Heterocyclic GLP-1 agonists

Abstract

The present disclosure relates generally to GLP-1 agonists and pharmaceutical compositions comprising the same and methods for treating GLP-1 related diseases, disorders, or conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of International Patent Application No. PCT / CN2022 / 086863 filed on April 14, 2022, which is incorporated herein by reference in its entirety. Technical Field

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

[0003] Incretin hormones including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in the regulation of glucose homeostasis. Agents targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes (T2DM), is an acquired condition that accounts for more than 90% of diabetes cases. Typical attacks occur in obese adults or other sedentary adults and begin with insulin resistance. Although lifestyle changes can be used to effectively manage this disorder, T2DM patients may need to take antidiabetic drugs, especially including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors and sulfonylureas.

[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 intake. Although this incretin effect is significantly attenuated (if present) in cases of T2DM, GLP-1 retains insulinotropic properties even though the endocrine pancreatic response to GIP is effectively terminated. Therefore, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the invention

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

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

[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 for 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 for treating type 2 diabetes in a patient, the method 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, the method comprising determining that the patient suffers from 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, the step of determining that the patient suffers from 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 hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is greater than or about 6.5%. In some embodiments, the level of fasting plasma glucose is greater than or about 126 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 200 mg / dL.

[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) greater than or about 22 kg / m 2 In some embodiments, the patient's BMI is greater than or about 30 kg / m 2 .

[0013] In some embodiments, the method for treating type 2 diabetes comprises reducing fasting plasma glucose levels. In some embodiments, the fasting plasma glucose levels are reduced to about or below 100 mg / dL.

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

[0015] In some embodiments, the method for treating type 2 diabetes comprises lowering glucagon levels.

[0016] In some embodiments, the method for treating type 2 diabetes comprises increasing insulin levels.

[0017] In some embodiments, the method for treating type 2 diabetes comprises reducing BMI. In some embodiments, the BMI is reduced to about or below 25 kg / m 2 .

[0018] In some embodiments, the 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 includes administering another therapy or therapeutic agent to the patient. In some embodiments, the other therapy or therapeutic agent is selected from antidiabetic agents, antiobesity agents, GLP-1 receptor agonists, agents for treating nonalcoholic steatohepatitis (NASH), antiemetics, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from biguanide, sulfonylurea, glitazar, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, meglitinide, sodium-glucose cotransporter 2 (SGLT2) inhibitor, glitazone, GRP40 agonist, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitor, or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, 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, zonisamide, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In some embodiments, the GLP-1 receptor agonist is selected from liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the agent for treating NASH is selected from 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, nicotinic acid analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinases (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof.In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered sequentially in any order as separate doses.

[0020] Also provided herein is a method for regulating insulin levels in a patient in need of such regulation, the method 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 some embodiments, the regulation results in an increase in insulin levels.

[0021] Also provided herein is a method for regulating the glucose level of a patient in need of such regulation, the method 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 some embodiments, the regulation results in a decrease in glucose levels.

[0022] Also provided herein is a method for treating a GLP-1 related 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 some embodiments, the disease, disorder or condition is selected from 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), latent autoimmune diabetes of adults (LADA), obesity, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral 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 lipidosis, 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, 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 ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In some embodiments, the disease, disorder or condition is selected from type 2 diabetes, early onset type 2 diabetes, obesity, weight gain caused by the use of other agents, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney 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 lipidosis, metabolic acidosis, ketone disease, 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 ulcers, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In some 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 use of other medications, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipidosis, 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 ulcers, or any combination thereof.

[0023] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0024] Before describing the compounds and methods of the present disclosure, it should be understood that the present disclosure is not limited to the described methods, protocols, cell lines, assays, and reagents, as these may vary. It should also be understood that the terminology used herein is intended to describe embodiments of the present disclosure and is by no means intended to limit the scope of the present disclosure as set forth in the appended claims. definition

[0025] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," 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 those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices and materials are now described. For the purpose of describing and disclosing methods, reagents and tools reported in publications that may be used in conjunction with the present disclosure, all publications cited herein are incorporated herein by reference in their entirety.

[0027] When values ​​are described as a range, it should be understood that such disclosure includes disclosure of all possible sub-ranges within such range, as well as specific values ​​falling within such range, regardless of whether a specific value or a specific sub-range is explicitly stated.

[0028] Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM as well as other conditions where activation of GLP-1 activity is useful.

[0029] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. In some embodiments, the stereochemistry of a given compound is as depicted by the chemical structure shown in Table 1. Unless otherwise stated, a compound identified herein as a particular tautomeric form by name or structure is intended to include other tautomeric forms.

[0030] As used herein, the term "tautomer" refers to compounds whose structures differ significantly in the arrangement of atoms but exist in a readily and rapidly equilibrium manner, and it is understood that the compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to fall within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0031] "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 may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0032] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt (particularly a pharmaceutically acceptable addition salt) can be produced 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 acids 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, NH 3 or a salt of a primary, secondary or tertiary amine, such as a salt derived from a N-containing heterocyclic ring, a N-containing heteroaryl ring or a group of formula N(R N ) 3 (For example, HN + (R N ) 3 or (alkyl) N + (R N ) 3 ) wherein each R N is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) 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(isopropyl)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, "(C 1 -C 6The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical having one to six 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 group containing the indicated number of carbon atoms. For example, "(C 1 -C 3 )Alkylene refers to a divalent alkyl group having three carbon atoms (e.g., -CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -). Similarly, the terms "cycloalkylene", "heterocycloalkylene", "arylene" and "heteroarylene" refer to divalent cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups, 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, "(C 2 -C 6 ")Alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain having two to six 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, "(C 2 -C 6 ")alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain having two to six 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, wherein the group is on the oxygen atom. For example, "C 1-6 "Alkoxy" refers to -O-(C 1-6 The term "haloalkoxy" as used herein refers to an -O-haloalkyl group, wherein the group is on the oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group 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, "(C 3 -C 6") Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon having three to six ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl may be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyl include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. The cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl 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, and the like. [3.5]nonane, spiral [4.4]nonane, spiral [2.6]nonane, spiral [4.5]decane, spiral [3.6]decane, spiral [5.5]undecane, etc.

[0039] As used herein, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), which has 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N, S or S(O). 1-2 (e.g., carbon atoms, and 1-3, 1-6, or 1-9 N, O, S, or S(O) in the case of a monocyclic, bicyclic, or tricyclic ring, respectively) 1-2) wherein 0, 1, 2 or 3 atoms of each ring may be substituted with a substituent. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc. Heterocycloalkyl may be partially unsaturated. Non-limiting examples of partially unsaturated heterocycloalkyl include dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, dihydrofuranyl, dihydropyranyl, etc. Heterocycloalkyl may include multiple fused rings and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups 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 1 .0]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 spirocycles (e.g., spirobicycles in which the two rings are connected via 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-oxo[4.5] ... Spiro[2.2]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 monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon radical containing the indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., C 6 Single ring, C 10 Bicyclic or C 14 A tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0041] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms); wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolyl, e.g., tetrahydroquinolyl), and at least one ring in the system contains one or more heteroatoms independently selected from N, O, and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, b]pyridyl, quinazolinyl, quinolyl, thieno[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc.

[0042] As used herein, the term "halo" or "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl (sometimes referred to herein as "chloro" or "chloros"), -Br (sometimes referred to herein as "bromo" or "bromos"), and -I (sometimes referred to herein as "iodo" or "iodos").

