compounds and methods are described, it is to be understood that this disclosure is not limited to the described methodology, protocols, cell lines, assays, and reagents, as these may vary. It is also to be understood that the terminology used herein is intended to describe embodiments of the invention, but is not intended to limit the scope of the invention, which is set by the appended claims.

[0025] definition It should be noted that as used in this specification and the appended claims, the singular forms "a," "the," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods, devices, and materials are described herein. All publications cited herein are incorporated by reference in their entirety for the purpose of describing and disclosing the methods, reagents, and tools described therein, which are used in connection with the present invention.

[0027] When values ​​are described in ranges, it is understood that such disclosure includes all possible subranges within such ranges as well as specific numerical values ​​falling within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

[0028] Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM and other conditions in which activation of GLP-1 activity is beneficial.

[0029] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. In certain embodiments, the stereochemistry of a compound is as depicted in the chemical structure set forth in Table 1. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

[0030] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in ready and rapid equilibrium; the compounds provided herein may be described as various tautomers; it should be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the name of the compound does not exclude any tautomers.

[0031] A "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. For example, the compounds of Table 1 and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0032] The term "pharmaceutically acceptable salt" of a compound refers to a salt that retains the biological effectiveness and properties of the compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include salts of NH or primary, secondary, and tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryls, or compounds of the formula N(R N )3 (e.g., HN + (R N )3 or (alkyl)N + (R N )3)(In the formula, each R Nare independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with, for example, one or more (e.g., 1 to 5 or 1 to 3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0033] As used herein, the term "alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "(C1-C6)alkyl" refers to a saturated straight- or branched-chain monovalent hydrocarbon radical of 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.

[0034] As used herein, the term "alkylene" refers to a divalent alkyl containing the indicated number of carbon atoms. For example, "(C-C)alkylene" refers to a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH-, -CH(CH)-, -CHCH-, or -CHCHCH-). Similarly, the terms "cycloalkylene," "heterocycloalkylene," "arylene," and "heteroarylene" refer to divalent cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively.

[0035] As used herein, the term "alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "(C2-C6)alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain of 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0036] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "(C2-C6)alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain having from 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0037] As used herein, the term "alkoxy" refers to an -O-alkyl group in which the radical is on the oxygen atom. For example, "C 1-6 "Alkoxy" means that the radical is on the oxygen atom -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl radical. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, the term "haloalkoxy," as used herein, refers to an -O-haloalkyl group in which the radical is on the oxygen atom.

[0038] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "(C3-C6)cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls can be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyls can contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged 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, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0039] As used herein, the term "heterocycloalkyl" refers to a mono-, bi-, tri-, or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system) having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, where the heteroatoms are O, N, S, or S(O). 1-2 (e.g., carbon atoms and N, O, S, or S(O) if monocyclic, bicyclic, or tricyclic, respectively) 1-2Heterocycloalkyl groups are selected from the group consisting of 1 to 3, 1 to 6, or 1 to 9 heteroatoms, where 0, 1, 2, or 3 atoms in each ring may be substituted by a substituent. Examples of heterocycloalkyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocycloalkyl groups can be partially unsaturated. Non-limiting examples of partially unsaturated heterocycloalkyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, dihydropyranyl, and the like. Heterocycloalkyls can include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls 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, 3-azabicyclo [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, 3-oxabicyclo[3.2.1]octane, etc. Heterocycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom).Non-limiting examples of spirocyclic 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, 2-oxaspiro[2.6]nonane, 1,7-dia ... .2]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, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0040] As used herein, the term "aryl" refers to a mono-, bi-, tri-, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, in which at least one ring in the system is aromatic (e.g., C monocyclic, C 10 Bicyclic or C 14 Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0041] As used herein, the term "heteroaryl" refers to a mono-, bi-, tri-, 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), where at least one ring in the system is aromatic (but need not contain heteroatoms, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-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]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, and others.

[0042] The term "halo" or "halogen," as used herein, refers to -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").

[0043] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced 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.

[0044] Used here [ka] represents an optional single or double bond where valence allows. [ka] indicates the point of attachment to the parent molecule.

[0045] As used herein, when a ring is described as being "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Thus, when a ring system containing at least two rings is described as "non-aromatic," it means that none of the rings comprising the ring system are aromatic.

[0046] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation inherent in the ring itself; e.g., one or more double bonds between constituent ring atoms), unless the ring is aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system containing at least two rings is described as "partially unsaturated," it means that the ring system contains one or more degrees of partial unsaturation, provided that none of the constituent rings of the ring system is aromatic.

[0047] As used herein, the term "GLP-1R" or "GLP-1 receptor" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various species and active fragments thereof.

[0048] As used herein, the term "GLP-1 associated disease" is meant to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0049] As used herein, the term "GLP-1 agonist" or "GLP-1 RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriate increases in 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-1 RAs have been shown to treat type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, albiglutide (TANZEUM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXUMIA®), semaglutide (OZEMPIC®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in U.S. Patents 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 RE45313.

[0050] As used herein, the term "pharmaceutically acceptable" refers to a compound or salt or composition thereof that is chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or with the patient being treated therewith.

[0051] As used herein, the term "therapeutic compound" is intended to include, but is not limited to, a compound disclosed herein (e.g., a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof) and all compositions (e.g., pharmaceutical compositions) in which a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is a component of the composition.

[0052] The terms "administration" or "administering" refer to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0053] As used herein, the term "effective amount" or "effective dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient quantity of a chemical entity (e.g., a compound disclosed herein (e.g., a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof)) to relieve to some extent one or more of the symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case will be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0054] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in that it is compatible with the other components of the pharmaceutical formulation, is suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0055] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound in Table 1 or a pharmaceutically acceptable salt or solvate thereof) and other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0056] The terms "treatment" and "treating" in the context of treating a disease, disorder, or condition are intended to include alleviating or arresting the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition; or preventing the progression, spread, or worsening of the disease, disorder, or condition or one or more of its symptoms.

[0057] As used herein, the term "prevention" refers to the prevention of the onset, recurrence or spread of a disease or condition described herein or its symptoms, in whole or in part.

[0058] As used herein, the terms "subject," "patient," or "individual" are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or necessary. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0059] The terms "treatment regimen" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combinations described herein.

[0060] As used herein, the term "pharmaceutical combination" refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients.

[0061] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., combination elements or combination partners), where the therapeutically active agents are administered together or separately as prescribed by a healthcare professional or in accordance with regulatory authorities as defined herein.

[0062] As used herein, the term "modulation" refers to regulation or adjustment (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0063] It is to be understood that the substituents defined herein are not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluoro groups or a hydroxy group attached to an ethenyl group or an acetylene group), such impermissible substitution patterns being well known to those of skill in the art.

[0064] compound Provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14]

[0065] The compounds of Table 1 include pharmaceutically acceptable salts thereof. Additionally, the compounds of Table 1 include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, but that may be useful as intermediates in the preparation of the compounds of Table 1 and / or in the separation of enantiomers of the compounds of Table 1. Non-limiting examples of pharmaceutically acceptable salts of the compounds of Table 1 include trifluoroacetate salts.

[0066] It is further recognized that the compounds of Table 1 or salts thereof may be isolated in the form of a solvate, and therefore, all such solvates are included within the scope of the present invention.

[0067] In certain embodiments, the compounds of Table 1 are in the depicted stereochemical form or a pharmaceutically acceptable salt thereof.

[0068] Pharmaceutical Compositions and Administration When used as pharmaceuticals, the compounds described herein (e.g., compounds in Table 1 or pharmaceutically acceptable salts or solvates thereof) can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes of administration, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (to mucous membranes, including transdermal, epithelial, ocular, and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0069] Also provided herein are pharmaceutical compositions comprising a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient together with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed in a carrier, such as a capsule, sachet, paper, or other container form. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation, hi some embodiments, the composition is formulated as a tablet or capsule.

[0070] Also provided herein is a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, as the active ingredient can be prepared by intimately admixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired route of administration (e.g., oral, parenteral, etc.). In certain embodiments, the composition is a solid oral composition.

[0071] Suitable pharmaceutically acceptable carriers are well known in the art, and a description of some 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.

[0072] Methods for formulating pharmaceutical compositions are described in numerous publications, such as 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.

[0073] In some embodiments, compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical additives.Pharmaceutically acceptable additives include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymeric delivery materials, serum proteins such as human serum albumin, buffer substances such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder consisting of non-toxic additives. Contemplated compositions may contain 0.001% to 100%, in some embodiments 0.1 to 95%, in other embodiments 75 to 85%, and in further embodiments 20 to 80%, of the chemicals described herein. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0074] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intra-arterial, intrabronchial, intra-synovial, intracerebral, intracapsular, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the route of administration is parenteral (eg, intratumoral).

[0075] In some embodiments, the compounds of Table 1 described herein, or their pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof, can be formulated for parenteral administration, for example, intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal injection. For example, such compositions can be prepared as injections in the form of liquid solutions or suspensions; solid forms suitable for use in preparing solutions or suspensions by adding liquid before injection can also be prepared; and formulations can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of the present disclosure. In some embodiments, devices are used for parenteral administration. For example, such devices can include needle injectors, microneedle injectors, needleless injectors, and infusion techniques.

[0076] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.In some embodiments, the form must be inorganic and fluid enough to be easily squirted.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be protected against the activity of microorganisms such as bacteria and fungi.

[0077] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In some embodiments, the prevention of microbial activity can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be brought about by the use of absorption delaying agents, for example, aluminum monostearate and gelatin in the composition.

[0078] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of the compound of Table 1 or its pharmaceutically acceptable salt or solvate into a solvent, and optionally other ingredients listed above, followed by filtration sterilization.In some embodiments, dispersion is prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary ingredients listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, the preparation method is vacuum filtration and freeze-drying technology, which produces a powder of the active ingredient and additional desired ingredients from the previously sterilized solution.

[0079] In some embodiments, pharmaceutically acceptable additives that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide. The inactive ingredients may include, but are not limited to, one or more of SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0080] In some embodiments, suppositories can be prepared by mixing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof or pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and will therefore melt in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0081] In certain embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for local delivery to the digestive or GI tract by oral administration (e.g., in solid or liquid dosage form).

[0082] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, dosage forms may also comprise buffering agents. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0083] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet. Thus, the composition may contain a diluent such as lactose, sucrose, dicalcium phosphate, a lubricant such as magnesium stearate, and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, or a cellulose derivative, together with the compound of Table 1 provided herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, other solid dosage forms, such as powders, quince, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). In some embodiments, unit dosage forms in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also contemplated; for example, capsules (or tablets in capsules) of granules of each drug; bilayer tablets; two-compartment gel caps, etc. In some embodiments, enteric-coated or sustained-release oral dosage forms are also contemplated.

[0084] In certain embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful in preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0085] In some embodiments, the additives are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, sterility is not required for various oral dosage form additives, such as tablets and capsules. For example, the United States Pharmacopeia / National Formulary standard may be sufficient.

[0086] In some embodiments, the compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for ocular administration. In some embodiments, the ophthalmic composition may include any one or more of the following, but is not limited to: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0087] In some embodiments, the compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing a selected active agent are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, generally consists of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, ointment bases, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0088] In any of the above embodiments, the pharmaceutical compositions described herein can include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0089] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0090] Formulation Example 1 - Tablet Formulation The following ingredients are intimately mixed and compressed into scored tablets: [Table 15]

[0091] Formulation Example 2 - Capsule Formulation The following ingredients are intimately mixed and loaded into a hard shell gelatin capsule: [Table 16]

[0092] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: [Table 17]

[0093] Formulation Example 4 - Injectable formulation The following ingredients are mixed to form an injectable formulation: [Table 18]

[0094] Formulation Example 5 - Suppository Formulation Suppositories weighing 2.5 g total are prepared by mixing a compound of the present disclosure with Witepsol® H-15 (saturated vegetable fatty acid triglyceride; Riches-Nelson, Inc., New York) and have the following composition: [Table 19]

[0095] In some embodiments, the dosage of the compound in Table 1 or its pharmaceutically acceptable salt or solvate is determined based on several factors, including but not limited to, patient type, age, weight, sex, medical condition, severity of patient's medical condition, route of administration and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dosage for a particular situation can be determined by those skilled in the medical field.In some embodiments, the total daily dosage can be divided and administered in portions throughout the day or by a means that provides continuous delivery.

[0096] In certain embodiments, a compound in Table 1 or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 0.01 to about 1000 mg. For example, 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 certain embodiments, the dose is a therapeutically effective amount.

[0097] In certain embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose of about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg). Kg; approx. 0.0002 mg / Kg ~ approx. 1 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 0.5 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 0.1 mg / Kg; approx. 0.001 mg / K g ~ approx. 50 mg / Kg; approx. 0.001 mg / Kg ~ approx. 25 mg / Kg; approx. 0.001 mg / Kg ~ approx. 10 mg / Kg; approx. 0.001 mg / Kg ~ approx. 5 mg / Kg; approx. 0.001 m g / Kg ~ approx. 1mg / Kg; approx. 0.001mg / Kg ~ approx. 0.5mg / Kg; approx. 0.001mg / Kg ~ approx. 0.1mg / Kg; approx. 0.01mg / Kg ~ approx. 50mg / Kg; approx. 0. 01mg / Kg ~ approx. 25mg / Kg; approx. 0.01mg / Kg ~ approx. 10mg / Kg; approx. 0.01mg / Kg ~ approx. 5mg / Kg; approx. 0.01mg / Kg ~ approx. 1mg / Kg; approx. 0.01 In some embodiments, a compound of Table 1 described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 100 mg / kg.

[0098] In certain embodiments, the dosages of the compounds of Table 1 or pharmaceutically acceptable salts or solvates thereof may be administered daily (e.g., in a single dose or in two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, every two weeks, or once a month).

[0099] In certain embodiments, the administration period of a compound of Table 1 described herein, 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 more. In some embodiments, the period of time during which administration is stopped is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient for a period of time, followed by another period of time during which administration of the compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is stopped. In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered for a first period of time, followed by a second period during which administration is stopped, followed by a third period during which administration of the compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is initiated, and then a fourth period during which administration is stopped. For example, a period of administration of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, followed by a period during which administration is discontinued, is repeated for a determined or undetermined period of time. In some embodiments, the period 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 more. In some embodiments, the period of time for which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0100] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to a patient one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0101] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered parenterally to a patient one or more times daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0102] In certain embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered parenterally to a patient weekly.

[0103] Treatment method In certain embodiments, the present invention relates to methods of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., suppressed or impaired and / or elevated or unwanted GLP-1R) is beneficial to the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or further include, treatment of one or more concurrent or secondary conditions associated with any one or more of the conditions described herein.

[0104] Provided herein are methods for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Table 1 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0105] In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), slow-onset autoimmune diabetes in adults (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 cravings, high triglycerides of creatine phosphate (ATP), and steroids. Triglyceridemia, dyslipidemia, nutritional deficiency-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial 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, angiogenesis Postoperative restenosis, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, Including, but not limited to, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0106] In certain embodiments, the disease, disorder, or condition is 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 cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease (e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubule), adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis. , ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS) or any combination thereof.

[0107] In certain embodiments, the disease, disorder, or condition includes, but is 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 cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0108] In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients described herein induce one or more of: reduced blood glucose (e.g., lowered blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, enhanced insulin synthesis, stimulated insulin secretion, increased beta-cell mass, regulated gastric acid secretion, regulated gastric emptying, reduced body mass index (BMI), and / or reduced glucagon production (e.g., levels). In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients described herein can reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, enhanced insulin synthesis, stimulated insulin secretion, increased beta-cell mass, regulated gastric acid secretion, regulated gastric emptying, reduced body mass index (BMI), reduced glucagon production (e.g., levels), or any combination thereof. In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein is a method for regulating glucose or insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Table 1 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0109] In certain embodiments, provided herein are methods of reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by approximately at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), comprising administering to the patient an effective amount of a compound of Table 1 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In some embodiments, the patient is an adult diagnosed with heart disease. In some embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0110] Indications obesity In some embodiments, the condition, disease, or disorder is obesity and conditions, diseases, or disorders associated with or related to obesity. Obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0111] In some embodiments, the condition, disease or disorder is associated with obesity.Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obese diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual flow and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome.In some embodiments, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients who show symptoms of both obesity and insulin deficiency.

[0112] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity diabetes, autoimmune diabetes and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0113] Provided herein are methods for treating diabetes in a patient, the method comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as disclosed herein.

[0114] Provided herein are methods for treating type 2 diabetes in a patient, the method comprising administering to the patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0115] 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 Table 1 disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0116] In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce HbA1c levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce glucagon levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein increase insulin levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce BMI.

[0117] In certain embodiments, a reduction of about 5% to about 95% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction in fasting blood glucose levels to about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less indicates treatment of type 2 diabetes.

[0118] In certain embodiments, a reduction of about 5% to about 95% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of non-fasting blood glucose levels to about 200 mg / L or less, about 150 mg / L or less, or about 130 mg / L or less indicates treatment of type 2 diabetes.

[0119] In certain embodiments, a reduction of about 5% to about 95% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of HbA1c levels to about 6.5% or less, about 6.0% or less, or about 5.0% or less indicates treatment of type 2 diabetes.

[0120] In some embodiments, a decrease of about 5% to about 95% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, a decrease of about 15% to about 80% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, a decrease of about 25% to about 60% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 5% to about 95% in insulin levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 15% to about 80% in insulin levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 25% to about 60% in insulin levels indicates treatment of type 2 diabetes.

[0121] In certain embodiments, a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI to 40 or less, 30 or less, or 20 or less indicates treatment of type 2 diabetes.

[0122] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., diabetic complications).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmotic diabetic coma, infectious diseases (e.g., respiratory infection, urinary tract infection, digestive infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hyperacusis, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation 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.

[0123] Non-limiting examples of other disorders associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic syndrome X, a metabolic disorder in which activation of GLP-1R is beneficial), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0124] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are also useful for improving the effectiveness of metformin.

[0125] Disorders of metabolically important tissues In some embodiments, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of disorders of metabolically important tissue include the liver, adipose tissue, pancreas, kidney, and intestine.

[0126] In some embodiments, the condition, disease or disorder is fatty liver disease.Fatty liver disease includes, but is not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy and lipodystrophy.

[0127] Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases occurring in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children, ultimately leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, isolated, primarily macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90).

[0128] Non-limiting examples of other disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthropathy), steatosis (e.g., of the liver); fibrosis (e.g., of the liver); cirrhosis (e.g., of the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism such as osteoporosis, including menopausal osteoporosis, decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures and nutritional disorders, 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 certain embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving post-operative recovery and / or preventing the catabolic response caused by surgical trauma.

[0129] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular disease 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 insufficiency, myocardial infarction, hypertension (e.g., 130 / 85 mmHg or higher), and prothrombotic conditions (exemplified by high fibrinogen or plasminogen activator inhibitor levels in the blood).

[0130] In some embodiments, the condition, disease, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0131] Neurological disorders In some embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include 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, hyperactivity, mania, Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage with amyloidosis I, brain inflammation, 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). See, for example, US Publication 20060275288A1.

[0132] In some embodiments, the condition, disease, or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by elevated intracranial pressure and papilledema. See, e.g., Virdee et al. Ophthalmol Ther. 2020;9(4):767-781. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce one or more symptoms in patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension include severe headache and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is female. In some embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In some embodiments, the patient with idiopathic intracranial hypertension is obese.

[0133] In some embodiments, the condition, disease, or disorder is Wolfram syndrome. Wolfram syndrome is caused by a biallelic Wolfram mutation in the ER transmembrane glycoprotein (Wfs1) gene. See, e.g., Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome initially manifests as diabetes, followed by optic atrophy, hearing loss, and neurodegenerative symptoms. Patients with Wolfram syndrome may experience symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and taste loss due to brainstem atrophy. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation is reduced in the inferior olive in patients with Wolfram syndrome. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds, pharmaceutical compositions, and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In certain embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (e.g., any of the symptoms described herein) in a patient with Wolfram Syndrome.