[0043] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by 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] As used herein, indicates optional single or double bonds as allowed by the valence. As used herein, The point of attachment to the parent molecule is indicated.

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

[0046] As used herein, when a ring is described as "partially unsaturated", this means that the ring has one or more additional unsaturations (in addition to the unsaturation attributed to the ring itself; for example, one or more double bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc. When a ring system comprising at least two rings is described as "partially unsaturated", this means that the ring system comprises one or more partially unsaturated rings, provided that none of the constituent rings of the ring system are aromatic.

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

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

[0049] As used herein, the term "GLP-1 agonist" or "GLP-1RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RA enhances glucose-dependent insulin secretion; suppresses inappropriately elevated glucagon levels in both the fasting and postprandial states; and slows 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-1RA has been shown to treat type 2 diabetes. Examples of GLP-1RA include, but are not limited to, albiglutide Dulaglutide (LY2189265, ), efpeglenatide, exenatide Exendin-4), liraglutide ( NN2211), lixisenatide Semaglutide Tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in the following U.S. Patent Nos.: 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313.

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

[0051] As used herein, the term "therapeutic compound" is intended to include, without limitation, the compounds disclosed herein (e.g., compounds of Table 1 or pharmaceutically acceptable salts or solvates 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 term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish or amphibian. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

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

[0054] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In some embodiments, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., 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 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 of Table 1 or a pharmaceutically acceptable salt or solvate thereof) as described herein with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate administration of compounds to an organism. There are a variety of techniques for administering compounds in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

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

[0057] As used herein, the term "preventing" or "preventing" is the complete or partial prevention of the onset, recurrence, or spread of a disease or disorder as described herein, or symptoms thereof.

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

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

[0060] As used herein, the term "pharmaceutical combination" refers to a medical therapy that results from the admixture or combination 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 (ie, components of the combination or combination partners) wherein the therapeutically active agents are administered together or separately in a manner prescribed by a healthcare practitioner or according to a regulatory regime as defined herein.

[0062] As used herein, the term "modulate" means to regulate or adjust (eg, increase or decrease), and may include, for example, agonism, partial agonism, or antagonism.

[0063] It is understood that substituents as defined herein are not intended to include impermissible substitution patterns (e.g., a methyl group substituted with 5 fluorine groups or a hydroxyl group attached to an olefinic or acetylenic carbon atom). Such impermissible substitution patterns are well known to the skilled artisan. Compound

[0064] Provided herein is a compound selected from Table 1 or a pharmaceutically acceptable salt or solvate thereof: Table 1

[0065] The compounds of Table 1 include pharmaceutically acceptable salts thereof. In addition, the compounds of Table 1 also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compounds of Table 1 and / or separating the enantiomers of the compounds of Table 1. Non-limiting examples of pharmaceutically acceptable salts of the compounds of Table 1 include trifluoroacetate.

[0066] It will be further appreciated that the compounds of Table 1 or salts thereof may be isolated in the form of solvates, and accordingly, any such solvates are included within the scope of the present disclosure.

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

[0068] When used as a medicament, the compounds as described herein (e.g., compounds of Table 1 or pharmaceutically acceptable salts or solvates thereof) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by various routes, depending on whether local treatment or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular and mucosal, including 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, intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous infusion 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 is a pharmaceutical composition containing a combination of a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and 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. In the manufacture of the composition provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated in such a carrier, which is in the form of, for example, a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it can be a solid, semisolid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, 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. In some embodiments, the composition is formulated as a tablet or capsule.

[0070] Further provided herein is a pharmaceutical composition containing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition containing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by uniformly mixing a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take many forms, depending on the desired route of administration (e.g., oral, parenteral, etc.). In some embodiments, the composition is a solid oral composition.

[0071] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions 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 of formulating pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd 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. and published by Marcel Dekker, Inc.

[0073] In some embodiments, the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopheryl polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffer substances, such as phosphate, tris, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein. A dosage form or composition containing a chemical entity as described herein in the range of 0.005% to 100% and the remainder being supplemented by a non-toxic excipient can be prepared. The contemplated composition can contain 0.001%-100% of the chemical entity provided herein, in one embodiment 0.1%-95%, in another embodiment 75%-85%, in another embodiment 20%-80%. The actual method of preparing such dosage forms is known or will be clear to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0074] In some 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, dermal, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In some embodiments, the route of administration is parenteral (e.g., intratumoral).

[0075] In some embodiments, the compounds of Table 1 as described herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared as injectables, as liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions after adding liquids prior to injection may also be prepared; and the formulations may also be emulsified. In view of the present disclosure, the preparation of such formulations will be known to those skilled in the art. In some embodiments, a device is used for parenteral administration. For example, such devices may include needle syringes, microneedle syringes, needle-free syringes, and infusion techniques.

[0076] In some embodiments, pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form should be stable under the conditions of manufacture and storage, and must be preserved against the contaminating effects of microorganisms such as bacteria and fungi.

[0077] In some embodiments, carrier can also be solvent or dispersion medium, and described solvent or dispersion medium contain water, ethanol, polyol (for example, glycerine, propylene glycol and liquid polyethylene glycol etc.), its suitable mixture and vegetable oil.In some embodiments, for example, by using coating (such as lecithin), by maintaining required particle size in the case of dispersion, and by using surfactant, suitable fluidity can be maintained.In some embodiments, the effect of preventing microorganism can be reached by various antibacterial and antifungal agents (for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal etc.).In some embodiments, include isotonic agent, for example sugar or sodium chloride.In some embodiments, by using the medicament (for example, aluminum monostearate and gelatin) of delayed absorption in composition, the absorption of injectable composition can be prolonged.

[0078] In some embodiments, sterile injectable solutions are prepared in the following manner: the desired amount of the compound of Table 1 or its pharmaceutically acceptable salt or solvate is incorporated into an appropriate solvent with various other ingredients listed above (as required), followed by filtration sterilization. In some embodiments, dispersions are prepared in the following manner: various sterile active ingredients are incorporated into sterile vehicles, the vehicle containing basic dispersion medium and other ingredients required from those ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze drying technology, which produces active ingredients plus any additional desired ingredients from its previously sterile filtered solution.

[0079] In some embodiments, pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinyl pyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaoxybenzoate, sodium propylparaoxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, polyethylene glycol cetearyl ether, cocoyl capryloyl caprate, caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium EDTA, 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 a pharmaceutical composition as described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, a suppository wax, and which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum and releases the active compound. In some embodiments, compositions for rectal administration are in the form of enemas.

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

[0082] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the 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 the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. For example, in the case of capsules, tablets and pills, the dosage form may also contain a buffer. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0083] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and thus, the composition contains a diluent such as lactose, sucrose, dicalcium phosphate, etc., together with a compound of Table 1 as provided herein or a pharmaceutically acceptable salt or solvate thereof; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a powder, spherical granulation (marume), solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) as another solid dosage form is encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, a unit dosage form in which one or more compounds and a pharmaceutical composition or an additional active agent are physically separated as provided herein is also contemplated; for example, a capsule (or tablet in a capsule) with particles of each drug; a two-layer tablet; a two-chamber capsule (gel cap), etc. In some embodiments, enteric coating or delayed release oral dosage forms are also contemplated.

[0084] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants or preservatives that are particularly useful for preventing the growth or activity of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0085] In some embodiments, excipients are sterile and generally do not contain undesirable substances. For example, these compositions can be sterilized by conventional well-known sterilization techniques. In some embodiments, for various oral dosage form excipients, such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (United States Pharmacopeia / National Formulary, USP / NF) standards can be sufficient.

[0086] In some embodiments, the compounds of Table 1 as described herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, are formulated for oral administration. In some embodiments, the ocular composition may include, but is not limited to, any one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., Benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorine complex; Allergan, Inc.)).

[0087] In some embodiments, the compounds of Table 1 as described herein or their pharmaceutically acceptable salts or solvates or their pharmaceutical compositions can be formulated for topical application to the skin or mucosa (e.g., percutaneous or transdermal). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are semisolid preparations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semisolid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, typically includes paraffin fats and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not required, the volume of the aqueous phase typically exceeds the oil phase, and typically contains a moisturizer. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0088] In any of the foregoing embodiments, the pharmaceutical composition as described herein may comprise 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-loaded lipid bilayers.

[0089] The amount of the compound in the pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, based on weight percentage (wt%), the formulation will contain a compound of the present disclosure of about 0.01-99.99wt% of the total formulation, and the balance is one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80wt%. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet Formulation

[0090] The following ingredients are intimately mixed and compressed into single scored tablets. Element Amount, tablet, mg Compounds of the Disclosure 400 Corn starch 50 Croscarmellose Sodium 25 lactose 120 Magnesium Stearate 5 Formulation Example 2 - Capsule Formulation

[0091] The following ingredients are intimately mixed and loaded into hard shell gelatin capsules. Element Quantity, capsule, mg Compounds of the Disclosure 200 Lactose, spray dried 148 Magnesium Stearate 2 Formulation Example 3 - Suspension Formulation

[0092] The following ingredients are mixed to form a suspension for oral administration. Element quantity Compounds of the Disclosure 1.0g Fumaric Acid 0.5g Sodium chloride 2.0g Methylparaben 0.15g Propylparaben 0.05g granulated sugar 25.0g Sorbitol (70% solution) 13.00g Veegum K (Vanderbilt Co.) 1.0g Flavoring 0.035mL Colorants 0.5mg Distilled water Take the appropriate amount to reach 100mL Formulation Example 4 - Injectable Formulation

[0093] The following ingredients are mixed to form an injectable formulation. Element quantity Compounds of the Disclosure 0.2mg-20mg Sodium acetate buffer solution, 0.4 M <![CDATA[2.0 m L]]> HCl (1N) or NaOH (1N) Amount to achieve the right pH Water (distilled, sterile) Take as much as you want to reach 20mL Formulation Example 5 - Suppository Formulation

[0094] By combining the compounds of the present disclosure with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5 g, and the suppository had the following composition:

[0095] In some embodiments, the dosage of the compound of Table 1 or its pharmaceutically acceptable salt or solvate is determined based on a variety of factors, including but not limited to the type, age, weight, sex, medical condition of the patient; the severity of the patient's medical condition; the 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 a medical technician. In some embodiments, the total daily dose can be divided into multiple portions and administered in multiple portions throughout the day or by providing continuous delivery.

[0096] In some embodiments, the compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 0.01 mg to about 1000 mg. For example, about 0.1 mg to about 30 mg, about 10 mg to about 80 mg, about 0.5 mg 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 some embodiments, the dose is a therapeutically effective amount.

[0097] In some embodiments, a compound of Table 1 as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at about 0.0002 mg / Kg to about 100 mg / Kg (e.g., about 0.0002 mg / Kg to about 50 mg / Kg; about 0.0002 mg / Kg to about 25 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg; about 0.0002 mg / Kg to about 5 mg / Kg; about 0.0002 mg / Kg to about 10 mg / Kg). 0.02mg / Kg to about 1mg / Kg; about 0.0002mg / Kg to about 0.5mg / Kg; about 0.0002mg / Kg to about 0.1mg / Kg; about 0.001mg / Kg to about 50mg / Kg; about 0.001mg / Kg to about 25mg / Kg; about 0.001mg / Kg to about 10mg / Kg; about 0.001mg / Kg to about 5mg / Kg; about 0.001mg / Kg to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 In some embodiments, the compound of Table 1 as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 100 mg / Kg.

[0098] In some embodiments, the foregoing doses of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, can be administered daily (e.g., in a single dose or two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

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

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

[0101] In some embodiments, a compound of Table 1 or a pharmaceutically acceptable salt or solvate thereof is administered to a patient by parenteral administration once or more per day (e.g., 1 to 4 times per day, twice per day, three times per day, four times per day, or a single daily dose).

[0102] In some embodiments, a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient weekly by parenteral administration. Treatment

[0103] In some embodiments, the disclosure features methods for treating a patient (e.g., a human) having a disease, disorder, or condition, wherein modulation of GLP-1R (e.g., inhibition or attenuation and / or elevation or unwanted GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein can include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

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

[0105] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, 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), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain with other medications, idiopathic intracranial hypertension, Wolfram's syndrome, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, vascular compliance restriction. damage, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, 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, leukoencephalopathy , glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0106] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes in the proximal tubules), 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, atherosclerosis cardiovascular disease, hyperglycemia, postprandial lipidosis, 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 ulcers, psoriasis, primary polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0107] In some embodiments, the diseases, disorders, or conditions include but are not limited to type 2 diabetes, early onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain due to 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 lipidosis, 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 ulcers, or any combination thereof.

[0108] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein induce one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in beta cell mass, regulation of gastric acid secretion, regulation of gastric emptying, reduction in body mass index (BMI), and / or reduction in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein may reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase in beta cell mass, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), reduce glucagon production (e.g., levels), or any combination thereof. In certain embodiments, the compounds and 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 are methods for regulating glucose or insulin levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of Table 1 as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

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

[0110] In some embodiments, the condition, disease or disorder is obesity and a condition, disease or disorder related to obesity or relevant thereto. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity and abdominal obesity (central obesity characterized by excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudoparathyroid hypofunction, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome) and drug-induced obesity (e.g., steroids, phenothiazines, insulin, sulfonylurea agents or beta-blocker-induced obesity).

[0111] In some embodiments, the disease, disease or disorder is related to obesity. Examples of such diseases, diseases or disorders include, but are not limited to, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic fatty liver disease (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient cerebral ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip arthritis, deformed spondylitis, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick syndrome (Pickwickian syndrome)), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual volume and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome. In some embodiments, chemical compounds and pharmaceutical compositions described herein can be used to treat patients showing two symptoms of obesity and insulin deficiency. diabetes

[0112] In some embodiments, the condition, disease or disorder is diabetes. The non-limiting example of diabetes includes type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin), 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., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin).

[0113] Provided herein are methods for treating diabetes in a patient, the methods 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 as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0114] Provided herein are methods for 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 as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[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 as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

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

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

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

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

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

[0121] In some embodiments, a decrease in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease 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 some embodiments, a decrease in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes.

[0122] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmotic diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, slow 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 related to unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive dysfunction.

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

[0124] In some embodiments, the condition, disease or disorder is diabetes and obesity (diabetobias). In some embodiments, the compounds described herein may also be used to improve the therapeutic effectiveness of metformin. Disorders of metabolically important tissues

[0125] In some embodiments, the condition, disease or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include liver, fat, 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 acid 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, Wolmans disease, acute fatty liver of pregnancy, and lipid dystrophy.