[0134] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamines) and attention-deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful for improving behavioral responses to appropriate drugs, reducing drug dependence, preventing drug abuse relapse, and reducing anxiety caused by the absence of certain addictive substances. See, e.g., U.S. Publication 20120021979A1.

[0135] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for learning and memory by promoting neuroplasticity and cell differentiation, and for preserving dopaminergic neuronal and motor function in Parkinson's disease.

[0136] Insulin-Related Conditions and Disorders In certain embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, high blood levels of fatty acids or glycerol, hypoglycemic states, insulin resistance syndrome, paresthesia due to hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and associated lethargic endpoints associated with insulin.

[0137] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes.

[0138] autoimmune disorders In some embodiments, condition, disease or disorder is autoimmune disorder.Non-limiting examples of autoimmune disorder include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder 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, US Publication 20120148586A1.

[0139] Stomach and bowel related disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy- and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0140] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need of treatment). In some embodiments, the weight gain in a patient can be due to excessive food intake or an unbalanced diet, or can be due to concomitant medication (e.g., an insulin sensitizer with PPARγ agonism, such as troglitazone, rosiglitazone, englitazone, ciglitazone, or pioglitazone). In some embodiments, the weight gain can be prior to reaching obesity or can be weight gain in an obese patient. In some embodiments, the weight gain can also be drug-induced weight gain or weight gain following smoking cessation. In some embodiments, the weight gain is reduced by the use of steroids or antipsychotics.

[0141] In some embodiments, the condition, disease or disorder is an eating disorder, eg, binge eating, hyperphagia, compulsive eating, or symptomatic obesity, eg, Prader-Willi and Bardet-Biedl syndrome.

[0142] inflammatory diseases In some embodiments, condition, disease or disorder is inflammatory disorder.Non-limiting examples of inflammatory disorder include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, bloating, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), and the inflammation and pro-inflammatory state (for example, elevated blood levels of pro-inflammatory cytokines or inflammatory C-reactive protein markers) in the disorders of metabolically important tissues, including liver, fat, pancreas, kidney and intestine.

[0143] cancer In some embodiments, the condition, disease, or disorder is cancer. Examples of suitable cancers include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, 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 carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). , colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small bowel cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, throat cancer. Head cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal gland astrocytoma, pilocytic astrocytoma, generalized astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g. For example, primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low malignant potential ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma, These include esophageal adenocarcinoma, nasal cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, childhood solid tumors (e.g., Wilms' tumor, childhood kidney 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).

[0144] Hypothalamic-pituitary disorders In some embodiments, the condition, disease, or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In other examples, the condition, disease, or disorder is associated with the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0145] In certain embodiments, the condition, disease or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0146] Pulmonary disease In some embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0147] In certain embodiments, the condition, disease or disorder associated with diabetes is a pulmonary disease.

[0148] Combination therapy In certain embodiments, the present invention contemplates both monotherapy and combination therapy regimens.

[0149] In certain embodiments, the methods described herein can further include the administration of 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 a compound described herein.

[0150] In some embodiments, the methods described herein include administration of a compound described herein in combination with dietary therapy (e.g., dietary monitoring, diabetic diet), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modifications.

[0151] In certain embodiments, the compounds of Table 1 described herein, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with one or more additional therapeutic agents.

[0152] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, antidiabetic agents, antidiabetic complication agents, antihyperlipidemic agents, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutic agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, drugs for treating frequent urination or urinary incontinence, NAFLD therapeutic agents, NASH therapeutic agents, dysuria therapeutic agents, and antiemetic agents.

[0153] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), peptide YY or analogs thereof, and catecholamines. Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme 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., orlistat, cetilista) β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., compounds described in International Publications WO2020 / 234726, WO2020 / 044266, and U.S. Patent No. 8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-284 31754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists, appetite suppressants (e.g., bombesin agonists),Thyroid hormone mimetics, dehydroepiandrosterone or its analogs, 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, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB- 219994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597, compounds described in International Publications WO2010 / 140092, WO2010 / 128425, WO2010 / 128414, WO2010 / 106457), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658, or GKM-001 compounds described in International Publications WO2010 / 103437, WO2010 / 103438, WO2010 / 013161, WO2007 / 122482, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428, and WO2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), drugs for improving leptin resistance, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin Agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (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 E. coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g.,P-57), human proizelet peptide (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, compounds described in International Publications WO2020 / 234726 and WO2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors These include steroid inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in International Publication WO2005 / 116034 and U.S. Publication 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators.

[0154] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antidiabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate), salts)), glucagon analogs (e.g., any of the glucagon analogs described in WO2010 / 011439), agents that antagonize the action of glucagon or reduce its secretion, sulfonylureas (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glycopyramide, glybuzole, glyburide, glipizide), thiazolidinediones (e.g., rosiglitazone, lobeglitazone, troglitazone, balaglitazone, rivoglitazone, losiglitazone, beglitazone or pioglitazone), glitazars (e.g., aleglitazar, tiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin acetaminophen, remogliflozin etabonate, ertugliflozin, compounds described in WO2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposine, camiglibose, pradimicin Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g.,Meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, aviglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5) and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, alogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0155] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPAR α / δ agonists (e.g., elafibranor), synthetic fatty acid-bile conjugates (e.g., aramchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors, galectin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ 3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and compounds described in International Publications WO2009 / 144554, WO2003 / 072197, WO2009 / 144555, and WO2008 / 065508), ketohexokinase (KHK) inhibitors (e.g., compounds described in WO2020 / 234726), apoptosis signal-regulating kinase 1 (ASK1) inhibitors (selonsertib), bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglyceryl acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO2020 / 234726 and U.S. Publication No. 2020 / 234726), 180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, Schisandra chinensis extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals and antioxidants.

[0156] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters 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., propyl mesylate), voxistaurin), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0157] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]azastatin, and the like). cetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, 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 esters 90).

[0158] In certain embodiments, the one or more additional therapeutic agents include those useful as, for example, antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazapril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol). Non-limiting examples of additional antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, dendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, triclinafen ethacrynate, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone), alpha adrenergic blockers, beta adrenergic blockers, calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine), blood vasoconstrictors (e.g., vasoconstrictors), and vasoconstrictors. These include ductal dilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrasentan, compounds described in U.S. Patents 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds described in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, the If channel blocker ivabradine, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0159] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0160] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunopotentiating activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0161] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, and 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, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIIa inhibitors, PAI-1 inhibitors, alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0162] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitrol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Examples of suitable vitamins include vitamin B1 and vitamin B12. Examples of suitable erectile dysfunction medications include apomorphine and sildenafil citrate. Examples of suitable therapeutic agents for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Examples of suitable therapeutic agents for dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0163] Other examples of additional 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 indicated for treating complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol sterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol, and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols, e.g., phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglyceryl acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO2009 / 016462, WO2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, torestatin, AL-3688), α-glucoside hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., the compounds described), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase enzyme inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators,PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILI beta modulators), ACAT inhibitors, MTP inhibitors (e.g., diliotapide, mitratapide, and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g., alirocumab and evolocumab), RXR alpha modulators, cysteamine, cystamine, RNA antisense constructs for inhibition of protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin proteins, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodasquemine, hiruthiosal extract, and Zhang et al. Drug Discovery Today. 2007, 12(9-10): 373-381), ezetimibe, betaine, pentoxifylline, alpha delta-9 desaturase, BCKDK inhibitors, branched-chain alpha keto acid dehydrogenase kinase (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, antihypertensive agents including adrenoceptor antagonists, e.g., beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin) and mixed alpha / beta blockers (e.g., labetalol), adrenoceptor agonists including alpha-2 agonists (e.g., clonidine), angiotensin converting agents, ACE inhibitors (e.g., lisinopril), calcium channel blockers such as dihydropyridines (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 such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide, torsemide, bemethanide, ethacrynic acid), thiazide-type diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide, methychlorothiazide, polythiazide,trichlormethiazide, indapamide), phthalimidine-type diuretics (e.g., chlorthalidone, metolazone), quinazoline-type diuretics (e.g., quinethazone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., compounds described in WO2020 / 117987), hemostatic modulators including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight derivatives 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-synthetase inhibitors, PDE inhibitors (e.g., pletal, dipyridamole)), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., thromboxane-A2 receptor antagonists (e.g., thromboxane-A2 synthet ... enzyme inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission modulators, e.g., selective serotonin receptor modulators, Serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276,compounds described in WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or agonists thereof, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-reducing agents, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, fat metabolism improving agents (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexia-inducing factors Antibodies against TNF-α, LIF, IL-6, and oncostatin M, metabolic modifying proteins or peptides, such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711), nerve regeneration promoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), arrhythmia drugs (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carbaziol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), anesthetic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local analgesics Pain medications (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 therapies (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin alpha4 / beta1 antibodies (e.g., , Tysabri), drugs acting on immunophilins (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), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, saroglitazar , muraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., nitrates), NO promoters (e.g., phosphodiesterase inhibitors).

[0164] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetic agents. As used herein, an "antiemetic" agent refers to any agent that counteracts (e.g., reduces or eliminates) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetic agents in combination with the compounds described herein in Table 1 may, for example, allow a patient to consume a normal diet, thereby allowing for the administration of higher doses of the compounds in Table 1, which may result in a more rapid response to treatment.

[0165] Non-limiting examples of antiemetic agents include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopamines / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0166] For example, the antiemetic agent may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopamines / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0167] In certain embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopiride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Non-limiting examples of other 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, lamosterone, licasetron, risperidone, ziprasidone, and zatosetron.

[0168] In some embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0169] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0170] In certain embodiments, the 5HT-3 receptor antagonists are granisetron, dolasetron and ondansetron.

[0171] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0172] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0173] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0174] In some embodiments, the antiemetic agent is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Disipal (Norflex orphenadrine mesylate), diphenhydramine, hydroxyzine, hyoscyamine, and Kemadrin (procyclidine hydrochloride).

[0175] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0176] In certain embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0177] Other non-limiting examples of NK1 receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j. Benserazide and carbidopa k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-alpha-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0178] In some embodiments, the antiemetic agent is an antidopamine / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0179] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), a cannabinoid agonist such as WIN 55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0180] Other exemplary antiemetic agents include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixalazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0181] Still other exemplary antiemetic agents include those disclosed in US20120101089A1; US10,071,088B2; US6,673,792B1; US6,197,329B1; US10,828,297B2; US10,322,106B2; US10,525,033B2; WO2009080351A1; WO2019203753A2; WO2002020001A2; US8,119,697B2; US5,039,528; US20090305964A1; and WO2006 / 111169, each of which is incorporated by reference in its entirety.

[0182] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contacting or administering the compounds and pharmaceutical compositions (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0183] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and pharmaceutical composition.For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to the patient in the same dosage form.In another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to the patient in separate dosage forms.

[0184] Patient Selection In certain embodiments, the methods described herein further include identifying a patient (e.g., subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0185] In certain embodiments, the methods described herein further include identifying a patient (e.g., a subject) having a disease, disorder, or condition (e.g., a GLP-1-associated disease, disorder, or condition) provided herein.

[0186] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) with type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine the level of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is between about 6.5% and about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or greater. In certain embodiments, the HbA1c level is about 8.0% or greater. In certain embodiments, the HbA1c level is about 10.0% or greater. In certain embodiments, the HbA1c level is about 12.0% or greater. In certain embodiments, the HbA1c level is about 14.0% or greater. In certain embodiments, the HbA1c level is about 16.0% or greater. In certain embodiments, the HbA1c level is about 18.0% or greater. In certain embodiments, the HbA1c level is about 20.0% or greater. In some embodiments, the level of HbA1c is about 22.0% or greater, In some embodiments, the level of HbA1c is about 24.0% or greater.

[0187] In some embodiments, the fasting blood glucose level is about 120 mg / dL or more to about 750 mg / dL or more. In some embodiments, the fasting blood glucose level is about 200 mg / dL or more to about 500 mg / dL or more. In some embodiments, the fasting blood glucose level is about 300 mg / dL or more to about 700 mg / dL or more.

[0188] In some embodiments, the non-fasting blood glucose level is about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting blood glucose level is about 250 mg / dL or more to about 450 mg / dL or more. In some embodiments, the non-fasting blood glucose level is about 400 mg / dL or more to about 700 mg / dL or more.

[0189] In certain embodiments, determining whether a patient has type 2 diabetes further comprises determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m2 More than ~ about 100kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 More than ~90kg / m 2 In one embodiment, the patient's BMI is about 40 kg / m 2 More than ~about 80kg / m 2 In one embodiment, the patient's BMI is about 50 kg / m 2 More than ~ about 70kg / m 2 That's all.

[0190] In some embodiments, additional factors (e.g., risk factors) used in determining whether a patient has type 2 diabetes further include the patient's age and ethnicity. In some embodiments, the patient is about 10 years or older. In some embodiments, the patient is about 15 years or older. In some embodiments, the patient is about 20 years or older. In some embodiments, the patient is about 25 years or older. In some embodiments, the patient is about 30 years or older. In some embodiments, the patient is about 35 years or older. In some embodiments, the patient is about 40 years or older. In some embodiments, the patient is about 42 years or older. In some embodiments, the patient is about 44 years or older. In some embodiments, the patient is about 46 years or older. In some embodiments, the patient is about 48 years or older. In some embodiments, the patient is about 50 years or older. In some embodiments, the patient is about 52 years or older. In some embodiments, the patient is about 54 years or older. In some embodiments, the patient is about 56 years or older. In some embodiments, the patient is about 58 years or older. In some embodiments, the patient is about 60 years or older. In some embodiments, the patient is about 62 years or older. In some embodiments, the patient is about 64 years or older. In some embodiments, the patient is about 66 years old or older. In some embodiments, the patient is about 68 years old or older. In some embodiments, the patient is about 70 years old or older. In some embodiments, the patient is about 72 years old or older. In some embodiments, the patient is about 74 years old or older. In some embodiments, the patient is about 76 years old or older. In some embodiments, the patient is about 78 years old or older. In some embodiments, the patient is about 80 years old or older. In some embodiments, the patient is about 85 years old or older. In some embodiments, the patient is about 90 years old or older. In some embodiments, the patient is about 95 years old or older. In some embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, Native Hawaiian, or Pacific Islander.

[0191] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (birth to 1 month); infants (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years (up to, but not including, the 22nd birthday)). 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 certain embodiments, the pediatric patient is between birth and 28 days old, between 29 days old and under 2 years old, between 2 and under 12 years old, or between 12 and 21 years old (up to but not including the 22nd birthday). In certain embodiments, the pediatric patient is between birth and 28 days old, between 29 days old and under 1 year old, between 1 month old and under 4 months old, between 3 months old and under 7 months old, between 6 months old and under 1 year old, between 1 year old and under 2 years old, between 2 years old and under 3 years old, between 2 years old and under 7 years old, between 3 years old and under 5 years old, between 5 years old and under 10 years old, between 6 years old and under 13 years old, between 10 years old and under 15 years old, or between 15 years old and under 22 years old. In certain embodiments, the patient is an adult patient. [Example]

[0192] General information: All evaporations were performed under reduced pressure using a rotary evaporator. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized with UV light (214 and 254 nm). Column and flash chromatographic purifications were performed using silica gel (100-400 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained using electrospray ionization on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series, 6110 or 6120 mass spectrometer unless otherwise indicated.

[0193] The description will be further understood with reference to the following examples, which are intended to be merely exemplary of the invention. The present invention is not limited in scope by the exemplary embodiments, which are intended as illustrations of only one aspect of the invention. Any methods that are functionally equivalent are within the scope of the invention. Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing and accompanying drawings. Such modifications fall within the scope of the appended claims.

[0194] Example 1: 2-[(2,4-difluorophenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 1) [ka] Step A: 2-Bromo-6-((2,4-difluorobenzyl)oxy)pyridine To a solution of (2,4-difluorophenyl)methanol (1.0 g, 6.97 mmol) in THF (15 mL) were added 2,6-dibromopyridine (1.64 g, 6.94 mmol) and t-BuOK (1 M in THF, 8.33 mL). The solution was stirred at RT for 2 h. After completion of the reaction, the mixture was diluted with HO (50 mL) and extracted with EA (40 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 20 / 1) to give 2-bromo-6-((2,4-difluorobenzyl)oxy)pyridine (2.3 g, yield: 92%). MS calculated: 299.0; MS found: 299.8 [M+H] + .

[0195] Step B: tert-butyl 6-((2,4-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate A mixture of 2-bromo-6-((2,4-difluorobenzyl)oxy)pyridine (2.1 g, 7.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.4 g, 7.73 mmol), Pd(dppf)Cl (256 mg, 0.35 mmol), and KCO (2.9 g, 21.1 mmol) in dioxane / HO (40.0 mL / 4.0 mL) was stirred at 90 °C for 3 h. After completion of the reaction, the mixture was diluted with HO (100 mL) and extracted with EA (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=20 / 1) to give tert-butyl 6-((2,4-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (2.6 g, yield: 93%). MS calculated: 402.2; MS found: 403.1 [M+H] + .

[0196] Step C: tert-butyl 4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate A solution of tert-butyl 6-((2,4-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (200 mg, 0.50 mmol), Pd / C (20 mg, 10% on carbon, approximately 55% water wet) in THF (4.0 mL) was stirred at RT for 1.5 h. After completion of the reaction, the mixture was filtered and the solid dried to give tert-butyl 4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (210 mg, crude). MS calculated: 404.2; MS found: 405.2 [M+H] + .

[0197] Step D: 2-((2,4-difluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt To a solution of tert-butyl 4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (210 mg, 0.52 mmol) in DCM (4 mL) was added TFA (0.8 mL). The solution was stirred at room temperature for 1 hour. The reactants were evaporated under reduced pressure to give 2-((2,4-difluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt (250 mg, crude). MS calculated: 304.1; MS found: 305.1 [M+H] + .

[0198] Step E: (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile A mixture of 2-((2,4-difluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt (250 mg, crude), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (100 mg, 0.38 mmol), DIEA (492 mg, 3.82 mmol) in DMF (4.0 mL) was stirred at 70 °C for 1 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with EA (15 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=100 / 1) to give (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (130 mg, yield: 64%). MS calculated: 530.2; MS found: 531.0 [M+H] + .

[0199] Step F: (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide A solution of (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (130 mg, 0.25 mmol), HONH2 HCl (100 mg, 1.47 mmol), and TEA (99 mg, 0.98 mmol) in EtOH (4.0 mL) was stirred at 70 °C for 1 h. After completion of the reaction, the mixture was filtered and the solid was dried to give (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (115 mg, yield: 83%). MS calculated: 563.2; MS found: 564.2 [M+H] + .

[0200] Step G: (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine To a solution of (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (115 mg, 0.20 mmol) in THF (4.0 mL) was added TFAA (86 mg, 0.41 mmol), and the mixture was stirred at RT for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (5.0 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to give (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (140 mg, crude). MS calculated: 641.2; MS found: 642.2 [M+H] + .

[0201] Step H: 2-[(2,4-difluorophenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine A mixture of (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (140 mg, 0.22 mmol) and N2H4·HO (22 mg, 0.44 mmol) in DMF (2.0 mL) was stirred at RT for 1 h. After completion of the reaction, the mixture was directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(2,4-difluorophenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (54 mg, yield: 39%). MS calculated: 640.2; MS found: 641.0 [M+H] + .

[0202] 1 H NMR (400MHz, DMSO-d6): δ 9.17 (s, 1 H), 8.29 (s, 1 H), 7.55-7.67 (m, 2 H), 7.22-7.33 (m, 1 H), 7.04-7.15 (m, 1 H), 6.88 (d, J=7.6 Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H), 5.37 (s, 2 H), 5.14-5.24 (m, 1 H), 4.88-4.99 (m, 1 H), 4.73-4.83 (m, 1 H), 4.39-4.55 (m, 2 H), 4.01 (d, J=14.0 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 2.99-3.08 (m, 1 H), 2.83-2.92 (m, 1 H), 2.56-2.80 (m, 2 H), 2.40-2.53 (m, 1 H), 2.17-2.35 (m, 2 H), 1.64-1.88 (m, 4 H). 19F NMR(377MHz, DMSO-d6): δ -63.68, -63.72, -110.21,-110.23, -113.85, -113.88.