[0127] Non-alcoholic fatty liver disease (NAFLD) refers to a series of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). It is believed that NAFLD is associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It may cause liver disease in adults and children and may eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35 (2): 373-9). The severity of NAFLD ranges from relatively benign isolated, mainly macrovesicular steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl: S186-90).

[0128] Other non-limiting examples of disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); fibrosis (e.g., in the liver); cirrhosis (e.g., in the liver); cholelithiasis; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; skeletal disorders characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, cancer Osteolytic metastasis in patients, osteodystrophy in liver disease, and bone metabolism changes caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection of fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, weakness, sexual dysfunction (e.g., erectile dysfunction) and geriatric syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing the decomposition reaction caused by surgical trauma. Cardiovascular and vascular disease

[0129] In some embodiments, the condition, disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic states (exemplified by high fibrinogen or plasminogen activator inhibitors in the blood).

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

[0131] In some embodiments, the condition, disease, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include idiopathic intracranial hypertension (IIH), brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Parkinson's disease (Morbus Parkinson), Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute disorganization disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., U.S. Publication No. 20060275288A1.

[0132] In some embodiments, the condition, disease or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by increased intracranial pressure and papilledema. See, e.g., Virdee et al. Ophthalmol Ther. 2020; 9(4): 767-781. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms of patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension may include severe headaches and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is a 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 biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may first appear as diabetes, followed by symptoms of optic atrophy, deafness, and neurodegeneration. Patients with Wolfram syndrome may have symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and taste loss due to brainstem atrophy. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation in the inferior olive nucleus of the patient is reduced. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (eg, any of the symptoms described herein) in a patient suffering from Wolfram's 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 can be used to improve behavioral responses to addictive drugs, reduce drug dependence, prevent relapse to drug abuse, and alleviate anxiety caused by the absence of a given addictive substance. See, e.g., U.S. Publication No. 20120021979A1.

[0135] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and also protect dopamine neurons and motor function in Parkinson's disease. Insulin-related conditions and disorders

[0136] In some embodiments, the condition, disease, or disorder is impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemic conditions, insulin resistance syndrome, paresthesias caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and concomitant insulin-related coma endpoints.

[0137] In some 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. Autoimmune disorders

[0138] In some embodiments, the condition, disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves disease. See, for example, U.S. Publication No. 20120148586A1. Stomach and intestinal disorders

[0139] In some embodiments, the condition, disease, or disorder is a gastric or intestinal related disorder. Non-limiting examples of such disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac 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 damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, 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 immunodeficiency syndrome). weight

[0140] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to make patients (e.g., patients in need) lose weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat or reduce food intake. In some embodiments, the patient's weight gain may be attributed to excessive food intake or an unbalanced diet, or may be due to weight gain from accompanying drugs (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, weight gain can be weight gain before reaching obesity, or it can be weight gain in obese patients. In some embodiments, weight gain can also be drug-induced weight gain or weight gain following cessation of smoking. In some embodiments, weight gain is induced by the use of steroids or antipsychotics.

[0141] In some embodiments, the condition, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome. Inflammatory diseases

[0142] In some embodiments, the condition, disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, deforming spondylitis, deforming arthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colorectal disease), inflammation in metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammatory-like C-reactive protein in the blood). cancer

[0143] In some embodiments, the condition, disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), stromal tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., Primary liver cancer, 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 cancer), parathyroid cancer, nasal cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinosarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms tumor, childhood kidney tumors), Kaposi sarcoma, Kaposi sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia). Hypothalamic-pituitary disorders

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

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

[0146] In some embodiments, the condition, disease or disorder is associated with a pulmonary disease. Pulmonary diseases include, but are 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 some embodiments, the condition, disease, or disorder associated with diabetes is a pulmonary disease. Combination therapy

[0148] In some embodiments, the present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0149] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0150] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., ) and dietary changes.

[0151] In some embodiments, a compound of Table 1 as described herein, or a pharmaceutically acceptable salt or solvate thereof, may 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, diabetes therapeutics, diabetic complications therapeutics, hyperlipidemia therapeutics, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutics, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence therapeutics, NAFLD therapeutics, NASH therapeutics, dysuria therapeutics, and antiemetics.

[0153] In some embodiments, the one or more additional therapeutic agents include those suitable for use 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 its analogs, cannabinoid receptor antagonists (e.g., rimonabant, tadalafil), tadalafil, ... taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase 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, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., International Publication No. WO 2020 / 234726, WO 2020 / 044266, and U.S. Pat. No. 8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g.,JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate etabonate or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte stimulating hormone analogs, 5HT2c agonists, galanin antagonists, anorectic agents (such as bombesin agonists), thyromimetic agents, 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, The invention also includes but is not limited to 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, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597 compounds described in International Publication Nos. WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g.,piragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, International Publication Nos. WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2008 / 050821, WO 2008 / 136428 and WO 2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving drugs, 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, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxytocin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli (Escherichia coli) or yeast gene synthesis of human FGF21 preparations; fragments or derivatives of FGF21), anorectics (e.g., P-57), human proinsulin peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), 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, International Publication Nos. WO 2020 / 234726 and WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake 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 No. WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators. ,

[0154] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, 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 synthesized using E. coli or yeast genes; 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)), glucagon analogs (e.g., WO any glucagon analogue described in 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glyburide, gliclazide, acetohexamide, glyburide, glybuzole, glyburide, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, troglitazone, basiglitazone, rivoglitazone, lobeglitazone, or pioglitazone), saglitazar (e.g., aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, repagliflozin, empagliflozin, canagliflozin, ipragliflozin, topagliflozin, sergliflozin edocarbonate, repagliflozin edocarbonate, erpagliflozin, described in WO 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), α-glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), for example, meglitinides (e.g.,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, abiglutide, tasiglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, Gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, 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 those useful, for example, in the treatment of NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / 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 International Publication No. WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), ketokinase (KHK) inhibitors (e.g., compounds described in WO 2020 / 234726), apoptosis signal regulating kinase 1 (ASK1) inhibitors (selonsertib), ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO 2020 / 234726 and U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, schisandra extract (schisandra chinensis extract), extract), ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinedione (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents, and antioxidants.

[0156] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, to treat diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their increasers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., lipoic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0157] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents useful, for example, for the treatment of hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as 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]acetyl

[0013] In some embodiments, the present invention relates to a pharmaceutical composition comprising: a pharmaceutically acceptable salt of hydroxypropyl hydroxylamine (hydroxylamine), a pharmaceutically acceptable salt of ...

[0158] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, as antihypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, zofenopril, fbsinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium), (e.g., 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).Other non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, m-ethylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem ), verapamil, nifedipine and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blocker ivabradin, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0159] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlorothiazide, hydrochlorothiazide, hydrofluthiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[0160] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering methods (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 those that can be used as, for example, anti-embolic 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, described in WO 02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823 and WO2005 / 113504), thrombolytic agents (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIIa inhibitors, P AI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, icosapent ethyl, beraprost sodium, and sarpogrelate hydrochloride).

[0162] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Suitable examples of agents for treating frequent urination or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of agents for treating 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 exemplary additional therapeutic agents include agents that regulate hepatic glucose homeostasis (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of long-term hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents for treating 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-452 2), HMG-CoA synthase inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols, such as phytosterols), cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO 2009 / 016462, WO 2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., tendamistat, trestatin, AL-3688), α-glucosidase hydroxylase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase 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., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g.,alirocumab and evolocumab), RXRα modulators, cysteamine, cystamine, RNA antisense constructs that inhibit protein tyrosine phosphatase PTPRU, vitamin B complex, pentraxin protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10):373-381), ezetimibe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitors, branched-chain α-ketoacid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF1 9 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents (including adrenergic receptor antagonists (such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin) and mixed alpha / beta blockers (e.g., labetalol)), adrenergic receptor agonists (including alpha-2 agonists (e.g., clonidine)), angiotensin converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and benzthiazepines (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, bumetanide, ethacrynic acid, thiazide-type diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, indapamide), phthalimide-type diuretics (e.g., chlorthalidone, metolazone), quinazoline-type diuretics (e.g., quinethazolone), potassium-sparing diuretics (e.g., triaminotrexate and amiloride), thyroid receptor agonists (e.g., WO 2020 / 117987), hemostatic modulators (including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors and 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., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), anti-(abcixima)), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulating agents, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission modulators such as selective serotonin reuptake inhibitors (SSRI) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARI), norepinephrine-serotonin reuptake inhibitors (SNRI) and monoamine oxidase inhibitors (MAOI) (e.g., toloxatone and amiflamine), in WO Compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonist, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improving agents such as cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents for improving fat metabolism (e.g.,eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6 and oncostatin M, metabolic modification 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, PDE 5 inhibitors, glycosylation inhibitors (e.g., ALT-711), drugs that promote nerve regeneration (e.g., Y-128, VX853, neurotrophic peptides (prosaptide)), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, levetiracetam (keppra), zonisamide (zonegran), prilocaine (prednisolone)), Bahrain, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K+ channel openers, mexiletine, propafenone, metoprolol, atenolol, carvedilol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, and verapamil), acetyl Cholinergic receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), alpha2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depleting therapies (e.g., anti-CD20 antibodies (e.g., rituximab), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF binding proteins (e.g., circulating receptors), immunosuppressants (e.g.,mycophenolate mofetil), meglitazone, AMG-131, balaglitazone, MBX-2044, riglitazone, aleglitazar, siglitazar, saroglitazar, muraglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, dapoxetine Exendin-4, memantine, midazolam, ketoconazole, icosapentaenoic acid ethyl, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0164] In some embodiments, the one or more additional therapeutic agents include therapeutic agents that can be used, for example, as antiemetics. As used herein, an "antiemetic" agent refers to any agent that resists (e.g., reduces or eliminates) nausea or vomiting (spitting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with the compounds of Table 1 described herein can allow for administration of a higher dose of the compounds of Table 1, for example, because the patient may be able to take in food normally and therefore respond faster to treatment.

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

[0166] For example, the antiemetic may be selected from neuroleptics, antihistamines, anticholinergics, steroids, 5HT3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0167] In some embodiments, the antiemetic 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, bemisetron, zatisetron, batapride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropane-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, qamosetron, ramosteron, licarsetron, risperidone, ziprasidone and zatosetron.

[0168] In certain embodiments, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropane-3,5-dimethylbenzoic acid, 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleic acid, zacopride hydrochloride, and mirtazapine.

[0169] In certain embodiments, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, zatisetron.

[0170] In certain embodiments, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron.

[0171] In certain embodiments, the 5HT3 receptor antagonist is granisetron.

[0172] In certain embodiments, the 5HT3 receptor antagonist is ondansetron.

[0173] In some embodiments, the antiemetic 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 is an anticholinergic agent (an acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, Trihexy-5 (benzhexol hydrochloride), benztropine (benztropine mesylate), Ankejing (biperiden hydrochloride), Disipal (orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatelin (procyclidine hydrochloride).

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

[0176] In some embodiments, the antiemetic is a NK1 receptor antagonist (eg, a neurokinin substance 1P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include: aprepitant, casopitant, elopitant, fosaprepitant, maropitant, netupitant, lolapitant, and viltepitant.

[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 (besylate / nopitant chloride), LY 303870 (lanepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35 375, 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]diazooctano[2,1-g][1,7]naphthyridine-6,13-dione], PD154075 ([(2-benzofuran)-CH 2 OCO]-(R)-α-MeTrp-(S)-NHCH(CH 3 )Ph), FK888 and (D-Pro4,D-Trp7,9,10,Phe11)SP4-11.

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

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

[0180] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / antipsychotics (e.g., dexrazine, haloperidol, and prochlorperazine); ); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphoric acid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0181] Still other exemplary antiemetics include those disclosed in US20120101089A1; US10,071,088B2; US 6,673,792B1; US ​​6,197,329 B1; US10,828,297B2; US10,322,106B2; US 10,525,033B2; WO 2009080351A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated by reference in its entirety.

[0182] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact with or administration of the compounds and pharmaceutical compositions (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[0183] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about 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 provided to the patient simultaneously in the same dosage form. For another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient in separate dosage forms in parallel. Patient selection

[0184] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, subject) in need of such treatment (eg, by blood assays, body mass index, or other routine methods known in the art).

[0185] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, a patient) suffering from a disease, disorder, or condition (eg, a GLP-1 related disease, disorder, or condition) as provided herein.

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

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

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

[0189] In some embodiments, determining whether the patient suffers from type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is greater than or about 22kg / m2 to greater than or about 100kg / m2. In some embodiments, the patient's BMI is greater than or about 30kg / m2 to greater than or about 90kg / m2. In some embodiments, the patient's BMI is greater than or about 40kg / m2 to greater than or about 80kg / m2. In some embodiments, the patient's BMI is greater than or about 50kg / m2 to greater than or about 70kg / m2.

[0190] In some embodiments, the additional factors (e.g., risk factors) used to determine whether a patient suffers from type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or about 10 years old. In some embodiments, the patient's age is greater than or about 15 years old. In some embodiments, the patient's age is greater than or about 20 years old. In some embodiments, the patient's age is greater than or about 25 years old. In some embodiments, the patient's age is greater than or about 30 years old. In some embodiments, the patient's age is greater than or about 35 years old. In some embodiments, the patient's age is greater than or about 40 years old. In some embodiments, the patient's age is greater than or about 42 years old. In some embodiments, the patient's age is greater than or about 44 years old. In some embodiments, the patient's age is greater than or about 46 years old. In some embodiments, the patient's age is greater than or about 48 years old. In some embodiments, the patient's age is greater than or about 50 years old. In some embodiments, the patient's age is greater than or about 52 years old. In some embodiments, the patient's age is greater than or about 54 years old. In some embodiments, the patient's age is greater than or about 56 years old. In some embodiments, the age of the patient is greater than or about 58 years old. In some embodiments, the age of the patient is greater than or about 60 years old. In some embodiments, the age of the patient is greater than or about 62 years old. In some embodiments, the age of the patient is greater than or about 64 years old. In some embodiments, the age of the patient is greater than or about 66 years old. In some embodiments, the age of the patient is greater than or about 68 years old. In some embodiments, the age of the patient is greater than or about 70 years old. In some embodiments, the age of the patient is greater than or about 72 years old. In some embodiments, the age of the patient is greater than or about 74 years old. In some embodiments, the age of the patient is greater than or about 76 years old. In some embodiments, the age of the patient is greater than or about 78 years old. In some embodiments, the age of the patient is greater than or about 80 years old. In some embodiments, the age of the patient is greater than or about 85 years old. In some embodiments, the age of the patient is greater than or about 90 years old. In some embodiments, the age of the patient is greater than or about 95 years old. In some embodiments, the patient's race may be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or 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 different subgroups, including: newborns (from birth to the first month of life); infants (1 month to two years old); children (two years old to 12 years old); and adolescents (12 to 21 years old (until but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Edition Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st Edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Edition Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than two years of age, two years to less than 12 years of age, or 12 years to 21 years of age (up to but not including the 22nd birthday). In some embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than 1 year of age, one month to less than four months of age, three months to less than seven months of age, six months to less than 1 year of age, 1 year to less than 2 years of age, 2 years to less than 3 years of age, 2 years to less than seven years of age, 3 years to less than 5 years of age, 5 years to less than 10 years of age, 6 years to less than 13 years of age, 10 years to less than 15 years of age, or 15 years to less than 22 years of age. In some embodiments, the patient is an adult patient. Example