[0203] Example 2: (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 2) [ka] Step A: (4-chloro-2-methoxyphenyl)methanol To a solution of 4-chloro-2-methoxybenzoic acid (2.0 g, 10.7 mmol) in THF (10.0 mL) was added BH3·THF (22 mL, 22 mmol, 1 M in toluene) dropwise at 0 °C. The solution was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with MeOH (8 mL). Brine (30 mL × 2) was added to the mixture, and it was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA = 2 / 1) to give (4-chloro-2-methoxyphenyl)methanol (1.8 g, 97.3% yield).

[0204] Step B: 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine To a solution of (4-chloro-2-methoxyphenyl)methanol (500 mg, 2.9 mmol) in THF (5.0 mL) was added 2-bromo-6-fluoropyridine (511 mg, 2.9 mmol) and t-BuOK (389 mg, 3.5 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. After completion of the reaction, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with ethyl acetate (30 ml × 3). The organic layers were combined, washed with brine (30 ml × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (1.0 g, crude). MS calculated: 327.0; MS found: 328.0 [M+H] + .

[0205] Step C: (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (12.9 mg) was obtained in a manner similar to Example 1. MS calculated: 668.2; MS found: 669.0 [M+H] + .

[0206] 1H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.62 (t, J=8.0 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.12 (m, 1 H), 7.00 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.86 (d, J=7.2 Hz, 1 H), 6.66 (d, J=8.0 Hz, 1 H), 5.29 (s, 2 H), 5.18 (m, 1 H), 4.87-4.96 (m, 1 H), 4.71-4.80 (m, 1 H), 4.38-4.53 (m, 2 H), 4.01 (d, J=13.6 Hz, 1 H), 3.81-3.89 (m, 4 H), 2.99-3.07 (m, 1 H), 2.84-2.91 (m, 1 H), 2.73-2.77 (m, 1 H), 2.56-2.68 (m, 1 H), 2.40-2.48 (m, 1 H), 2.16-2.40 (m, 2 H), 1.63-1.87 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.54.

[0207] Example 3: (S)-2-((4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (compound 3) [ka] Step A: (2,4-Difluoro-3-methoxyphenyl)methanol To a solution of 2,4-difluoro-3-methoxybenzoic acid (1.2 g, 6.4 mmol) in THF (13 mL) was added dBH THF (19.1 mL, 19.1 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with HO (50 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give (2,4-difluoro-3-methoxyphenyl)methanol (920 mg, yield: 83%).

[0208] Step B: tert-butyl 4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate To a solution of (2,4-difluoro-3-methoxyphenyl)methanol (920 mg, 5.3 mmol) and t-BuOK (5.3 ml, 5.3 mmol) in THF (16 ml) was added tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (888 mg, 3.2 mmol) at 0 °C. The solution was stirred at room temperature for 1 h. The mixture was quenched with HO (50 mL) and extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (30 ml). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give tert-butyl 4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate (1.01 g, yield: 44%).

[0209] Step C: (S)-2-((4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (66.6 mg) was obtained in a manner similar to Example 1. MS calculated: 670.0; MS found: 671.0 [M+H].

[0210] 1 H NMR: δ 9.16 (s, 1 H), 8.29 (s, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 7.22-7.30 (m, 1 H), 7.09-7.18 (m, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.67 (d, J=8.0 Hz, 1 H), 5.36 (s, 2 H), 5.14-5.24 (m, 1 H), 4.89-4.99 (m, 1 H), 4.72-4.81 (m, 1 H), 4.38-4.55 (m, 2 H), 4.02 (d, J=14.0 Hz, 1 H), 3.90 (s, 3 H), 3.87 (d, J=13.6 Hz, 1 H), 2.98-3.07 (m, 1 H), 2.84-2.93 (m, 1 H), 2.69-2.80 (m, 1 H), 2.57-2.67 (m, 1 H), 2.39-2.50 (m, 1 H), 2.17-2.34 (m, 2 H), 1.64-1.87 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.68, -128.73, -132.96.

[0211] Example 4: 2-[(4-chloro-2-fluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 4) [ka] Step A: (4-chloro-2-fluoro-3-methylphenyl)methanol To a solution of 4-chloro-2-fluoro-3-methylbenzoic acid (400 mg, 2.1 mmol) in THF (4 mL) was added borane-tetrahydrofuran complex (1 M in THF, 6.5 mL, 6.5 mmol) at 0 °C. The mixture was stirred at RT for 2 h, quenched with aqueous NH4Cl (30 mL), and extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give (4-chloro-2-fluoro-3-methylphenyl)methanol (330 mg, crude).

[0212] Step B: 2-Bromo-6-((4-chloro-2-fluoro-3-methylbenzyl)oxy)pyridine To a solution of (4-chloro-2-fluoro-3-methylphenyl)methanol (280 mg) in THF (2.0 mL) were added 2-bromo-6-fluoropyridine (312 mg, 1.77 mmol) and t-BuOK (217 mg, 1.93 mmol) at 0 °C. The mixture was stirred at RT for 2 h, quenched with aqueous NH4Cl (30 mL), and extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 1 / 0) to give 2-bromo-6-((4-chloro-2-fluoro-3-methylbenzyl)oxy)pyridine (330 mg, yield: 62.5%). MS calculated: 329.0; MS found: 330.0 [M+H] + .

[0213] Step C: 2-[(4-chloro-2-fluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine 2-[(4-chloro-2-fluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (26.2 mg) was obtained in a manner similar to Example 1. MS calculated: 670.2; MS found: 671.0 [M+H] + .

[0214] 1 H NMR (400MHz, DMSO-d6): δ 9.14 (s, 1 H), 8.27 (s, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 7.39 (t, J=8.4 Hz, 1 H), 7.29 (d, J=8.4 Hz, 1 H), 6.87 (d, J=7.2 Hz, 1 H), 6.67 (d, J=8.0 Hz, 1 H), 5.38 (s. 2 H), 5.12-5.24 (m. 1 H), 4.87-4.97 (m. 1 H), 4.71-4.82 (m, 1 H), 4.47-4.55 (m, 1 H), 4.38-4.46 (m, 1 H), 4.00 (d, J=13.6 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 2.98-3.08 (m, 1 H), 2.84-2.93 (m, 1 H), 2.68-2.78 (m, 1 H), 2.55-2.68 (m, 1 H), 2.39-2.51 (m, 1 H), 2.15-2.33 (m, 5 H), 1.62-1.87 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.26, -116.98.

[0215] Example 5: 2-[(2,4-difluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 5) [ka] Starting from 2,4-difluoro-3-methylbenzoic acid, 2-[(2,4-difluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine was obtained in a manner similar to that described herein.

[0216] MS calculated: 654.2; MS found: 655.2 [M+H] + .

[0217] 1H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.62 (t, J=7.6 Hz 1 H), 7.38-7.46 (m, 1 H), 7.05 (t, J=8.4 Hz, 1 H), 6.87 (d, J=7.2 Hz, 1 H), 6.65 (d, J=8.0 Hz, 1 H), 5.35 (s, 2 H), 5.14-5.23 (m, 1 H), 4.88-4.97 (m, 1 H), 4.73-4.81 (m, 1 H), 4.39-4.53 (m, 2 H), 4.01 (d, J=13.6 Hz, 1 H), 3.86 (d, J=13.2 Hz, 1 H), 2.99-3.08 (m, 1 H), 2.85-2.92 (m, 1H), 2.70-2.80 (m, 1 H), 2.58-2.70 (m, 1 H), 2.18-2.35 (m, 3 H), 2.15 (s, 3 H), 1.69-1.88 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.49, -114.79,-114.81, -118.52,-118.54.

[0218] Example 6: (S)-2-((4-(6-((4-chloro-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 6) [ka] Step A: (4-chloro-2,6-difluorophenyl)methanol To a mixture of 4-chloro-2,6-difluorobenzaldehyde (1.0 g, 5.66 mmol) in THF / EtOH (15 mL / 2 mL) was added NaBH (215 mg, 5.68 mmol) at 0 °C. The reaction was stirred at 0 °C for 20 minutes. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified on silica gel (PE / EA = 10 / 1) to give (4-chloro-2,6-difluorophenyl)methanol (849 mg, yield: 84.2%).

[0219] Step B: 2-Bromo-6-((4-chloro-2,6-difluorobenzyl)oxy)pyridine A mixture of (4-chloro-2,6-difluorophenyl)methanol (400 mg, 2.2 mmol), 2-bromo-6-fluoropyridine (435 mg, 2.5 mmol), and t-BuOK (504 mg, 4.5 mmol) in THF (8 mL) was stirred at 70 °C for 1 day. After completion of the reaction, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (PE = 100%) to give 2-bromo-6-((4-chloro-2,6-difluorobenzyl)oxy)pyridine (272 mg, yield: 36.4%). MS calculated: 332.9; MS found: 333.9 [M+1] + .

[0220] Step C: (S)-2-((4-(6-((4-chloro-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((4-chloro-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (64.6 mg) was obtained in a manner similar to Example 1. MS calculated: 674.2; MS found: 675.2 [M+H] + .

[0221] 1 H NMR (400MHz, DMSO-d6): δ 9.16 (s, 1 H), 8.28 (d, J=0.8 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 7.37-7.45 (m, 2 H), 6.89 (d, J=7.2 Hz, 1 H), 6.64 (d, J=8.0 Hz, 1 H), 5.37 (s, 2 H), 5.14-5.25 (m, 1 H), 4.89-4.99 (m, 1 H), 4.73-4.84 (m, 1 H), 4.39-4.55 (m, 2 H), 4.02 (d, J=14.0 Hz, 1 H), 3.87 (d, J=13.6 Hz, 1 H), 2.99-3.08 (m, 1 H), 2.84-2.93 (m, 1 H), 2.69-2.80 (m, 1 H), 2.57-2.68 (m, 1 H), 2.43-2.48 (m, 1 H), 2.17-2.35 (m, 2 H);1.67-1.88 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.54, -112.14.

[0222] Example 7: 2-{[6-(difluoromethoxy)pyridin-3-yl]methoxy}-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 7) [ka] Step A: Ethyl 6-(difluoromethoxy)nicotinate A mixture of 5-bromo-2-(difluoromethoxy)pyridine (900 mg, 4.0 mmol), Pd(dppf)Cl2 (294 mg, 0.4 mmol), and KOAc (788 mg, 8.0 mmol) in EtOH (10 mL) was stirred at 75 °C for 2 hours under CO (1 atm). After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 4:1) to give ethyl 6-(difluoromethoxy)nicotinate (800 mg, 91% yield). MS calculated: 217.1; MS found: 218.1 [M+H] + .

[0223] Step B: (6-(difluoromethoxy)pyridin-3-yl)methanol To a solution of ethyl 6-(difluoromethoxy)nicotinate (650 mg, 3.0 mmol) in THF (10 mL) was added LiAlH4 (285 mg, 7.5 mmol). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with EA (10 mL) and NaOH solution (2 M, 5 mL). The mixture was dried and filtered. The residue was concentrated under reduced pressure and purified by column chromatography (PE:EA=1:1) to give (6-(difluoromethoxy)pyridin-3-yl)methanol (400 mg, 76% yield). MS calculated: 175.0; MS found: 176.1 [M+H] + .

[0224] Step C: tert-butyl 4-(6-((6-(difluoromethoxy)pyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate A mixture of (6-(difluoromethoxy)pyridin-3-yl)methanol (400 mg, 2.3 mmol), tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (424 mg, 1.5 mmol), and NaOH (121 mg, 3.0 mmol) in DMF (5 mL) was stirred at 70° C. for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to give tert-butyl 4-(6-((6-(difluoromethoxy)pyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (400 mg, 61% yield). MS calculated: 435.2; MS found: 458.2 [M+Na] + .

[0225] Step D: 2-(Difluoromethoxy)-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridine TFA salt To a solution of tert-butyl 4-(6-((6-(difluoromethoxy)pyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (200 mg, 0.46 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure to give 2-(difluoromethoxy)-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridine TFA salt (210 mg, crude). MS calculated: 335.1; MS found: 336.1 [M+H] + .

[0226] Step E: 2-{[6-(difluoromethoxy)pyridin-3-yl]methoxy}-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (compound 7) 2-{[6-(Difluoromethoxy)pyridin-3-yl]methoxy}-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (29.9 mg) was obtained in a manner similar to that described in Example 1.

[0227] MS calculated: 671.2; MS found: 672.0 [M+H] + .

[0228] 1 H NMR (400MHz, DMSO-d6): 1 H NMR: δ 9.16 (d, J=0.8 Hz, 1 H), 8.38 (d, J=2.0 Hz, 1 H), 8.29 (d, J=0.8 Hz, 1 H), 8.02 (dd, J=8.4 Hz, J=2.4 Hz, 1 H), 7.51-7.87 (m, 2 H), 7.10 (d, J=8.4 Hz, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.67 (d, J=8.0 Hz, 1 H), 5.37 (s, 2 H), 5.14-5.23 (m, 1 H), 4.89-4.98 (m, 1 H), 4.73-4.82 (m, 1H), 4.38-4.54 (m, 2 H), 4.02 (d, J=14.0 Hz, 1 H), 3.87 (d, J=13.6 Hz, 1 H), 3.00-3.07 (m, 1 H), 2.85-2.93 (m, 1 H), 2.68-2.80 (m, 1 H), 2.58-2.64 (m, 1 H), 2.43-2.53 (m, 1 H), 2.17-2.34 (m, 2 H), 1.67-1.88 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.66, -87.30.

[0229] Example 8: (S)-2-((4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 8) [ka] Step A: Ethyl 2-(difluoromethoxy)isonicotinate To a mixture of 4-bromo-2-(difluoromethoxy)pyridine (1.0 g, 4.46 mmol) in EtOH (16.0 mL) was added PdCl(dppf) (326 mg, 0.44 mmol) and KOAc (875 mg, 8.93 mmol). The mixture was stirred at 75 °C for 2 hours under CO. After completion of the reaction, the reaction was quenched with HO (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by column chromatography (PE / EA = 10 / 1) to give ethyl 2-(difluoromethoxy)isonicotinate (740 mg, yield: 76%). MS calculated: 217.1; MS found: 218.1 [M+H] + .

[0230] Step B: (2-(difluoromethoxy)pyridin-4-yl)methanol To a solution of ethyl 2-(difluoromethoxy)isonicotinate (740 mg, 3.41 mmol) in THF (8 mL) was added LiBH (225 mg, 10.23 mmol). The solution was stirred at 40 °C overnight. The mixture was quenched with MeOH (8 mL) and HO (30 ml) and extracted with EA (50 mL × 2). The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (DCM / MeOH = 97 / 3) to give (2-(difluoromethoxy)pyridin-4-yl)methanol (370 mg, yield: 66%). MS calculated: 175.0; MS found: 176.1 [M+H]+ .

[0231] Step C: 4-(((6-bromopyridin-2-yl)oxy)methyl)-2-(difluoromethoxy)pyridine To a solution of 2-bromo-6-fluoropyridine (143 mg, 0.82 mmol) in THF (4 mL) was added (2-(difluoromethoxy)pyridin-4-yl)methanol (130 mg, 0.74 mmol) and t-BuOK (1 M in THF, 0.66 mL). The solution was stirred at 0 °C for 2 hours. After completion of the reaction, the reaction was quenched with HO (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (25 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by column chromatography (PE / EA = 10 / 1) to give 4-(((6-bromopyridin-2-yl)oxy)methyl)-2-(difluoromethoxy)pyridine (180 mg, yield: 73%). MS calculated: 330.0; MS found: 331.0 [M+H] + .

[0232] Step D: tert-Butyl 6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate A mixture of 4-(((6-bromopyridin-2-yl)oxy)methyl)-2-(difluoromethoxy)pyridine (180 mg, 0.54 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (360 mg, 1.16 mmol), Pd(dppf)Cl (20 mg, 0.027 mmol), and KCO (226 mg, 1.64 mmol) in dioxane / HO (10.0 mL / 1.0 mL) was stirred at 90 °C for 3 h. After completion of the reaction, the reaction was quenched with HO (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (25 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA=15 / 1) to give tert-butyl 6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (190 mg, yield: 72%). MS calculated: 433.2; MS found: 378.3 [M-56+H] + .

[0233] Step E: tert-butyl 4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate A solution of tert-butyl 6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (190 mg, 0.44 mmol), Pd / C (95 mg, 10% on carbon, approximately 55% water wet) in THF (5.0 mL) was stirred at RT for 30 min. After completion of the reaction, the mixture was filtered and the solid was dried to give tert-butyl 4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (80 mg, 42% yield). MS calculated: 435.2; MS found: 458.2 [M+Na] + .

[0234] Step F: (S)-2-((4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (14.8 mg) was then obtained in a manner similar to Example 1. MS calculated: 671.2; MS found: 672.4 [M+H] + .

[0235] 1 H NMR: δ 9.15 (s, 1 H), 8.28 (s, 1 H), 8.23 ​​(d, J=5.2 Hz, 1 H), 7.49-7.90 (m, 2 H), 7.29 (d, J=5.2 Hz, 1 H), 7.08 (s, 1 H), 6.90 (d, J=7.2 Hz, 1 H), 6.77 (d, J=8.0 Hz, 1 H), 5.43 (s, 2 H), 5.12-5.20 (m, 1 H), 4.87-4.96 (m, 1 H), 4.73-4.77 (m, 1 H), 4.48-4.54 (m, 1 H), 4.38-4.45 (m, 1 H), 3.98 (d, J=14.0 Hz, 1 H), 3.85 (d, J=14.0 Hz, 1 H), 2.95-3.02 (m, 1 H), 2.81-2.88 (m, 1 H), 2.66-2.78 (m, 1 H), 2.54-2.63 (m, 1 H), 2.38-2.45 (m, 1 H), 2.14-2.31 (m, 2 H), 1.57-1.83 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.58, -87.32.

[0236] Example 9: (S)-2-((4-(6-((6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 9) [ka] Starting from 2-bromo-6-(difluoromethoxy)pyridine, (S)-2-((4-(6-((6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained in a manner analogous to Example 8. MS calculated: 671.2; MS found: 672.0 [M+H] + .

[0237] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (m, 1 H), 8.46-8.21 (m, 3 H), 7.30 (d, J=7.6 Hz, 1 H), 6.99 (d, J=8.4 Hz, 1 H), 6.89 (d, J=7.2 Hz, 1 H), 6.76 (d, J=8.4 Hz, 1 H), 5.38 (s, 2 H), 5.12-5.23 (m, 1 H), 4.85-4.96 (m, 1 H), 4.69-4.79 (m, 1 H), 4.38-4.55 (m, 2 H), 3.99 (d, J=13.6 Hz, 1 H), 3.83 (d, J=13.6 Hz, 1 H), 2.94-3.03 (m, 1 H), 2.80-2.88 (m, 1 H), 2.67-2.79 (m, 1 H), 2.55-2.64 (m, 1 H), 2.39-2.45 (m, 1 H), 2.13-2.30 (m, 2 H), 1.59-1.82 (m, 4 H). 19F NMR(377MHz, DMSO-d6): δ -63.58, -87.21.

[0238] Example 10: (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((6-(trifluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 10) [ka] Step A: Ethyl 6-(trifluoromethoxy)picolinate To a mixture of 2-chloro-6-(trifluoromethoxy)pyridine (1.26 g, 6.4 mmol) in EtOH (20 mL) was added PdCl(dppf) (467 mg, 0.64 mmol) and KOAc (1.25 g, 12.8 mmol). The mixture was stirred at 75 °C for 2 h under CO. After completion of the reaction, the reaction mixture was filtered. The filtrate was diluted with HO (80 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 1 / 10) to give ethyl 6-(trifluoromethoxy)picolinate (1.13 g, yield: 75%). MS calculated: 235.0; MS found: 236.3 [M+H] + .

[0239] Step B: (6-(trifluoromethoxy)pyridin-2-yl)methanol To a solution of ethyl 6-(trifluoromethoxy)picolinate (1.13 g, 4.81 mmol) in THF (10 mL) and MeOH (10 mL) was added LiBH (317 mg, 14.42 mmol). The solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with HO (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 1 / 4) to give (6-(trifluoromethoxy)pyridin-2-yl)methanol (740 mg, yield: 80%). MS calculated: 193.0; MS found: 194.1 [M+H] + .