[0192] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mm Hg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates with spots visualized using UV light (214 and 254 nm). Purification was performed by column and flash chromatography 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 as δ values ​​in ppm with 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), integration. LCMS spectra were obtained by electrospray ionization on a SHIMADZULC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series 6110 or 6120 mass spectrometer unless otherwise indicated.

[0193] The present disclosure is further understood by reference to the following examples, which are intended to illustrate the present disclosure simply. The scope of the present disclosure is not limited by the exemplary embodiments, which are intended to illustrate only a single aspect of the present disclosure. Any method that is functionally equivalent is within the scope of the present disclosure. In addition to those described herein, various modifications of the present disclosure will also become clear to those skilled in the art due to the foregoing description and accompanying drawings. Such modifications fall within the scope of the appended claims. Example 1: 2-[(2,4-difluorophenyl)methoxy]-6-{1-[(3-{[(2S)-oxetane-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidine -4-yl}pyridine (Compound 1) Step A: 2-Bromo-6-((2,4-difluorobenzyl)oxy)pyridine

[0194] To a solution of (2,4-difluorophenyl)methanol (1.0 g, 6.97 mmol) in THF (15 mL) was 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 room temperature for 2 h. After the reaction was complete, the mixture was washed with H 2O (50mL), extracted with EA (40mL×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 value: 299.0; MS found value: 299.8 [M+H] + . Step B: tert-Butyl 6-((2,4-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0195] 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 2 (256 mg, 0.35 mmol), K 2 CO 3 (2.9 g, 21.1 mmol) in dioxane / H 2 The mixture in 2% O (40.0 mL / 4.0 mL) was stirred at 90 °C for 3 h. After the reaction was completed, the mixture was washed with H 2 O (100mL), extracted with EA (50mL×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 tert-butyl 6-((2,4-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (2.6 g, yield: 93%). MS calculated value: 402.2; MS found value: 403.1 [M+H] + . Step C: tert-Butyl 4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0196] 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, wetted with approximately 55% water) in THF (4.0 mL) was stirred at room temperature for 1.5 h. After the reaction was complete, the mixture was filtered and the solid was 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] + . Step D: 2-((2,4-difluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt

[0197] 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 reaction was removed in vacuo 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] + . 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

[0198] 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), and DIEA (492 mg, 3.82 mmol) in DMF (4.0 mL) was stirred at 70° C. for 1 hour. After the reaction was complete, the mixture was washed with H 2O (20mL), extracted with EA (15mL×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 (DCM / MeOH=100 / 1) to give (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (130mg, yield: 64%). MS calculated value: 530.2; MS found value: 531.0[M+H] + . 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

[0199] (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), HONH 2 A solution of HCl (100 mg, 1.47 mmol), TEA (99 mg, 0.98 mmol) in EtOH (4.0 mL) was stirred at 70 °C for 1 h. After the reaction was completed, 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] + . 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

[0200] To a solution of (S)-2-((4-(6-((2,4-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(oxetanes-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 room temperature for 1 hour. After the reaction was complete, 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 and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo 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 Calcd: 641.2; MS Found: 642.2 [M+H] + . 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

[0201] (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 N 2 H 4 ·H 2 A mixture of O (22 mg, 0.44 mmol) in DMF (2.0 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was directly purified by preparative HPLC (0.1% FA / H 2 O / CH 3 CN) 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 value: 640.2; MS found value: 641.0 [M+H]+ .

[0202] 1 H NMR (400MHz, DMSO-d6): δ9.17(s,1H),8.29(s,1H),7.55-7.67(m,2H),7.22-7.33(m,1H),7.04-7.15( m,1H),6.88(d,J=7.6Hz,1H),6.66(d,J=8.4Hz,1H),5.37(s,2H),5.14-5.24(m,1H),4.88-4.99(m,1H ),4.73-4.83(m,1H),4.39-4.55(m,2H),4.01(d,J=14.0Hz,1H),3.86(d,J=13.6Hz,1H),2.99-3.08(m ,1H),2.83-2.92(m,1H),2.56-2.80(m,2H),2.40-2.53(m,1H),2.17-2.35(m,2H),1.64-1.88(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.68,-63.72,-110.21,-110.23,-113.85,-113.88. Example 2: (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 2) Step A: (4-chloro-2-methoxyphenyl)methanol

[0203] To a solution of 4-chloro-2-methoxybenzoic acid (2.0 g, 10.7 mmol) in THF (10.0 mL) was added BH2SO4 dropwise at 0 °C. 3 ·THF (22mL, 22mmol, 1M in toluene). The solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was quenched with MeOH (8mL). Salt water (30ml x 2) was added to the mixture and extracted with ethyl acetate (30ml x 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EA=2 / 1) to obtain (4-chloro-2-methoxyphenyl)methanol (1.8g, 97.3% yield). Step B: 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine

[0204] 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 room temperature for 1 h. After the reaction was complete, the reaction mixture was quenched by adding saturated NH 4 Cl aqueous solution was quenched and extracted with ethyl acetate (30 ml x 3). The organic layers were combined and washed with brine (30 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuo 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] + . 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

[0205] (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 by a similar method to Example 1. MS calculated value: 668.2; MS found value: 669.0 [M+H] + .

[0206] 1H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),7.62(t,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),7.12(m,1H),7 .00(dd,J=8.4Hz,2.0Hz,1H),6.86(d,J=7.2Hz,1H),6.66(d,J=8.0Hz,1H),5.29(s,2H),5.18(m,1H),4.87-4.96 (m,1H),4.71-4.80(m,1H),4.38-4.53(m,2H),4.01(d,J=13.6Hz,1H),3.81-3.89(m,4H),2.99-3.07(m,1H),2. 84-2.91(m,1H),2.73-2.77(m,1H),2.56-2.68(m,1H),2.40-2.48(m,1H),2.16-2.40(m,2H),1.63-1.87(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.54. Example 3: (S)-2-((4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[1- ... [4,5-c]pyridine (Compound 3) Step A: (2,4-difluoro-3-methoxyphenyl)methanol

[0207] To a solution of 2,4-difluoro-3-methoxybenzoic acid (1.2 g, 6.4 mmol) in THF (13 ml) was added BH2SO4 dropwise at 0 °C. 3 ·THF (19.1 ml, 19.1 mmol). The mixture was stirred at room temperature for 2 hours. 2 O (50 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (30 ml) and purified by Na 2 SO 4 Dried, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluted with PE / EA (3 / 1)) to give (2,4-difluoro-3-methoxyphenyl)methanol (920 mg, yield: 83%). Step B: tert-Butyl 4-(6-((2,4-difluoro-3-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0208] 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 hour. The mixture was washed with H 2 The mixture was quenched with 1% O (50 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (30 ml). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (eluted 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%). 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

[0209] (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 by a similar method to Example 1. MS calculated value: 670.0; MS found value: 671.0 [M+H]+.