[0240] Step C: (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((6-(trifluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((6-(trifluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (63.7 mg) was then obtained in a manner similar to Example 3. MS calculated: 689.2; MS found: 690.4 [M+H] + .

[0241] 1H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 8.00 (t, J=8.0 Hz, 1 H), 7.66 (t, J=8.0 Hz, 1 H), 7.44 (d, J=7.2 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.77 (d, J=8.4 Hz, 1 H), 5.41 (s, 2 H), 5.12-5.22 (m, 1 H), 4.85-4.97 (m, 1 H), 4.71-4.76 (m, 1 H), 4.36-4.56 (m, 2 H), 3.98 (d, J=13.6 Hz, 1 H), 3.83 (d, J=13.6 Hz, 1 H), 2.92-3.02 (m, 1 H), 2.78-2.85 (m, 1 H), 2.67-2.77 (m, 1 H), 2.55-2.62 (m, 1 H), 2.39-2.46 (m, 1 H), 2.12-2.31 (m, 2 H), 1.53-1.78 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -55.12, -63.62.

[0242] Example 11: (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((3-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 11) [ka] Starting from (3-(trifluoromethoxy)phenyl)methanol, (S)-3-(oxetan-2-ylmethyl)-2-((4-(6-((3-(trifluoromethoxy)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained in a manner analogous to Example 3. MS calculated: 688.2; MS found: 689.1 [M+H]+.

[0243] 1 H NMR (400MHz, DMSO-d6) δ 9.30 (s, 1 H), 8.41 (s, 1 H), 7.71 (t, J=8.0 Hz, 1 H), 7.49-7.55 (m, 2 H), 7.43 (s, 1 H), 7.31 (d, J=7.6 Hz, 1 H), 6.94 (d, J=7.2 Hz, 1 H), 6.78 (d, J=8.0 Hz, 1 H), 5.45 (s, 2 H), 5.08-5.14 (m, 1 H), 4.85-4.97 (m, 3 H), 4.73-4.77 (m, 1 H), 4.50-4.56 (m, 1 H), 4.37-4.43 (m, 1 H), 3.74-3.84 (m, 2 H), 3.26-3.43 (m, 2 H), 2.91-3.01 (m, 1 H), 2.70-2.81 (m, 1 H), 2.33-2.39 (m, 1 H), 2.01-2.17 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -56.70, -63.76.

[0244] Example 12: (S)-2-((4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 12) [ka] Step A: 2-(Methoxycarbonyl)-5-methylpyridine 1-oxide To a mixture of methyl 5-methylpicolinate (2.0 g, 13.2 mmol) in DCM (50 mL) at 0 °C under N was added m-CPBA (4.6 g, 26.5 mmol). The mixture was stirred at 30 °C for 2 h. After completion of the reaction, the reaction mass was cooled to 0 °C. The mixture was quenched with NaHCO (eq, 50 mL) and extracted with DCM and MeOH (DCM / MeOH = 20 / 1, 3 × 80 mL). The combined organic layer was washed with brine (60 ml). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 1) to give 2-(methoxycarbonyl)-5-methylpyridine 1-oxide (2.1 g, yield: 93.1%). MS calculated: 167.1; MS found: 168.1 [M+H] + .

[0245] Step B: Methyl 6-hydroxy-5-methylpicolinate To a mixture of 2-(methoxycarbonyl)-5-methylpyridine 1-oxide (2.1 g, 12.3 mmol) in DMF (20 mL) was added TFAA (15.5 g, 74.0 mmol) at RT. The mixture was stirred at 35 °C for 2 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 1) to give methyl 6-hydroxy-5-methylpicolinate (1.7 g, yield: 81.1%). MS calculated: 167.1; MS found: 168.1 [M+H] + .

[0246] Step C: Methyl 6-(difluoromethoxy)-5-methylpicolinate To a mixture of methyl 6-hydroxy-5-methylpicolinate (600 mg, 3.6 mmol) in ACN (10 mL) was added NaH (259 mg, 10.79 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (959 mg, 5.4 mmol) was added. The mixture was stirred at RT for 3 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column silica gel chromatography (EA / PE = 1 / 3) to give methyl 6-(difluoromethoxy)-5-methylpicolinate (770 mg, yield: 98.8%). MS calculated: 217.1; MS found: 218.1 [M+H] + .

[0247] Step D: (6-(difluoromethoxy)-5-methylpyridin-2-yl)methanol To a mixture of methyl 6-(difluoromethoxy)-5-methylpicolinate (740 mg, 3.4 mmol) in THF (8 mL) at RT under N was added LiBH (300 mg, 13.6 mmol). The mixture was stirred at 40 °C for 30 min. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 3) to give (6-(difluoromethoxy)-5-methylpyridin-2-yl)methanol (470 mg, 72.9%). MS calculated: 189.1; MS found: 190.1 [M+H] + .

[0248] Step E: tert-butyl 4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate To a solution of (6-(difluoromethoxy)-5-methylpyridin-2-yl)methanol (470 mg, 2.5 mmol) in DMF (10 mL) was added tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (836 mg, 3.0 mmol) and NaOH (199 mg, 5.0 mmol) at RT. The resulting mixture was stirred at 70° C. for 16 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE=2 / 1) to give tert-butyl 4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (620 mg, 55.5% yield). MS calculated: 449.2; MS found: 472.2 [M+H+23] + .

[0249] Step F: (S)-2-((4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (86.8 mg) was obtained in a manner similar to Example 1. MS calculated: 685.2; MS found: 686.1 [M+H] + .

[0250] 1H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.45-7.88 (m, 3 H), 7.23 (d, J=7.6 Hz, 1 H), 6.89 (d, J=7.2 Hz, 1 H), 6.74 (d, J=8.0 Hz, 1 H), 5.33 (s, 2 H), 5.12-5.22 (m, 1 H), 4.85-4.96 (m, 1 H), 4.70-4.79 (m, 1 H), 4.51-4.55 (m, 1 H), 4.37-4.43 (m, 1 H), 3.99 (d, J=14.0 Hz, 1 H), 3.84 (d, J=13.6 Hz, 1 H), 2.95-3.04 (m, 1 H), 2.80-2.89 (m, 1 H), 2.68-2.78 (m, 1 H), 2.53-2.64 (m, 2 H), 2.21-2.34 (m, 2 H), 2.19 (s, 3 H), 1.60-1.84 (m, 4H). 19 F NMR(377MHz, DMSO-d6): δ -63.58, -86.96.

[0251] Example 13: (S)-2-((4-(6-((5-chloro-6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 13) [ka] Starting from 5-chloropicolinic acid, (S)-2-((4-(6-((5-chloro-6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (31.6 mg) was obtained in a manner similar to that described herein. MS calculated: 705.20; MS found: 705.9 [M+H]+.

[0252] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 8.10 (d, J=8.0 Hz, 1 H), 7.51-7.90 (m, 2 H), 7.33 (d, J=8.0 Hz, 1 H), 6.90 (d, J=7.2 Hz, 1 H), 6.77 (d, J=8.4 Hz, 1 H), 5.37 (s, 2 H), 5.13-5.22 (m, 1 H), 4.87-4.94 (m, 1 H), 4.71-4.77 (m, 1 H), 4.38-4.54 (m, 2 H), 3.49 (d, J=13.6 Hz, 1 H), 3.84 (d, J=13.6 Hz, 1 H), 2.94-3.03 (m, 1 H), 2.80-2.88 (m, 1 H), 2.65-2.77 (m, 1 H), 2.53-2.63 (m, 1 H), 2.41-2.47 (m, 1 H), 2.13-2.30 (m, 2 H), 1.55-1.83 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.59, -87.67.

[0253] Example 14: (S)-2-((4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 14) [ka] Step A: Methyl 5-fluoropicolinate To a mixture of 5-fluoropicolinic acid (2.0 g, 14.2 mmol) in MeOH (20 mL) at 0 °C under N was added SOCl (10.1 g, 85.1 mmol). The mixture was stirred at 0 °C for 10 min, warmed to rt over 10 min, and then heated at 70 °C for 16 h. After completion, the reaction was concentrated to dryness under reduced pressure to give methyl 5-fluoropicolinate (2.0 g, 93.3% yield). MS calculated: 155.0; MS found: 156.1 [M+H] + .

[0254] Step B: 5-Fluoro-2-(methoxycarbonyl)pyridine 1-oxide To a mixture of methyl 5-fluoropicolinate (2.0 g, 12.9 mmol) in DCM (20 mL) at 0 °C under N2, m-CPBA (6.7 g, 38.7 mmol) was added. The mixture was stirred at RT for 16 h. After completion of the reaction, the reaction was cooled to 0 °C and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE=1 / 1) to give 5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (1.2 g, yield: 54.5%). MS calculated: 171.0; MS found: 172.1 [M+H] + .

[0255] Step C: Methyl 5-fluoro-6-hydroxypicolinate To a mixture of 5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (1.1 g, 6.4 mmol) in DMF (10 mL) was added TFAA (7.7 g, 38.6 mmol) at RT. The mixture was stirred at 35 °C for 2 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 1) to give methyl 5-fluoro-6-hydroxypicolinate (950 mg, yield: 86.4%). MS calculated: 171.0; MS found: 172.1 [M+H] + .

[0256] Step D: Methyl 6-(difluoromethoxy)-5-fluoropicolinate To a mixture of methyl 5-fluoro-6-hydroxypicolinate (920 mg, 5.4 mmol) in ACN (10 mL) was added NaH (387 mg, 16.1 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.43 g, 8.1 mmol) was added. The mixture was stirred at RT for 3 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column silica gel chromatography (EA / PE = 1 / 3) to give methyl 6-(difluoromethoxy)-5-fluoropicolinate (720 mg, yield: 60.6%). MS calculated: 221.0; MS found: 222.1 [M+H] + .

[0257] Step E: (6-(difluoromethoxy)-5-fluoropyridin-2-yl)methanol To a mixture of methyl 6-(difluoromethoxy)-5-fluoropicolinate (720 mg, 3.3 mmol) in THF (5 mL) at RT under N was added LiBH (287 mg, 13.0 mmol). The mixture was stirred at 40 °C for 30 min. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE = 1 / 3) to give (6-(difluoromethoxy)-5-fluoropyridin-2-yl)methanol (660 mg, crude). MS calculated: 193.0; MS found: 194.1 [M+H] + .

[0258] Step F: tert-butyl 4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate To a solution of (6-(difluoromethoxy)-5-fluoropyridin-2-yl)methanol (200 mg, 1.0 mmol) in THF (10 mL) was added tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (518 mg, 1.9 mmol), PPh3 (543 mg, 2.1 mmol), and DIAD (418 mg, 2.072 mmol) at 0 °C. The resulting mixture was stirred at RT for 2 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE=2 / 1) to give tert-butyl 4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (180 mg, 38.3% yield). MS calculated: 453.2; MS found: 454.1 [M+H] + .

[0259] Step G: (S)-2-((4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (13.3 mg) was obtained in a manner similar to Example 1. MS calculated: 689.2; MS found: 690.0 [M+H] + .

[0260] 1 H NMR (400MHz, DMSO-d6): δ 9.14 (s, 1 H), 8.27 (s, 1 H), 7.50-7.97 (m, 3 H), 7.37 (dd, J=8.4 Hz, J=3.2 Hz, 1 H), 6.90 (d, J=7.6 Hz, 1 H), 6.75 (d, J=8.0 Hz, 1 H), 5.34 (s, 2 H), 5.12-5.22 (m, 1 H), 4.85-4.96 (m, 1 H), 4.67-4.78 (m, 1 H), 4.47-4.55 (m, 1 H), 4.39-4.46 (m, 1 H), 3.99 (d, J=14.0 Hz, 1 H), 3.84 (d, J=13.6 Hz, 1 H), 2.95-3.03 (m, 1 H), 2.86-2.95 (m, 1 H), 2.69-2.81 (m, 1 H), 2.55-2.63 (m, 1 H), 2.42-2.47 (m, 1 H), 2.14-2.31 (m, 2 H), 1.59-1.84 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.40, -86.99, -140.71.

[0261] Example 15: (S)-2-((4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 15) [ka] Step A: tert-Butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate To a mixture of 6-bromopyridin-2-ol (2.0 g, 11.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.33 g, 17.2 mmol), and K2CO3 (3.2 g, 23.0 mmol) in dioxane / HO (10 mL / 1 mL) was added Pd(dppf)Cl2·DCM (938 mg, 1.15 mmol) at RT under N2. The mixture was stirred at 95 °C for 16 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE=1 / 1) to give tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (1.0 g, yield: 31.5%). MS calculated: 276.2; MS found: 277.2 [M+H] + .

[0262] Step B: tert-butyl 4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate To a mixture of tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (1.0 g, 3.62 mmol) in THF (10 mL) was added Pd / C (500 mg, 10% on carbon, approximately 55% water wet) at RT. The mixture was stirred at RT for 1 h under H2. After completion of the reaction, the mixture was filtered and the filtrate was evaporated to give tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (1.5 g, crude). MS calculated: 278.2; MS found: 279.2 [M+H] + .

[0263] Step C: tert-butyl 4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (264 mg, 0.95 mmol), (2-(difluoromethoxy)-6-methylpyridin-3-yl)methanol (150 mg, 0.79 mmol), and PPh3 (415 mg, 1.6 mmol) in THF (5.0 mL) was added dropwise successively at 0 °C. The resulting mixture was stirred at RT for 2 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (EA / PE=1 / 1) to give tert-butyl 4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (40 mg, 11.2% yield). MS calculated: 449.2; MS found: 450.2 [M+H] + .

[0264] Step D: (S)-2-((4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (4.8 mg) was then obtained in a manner similar to Example 1. MS calculated: 685.2; MS found: 686.0 [M+H] + .

[0265] 1 H NMR (400MHz, DMSO-d6): δ9.15 (s, 1 H), 8.28 (s, 1 H), 7.51-7.95 (m, 3 H), 7.12 (d, J=7.6 Hz, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.68 (d, J=8.0 Hz, 1 H), 5.32 (s, 2 H), 5.13-5.23 (m, 1 H), 4.87-4.97 (m, 1 H), 4.71-4.80 (m, 1 H), 4.37-4.55 (m, 2 H), 4.00 (d, J=14.0 Hz, 1 H), 3.85 (d, J=13.6 Hz, 1 H), 2.98-3.06 (m, 1 H), 2.83-2.91 (m, 1 H), 2.68-2.79 (m, 1 H), 2.58-2.65 (m, 1 H), 2.37-2.47 (m, 4 H), 2.16-2.35 (m, 2 H), 1.59-1.87 (m, 4 H).

[0266] 19 F NMR(377MHz, DMSO-d6):δ -63.51, -86.91.

[0267] Example 16: (S)-2-((4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 16) [ka] Step A: 3-Bromo-6-chloro-2-hydroxybenzaldehyde A mixture of paraformaldehyde (11.2 g, 124.4 mmol), MgCl (7.88 g, 82.9 mmol) in THF (150 mL) and TEA (11.5 mL) was stirred at 70 °C for 15 min under Ar. 2-Bromo-5-chlorophenol (8.5 g, 41.5 mmol) was then added, and the reaction was stirred at 70 °C overnight under Ar. After completion of the reaction, the reaction mixture was filtered, quenched with HO (150 mL), and extracted with ethyl acetate (150 mL × 3). The organic layers were combined, washed with brine (80 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by column chromatography (PE = 100%) to give 3-bromo-6-chloro-2-hydroxybenzaldehyde (6.6 g, yield: 68%).

[0268] Step B: 3-Bromo-6-chlorobenzene-1,2-diol To a mixture of 3-bromo-6-chloro-2-hydroxybenzaldehyde (2.0 g, 8.55 mmol) in HO (5 mL, 30% aqueous solution) and THF (20 mL), NaOH (5 mL, 2 M in water) was added and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with HO (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 1 / 3) to give 3-bromo-6-chlorobenzene-1,2-diol (1.33 g, yield: 70%).

[0269] Step C: 4-Bromo-7-fluorobenzo[d][1,3]dioxole To a solution of 3-bromo-6-fluorobenzene-1,2-diol (550 mg, 2.5 mmol) in DMF (16 mL) was added dibromomethane (4.3 g, 24.77 mmol) and K2CO3 (1.03 g, 7.46 mmol). The reaction was stirred at 110 °C for 2 h. After completion of the reaction, the mixture was quenched with HO (40 mL) and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by column chromatography (PE / EA = 1 / 10) to give 4-bromo-7-fluorobenzo[d][1,3]dioxole (470 mg, yield: 89%).

[0270] Step D: Ethyl 7-chlorobenzo[d][1,3]dioxole-4-carboxylate To a mixture of 4-bromo-7-fluorobenzo[d][1,3]dioxole (470 mg, 2.00 mmol) in EtOH (8.0 mL) was added PdCl(dppf) (147 mg, 0.20 mmol) and KOAc (394 mg, 4.02 mmol). The mixture was stirred at 75 °C for 2 h under CO. After completion of the reaction, the mixture was quenched with HO (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 10 / 1) to give ethyl 7-chlorobenzo[d][1,3]dioxole-4-carboxylate (360 mg, yield: 79%).

[0271] Step E: (7-chlorobenzo[d][1,3]dioxol-4-yl)methanol To a solution of ethyl 7-fluorobenzo[d][1,3]dioxole-4-carboxylate (360 mg, 1.58 mmol) in THF (3 mL) and MeOH (3 mL) was added LiBH (144.7 mg, 6.58 mmol). The solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was quenched with HO (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 3 / 1) to give (7-chlorobenzo[d][1,3]dioxol-4-yl)methanol (190 mg, yield: 65%).

[0272] Step F: tert-Butyl 4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate A mixture of (7-chlorobenzo[d][1,3]dioxol-4-yl)methanol (190 mg, 1.02 mmol), tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (343.2 mg, 1.22 mmol), and NaOH (81.72 mg, 2.04 mmol) in DMF (4.5 mL) was stirred at 70 °C overnight. After completion of the reaction, the mixture was quenched with HO (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA=3 / 1) to give tert-butyl 4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (270 mg, yield: 59%). MS calculated: 446.2; MS found: 447.2 [M+H] + .

[0273] Step G: (S)-2-((4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (65.7 mg) was obtained in a similar manner to Example 1. MS calculated: 682.2; MS found: 683.3 [M+H] + .

[0274] 1 H NMR: δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.62 (t, J=8.0 Hz, 1 H), 6.98 (d, J=8.4 Hz, 1 H), 6.92 (d, J=8.4 Hz, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.67 (d, J=8.4 Hz, 1 H), 6.18 (s, 2 H), 5.28 (s, 2 H), 5.14-5.22 (m, 1 H), 4.87-4.96 (m, 1 H), 4.74-4.78 (m, 1 H), 4.39-4.53 (m, 2 H), 4.01 (d, J=13.6 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 3.00-3.08 (m, 1 H), 2.84-2.92 (m, 1 H), 2.69-2.78 (m, 1 H), 2.58-2.65 (m, 1 H), 2.38-2.45 (m, 1 H), 2.17-2.31 (m, 2 H), 1.65-1.87 (m, 4 H).

[0275] 19 F NMR(377MHz, DMSO-d6):δ -63.56.

[0276] Example 17: (S)-2-((4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 17) [ka] Step A: 4-Bromo-7-fluorobenzo[d][1,3]dioxole To a solution of 3-bromo-6-fluorobenzene-1,2-diol (1.50 g, 7.28 mmol) in DMF (30 mL) were added dibromomethane (6.33 g, 36.41 mmol) and K2CO3 (3.01 g, 21.84 mmol). The solution was stirred at 110 °C for 2 h. After completion of the reaction, the mixture was diluted with HO (50 mL) and extracted with EA (60 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 4-bromo-7-fluorobenzo[d][1,3]dioxole (1.47 g, yield: 93%).

[0277] Step B: Ethyl 7-fluorobenzo[d][1,3]dioxole-4-carboxylate To a mixture of 4-bromo-7-fluorobenzo[d][1,3]dioxole (700 mg, 3.21 mmol) in EtOH (10.0 mL) was added PdCl(dppf) (469.89 mg, 0.64 mmol) and KOAc (943.74 g, 9.63 mmol). The mixture was stirred at 75 °C for 2 hours under CO. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 8 / 1) to give ethyl 7-fluorobenzo[d][1,3]dioxole-4-carboxylate (530 mg, yield: 78%).