[0210] 1H NMR: δ9.16(s,1H),8.29(s,1H),7.63(t,J=8.0Hz,1H),7.22-7.30(m,1H),7.09-7.18(m,1H),6.88(d,J=7 .2Hz,1H),6.67(d,J=8.0Hz,1H),5.36(s,2H),5.14-5.24(m,1H),4.89-4.99(m,1H),4.72-4.81(m,1H),4. 38-4.55(m,2H),4.02(d,J=14.0Hz,1H),3.90(s,3H),3.87(d,J=13.6Hz,1H),2.98-3.07(m,1H),2.84-2. 93(m,1H),2.69-2.80(m,1H),2.57-2.67(m,1H),2.39-2.50(m,1H),2.17-2.34(m,2H),1.64-1.87(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.68, -128.73, -132.96. Example 4: 2-[(4-chloro-2-fluoro-3-methylphenyl)methoxy]-6-{1-[(3-{[(2S)-oxetane-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) Step A: (4-Chloro-2-fluoro-3-methylphenyl)methanol

[0211] 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 room temperature for 2 hours and washed with NH 4 The mixture was quenched with aqueous Cl solution (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). Step B: 2-Bromo-6-((4-chloro-2-fluoro-3-methylbenzyl)oxy)pyridine

[0212] To a solution of (4-chloro-2-fluoro-3-methylphenyl)methanol (280 mg) in THF (2.0 mL) was 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 room temperature for 2 h and washed with NH 4 The product was quenched with Cl aqueous solution (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 value: 329.0; MS found value: 330.0 [M+H] + . 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

[0213] 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 by a similar method to Example 1. MS calculated value: 670.2; MS found value: 671.0 [M+H] + .

[0214] 1H NMR (400MHz, DMSO-d6): δ9.14(s,1H),8.27(s,1H),7.63(t,J=8.0Hz,1H),7.39(t,J=8.4Hz,1H),7.29(d,J=8.4Hz ,1H),6.87(d,J=7.2Hz,1H),6.67(d,J=8.0Hz,1H),5.38(s.2H),5.12-5.24(m.1H),4.87-4.97(m.1H),4.71-4.82 (m,1H),4.47-4.55(m,1H),4.38-4.46(m,1H),4.00(d,J=13.6Hz,1H),3.86(d,J=13.6Hz,1H),2.98-3.08(m,1H), 2.84-2.93(m,1H),2.68-2.78(m,1H),2.55-2.68(m,1H),2.39-2.51(m,1H),2.15-2.33(m,5H),1.62-1.87(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.26,-116.98. 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]piperidine -4-yl}pyridine (Compound 5)

[0215] 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 using similar procedures as described herein.

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

[0217] 1H NMR (400MHz, DMSO-d6): δ9.15 (s, 1H), 8.28 (s, 1H), 7.62 (t, J = 7.6Hz 1H),7.38-7.46(m,1H),7.05(t,J=8.4Hz,1H),6.87(d,J=7.2Hz,1H),6.65(d,J=8.0Hz,1 H),5.35(s,2H),5.14-5.23(m,1H),4.88-4.97(m,1H),4.73-4.81(m,1H),4.39-4.53(m,2 H),4.01(d,J=13.6Hz,1H),3.86(d,J=13.2Hz,1H),2.99-3.08(m,1H),2.85-2.92(m,1H), 2.70-2.80(m,1H),2.58-2.70(m,1H),2.18-2.35(m,3H),2.15(s,3H),1.69-1.88(m,4H). 19 FNMR(377MHz, DMSO-d6): δ-63.49,-114.79,-114.81,-118.52,-118.54. Example 6: (S)-2-((4-(6-((4-chloro-2,6-difluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 6) Step A: (4-Chloro-2,6-difluorophenyl)methanol

[0218] 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 4 (215 mg, 5.68 mmol). The reaction was stirred at 0 °C for 20 min. After the reaction was completed, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo.The residue was purified by silica gel (PE / EA=10 / 1) to give (4-chloro-2,6-difluorophenyl)methanol (849 mg, yield: 84.2%). Step B: 2-Bromo-6-((4-chloro-2,6-difluorobenzyl)oxy)pyridine

[0219] A mixture of (4-chloro-2,6-difluorophenyl)methanol (400 mg, 2.2 mmol), 2-bromo-6-fluoropyridine (435 mg, 2.5 mmol), t-BuOK (504 mg, 4.5 mmol) in THF (8 mL) was stirred at 70 ° C for 1 day. After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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 value: 332.9; MS found value: 333.9 [M+1] + . 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

[0220] (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 by a similar method to Example 1. MS calculated value: 674.2; MS found value: 675.2 [M+H] + .

[0221] 1H NMR (400MHz, DMSO-d6): δ9.16 (s, 1H), 8.28 (d, J = 0.8Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 7.37-7.45 (m, 2H), 6 .89(d,J=7.2Hz,1H),6.64(d,J=8.0Hz,1H),5.37(s,2H),5.14-5.25(m,1H),4.89-4.99(m,1H),4.73-4.8 4(m,1H),4.39-4.55(m,2H),4.02(d,J=14.0Hz,1H),3.87(d,J=13.6Hz,1H),2.99-3.08(m,1H),2.84-2.9 3(m,1H),2.69-2.80(m,1H),2.57-2.68(m,1H),2.43-2.48(m,1H),2.17-2.35(m,2H);1.67-1.88(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.54,-112.14. 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) Step A: 6-(difluoromethoxy)nicotinate ethyl ester

[0222] 5-Bromo-2-(difluoromethoxy)pyridine (900 mg, 4.0 mmol) and Pd(dppf)Cl 2 A mixture of (294 mg, 0.4 mmol) and KOAc (788 mg, 8.0 mmol) in EtOH (10 mL) was stirred at 75 ° C under CO (1 atm) for 2 hours. After the reaction was completed, the reaction was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA = 4: 1) to give 6- (difluoromethoxy) nicotinate ethyl ester (800 mg, 91% yield). MS calculated value: 217.1; MS found value: 218.1 [M + H] + . Step B: (6-(difluoromethoxy)pyridin-3-yl)methanol

[0223] To a solution of ethyl 6-(difluoromethoxy)nicotinate (650 mg, 3.0 mmol) in THF (10 mL) was added LiAlH 4(285mg, 7.5mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with EA (10mL) and NaOH solution (2M, 5mL). The mixture was dried and filtered. The residue was concentrated in vacuo and purified by column chromatography (PE:EA=1:1) to give (6-(difluoromethoxy)pyridin-3-yl)methanol (400mg, 76% yield). MS calculated value: 175.0; MS found value: 176.1[M+H] + . Step C: tert-Butyl 4-(6-((6-(difluoromethoxy)pyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

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

[0225] 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 the reaction was complete, the reaction was concentrated in vacuo to give 2-(difluoromethoxy)-5-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridine TFA salt (210 mg, crude). MS calculated value: 335.1; MS found value: 336.1 [M+H] + . 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)

[0226] 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 similar manner to Example 1.