[0278] Step C: (7-fluorobenzo[d][1,3]dioxol-4-yl)methanol To a solution of ethyl 7-fluorobenzo[d][1,3]dioxole-4-carboxylate (500 mg, 2.36 mmol) in THF (4 mL) was added LiBH (102.74 mg, 4.72 mmol). The solution was stirred at 40 °C for 16 h. After the reaction was complete, the mixture was diluted with aqueous NH Cl (30 mL) and extracted with DCM (30 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated to dryness under reduced pressure to give (7-fluorobenzo[d][1,3]dioxol-4-yl)methanol (340 mg, yield: 85%).

[0279] Step D: tert-Butyl 4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate A mixture of (7-fluorobenzo[d][1,3]dioxol-4-yl)methanol (290 mg, 1.7 mmol), tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (569 mg, 2.0 mmol), PPh3 (896 mg, 3.4 mmol), and DIAD (691 mg, 3.4 mmol) in THF (6 mL) was stirred at RT for 3 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with EA (30 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 8 / 1) to give tert-butyl 4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (100 mg, yield: 14%). MS calculated: 430.2; MS found: 431.0 [M+H] + .

[0280] Step E: (S)-2-((4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained in a manner similar to Example 1 (6.8 mg). MS calculated: 666.2; MS found: 667.1 [M+H] + .

[0281] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 6.96-7.02 (m, 1 H), 6.80-6.90 (m, 2 H), 6.65 (d, J=8.0 Hz, 1 H), 6.17 (s, 2 H), 5.27 (s, 2 H), 5.15-5.21 (m, 1 H), 4.88-4.96 (m, 1 H), 4.73-4.80 (m, 1 H), 4.39-4.53 (m, 2 H), 4.02 (d, J=13.2 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 3.01-3.08 (m, 1 H), 2.86-2.93 (m, 1 H), 2.70-2.79 (m, 2 H), 2.43-2.48 (m, 1 H), 2.18-2.35 (m, 2 H), 1.71-1.87 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.37, -139.35.

[0282] Example 18: (S)-2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 18) [ka] Starting from (2,2-difluorobenzo[d][1,3]dioxol-4-yl)methanol, (S)-2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained in a manner analogous to Example 3. MS calculated: 684.2; MS found: 685.4 [M+H] + .

[0283] 1 H NMR: δ 9.16 (s, 1 H), 8.28 (s, 1 H), 7.64 (t, J=8.0 Hz, 1 H), 7.35 (dd, J=1.2 Hz, J=8.0 Hz, 1 H), 7.29 (d, J=7.2 Hz, 1 H), 7.19 (t, J=8.0 Hz, 1 H), 6.88 (d, J=7.2 Hz, 1 H), 6.70 (d, J=8.0 Hz, 1 H), 5.44 (s, 2 H), 5.14-5.21 (m, 1 H), 4.88-4.96 (m, 1 H), 4.74-4.78 (m, 1 H), 4.47-4.54 (m, 1H), 4.38-4.46 (m, 1 H), 4.00 (d, J=13.6 Hz, 1 H), 3.85 (d, J=13.6 Hz, 1 H), 2.96-3.04 (m, 1 H), 2.83-2.89 (m, 1 H), 2.70-2.78 (m, 1 H), 2.55-2.66 (m, 1 H), 2.38-2.44 (m, 1 H), 2.14-2.31 (m, 2 H), 1.60-1.84 (m, 4 H). 19 F NMR:(377MHz, DMSO-d6): δ -48.85, -63.63.

[0284] Example 19: (S)-2-((4-(6-((benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 19) [ka] Step A: 4-Bromobenzo[d][1,3]dioxole-2,2-d2 To a solution of 3-bromobenzene-1,2-diol (1.0 g, 5.3 mmol) in DMF (15 mL), dibromomethane-d2 (1.8 g, 10.6 mmol) and K2CO3 (2.2 g, 15.9 mmol) were added at room temperature. The reaction was stirred at 110 °C for 2 h. After completion of the reaction, the mixture was quenched with HO (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by column chromatography (PE / EA = 1 / 100) to give 4-bromobenzo[d][1,3]dioxole-2,2-d2 (829 mg, yield: 77%).

[0285] Step B: Ethyl benzo[d][1,3]dioxole-4-carboxylate-2,2-d2 To a mixture of 4-bromobenzo[d][1,3]dioxole-2,2-d2 (829 mg, 4.1 mmol) in EtOH (12 mL) was added PdCl2(dppf) (300 mg, 0.41 mmol) and KOAc (1.0 g, 10.2 mmol) at room temperature. The mixture was stirred at 75 °C for 2 h under CO. After the reaction was complete, the mixture was quenched with HO (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 10 / 1) to give ethyl benzo[d][1,3]dioxole-4-carboxylate-2,2-d2 (660 mg, yield: 81.6%) as a white solid. MS calculated: 196.1; MS found: 197.1 [M+H] + .

[0286] Step C: (benzo[d][1,3]dioxol-4-yl-2,2-d2)methanol To a solution of ethyl benzo[d][1,3]dioxole-4-carboxylate-2,2-d2 (560 mg, 2.86 mmol) in THF (10 mL) was added LiAlH4 (130 mg, 3.42 mmol) at room temperature. The solution was stirred at room temperature for 1.5 h. After the reaction was complete, EA (20 mL) and HO (0.15 mL) were added to the mixture and stirred at room temperature for 10 min. Then, NaOH solution (2 M, 0.15 mL) and HO (0.35 mL) were added. The resulting mixture was stirred at room temperature for 15 min. Finally, the mixture was dried over sodium sulfate, stirred at room temperature for 15 min, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 4 / 1) to give (benzo[d][1,3]dioxol-4-yl-2,2-d2)methanol (366 mg, yield: 83%).

[0287] Step D: tert-Butyl 4-(6-((benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidine-1-carboxylate A mixture of (benzo[d][1,3]dioxol-4-yl-2,2-d)methanol (366 mg, 2.38 mmol), tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (560 mg, 2.00 mmol), and NaOH (160 mg, 4.00 mmol) in DMF (10.0 mL) was stirred at 70 °C for 4 hours at room temperature. After completion of the reaction, the mixture was quenched with HO (60 mL) and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with brine (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA=97 / 4) to give tert-butyl 4-(6-((benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidine-1-carboxylate (550 mg, yield: 56%). MS calculated: 414.2; MS found: 415.3 [M+H] + .

[0288] Step E: (S)-2-((4-(6-((benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (61.3 mg) was obtained in a manner similar to Example 1. MS calculated: 650.3; MS found: 651.4 [M+H] + .

[0289] 1H NMR (400MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.29 (s, 1 H), 7.62 (t, J=5.6 Hz, 1 H), 6.92-6.98 (m, 1 H), 6.78-6.90 (m, 3H), 6.65 (d, J=8.0 Hz, 1 H), 5.30 (s, 2 H), 5.11-5.23 (m, 1 H), 4.86-4.97 (m, 1 H), 4.74-4.78 (m, 1 H), 4.36-4.53 (m, 2 H), 4.01 (d, J=13.2 Hz, 1 H), 3.86 (d, J=13.2 Hz, 1 H), 2.98-3.08 (m, 1 H), 2.82-2.93 (m, 1 H), 2.68-2.78 (m, 1 H), 2.57-2.67 (m, 1 H), 2.14-2.37 (m, 3 H), 1.63-1.91 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.64.

[0290] Example 20: (S)-2-(((6-(1-((3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzo[d]thiazole (Compound 20) [ka] Starting from benzo[d]thiazol-2-ylmethanol, (S)-2-(((6-(1-((3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzo[d]thiazole was obtained in a manner analogous to Example 3. MS calculated: 661.22; MS found: 662.2 [M+H] + .

[0291] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.27 (s, 1 H), 8.06 (d, J=7.6 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 7.67-7.75 (m, 1 H), 7.45-7.51 (m, 1 H), 7.38-7.44 (m, 1 H), 6.94 (d, J=7.6 Hz, 1 H), 6.81 (d, J=8.0 Hz, 1 H), 5.81 (s, 2 H), 5.11-5.21 (m, 1 H), 4.84-4.96 (m, 1 H), 4.68-4.77 (m, 1H), 4.36-4.50 (m, 2 H), 3.98 (d, J=13.6 Hz, 1 H), 3.82 (d, J=13.6 Hz, 1 H), 2.94-3.01 (m, 1 H), 2.82-2.85 (m, 1 H), 2.66-2.75 (m, 1 H), 2.56-2.63 (m, 1 H), 2.37-2.46 (m, 1 H), 2.12-2.29 (m, 2 H), 1.59-1.85 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.54.

[0292] Example 21: 3-methyl-6-{[(6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridin-2-yl)oxy]methyl}pyridazine (Compound 21) [ka] Step A: (6-methylpyridazin-3-yl)methanol To a solution of methyl 6-methylpyridazine-3-carboxylate (500 mg, 3.29 mmol) in MeOH (10 mL) was slowly added LiBH4 (217 mg, 9.87 mmol). The mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was quenched with water (1 mL) and filtered. The filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (DCM / MeOH=12 / 1) to give (6-methylpyridazin-3-yl)methanol (350 mg, 86.0% yield). MS calculated: 124.1. MS found: 125.2 [M+H] + .

[0293] Step B: tert-butyl 4-(6-((6-methylpyridazin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate A mixture of (6-methylpyridazin-3-yl)methanol (350 mg, 2.82 mmol), tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (541 mg, 2.82 mmol), and t-BuOK (1.9 g, 16.9 mmol) in THF (10 mL) was stirred at 70 °C for 5 h. After completion of the reaction, the mixture was diluted with EA (20 mL), washed with HO (10 mL), and extracted with EA (50 mL × 2). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column silica gel chromatography (PE / EA = 3 / 1) to give tert-butyl 4-(6-((6-methylpyridazin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (600 mg, 55.4% yield). MS calculated: 384.2; MS found: 385.3 [M+H] + .

[0294] Step C: 3-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridazine TFA salt A solution of tert-butyl 4-(6-((6-methylpyridazin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (222 mg, 0.577 mmol), TFA (0.1 mL) in DCM (2 mL) was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated to give 3-methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridazine TFA salt (250 mg, crude). MS calculated: 284.2. MS found: 285.2 [M+H] + .

[0295] Step D: 3-methyl-6-{[(6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridin-2-yl)oxy]methyl}pyridazine 3-Methyl-6-{[(6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridin-2-yl)oxy]methyl}pyridazine (compound 21) (67.6 mg) was obtained in a manner similar to that described in Example 1. MS calculated: 620.3; MS found: 621.4 [M+H] + .

[0296] 1H NMR (400MHz, DMSO-d6): δ 9.31 (s, 1 H), 8.40 (s, 1 H), 7.73 (t, J=8.0 Hz, 1 H), 7.66 (d, J=8.4 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 6.92-7.00 (m, 1 H), 6.82 (d, J=8.0 Hz, 1 H), 5.63 (s, 2 H), 5.08-5.17 (m, 1 H), 4.84-4.99 (m. 3 H), 4.73-4.82 (m, 1 H), 4.48-4.56 (m, 1 H), 4.36-4.46 (m, 1 H), 3.65-3.86 (m, 2 H), 3.21-3.41 (m, 2 H), 2.82-3.05 (m, 1 H), 2.70-2.81 (m, 1 H), 2.62 (s, 3 H), 2.30-2.43 (m, 1 H), 2.00-2.15 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.71.

[0297] Example 22: (S)-2-((4-(6-((1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 22) [ka] Step A: Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate A mixture of methyl 1H-pyrazole-3-carboxylate (2.0 g, 15.9 mmol), cyclopropylboronic acid (2.7 g, 31.7 mmol), Na2CO3 (3.4 g, 31.8 mmol), Cu(OAc)2 (2.9 g, 15.9 mmol), and 2,2'-dipyridyl (2.5 g, 15.9 mmol) in DCE (30 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with HO (60 mL), and extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (40 mL). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (1.7 g, yield: 64.9%). MS calculated: 166.1; MS found: 167.1 [M+H] + .

[0298] Step B: Methyl 1-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylate A mixture of methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (1.5 g, 9.0 mmol) and Selectfluor (9.6 g, 27.1 mmol) in CHCN (20 mL) was stirred at 70 °C for 36 h under N. The reaction mixture was cooled to room temperature. The mixture was quenched with HO (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (30 mL). The organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give methyl 1-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylate (1.5 g, yield: 90.3%).

[0299] Step C: (1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methanol To a solution of methyl 1-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylate (1.11 g, 6.03 mmol) in THF (15 mL) was added LiBH (0.265 g, 12.06 mmol) at 0 °C. The mixture was stirred at 50 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with HO (50 mL), and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (30 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4 / 1) to give (1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methanol (510 mg, yield: 54.2%).

[0300] Step D: (S)-2-((4-(6-((1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(6-((1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (30.8 mg) was obtained in a manner similar to compound 3. MS calculated: 652.26; MS found: 653.0 [M+H].

[0301] 1H NMR (400MHz, DMSO-d6) : δ 9.15 (s, 1 H), 8.28 (s, 1 H), 7.91 (d, J=4.4 Hz, 1 H), 7.61 (t, J=7.6 Hz, 1 H), 6.87 (d, J=7.6 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 5.25 (s, 2 H), 5.15-5.22 (m, 1 H), 4.90-4.96 (m, 1 H), 4.73-4.79 (m, 1 H), 4.47-4.53 (m, 1 H), 4.40-4.45 (m, 1 H), 4.01 (d, J=13.6 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 3.62-3.68 (m, 1 H), 2.99-3.09 (m, 1 H), 2.84-2.94 (m, 1 H), 2.71-2.79 (m, 1 H), 2.59-2.65 (m, 1 H), 2.44-2.48 (m, 1 H), 2.16-2.35 (m, 2 H), 1.71-1.90 (m, 4 H), 0.96-1.03 (m, 2 H), 0.86-0.94(m, 2 H). 19 F NMR(377MHz, DMSO-d6): δ -63.53, -176.75.

[0302] Example 23: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 23) [ka] Step A: 6-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine TsOH salt (545 mg, 1.0 mmol) in DMF (10 mL) was added TEA (377 mg, 3.1 mmol). After stirring for 2 min, (S)-6-bromo-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine (332 mg, 1.0 mmol) was added. The resulting mixture was stirred at 60 °C for 2 h. After completion of the reaction, the mixture was diluted with EA (100 mL) and washed with HO (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to give 6-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine (535 mg, yield: 81.6%). MS calculated: 626.1; MS found: 627.1 [M+H] + .

[0303] Step B: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylate To a mixture of 6-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine (535 mg, 0.85 mmol) in EtOH (10 mL) was added Pd(dppf)Cl (125 mg, 0.17 mmol) and KOAc (250 mg, 2.56 mmol). The mixture was stirred at 70 °C for 16 h under a CO atmosphere (balloon). The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM / MeOH=20 / 1) to give ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylate (400 mg, yield: 75.6%). MS calculated: 620.2; MS found: 620.9 [M+H] + .

[0304] Step C: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid To a solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylate (400 mg, 0.64 mmol) in MeOH (6 mL) was added NaOH (2 mL, 2 M aqueous solution). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5 mL), and then the mixture was adjusted to pH 5-6 with 1 N HCl (aqueous). The solid was collected and dried to give 140 mg of crude product as a white solid. 40 mg of the crude product was purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (6.3 mg, yield: 16.5%). MS calculated: 592.2; MS found: 593.0 [M+H] + .

[0305] 1 H NMR (400MHz, DMSO-d6) δ 9.09 (s, 1 H), 8.27 (s, 1 H), 7.49-7.59 (m, 2 H), 7.29-7.34 (m, 1 H), 6.69-6.80 (m, 3 H), 5.13-5.18 (m, 1 H), 4.86-4.92 (m, 1 H), 4.72-4.75 (m, 1 H), 4.46-4.51 (m, 1 H), 4.38-4.44 (m, 1 H), 3.99-4.02 (m, 1 H), 3.83-3.86 (m, 1 H), 2.97-3.01 (m, 1 H), 2.85-2.88 (m, 1 H), 2.63-2.74 (m, 2 H), 2.21-2.27 (m, 2 H), 1.98-2.02 (m, 4 H), 1.65-1.77 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -110.78.

[0306] Example 24: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-methyl-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (Compound 24) [ka] A mixture of (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(cyclobutylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (50 mg, 0.08 mmol), methanamine (8 mg, 0.13 mmol), HATU (32 mg, 0.13 mmol), DIEA (48 mg, 0.38 mmol) in DMF (1.5 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was directly purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-methyl-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (15.93 mg, yield: 31.2%). MS calculated: 605.2; MS found: 606.1 [M+H] + .

[0307] 1H NMR (400MHz, DMSO-d6) δ 9.02 (s, 1 H), 8.71 (q, J=4.8 Hz, 1 H), 8.21 (s, 1 H), 7.53-7.59 (m, 2 H), 7.33 (dd, J=8.4 Hz, J=1.6 Hz, 1 H), 6.73-6.80 (m, 3 H), 5.13-5.19 (m, 1 H), 4.88-4.92 (m, 1 H), 4.73 (dd, J=15.2 Hz, J=2.8 Hz, 1 H), 4.47-4.52 (m, 1 H), 4.38-4.43 (m, 1 H), 3.99 (d, J=13.6 Hz, 1 H), 3.83 (d, J=13.6 Hz, 1 H), 3.02-3.04 (m, 1 H), 2.84-2.86 (m, 4 H), 2.62-2.76 (m, 2 H), 2.41-2.48 (m, 1 H), 2.19-2.31 (m, 2 H), 2.03 (s, 3 H), 1.65-1.80 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -110.79.

[0308] Example 25: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-N-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (Compound 25) [ka] A mixture of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (50 mg, 0.08 mmol), 2,2,2-trifluoroethan-1-amine (12 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), DIEA (16 mg, 0.13 mmol) in DMF (1.5 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was directly purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-N-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (24.3 mg, yield: 42.8%). MS calculated: 673.21; MS found: 674.1 [M+H] + .

[0309] 1 H NMR (400MHz, DMSO-d6) δ 9.33 (t, J=6.4 Hz, 1 H), 9.22 (s, 1 H), 8.39 (s, 1 H), 7.56-7.64 (m, 2 H), 7.35 (dd, J=8.4 Hz, J=1.6 Hz, 1 H), 6.86 (d, J=4.0 Hz, 2 H), 6.73-6.81 (m, 1 H), 5.05-5.15 (m, 1 H), 4.84-4.96 (m, 3 H), 4.73-4.76 (m, 1 H), 4.47-4.55 (m, 1 H), 4.34-4.42 (m, 1 H), 4.08-4.19 (m, 2 H), 3.69-3.84 (m, 2 H), 3.29-3.41 (m, 2 H), 2.94-3.05 (m, 1 H), 2.71-2.80 (m, 1 H), 2.33-2.40 (m, 1 H), 1.98-2.20 (m, 7 H). 19F NMR (377MHz, DMSO-d6): δ -70.35, -110.50.

[0310] Example 26: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-(2-methoxyethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (Compound 26) [ka] A mixture of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (90 mg, 0.15 mmol), 2-methoxyethan-1-amine (23 mg, 0.30 mmol), T3P (95 mg, 0.30 mmol), and DIEA (58 mg, 0.45 mmol) in DMF (1.5 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with EA (30 mL) and washed with HO (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was directly purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-N-(2-methoxyethyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (34.3 mg, yield: 62.5%). MS calculated: 649.25; MS found: 650.0 [M+H] + .

[0311] 1H NMR (400MHz, DMSO-d6) δ 9.17 (d, J=0.8 Hz, 1 H), 8.69-8.75 (m, 1 H), 8.34 (d, J=0.8 Hz, 1 H), 7.56-7.64 (m, 2 H), 7.35 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.86-6.87 (m, 2 H), 6.74-6.80 (m, 1 H), 5.05-5.14 (m, 1 H), 4.84-4.96 (m, 3 H), 4.73-4.77 (m, 1 H), 4.48-4.53 (m, 1 H), 4.35-4.40 (m, 1H), 3.61-3.77 (m, 6 H), 3.49-3.52 (m, 3 H), 3.31-3.42 (m, 2 H), 2.95-3.06 (m, 1 H), 2.71-2.79 (m, 1 H), 2.31-2.39 (m, 1 H), 1.96-2.21 (m, 7 H). 19 F NMR (377MHz, DMSO-d6): δ -110.50.

[0312] Example 27: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound 27) [ka] Starting from (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine TsOH salt and (S)-5-bromo-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid was obtained in a manner similar to Example 23. MS calculated: 609.2; MS found: 610.0 [M+H] + .

[0313] 1 H NMR (400MHz, DMSO-d6) δ: 7.69-7.76 (m, 1 H), 7.50-7.59 (m, 3 H), 7.33 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.72-6.82 (m, 3 H), 5.08-5.16 (m, 1 H), 4.73-4.79 (m, 1 H), 4.59-4.66 (m, 1 H), 4.35-4.50 (m, 2 H), 3.95 (d, J=13.6 Hz, 1 H), 3.79 (d, J=13.2 Hz, 1 H), 2.97-3.05 (m, 1 H), 2.82-2.90 (m, 1 H), 2.61-2.74 (m, 2 H), 2.39-2.46 (m, 1 H), 2.14-2.30 (m, 2 H), 2.03 (s, 1 H), 1.65-1.83 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -110.79, -124.83.

[0314] Example 28: (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 28) [ka] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt, (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid was obtained in a manner analogous to Example 23. MS calculated: 565.2; MS found: 566.2 [M+H] + .

[0315] 1 H NMR (400MHz, DMSO-d6) δ 9.23 (s, 1 H), 8.39 (d, J=0.4 Hz, 1 H), 7.70 (t, J=7.6 Hz, 1 H), 7.60 (t, J=8.0 Hz, 1 H), 7.49 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.33 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.92-6.97 (m, 1 H), 6.75 (d, J=8.4 Hz, 1 H), 5.41 (s, 2 H), 5.06-5.12 (m, 1 H), 4.85-4.96 (m, 3 H), 4.71-4.79 (m, 1 H), 4.48-4.54 (m, 1 H), 4.35-4.41 (m, 1 H), 3.75-3.82 (m, 2 H), 3.22-3.36 (m, 2 H), 2.89-3.01 (m, 1 H), 2.69-2.79 (m, 1 H), 2.31-2.39 (m, 1 H), 2.02-2.19 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -115.20.

[0316] Example 29: (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 29) [ka] Starting from 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine HCl salt, (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid was obtained in a manner analogous to Example 23. MS calculated: 563.2; MS found: 564.0 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d6) δ 9.08 (s, 1 H), 8.28 (s, 1 H), 7.69 (t, J=7.6 Hz, 1 H), 7.55 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.30 (dd, J=8.4 Hz, 1.6 Hz, 1 H), 7.09 (d, J=7.6 Hz, 1 H), 6.70-6.78 (m, 2 H), 5.40 (s, 2 H), 5.06-5.15 (m, 1 H), 4.84-4.94 (m, 1 H), 4.69-4.78 (m, 1H), 4.45-4.51 (m, 1 H), 4.35-4.41 (m, 1 H), 4.11 (d, J=13.6 Hz, 1 H), 3.99 (d, J=13.6 Hz, 1 H), 3.18-3.26 (m, 4 H), 2.75-2.82 (m, 2 H), 2.64-2.70 (m, 1 H), 2.37-2.44 (m, 1 H). 19F NMR (377MHz, DMSO-d6): δ -115.27.

[0318] Example 30: (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 30) [ka] Starting from 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine TFA salt, (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid was obtained in a manner analogous to Example 23. MS calculated: 580.2; MS found: 581.1 [M+H] +

[0319] 1 H NMR (400MHz, CD3OD-d4): δ 9.10 (s, 1 H), 8.51 (s, 1 H), 7.54 (t, J=7.4 Hz, 1 H), 7.29 - 7.17 (m, 3 H), 7.12 - 7.02 (m, 2 H), 6.09 (s, 1 H), 5.28 - 5.16 (m, 3 H), 4.69 - 4.59 (m, 2 H), 4.52 - 4.39 (m, 4 H), 3.55 - 3.48 (m, 2 H), 3.21 - 3.01 (m, 3 H), 2.84 - 2.77 (m, 1 H), 2.70 - 2.63 (m, 1 H), 2.56 - 2.48 (m, 1 H). 19 F NMR (377MHz, CD3OD-d4): δ (-117.54).

[0320] Example 31: (S)-2-((4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 31) [ka] Step A: tert-butyl 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of (4-chloro-2-methoxyphenyl)methanol (100 mg, 0.58 mmol), tert-butyl 4-(4-fluoro-3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.58 mmol) in THF (5.0 mL) was added PPh (183 mg, 0.70 mmol) and DIAD (178 mg, 0.88 mmol) at 0 °C, and the mixture was stirred at 0 °C for 3 h. After completion of the reaction, the mixture was quenched with HO (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with brine (25 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA=5 / 1) to give tert-butyl 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, yield: 65%). MS calculated: 447.2; MS found: 391.9 [M-56+H] + .

[0321] Step B: 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine HCl salt To a solution of tert-butyl 4-(3-((4-chloro-2-fluoro-6-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.34 mmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL) at room temperature. The solution was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to give 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine HCl salt (168 mg, crude). MS calculated: 347.1; MS found: 348.2 [M+H] + .

[0322] Step C: (S)-2-((4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (S)-2-((4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (26.9 mg) was obtained in a manner similar to that described herein. MS calculated: 683.2; MS found: 684.5 [M+H] + .

[0323] 1H NMR (400MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.30 (s, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.25 (dd, J=2.0 Hz, J=8.4 Hz, 1 H), 7.12-7.20 (m, 2 H), 7.03-7.09 (m, 1 H), 6.94-7.01 (m, 1 H), 6.12-6.16 (m, 1 H), 5.13 (s, 3 H), 4.88-4.97 (m, 1 H), 4.71-4.81 (m, 1 H), 4.46-4.53 (m, 1 H), 4.37-4.44 (m, 1 H), 4.11 (d, J=13.6 Hz, 1 H), 3.99 (d, J=13.6 Hz, 1 H), 3.84 (s, 3 H), 3.14-3.26 (m, 2 H), 2.63-2.83 (m, 3 H), 2.33-2.45 (m, 3 H). 19 F NMR(377MHz, DMSO-d6): δ -63.60, -136.52.

[0324] Example 32: (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (Compound 32) [ka] Step A: (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile A mixture of (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (220 mg, 0.84 mmol), 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine 2,2,2-trifluoroacetate (378 mg, 0.84 mmol), TEA (0.35 mL, 2.52 mmol), and KCO (348 mg, 2.52 mmol) in DMSO (3 mL) was stirred at 60 °C for 3 h. The mixture was poured into water (50 mL) and extracted with DCM (2×50 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated to give (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (480 mg). MS calculated: 561.2; MS found: 562.2 [M+H] +

[0325] Step B: Methyl (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate A mixture of (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (240 mg, 0.428 mmol) and NaOMe (240 mg, 4.28 mmol) in DCM / MeOH (2 mL / 2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by column chromatography on silica gel to give methyl (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate (105 mg, yield: 48.7%). MS calculated: 593.2; MS found: 594.2 [M+H] +

[0326] Step C: (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide A mixture of methyl (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate (105 mg, 0.18 mmol), 2-hydrazinyl-2-oxoacetamide (36 mg, 0.35 mmol) and DIEA (0.15 mL, 0.88 mmol) in n-BuOH (5 mL) was stirred at 120° C. for 16 hours. The mixture was purified by preparative HPLC to give (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (47.5 mg, yield: 41.5%). MS calculated: 646.2; MS found: 647.2 [M+H] +

[0327] 1 H NMR (400MHz, CD3OD-d4): δ 9.12 (s, 1 H), 8.48 (s, 1 H), 7.54 (t, J=8.0 Hz, 1 H), 7.27 - 7.24 (m, 2 H), 7.20 (d, J=9.2 Hz, 1 H), 7.09 - 7.02 (m, 2 H), 6.11 - 6.05 (m, 1 H), 5.31 - 5.25 (m, 1 H), 5.20 (s, 2 H), 4.99 - 4.93 (m, 1 H), 4.83 - 4.78 (m, 1 H), 4.69 - 4.63 (m, 1 H), 4.53 - 4.46 (m, 1 H), 4.18 (d, J=14.0 Hz, 1 H), 4.05 (d, J=14.0 Hz, 1 H), 3.29 - 3.19 (m, 2 H), 2.91 - 2.76 (m, 3 H), 2.59 - 2.53 (m, 3 H). 19 F NMR (377MHz, CD3OD-d4): δ (-117.52), (-137.79).

[0328] Example 33: (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile (Compound 33) [ka] A mixture of (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (30 mg, 0.046 mmol) and Burgess (300 mg) in DCM (3 mL) was stirred at room temperature for 2 hours. The mixture was poured into water (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the residue was concentrated. The residue was purified by preparative HPLC to give (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile (3.9 mg, yield: 13.5%). MS calculated: 628.2; MS found: 629.2 [M+H] +

[0329] 1H NMR (400MHz, CD3OD-d4): δ 9.06 (s, 1 H), 8.35 (s, 1 H), 7.54 (t, J=8.0 Hz, 1 H), 7.26 (d, J=7.6, 2 H), 7.20 (d, J=8.0 Hz, 1 H), 7.09 - 7.05 (m, 2 H), 6.08 (s, 1 H), 5.31 - 5.24 (m, 1 H), 5.20 (s, 2 H), 4.98 - 4.92 (m, 1 H), 4.81 - 4.75 (m, 1 H), 4.68 - 4.62 (m, 1 H), 4.52 - 4.46 (m, 1 H), 4.17 (d, J=13.6 Hz, 1 H), 4.05 (d, J=13.6 Hz, 1 H), 3.28 - 3.22 (m, 2 H), 2.89 - 2.83 (m, 2 H), 2.82 - 2.76 (m, 1 H), 2.60 - 2.50 (m, 3 H). 19 F NMR (377MHz, CD3OD-d4): δ (-117.52), (-137.88).

[0330] Example 34: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 34) [ka] Step A: 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole To a mixture of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine TsOH salt (187.20 mg, 0.36 mmol) in DMF (4.0 mL) was added (S)-5-bromo-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (100 mg, 0.30 mmol) and DIEA (388.55 mg, 3.01 mmol). The mixture was stirred at 60 °C for 1 h. After completion of the reaction, the mixture was diluted with HO (40 mL) and extracted with EA (30 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH=100 / 1) to give 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (170 mg, yield: 87.8%). MS calculated: 643.10; MS found: 644.3 / 646.3 [M+H] + .

[0331] Step B: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile A solution of 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (130 mg, 0.20 mmol), Zn(CN) (11.87 mg, 0.10 mmol), and Ruphos-Pd-G (33.44 mg, 0.04 mmol) in NMP (2.0 mL) was stirred at 115 °C for 1.5 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with EA (20 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH=80 / 1) to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (120 mg impure, 59% purity, 100% yield). MS calculated: 590.2; MS found: 591.5 [M+H] + .

[0332] Step C: (Z)-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-N'-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide A solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (80 mg, 0.14 mmol), HONH HCl (59.64 mg, 0.81 mmol), and TEA (56.67 mg, 0.56 mmol) in EtOH (4.0 mL) was stirred at 40 °C for 5 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with EA (15 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give (Z)-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-N'-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide (86 mg, crude). MS calculated: 623.21; MS found: 624.2 [M+H] + .

[0333] Step D: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one A mixture of (Z)-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-N'-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide (86 mg, 0.14 mmol) and CDI (112 mg, 0.69 mmol) in THF (2.0 mL) was stirred at 50°C for 3 hours. After completion of the reaction, the mixture was directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (11.41 mg, 12.8% yield). MS calculated: 649.2; MS found: 650.1 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6): δ 6.69 (d, J=8.8 Hz, 1 H), 7.50-7.62 (m, 3 H), 7.34 (d, J=8.8 Hz, 1 H), 6.71-6.84 (m, 3 H), 5.09-5.17 (m, 1 H), 4.75-4.84 (m, 1 H), 4.61-4.71 (m, 1 H), 4.35-4.53 (m, 2 H), 3.99 (d, J=13.2 Hz, 1 H), 3.83 (d, J=13.6 Hz, 1 H), 2.98-3.09 (m, 1 H), 2.84-2.93 (m, 1H), 2.61-2.76 (m, 2 H), 2.38-2.47 (m, 1 H), 2.16-2.35 (m, 2 H), 2.03 (s, 2 H), 1.66-1.84 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -110.78, -126.12.

[0335] Example 35: (S)-3-(2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 35) [ka] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine HCl salt, (S)-3-(2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one was obtained in a manner similar to Example 34.

[0336] MS calculated: 622.19; MS found: 623.2 [M+H] + .

[0337] 1H NMR (400MHz, DMSO-d6): δ 12.74 (br s, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 7.53-7.60 (m, 2 H), 7.46 (dd, J=9.6 Hz, 2.0 Hz, 1 H), 7.30 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.88 (d, J=7.6 Hz, 1 H), 6.68 (d, J=8.0 Hz, 1 H), 5.38 (s, 2 H), 5.09-5.17 (m, 1 H), 4.76-4.85 (m, 1 H), 4.64-4.71 (m, 1 H), 4.44-4.51 (m, 1 H), 4.36-4.44 (m, 1 H), 3.99 (d, J=14.0 Hz, 1 H), 3.85 (d, J=13.6 Hz, 1 H), 2.98-3.06 (m, 1 H), 2.85-2.92 (m, 1 H), 2.61-2.75 (m, 2 H), 2.39-2.46 (m, 1 H), 2.20-2.33 (m, 2 H), 1.66-1.84 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.63, -111.38.

[0338] Example 36: 3-(2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 36) [ka] Starting from (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine, 3-(2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one was obtained in a manner similar to Example 34.

[0339] MS calculated: 632.20; MS found: 633.2 [M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6): δ 12.89 (br s, 1 H), 8.73 (d, J=2.4 Hz, 1 H), 8.02 (dd, J=8.4 Hz, 2.4 Hz, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.61-7.72 (m, 2 H), 6.83-6.89 (m, 2 H), 6.72-6.80 (m, 1 H), 5.01-5.11 (m, 1 H), 4.76-4.87 (m, 2 H), 4.61-4.70 (m, 1 H), 4.45-4.53 (m, 1 H), 4.30-4.38 (m, 1H), 3.65-3.81 (m, 2 H), 3.21-3.34 (m, 2 H), 2.89-3.04 (m, 1 H), 2.64-2.77 (m, 2 H), 2.25-2.38 (m, 1 H), 1.93-2.18 (m, 7 H). 19 F NMR (377MHz, DMSO-d6): δ -73.73, -124.85.

[0341] Example 37: 3-(2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 37) [ka] Step A: (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine HCl salt To a solution of tert-butyl (S)-4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (100 mg, 0.23 mmol) in dioxane (1 mL) was added HCl-dioxane (4 M, 1 mL) at room temperature. The solution was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine HCl salt (120 mg, crude). MS calculated: 330.11; MS found: 331.3 [M+H] + .

[0342] Step B: 5-bromo-2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole A mixture of (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine HCl salt (120 mg, crude), (S)-5-bromo-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (77 mg, 0.23 mmol), DIEA (91 mg, 0.70 mmol) in DMF (3.0 mL) was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction was concentrated under reduced pressure. The reaction mixture was purified by column chromatography (DCM:MeOH=95:5) to give 5-bromo-2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (120 mg, yield: 82.8%). MS calculated: 626.11; MS found: 627.5 [M+H] + .

[0343] Step C: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile A solution of 5-bromo-2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (120 mg, 0.19 mmol), Zn(CN) (66 mg, 0.38 mmol), dppf (8.0 mg, 0.015 mmol), and Pd(dba) (11 mg, 0.0096 mmol) in DMF (2 mL) was stirred at 125 °C for 16 h. After completion of the reaction, the reaction mixture was washed with HO (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (DCM:MeOH=95:5) to give 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 91.7% yield). MS calculated: 573.2; MS found: 574.4 [M+H] + .

[0344] Step D: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-N-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide A mixture of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 0.17 mmol), NHOH·HCl (18 mg, 0.26 mmol), and TEA (53 mg, 0.52 mmol) in EtOH (3.0 mL) was stirred at 30 °C for 16 h. After completion of the reaction, the reaction mixture was washed with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (DCM:MeOH=95:5) to give 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-N-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide (80 mg, 76.2% yield). MS calculated: 606.2; MS found: 607.3 [M+H] + .

[0345] Step E: 3-(2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one A mixture of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-N-hydroxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide (80 mg, 0.13 mmol) and CDI (43 mg, 0.26 mmol) in dioxane (1.0 mL) was stirred at 50° C. for 16 hours. After completion of the reaction, the reaction mixture was washed with water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was directly purified by preparative HPLC to give 3-(2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (25.4 mg, yield: 30.1%).

[0346] MS calculated: 632.20; MS found: 633.4 [M+H] + .

[0347] 1H NMR: δ 8.72 (d, J=2.4 Hz, 1 H), 8.01 (dd, J=2.4 Hz, J=8.4 Hz, 1 H), 7.93 (d, J=1.2 Hz, 1 H), 7.60 (d, J=8.4 Hz, 1 H), 7.50 (d, J=12.0 Hz, 1 H), 6.71-6.85 (m, 3 H), 5.07-5.17 (m, 1 H), 4.79-4.90 (m, 1 H), 4.67-4.71 (m, 1 H), 4.45-4.50 (m, 1 H), 4.34-4.39 (m, 1 H), 3.97 (d, J=13.6 Hz, 1 H), 3.84 (d, J=13.6 Hz, 1 H), 2.99-3.08 (m, 1 H), 2.88-2.97 (m, 1 H), 2.62-2.77 (m, 2 H), 2.41-2.50 (m, 1 H), 2.17-2.31 (m, 2 H), 2.01 (s, 3 H), 1.68-1.83 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -130.81.

[0348] Example 38: (S)-3-(2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 38) [ka] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine hydrochloride, (S)-3-(2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one was obtained in a manner similar to Example 37.

[0349] MS calculated: 622.2; MS found: 623.3 [M+H] + .

[0350] 1 H NMR (400MHz, CD3OD-d4): δ 7.97 (s, 1 H), 7.62 - 7.50 (m, 3 H), 7.24 - 7.19 (m, 2 H), 6.86 (d, J=7.2 Hz, 1 H), 6.66 (d, J=8.0 Hz, 1 H), 5.44 (s, 2 H), 5.33 - 5.26 (m, 1 H), 5.03 (dd, J=7.2 Hz / J=15.6 Hz, 1 H), 4.86 - 4.85 (m, 1 H), 4.69 - 4.63 (m, 1 H), 4.51 - 4.45 (m, 1 H), 4.08 (dd, J=13.2 Hz / J=39.6 Hz, 2 H), 3.16 - 3.14 (m, 1 H), 3.08 - 3.04 (m, 1 H), 2.90 - 2.81 (m, 1 H), 2.75 - 2.66 (m, 1 H), 2.59 - 2.53 (m, 1 H), 2.50 - 2.36 (m, 2 H), 1.99 - 1.87 (m, 4 H). 19 F NMR (377MHz, CD3OD-d4): δ (-117.63), (-133.66).

[0351] Example 39: 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 39) [ka] Starting from 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine HCl salt, 3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one was obtained in a manner similar to Example 37.

[0352] MS calculated: 647.17; MS found: 648.3 [M+H] + .

[0353] 1 H NMR: δ 7.93(s, 1 H), 7.45-7.62 (m, 3 H), 7.32-7.35 (m, 1 H), 6.82-6.88 (m, 3 H), 6.35-6.42 (m, 1 H), 5.04-5.14 (m, 1 H), 4.80-4.90 (m, 1 H), 4.65-4.75 (m, 1 H), 4.47-4.52 (m, 1 H), 4.32-4.43 (m, 1 H), 4.02-4.10 (m, 1 H), 3.88-3.99 (m, 1 H), 3.20-3.27 (m, 2 H), 2.69-2.82 (m, 3 H), 2.55-2.62 (m, 1 H), 2.36-2.46 (m, 2 H), 2.03 (s, 3 H). 19 F NMR (377MHz, DMSO-d6): δ -110.90, -131.21.

[0354] Example 40: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (Compound 40) [ka] Step A: 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole A mixture of (S)-5-bromo-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (78 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol), and TEA (76 mg, 0.75 mmol) in DMSO (5 mL) was stirred at room temperature for 10 min. To the mixture was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine.TsOH (50 mg, 0.15 mmol), and the mixture was stirred for 3 h. The mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and purified by silica gel column chromatography (DCM:MeOH=30:1) to give 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (84 mg, yield: 87.3%). MS calculated: 643.1; MS found: 644.2 [M+H] +

[0355] Step B: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole 5-Bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (84 mg, 0.13 mmol), 3-methyl-4-((2-(trimethylsilyl)ethoxy) A mixture of (methyl)-4H-1,2,4-triazole (83 mg, 0.39 mmol), Pd(OAc) (3.0 mg, 0.013 mmol), pivalic acid (2.7 mg, 0.026 mmol), Pcy.HBF (3.0 mg, 0.0079 mmol), and KCO (133 mg, 0.79 mmol) with toluene (5 mL) was stirred at 115 °C for 16 h under Ar. The mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and purified by silica gel column chromatography (DCM:MeOH=30:1) to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (10 mg, yield: 9.8%). MS calculated: 776.3; MS found: 777.5 [M+H] +

[0356] Step C: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole A mixture of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (10 mg, 0.0129 mmol) and aqueous TBAF in THF (1 M, 0.5 mL) in THF (3 mL) was stirred at 50° C. for 4 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (4.7 mg, yield: 51.4%). MS calculated: 646.2; MS found: 647.4 [M+H] +

[0357] 1H NMR (400MHz, CD3OD-d4): δ 7.84 (s, 1 H), 7.58 (t, J=8.4 Hz, 2 H), 7.28 (dd, J1=10.4 Hz / J2=8.8 Hz, 1 H), 7.21 (d, J=8.8 Hz, 1 H), 6.79 - 6.68 (m, 3 H), 5.31 - 5.26 (m, 1 H), 4.92 - 4.81 (m, 1 H), 4.72 (d, J=15.2 Hz, 1 H), 4.66 - 4.61 (m, 1 H), 4.50 - 4.45 (m, 1 H), 4.04 (d, J=14.4 Hz, 1 H), 3.91 (d, J=13.6 Hz, 1 H), 3.13 - 3.07 (m, 1 H), 2.97 - 2.93 (m, 1 H), 2.84 - 2.79 (m, 1 H), 2.74 - 2.69 (m, 1 H), 2.57 - 2.44 (m, 4 H), 2.37 - 2.26 (m, 2 H), 2.03 (s, 3 H), 1.95 - 1.78 (m, 4 H). 19 F NMR (377MHz, CD3OD-d4): δ (-112.35), (-130.41).

[0358] Example 41: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (Compound 41) [ka] Step A: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole A mixture of 5-bromo-2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (50 mg, 0.078 mmol), Pd(OAc) (1.7 mg, 0.0078 mmol), pivalic acid (0.47 mg, 0.0047 mmol), Pcy.HBF (5.7 mg, 0.016 mmol), and KCO (65 mg, 0.47 mmol) was stirred with toluene (5 ml) at 120 °C for 16 h under Ar. The mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and purified by silica gel column chromatography (DCM:MeOH=30:1) to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (20 mg, yield: 33.1%). MS calculated: 776.3; MS found: 777.4 [M+H] +

[0359] Step B: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole A mixture of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (24 mg, 0.032 mmol) and TBAF (1 M, 1 ml) in THF (4 mL) was stirred at 50° C. for 4 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (4.3 mg, yield: 22.2%). MS calculated: 646.2; MS found: 647.2 [M+H] +

[0360] 1H NMR (400MHz, CD3OD-d4): δ 8.12 (s, 1 H), 7.69 (d, J=13.2 Hz, 1 H), 7.58 (t, J=8.4 Hz, 1 H), 7.27 (dd, J1=10.8 Hz / J2=9.2 Hz, 2 H), 7.20 (d, J=9.2 Hz, 1 H), 6.77 - 6.68 (m, 3 H), 5.28 (d, J=5.2 Hz, 1 H), 5.05 - 5.00 (m, 1 H), 4.80 - 4.79 (m, 1 H), 4.66 - 4.58 (m, 2 H), 4.49 - 4.45 (m, 1 H), 4.05 (d, J=12.8 Hz, 1 H), 3.94 (d, J=14.4 Hz, 1 H), 3.13 - 3.08 (m, 1 H), 3.02 - 2.98 (m, 1 H), 2.86 - 2.80 (m, 1 H), 2.75 - 2.70 (m, 1 H), 2.57 - 2.50 (m, 4 H), 2.36 - 2.31 (m, 2 H), 2.03 (s, 3 H), 1.97 - 1.79 (m, 4 H). 19 F NMR (377MHz, CD3OD-d4): δ (-112.37), (-134.90).

[0361] Example 42: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (Compound 42) [ka] 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole was obtained in a manner similar to Example 41. MS calculated: 629.2; MS found: 630.4 [M+H] +

[0362] 1 H NMR (400MHz, CD3OD-d4): δ 8.60 - 8.59 (m, 1 H), 8.13 (s, 1 H), 7.87 (dd, J1=8.4 Hz / J2=6 Hz, 1 H), 7.72 - 7.64 (m, 2 H), 6.79 - 6.65 (m, 3 H), 5.28 (s, 1 H), 5.03 - 4.92 (m, 1 H), 4.81 - 4.79 (m, 1 H), 4.63 (d, J=6.8 Hz, 1 H), 4.45 (d, J=13.2 Hz, 1 H), 4.09 - 4.04 (m, 1 H), 3.98 - 3.95 (m, 1 H), 3.15 - 3.04 (m, 2 H), 2.84 - 2.76 (m, 2 H), 2.50 (s, 4 H), 2.39 - 2.31 (m, 2 H), 2.01 (s, 3 H), 1.94 - 1.77 (m, 4 H). 19 F NMR (377MHz, CD3OD-d4): δ (-74.00), (-75.88).

[0363] Example 43: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole (Compound 43) [ka] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole was obtained in a manner similar to Example 41. MS calculated: 644.2; MS found: 645.3 [M+H] + .

[0364] 1 H NMR (400MHz, CD3OD-d4): δ 8.13 (s, 1 H), 7.69 (d, J=13.2 Hz, 1 H), 7.56 (t, J=9.2 Hz, 1H), 7.27 (d, J=9.6 Hz, 1 H), 7.20 (d, J=8.8 Hz, 1 H), 6.87 - 6.78 (m, 2 H), 6.74 (d, J=7.2 Hz, 1 H), 6.40 (s, 1 H), 4.65 - 4.58 (m, 5 H), 4.14 (d, J=14.0 Hz, 1 H), 4.03 (d, J=13.2 Hz, 1 H), 2.91 - 2.77 (m, 3H), 2.70 - 2.53 (m, 3 H), 2.50 (s, 5 H), 2.03 (s, 3 H). 19 F NMR (377MHz, CD3OD-d4): δ (-112.51), (-134.62).

[0365] Example 44: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 44) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained. MS calculated: 681.19; MS found: 682.0 [M+H] + .

[0366] 1 H NMR (400MHz, DMSO-d6): δ 9.13 (s, 1 H), 8.28 (s, 1 H), 7.51-7.60 (m, 2 H), 7.33 (d, J=8.0 Hz, 1 H), 6.81-6.88 (m, 3 H), 6.35-6.42 (m, 1 H), 5.09-5.18 (m, 1 H), 4.85-4.95 (m, 1 H), 4.70-4.78 (m, 1 H), 4.36-4.53 (m, 1 H), 4.07-4.15 (m, 1 H), 3.94-4.02 (m, 1 H), 3.17-3.32 (m, 2H), 2.65-2.84 (m, 3 H), 2.39-2.46 (m, 3 H), 2.03 (s, 3 H). 19 F NMR(377MHz, DMSO-d6): δ -63.15, -110.92.

[0367] Example 45: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine (Compound 45) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine was obtained. MS calculated: 681.19; MS found: 682.0 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6): δ 9.00 (d, J=2.0 Hz, 1 H), 8.58 (d, J=1.6 Hz, 1 H), 7.52-7.61 (m, 2 H), 7.34 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 6.81-6.90 (m, 3 H), 6.38-6.45 (m, 1 H), 5.13-5.22 (m, 1 H), 4.66-4.87 (m, 2 H), 4.33-4.53 (m, 2 H), 4.11 (d, J=13.6 Hz, 1 H), 4.02 (d, J=13.6 Hz, 1 H), 2.65-2.83 (m, 5 H), 2.39-2.45 (m, 3 H), 2.04 (s, 3 H). 19 F NMR(377MHz, DMSO-d6): δ -62.97, -110.90.

[0369] Example 46: 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-(((S)-oxetan-2-yl)methyl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-7H-imidazo[4,5-c]pyridazine (Compound 46) [ka] 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-7-(((S)-oxetan-2-yl)methyl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-7H-imidazo[4,5-c]pyridazine was obtained. MS calculated: 682.18; MS found: 683.0 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6): δ 8.53 (s, 1 H), 7.50-7.62 (m. 2 H), 7.33 (dd, J=8.4 Hz, 1.6 Hz, 1 H), 6.80-6.91 (m, 3 H), 6.36-6.44 (m, 1 H), 5.20-5.31 (m, 1 H), 4.84-5.06 (m, 2 H), 4.33-4.55 (m, 2 H), 4.09-4.24 (m, 2 H), 2.57-2.91 (m, 6 H), 2.30-2.46 (m, 2 H), 2.03 (s, 3 H). 19 F NMR(377MHz, DMSO-d6): δ -63.65, -110.89.

[0371] Example 47: 6-[(4-chloro-2-fluorophenyl)methoxy]-3-fluoro-2-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 47) [ka] Step A: 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine To a solution of 2-bromo-3,6-difluoropyridine (300 mg, 1.55 mmol) and (4-chloro-2-fluorophenyl)methanol (250 mg, 1.55 mmol) in THF (6 mL) was added t-BuOK (1.71 mL, 1 mol / L, 1.71 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under N 2 . The reaction was quenched with HO (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 10 / 1) to give 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (446 mg, 86.2% yield) as a white solid.

[0372] Step B: tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate To a solution of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (446 mg, 1.34 mmol) in dioxane (15 mL) and HO (1.5 mL) was added Pd(dppf)Cl·DCM (109 mg, 0.13 mmol), KCO (554 mg, 4.01 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (455 mg, 1.47 mmol). The mixture was stirred at 95 °C for 16 h under N. The reaction was quenched with HO (50 mL) and extracted with ethyl acetate (70 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=10 / 1) to give tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (575 mg, 98.4% yield) as a colorless oil. MS calculated: 436.1; MS found: 437.0 [M+H] + .

[0373] Step C: tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)piperidine-1-carboxylate A mixture of tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (555 mg, 1.27 mmol) in THF (6 mL) was stirred at room temperature under H for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated to give tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)piperidine-1-carboxylate (450 mg, crude) as a yellow oil. MS calculated: 438.2; MS found: 383.0 [M+H-56]. + .

[0374] Step D: 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-2-(piperidin-4-yl)pyridine To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate (250 mg) in DCM (2.4 mL) was added TFA (0.6 mL). The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to give 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-2-(piperidin-4-yl)pyridine TFA salt (325 mg, crude). MS calculated: 338.1; MS found: 339.3 [M+H] + .

[0375] Step E: 6-[(4-chloro-2-fluorophenyl)methoxy]-3-fluoro-2-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine 6-[(4-chloro-2-fluorophenyl)methoxy]-3-fluoro-2-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (compound 47) (61 mg) was obtained in a manner similar to that described in Example 1. MS calculated: 674.2; MS found: 675.2 [M+H] + .

[0376] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.27 (s, 1 H), 7.52-7.65 (m, 2 H), 7.47 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.27-7.33 (m, 1 H), 6.75 (dd, J=8.8, 2.8 Hz, 1 H), 5.37 (s, 2 H), 5.16-5.25 (m, 1 H), 4.87-4.97 (m, 1 H), 4.73-4.81 (m, 1 H), 4.39-4.54 (m, 2 H), 4.01 (d, J=13.6 Hz, 1 H), 3.86 (d, J=14.0 Hz, 1 H), 2.98-3.08 (m, 1 H), 2.84-2.96 (m, 2 H), 2.65-2.79 (m, 1 H), 2.18-2.36 (m, 3 H), 1.73-1.90 (m, 2 H), 1.61-1.73 (m, 2 H). 19 F NMR (377MHz, DMSO-d6): δ -63.37, -115.28, -138.88.

[0377] Example 48: 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazine (Compound 48) [ka] Step A: 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine To a solution of 2-bromo-3,5,6-trifluoropyridine (2 g, 9.43 mmol) in THF (40 mL) was added (4-chloro-2-fluorophenyl)methanol (1.59 g, 9.91 mmol) and t-BuOK (1 M, 10.37 mL). The solution was stirred at 0 °C for 2 h. After completion of the reaction, the mixture was diluted with HO (100 mL) and extracted with EA (60 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE) to give 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine (2.8 g, yield: 85%) as a white solid. MS calculated: 350.9; MS found: 351.9 [M+H] + .

[0378] Step B: tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine-1-carboxylate A mixture of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine (400 mg, 1.14 mmol), tert-butyl piperazine-1-carboxylate (318 mg, 1.71 mmol), Pd(dba) (104 mg, 0.12 mmol), Xantphos (139 mg, 0.24 mmol), and CsCO (741 mg, 42.3 mmol) in dioxane (10.0 mL) was stirred at 110 °C for 3 h. After completion of the reaction, the mixture was diluted with HO (40 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=20 / 1) to give tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine-1-carboxylate (660 mg, crude) as a yellow oil. MS calculated: 457.1; MS found: 402.1 [M-56+H] + .

[0379] Step C: 1-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine TFA salt To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine-1-carboxylate (350 mg, crude) in DCM (4 mL) was added TFA (1.0 mL). The solution was stirred at room temperature for 1 hour. The reactants were removed under reduced pressure to give 1-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine TFA salt (400 mg, crude) as a yellow oil. MS calculated: 357.1; MS found: 358.1 [M+H] + .

[0380] Step D: 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazine (Compound 48) 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazine (compound 48) (12.8 mg) was obtained in a manner similar to that described in Example 1.

[0381] MS calculated: 693.2; MS found: 693.9 [M+H] + .

[0382] 1 H NMR (400MHz, DMSO-d6): δ 9.28 (s, 1 H), 8.37 (s, 1 H), 7.85-7.95 (m, 1 H), 7.56 (t, J=8.0 Hz, 1 H), 7.49 (d, J=10.0 Hz, 2.0 Hz, 1 H), 7.33 (d, J=8.4 Hz, 2.0 Hz, 1 H), 5.42 (s, 2 H), 5.06-5.18 (m, 1 H), 4.87-4.98 (m, 1 H), 4.72-4.81 (m, 1 H), 4.48-4.56 (m, 1 H), 4.37-4.46 (m, 1 H), 3.11-3.40 (m, 7 H), 2.64-2.84 (m, 4 H), 2.29-2.46 (m, 1 H). 19 F NMR(377MHz, DMSO-d6): δ -63.72, -115.08, -135.46, -148.17.

[0383] Example 49: 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (Compound 49) [ka] Step A: tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate To a solution of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine (1.0 g, 2.85 mmol) in dioxane (30 mL) and HO (3 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (968 mg, 3.13 mmol), KCO (1.2 g, 8.55 mmol), and Pd(dppf)Cl DCM (204 mg, 0.28 mmol) at RT under N. The mixture was stirred at 95 °C for 16 h, cooled to room temperature, diluted with ethyl acetate (100 mL), and extracted with HO (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=20 / 1) to give tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (1.15 g, yield: 88.0%) as a yellow solid. MS calculated: 454.1; MS found: 399.0 [M-56+H] + .

[0384] Step B: tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidine-1-carboxylate To a solution of tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (600 mg, 1.32 mmol) in THF (6.0 mL) was added Pd / C (10% w / w, 360 mg). The solution was stirred at room temperature under a stream of H for 2 hours. The mixture was filtered, and the filtrate was evaporated to give tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidine-1-carboxylate (690 mg, crude) as a yellow oil. MS calculated: 456.1; MS found: 401.0 [M-56+H] + .

[0385] Step C: 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidine-1-carboxylate (690 mg, crude) in DCM (6.0 mL) was added TFA (2 mL). The solution was stirred at room temperature for 2 hours. The solvent was removed to give 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt (890 mg, crude) as a yellow oil. MS calculated: 356.1; MS found: 357.1 [M+H] + .

[0386] Step D: 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}pyridine (25.23 mg) was obtained in a manner similar to Example 1. MS calculated: 692.2; MS found: 693.0 [M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.27 (s, 1 H), 7.89 (t, J=9.6 Hz, 1 H), 7.60 (t, J=8.0 Hz, 1 H), 7.48 (dd, J=10.0 Hz, 1.6 Hz, 1 H), 7.32 (dd, J=8.0 Hz, 1.6 Hz, 1 H), 5.47 (s, 2 H), 5.15-5.24 (m, 1 H), 4.88-4.97 (m, 1 H), 4.73-4.81 (m, 1 H), 4.40-4.53 (m, 2 H), 4.00 (d, J=14.0 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 2.98-3.08 (m, 1 H), 2.85-2.97 (m, 2 H), 2.65-2.80 (m, 1 H), 2.42-2.49 (m, 1 H), 2.19-2.34 (m, 2 H), 1.60-1.90 (m, 4 H). 19 F NMR (377MHz, DMSO-d6): δ -63.30, -115.08, -133.85, -138.38.

[0388] Example 50: 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]piperidin-4-yl}pyridine (Compound 50) [ka] Step A: 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidine-1-carboxylate (690 mg, 1.51 mmol) in DCM (6 mL) was added TFA (2 mL). The solution was stirred at room temperature for 1 hour. The reactants were removed under reduced pressure to give 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt (890 mg, crude).

[0389] Step B: (S)-3-chloro-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt (600 mg, crude), (S)-3-chloro-6-(chloromethyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine (350 mg, 1.28 mmol), and KCO (648 mg, 5.00 mmol) in DMF (6 mL) was stirred at 60° C. for 3 h. After completion of the reaction, the mixture was diluted with HO (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=5 / 1) to give (S)-3-chloro-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine (400 mg, yield: 53%). MS calculated: 592.1; MS found: 593.0 [M+H]+ .

[0390] Step C: Ethyl (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate To a mixture of (S)-3-chloro-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine (360 mg, 0.62 mmol) in EtOH (6.0 mL) was added PdCl(dppf) (90.5 mg, 0.12 mmol) and KOAc (182 mg, 1.86 mmol). The mixture was stirred at 75° C. for 1 hour under CO. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=80 / 1) to give ethyl (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate (330 mg, yield: 76%). MS calculated: 630.2; MS found: 631.2 [M+H] + .

[0391] Step D: (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid To a mixture of ethyl (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate (330 mg, 0.52 mmol) in MeOH (4.0 mL) was added NaOH (2 M, 1.0 mL, aq.). The mixture was stirred at RT for 1 h. After completion of the reaction, the mixture was adjusted to pH = 7 with 1 N HCl (aq) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid (300 mg, yield: 95%). MS calculated: 602.2; MS found: 603.0 [M+H] + .

[0392] Step E: (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide A mixture of (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid (300 mg, 0.50 mmol), NH4Cl (40 mg, 0.75 mmol), HATU (285 mg, 0.75 mmol), DIEA (129 mg, 1.00 mmol) in DMF (5.0 mL) was stirred at RT for 1 h. After completion of the reaction, the mixture was diluted with HO (30 mL) and extracted with EA (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=80 / 1) to give (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide (220 mg, yield: 73%). MS calculated: 601.2; MS found: 602.2 [M+H] + .

[0393] Step F: (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile A mixture of (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide (220 mg, 0.37 mmol), Burgess reagent (349 mg, 1.46 mmol) in DCM (4.0 mL) was stirred at RT for 2 h. After completion of the reaction, the mixture was diluted with HO (20 mL) and extracted with EA (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH=60 / 1) to give (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile (140 mg, yield: 66%). MS calculated: 583.2; MS found: 584.1 [M+H] + .

[0394] Step G: (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide A solution of (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile (140 mg, 0.24 mmol), HONH2·HCl (100.13 mg, 1.44 mmol), and TEA (96.96 mg, 0.96 mmol) in EtOH (4 mL) was stirred at 90 °C for 1 h. After completion of the reaction, the mixture was filtered and the solid dried to give (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide (110 mg, yield: 74%) as a white solid. MS calculated: 616.2; MS found: 617.2 [M+H] + .

[0395] Step H: (S)-3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole To a solution of (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide (110 mg, 0.18 mmol) in THF (2 mL) was added TFAA (74.99 mg, 0.36 mmol), and the mixture was stirred at RT for 1 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (5.0 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=30 / 1) to give (S)-3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, yield: 65%) as a yellow solid. MS calculated: 694.2; MS found: 695.2 [M+H] + .

[0396] Step I: 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]piperidin-4-yl}pyridine (Compound 50) A mixture of (S)-3-(6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, 0.12 mmol) and N2H4·HO (12.00 mg, 0.24 mmol) in DMF (2 mL) was stirred at RT for 1 h. After completion of the reaction, the mixture was directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-3,5-difluoro-6-{1-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]piperidin-4-yl}pyridine (30.8 mg, 39% yield) as a white solid. MS calculated: 693.2; MS found: 694.0 [M+H] + .

[0397] 1 H NMR (400MHz, DMSO-d6): δ 8.49 (s, 1 H), 7.89 (t, J=9.2 Hz, 1 H), 7.58 (t, J=8.4 Hz, 1 H), 7.49 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.32 (dd, J=8.0 Hz, 1.6 Hz, 1 H), 5.46 (s, 2 H), 5.25-5.36 (m. 1 H), 4.99-5.09 (m. 1 H), 4.87-4.96 (m, 1 H), 4.39-4.55 (m, 2 H), 4.01-4.09 (m, 2 H), 2.86-3.06 (m, 3H), 2.70-2.82 (m, 1 H), 2.50-2.63 (m, 1 H), 2.26-2.38 (m, 2 H), 1.77-1.93 (m, 2 H), 1.64-1.75 (m, 2 H). 19F NMR(377MHz, DMSO-d6): δ -63.28, -114.99, -133.85, -138.37.

[0398] Example 51: 1-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one (Compound 51) [ka] Step A: tert-butyl 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate 4-Bromo-2-((4-chloro-2-fluorobenzyl)oxy)-1-fluorobenzene (1.0 g, 3.0 mmol), tert-butyl 3-oxopiperazine-1-carboxylate (602 mg, 3.0 mmol), CuI (57 mg, 0.3 mmol), K2CO3 (831 mg, 6.0 mmol), and (1R,2R)-N 1 ,N 2 A mixture of 43 mg (0.3 mmol) of 1,2-dimethylcyclohexane-1,2-diamine in 15 mL of dioxane was stirred at 120° C. for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=2:1) ​​to give tert-butyl 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate (498 mg, 81% yield) as a white solid. MS calculated: 452.1; MS found: 397.2 [M-56+H] + .

[0399] Step B: 1-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)piperazin-2-one TFA salt A mixture of tert-butyl 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate (150 mg, 0.33 mmol), TFA (1 mL) in DCM (3 mL) was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure to give 1-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)piperazin-2-one TFA salt (176 mg, crude) as a yellow oil. MS calculated: 352.1; MS found: 353.1 [M+H] + .

[0400] Step C: 1-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one 1-{3-[(4-chloro-2-fluorophenyl)methoxy]-4-fluorophenyl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one was obtained in a manner similar to that described in Example 1 (41.7 mg). MS calculated: 688.2; MS found: 689.3 [M+H] + .

[0401] 1 H NMR (400MHz, DMSO-d6): 1H NMR: δ 9.19 (s, 1 H), 8.32 (s, 1 H), 7.61 (t, J=8.4 Hz, 1 H), 7.51 (dd, J=10.0 Hz, J=2.0 Hz, 1 H), 7.32-7.38 (m, 2 H), 7.25 (dd, J=11.2 Hz, J=8.8 Hz, 1 H), 6.90-6.98 (m, 1 H), 5.10-5.19 (m, 3 H), 4.87-4.96 (m, 1 H), 4.73-4.81 (m, 1 H), 4.47-4.55 (m, 1 H), 4.38-4.44 (m, 1 H), 4.14 (d, J=14.0 Hz, 1 H), 4.05 (d, J=14.0 Hz, 1 H), 3.62-3.69 (m, 2 H), 3.38-3.47 (m, 2 H), 2.93-3.00 (m, 2 H), 2.69-2.80 (m, 1 H), 2.40-2.51 (m, 1 H). 19 F NMR (377MHz, DMSO-d6): δ -63.70, -115.03, -136.54.

[0402] Example 52: 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one (Compound 52) [ka] Step A: tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate To a solution of 6-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (600 mg, 2.08 mmol) in dioxane (25 mL) was added Xantphos (361 mg, 0.62 mmol), Pd(dba) (380 mg, 0.42 mmol), CsCO (1.35 g, 4.14 mmol), and tert-butyl 3-oxopiperazine-1-carboxylate (830 mg, 4.15 mmol). The mixture was stirred at 90 °C for 16 h under N. The reaction was quenched with HO (50 mL) and extracted with ethyl acetate (70 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA=4 / 1) to give tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate (230 mg, 24.5% yield) as a yellow oil. MS calculated: 453.1; MS found: 454.1 [M+H] + .

[0403] Step B: 1-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperazin-2-one To a solution of tert-butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate (210 mg, 0.46 mmol) in DCM (5 mL) was added TFA (1.25 mL). The solution was stirred at room temperature for 1 hour. The reactants were evaporated under reduced pressure to give 1-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperazin-2-one TFA salt (256 mg, crude) as a yellow oil. MS calculated: 353.1; MS found: 354.0 [M+H] + .

[0404] Step C: 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one 1-{6-[(4-chloro-2-fluorophenyl)methoxy]-5-fluoropyridin-2-yl}-4-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperazin-2-one (66.4 mg) was obtained in a manner similar to Example 1. MS calculated: 689.2; MS found: 690.1 [M+H] + .

[0405] 1 H NMR (400MHz, DMSO-d6): δ 9.18 (s, 1 H), 8.31 (s, 1 H), 7.75 (t, J=9.2 Hz, 1 H), 7.51-7.60 (m, 2 H), 7.48 (dd, J=10.4 Hz, 2.0 Hz, 1 H), 7.33 (dd, J=8.0 Hz, 1.6 Hz,1 H), 5.44 (s, 2 H), 5.09-5.18 (m, 1 H), 4.86-4.96 (m, 1 H), 4.72-4.81 (m, 1 H), 4.46-4.54 (m, 1 H), 4.37-4.43 (m, 1 H), 4.13 (d, J=13.6 Hz, 1 H), 4.03 (d, J=13.6 Hz, 1 H), 3.82-3.90 (m, 2 H), 3.383.51 (m, 2 H), 2.93-3.00 (m, 2 H), 2.65-2.77 (m, 1 H), 2.37-2.47 (m, 1 H). 19 F NMR (377MHz, DMSO-d6): δ -63.58, -115.00, -144.94.

[0406] Example 53: 4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidine (Compound 53) [ka] Starting from 4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine, 4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidine was obtained in a manner analogous to Example 1. MS calculated: 667.2; MS found: 668.0 [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6): δ 9.00 (d, J=2.0 Hz, 1 H), 8.59 (d, J=2.0 Hz, 1 H), 7.55-7.65 (m. 1 H), 7.30-7.40 (m. 1 H), 7.07-7.16 (m. 1 H), 6.70-6.83 (m. 3 H), 5.15-5.27 (m. 1 H), 4.82-4.91 (m. 1 H), 4.69-4.78 (m, 1 H), 4.44-4.53 (m, 1 H), 4.34-4.43 (m, 1 H), 3.90-4.04 (m, 2 H), 2.91-3.06 (m, 2 H), 2.61-2.74 (m, 2 H), 2.42-2.52 (m, 1 H), 2.20-2.36 (m, 2 H), 2.02 (s, 3 H), 1.69-1.87 (m, 4 H). 19F NMR(377MHz, DMSO-d6): δ -63.64, -108.51, -108.53, -109.09, -109.10, -109.11.

[0408] Example 54: 4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidine (Compound 54) [ka] Starting from 4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine, 4-[2-(2,4-difluorophenyl)-2-methyl-2H-1,3-benzodioxol-4-yl]-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidine was obtained in a manner analogous to Example 1. MS calculated: 667.2; MS found: 668.4 [M+H] + .

[0409] 1H NMR (400MHz, DMSO-d6): δ 9.17 (s, 1 H), 8.29 (s, 1 H), 7.57-7.64 (m. 1 H), 7.32-7.40 (m. 1 H), 7.08-7.15 (m. 1 H), 6.70-6.81 (m. 3 H), 5.14-5.23 (m. 1 H), 4.88-4.97 (m. 1 H), 4.72-4.79 (m, 1 H), 4.39-4.53 (m, 2 H), 4.02 (d, J=12.8 Hz, 1 H), 3.86 (d, J=13.6 Hz, 1 H), 3.00-3.08 (m, 1H), 2.85-2.93 (m, 1 H), 2.60-2.80 (m, 2 H), 2.43-2.52 (m, 1 H), 2.17-2.35 (m, 2 H), 2.02 (s, 3 H), 1.68-1.85 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.72, -108.48, -108.50, -109.07, -109.10, -109.11, -109.14.

[0410] Example 55: 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine (Compound 55) [ka] Step A: 2-methyl-5-((trimethylsilyl)ethynyl)pyridine A mixture of 5-bromo-2-methylpyridine (30.0 g, 174 mmol), ethynyltrimethylsilane (18.8 g, 192 mmol), CuI (663 mg, 3.5 mmol), and Pd(PPh)Cl (4.9 g, 7.0 mmol) in DMSO (300 mL) and TEA (24 mL) was stirred at 50 °C for 16 h. After completion of the reaction, the mixture was washed with HO (3 L × 2) and extracted with EA (1.5 L). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 10 / 1) to give 2-methyl-5-((trimethylsilyl)ethynyl)pyridine (29.5 g, 90% yield) as a yellow oil. MS calculated: 189.1; MS found: 190.1 [M+H] + .

[0411] Step B: 5-ethynyl-2-methylpyridine A mixture of 2-methyl-5-((trimethylsilyl)ethynyl)pyridine (29.5 g, 156 mmol), K2CO3 (107.7 g, 780 mmol) in MeOH (300 mL) was stirred at RT overnight. After completion of the reaction, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (PE / EA=15 / 1) to give 5-ethynyl-2-methylpyridine (4.1 g, 22.6% yield) as a pale yellow solid. MS calculated: 117.1; MS found: 118.2 [M+H] + .

[0412] Step C: 5-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-2-methylpyridine 3-Bromobenzene-1,2-diol (5.4 g, 28.5 mmol), 5-ethynyl-2-methylpyridine (4.0 g, 34.2 mmol), and Ru(CO) 12A mixture of (910 mg, 1.42 mmol) in toluene (40 mL) was stirred at 110 °C for 16 h under N2. After completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (PE / EA = 20 / 1) to give 5-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-2-methylpyridine (2.3 g, yield: 26.3%) as a yellow oil. MS calculated: 305.0; MS found: 305.9 [M+H] + .

[0413] Step D: tert-butyl 4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 5-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-2-methylpyridine (2.3 g, 7.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.7 g, 8.6 mmol), KCO (3.0 g, 21.6 mmol), and Pd(dppf)Cl (294 mg, 0.36 mmol) in dioxane / HO (20 mL / 2 mL) was stirred at 90 °C for 16 h. After completion of the reaction, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (PE / EA=3 / 1) to give tert-butyl 4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.5 g, yield: 84.9%) as a yellow oil. MS calculated: 408.2; MS found: 409.3 [M+H] + .

[0414] Step E: 2-((4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile To a solution of 2-methyl-5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine TFA salt (225 mg, crude) in DMF (2 mL) was added DIEA (315 mg, 2.4 mmol). After 2 minutes, (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (71 mg, 0.27 mmol) was added. The mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the mixture was evaporated to dryness. The residue was purified by preparative TLC (EA=100%) to give 2-((4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (110 mg, 84.1% yield) as a pale yellow solid. MS calculated: 536.2; MS found: 537.4 [M+H] +

[0415] Step H: N-hydroxy-2-((4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide A solution of 2-((4-(-2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (110 mg, 0.20 mmol), NHOH HCl (43 mg, 0.62 mmol), and DIEA (80 mg, 0.62 mmol) in EtOH (1 mL) was stirred at 60 °C for 1 h. After completion of the reaction, the mixture was filtered to give N-hydroxy-2-((4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (150 mg, crude) as a yellow solid. MS calculated: 569.3; MS found: 570.4 [M+H] + .

[0416] Step I: 2-methyl-5-(2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl)pyridine To a solution of N-hydroxy-2-((4-(2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (150 mg) in THF (2 mL) was added TFAA (5 drops), and the mixture was stirred at 60 °C for 1 h. After completion of the reaction, the reaction was quenched with aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=60 / 1) to give 2-methyl-5-(2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl)pyridine (105 mg, yield: 79.1%) as a yellow oil. MS calculated: 647.2; MS found: 648.4 [M+H] + .

[0417] Step J: 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine A mixture of 2-methyl-5-(2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl)pyridine (105 mg, 0.16 mmol) and N2H4·H2O (2 drops) in DMF (1 mL) was stirred at RT for 1 h. After completion of the reaction, the reaction mixture was directly purified by preparative HPLC to give 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine (32.8 mg, yield: 31.3%). MS calculated: 646.3; MS found: 647.3 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6): δ 9.15 (d, J=0.8 Hz, 1 H), 8.64 (d, J=2.0 Hz, 1 H), 8.28 (d, J=0.8 Hz, 1 H), 7.83 (dd, J=8.0 Hz, J=2.4 Hz 1 H), 7.30 (d, J=8.0 Hz, 1 H), 6.70-6.82 (m, 3 H), 5.13-5.22 (m, 1 H), 4.86-4.98 (m, 1 H), 4.71-4.79 (m. 1 H), 4.38-4.55 (m, 2 H), 4.02 (d, J=13.6 Hz, 1 H), 3.85 (d, J=13.6 Hz, 1 H), 3.00-3.10 (m, 1 H), 2.84-2.92 (m, 1 H), 2.60-2.80 (m, 2 H), 2.45-2.49 (m, 4 H), 2.17-2.37 (m, 2 H), 2.00 (s, 3 H), 1.65-1.86 (m, 4H). 19 F NMR (377MHz, DMSO-d6): δ -63.56.

[0419] Example 56: 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine (Compound 56) [ka] Step A: 2-((4-((S)-2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile A mixture of (S)-2-methyl-5-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine TFA salt (144 mg, crude), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (80 mg, 0.31 mmol), and TEA (0.6 mL) in DMF (2.5 mL) was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction was quenched with HO (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by pre-TLC (DCM:MeOH=30:1) to give 2-((4-((S)-2-methyl-2-(6-methylpyridin-3-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (100 mg, 61% yield) as a yellow oil. MS calculated: 536.2; MS found: 537.4 [M+H] + .

[0420] Step B: 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine 2-Methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-4-yl}-2H-1,3-benzodioxol-2-yl]pyridine (33.1 mg) was obtained in a manner similar to Example 55. MS calculated: 646.3; MS found: 647.5 [M+H] + .

[0421] 1 H NMR (400MHz, DMSO-d6): 1 H NMR: δ 8.99 (d, J=2.0 Hz, 1 H), 8.64 (d, J=2.4 Hz, 1 H), 8.56 (d, J=2.0 Hz, 1 H), 7.84 (dd, J=8.0 Hz, J=2.4 Hz 1 H), 7.31 (d, J=8.0 Hz, 1 H), 6.70-6.82 (m, 3 H), 5.16-5.25 (m, 1 H), 4.79-4.88 (m, 1 H), 4.68-4.76 (m. 1 H), 4.44-4.51 (m, 1 H), 4.34-4.42 (m, 1 H), 3.89-4.02 (m, 2H), 2.91-3.05 (m, 2 H), 2.60-2.75 (m, 2 H), 2.45-2.49 (m, 4 H), 2.20-2.35 (m, 2 H), 2.00 (s, 3 H), 1.68-1.84 (m, 4 H). 19 F NMR(377MHz, DMSO-d6): δ -63.05.

[0422] Example 57: (3,4-trans)-4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-3-ol (Compound 57) [ka] Step A: trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-ol TFA salt To a mixture of tert-butyl trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidine-1-carboxylate (175 mg, 0.40 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure to afford trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-ol TFA salt (235 mg, crude) as a yellow oil. MS calculated: 336.1; MS found: 337.3 [M+H] + .

[0423] Step B: 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile A mixture of trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-ol TFA salt (235 mg, crude) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (100 mg, 0.38 mmol) and TEA (0.5 mL) in DMF (3.5 mL) was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction was quenched with HO (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layers were combined, washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was purified by preparative TLC (DCM:MeOH=20:1) to give 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (180 mg, 80% yield) as a yellow oil. MS calculated: 562.2; MS found: 563.3 [M+H] + .

[0424] Step C: 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide To a solution of 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (180 mg, 0.32 mmol) and TEA (0.3 mL) in EtOH (3 mL) was added hydroxylamine hydrochloride (44 mg, 0.64 mmol). The reaction was stirred at 60° C. for 0.5 h. After completion of the reaction, the reaction was filtered and the solid collected and dried to give 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (132 mg, 69% yield) as a white solid. MS calculated: 595.2; MS found: 596.2 [M+H] + .

[0425] Step D: (3,4-trans)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-((3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)piperidin-3-ol To a solution of 2-((trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (130 mg, 0.22 mmol) in THF (3 mL) was added TFAA (101 mg, 0.48 mmol). The reaction was stirred at 60 °C for 1 hour. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3,4-trans)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-((3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)piperidin-3-ol (100 mg, crude) as a yellow oil. MS calculated: 673.2; MS found: 674.4 [M+H] + .

[0426] Step E: (3,4-trans)-4-{6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl}-1-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidin-3-ol To a solution of (3,4-trans)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-((3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)piperidin-3-ol (100 mg, crude) in DMF (2.5 mL) was added hydrazine hydrate (30 mg, 0.60 mmol)...

Claims

1. A compound selected from the following: or a pharma- ceutically acceptable salt or solvate thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】

2. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt or solvate thereof and a pharma- ceutically acceptable excipient.

3. 10. A method for treating a GLP-1 related disease, disorder or condition, comprising administering to a patient in need thereof an effective amount of the compound of claim 1 or a pharma- ceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 2.

4. The disease, disorder or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), slow-onset autoimmune diabetes in adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, nausea, vomiting, vomiting of the elderly, obesity, obesity, obesity of the elderly, obesity of the young, obesity of the elderly ... Sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial 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 lipemia, metabolic acidosis, ketosis 4. The method of claim 3, wherein the disease is selected from the group consisting of diabetes, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

5. A method of treating type 2 diabetes in a patient in need of treatment, comprising administering to the patient in need thereof an effective amount of the compound of claim 1 or a pharma- ceutically acceptable salt or solvate thereof or the pharmaceutical composition of claim 2.

6. A method for regulating insulin levels in a patient in need of such regulation, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 2.

7. A method for regulating glucose levels in a patient in need of such regulation, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt or solvate thereof or a pharmaceutical composition of claim 2.

8. The method of any of claims 3 to 7, further comprising administering to the patient an additional treatment or therapeutic agent.

9. 9. The method of claim 8, wherein the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an antiobesity agent, a GLP-1 receptor agonist, an antiemetic agent, a nonalcoholic steatohepatitis (NASH) treatment agent, gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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