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

[0228] 1 H NMR (400 MHz, DMSO-d 6 ):1H NMR: δ9.16(d,J=0.8Hz,1H),8.38(d,J=2.0Hz,1H),8.29(d,J=0.8Hz,1H),8.02(dd,J=8.4Hz,J=2.4Hz,1H),7.51-7. 87(m,2H),7.10(d,J=8.4Hz,1H),6.88(d,J=7.2Hz,1H),6.67(d,J=8.0Hz,1H),5.37(s,2H),5.14-5.23(m,1H),4.89- 4.98(m,1H),4.73-4.82(m,1H),4.38-4.54(m,2H),4.02(d,J=14.0Hz,1H),3.87(d,J=13.6Hz,1H),3.00-3.07(m,1H ),2.85-2.93(m,1H),2.68-2.80(m,1H),2.58-2.64(m,1H),2.43-2.53(m,1H),2.17-2.34(m,2H),1.67-1.88(m,4H). 19 F NMR (377 MHz, DMSO-d 6 ):δ-63.66,-87.30. Example 8: (S)-2-((4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 8) Step A: Ethyl 2-(difluoromethoxy)isonicotinate

[0229] To a mixture of 4-bromo-2-(difluoromethoxy)pyridine (1.0 g, 4.46 mmol) in EtOH (16.0 mL) was added PdCl 2 (dppf) (326 mg, 0.44 mmol) and KOAc (875 mg, 8.93 mmol). The mixture was stirred at 75 °C under CO for 2 h. After the reaction was complete, the reaction was washed with H 2 O (50mL) quenched and extracted with ethyl acetate (60mL x 3). The organic layers were combined and washed with brine (40mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by column chromatography (PE / EA=10 / 1) to give ethyl 2-(difluoromethoxy)isonicotinate (740mg, yield: 76%). MS calculated: 217.1; MS found: 218.1 [M+H] + . Step B: (2-(difluoromethoxy)pyridin-4-yl)methanol

[0230] To a solution of ethyl 2-(difluoromethoxy)isonicotinate (740 mg, 3.41 mmol) in THF (8 mL) was added LiBH 4 (225 mg, 10.23 mmol). The solution was stirred at 40 °C overnight. The mixture was washed with MeOH (8 mL) and H 2 O (30 ml) quenched, extracted with EA (50 mL × 2). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The reaction 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] + . Step C: 4-(((6-bromopyridin-2-yl)oxy)methyl)-2-(difluoromethoxy)pyridine

[0231] 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 the reaction was complete, the reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and washed with brine (25 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. 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 value: 330.0; MS found value: 331.0 [M+H] + . Step D: tert-Butyl 6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0232] 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 2 (20 mg, 0.027 mmol), K 2 CO 3 (226 mg, 1.64 mmol) in dioxane / H 2 The mixture in 2% O (10.0 mL / 1.0 mL) was stirred at 90 °C for 3 h. After the reaction was completed, the reaction was washed with H 2 O (20mL) quench and extract with ethyl acetate (30mL x 3). The organic layers are combined and washed with brine (25mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is 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 (190mg, yield: 72%). MS calculated value: 433.2; MS found value: 378.3 [M-56+H] + . Step E: tert-Butyl 4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0233] 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, wetted with approximately 55% water) in THF (5.0 mL) was stirred at room temperature for 30 min. After the reaction was complete, 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, yield: 42%). MS calculated: 435.2; MS found: 458.2 [M+Na] + . 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

[0234] Then, a similar method to Example 1 was used to obtain (S)-2-((4-(6-((2-(difluoromethoxy)pyridin-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (14.8 mg). MS calculated value: 671.2; MS found value: 672.4 [M+H] + .

[0235] 1H NMR: δ9.15(s,1H),8.28(s,1H),8.23(d,J=5.2Hz,1H),7.49-7.90(m,2H),7.29(d,J=5.2Hz,1H),7.08(s,1H),6 .90(d,J=7.2Hz,1H),6.77(d,J=8.0Hz,1H),5.43(s,2H),5.12-5.20(m,1H),4.87-4.96(m,1H),4.73-4.77(m,1 H),4.48-4.54(m,1H),4.38-4.45(m,1H),3.98(d,J=14.0Hz,1H),3.85(d,J=14.0Hz,1H),2.95-3.02(m,1H),2. 81-2.88(m,1H),2.66-2.78(m,1H),2.54-2.63(m,1H),2.38-2.45(m,1H),2.14-2.31(m,2H),1.57-1.83(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.58,-87.32. Example 9: (S)-2-((4-(6-((6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[1- ... [4,5-c]pyridine (Compound 9)

[0236] 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 using a procedure similar to Example 8. MS Calculated: 671.2; MS Found: 672.0 [M+H] + .

[0237] 1H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(m,1H),8.46-8.21(m,3H),7.30(d,J=7.6Hz,1H),6.99(d,J=8.4 Hz,1H),6.89(d,J=7.2Hz,1H),6.76(d,J=8.4Hz,1H),5.38(s,2H),5.12-5.23(m,1H),4.85-4.96(m,1H),4.6 9-4.79(m,1H),4.38-4.55(m,2H),3.99(d,J=13.6Hz,1H),3.83(d,J=13.6Hz,1H),2.94-3.03(m,1H),2.80- 2.88(m,1H),2.67-2.79(m,1H),2.55-2.64(m,1H),2.39-2.45(m,1H),2.13-2.30(m,2H),1.59-1.82(m,4H). 19 FNMR(377MHz, DMSO-d6): δ-63.58,-87.21. Example 10: (S)-3-(oxetane-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[3-(4-(6-(trifluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)- [4,5-c]pyridine (Compound 10) Step A: Ethyl 6-(trifluoromethoxy)picolinate

[0238] To a mixture of 2-chloro-6-(trifluoromethoxy)pyridine (1.26 g, 6.4 mmol) in EtOH (20 mL) was added PdCl 2 (dppf) (467 mg, 0.64 mmol) and KOAc (1.25 g, 12.8 mmol). The mixture was stirred at 75 °C under CO for 2 hours. After the reaction was completed, the reaction mixture was filtered. The filtrate was washed with H 2 O (80mL) and extracted with ethyl acetate (70mL x3). The organic layers were combined and washed with brine (50mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction 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] + . Step B: (6-(trifluoromethoxy)pyridin-2-yl)methanol

[0239] 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 4 (317 mg, 14.42 mmol). The solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with H 2 O (40mL) quenched and extracted with ethyl acetate (40mL x 3). The organic layers were combined and washed with brine (30mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE / EA=1 / 4) to give (6-(trifluoromethoxy)pyridin-2-yl)methanol (740mg, yield: 80%). MS calculated: 193.0; MS found: 194.1 [M+H] + . 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

[0240] Then, a similar method to Example 3 was used to obtain (S)-3-(oxetane-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). MS calculated value: 689.2; MS found value: 690.4 [M+H] + .

[0241] 1H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),8.00(t,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.44(d,J=7.2Hz, 1H),7.19(d,J=8.4Hz,1H),6.88(d,J=7.2Hz,1H),6.77(d,J=8.4Hz,1H),5.41(s,2H),5.12-5.22(m,1H),4.85-4.9 7(m,1H),4.71-4.76(m,1H),4.36-4.56(m,2H),3.98(d,J=13.6Hz,1H),3.83(d,J=13.6Hz,1H),2.92-3.02(m,1H), 2.78-2.85(m,1H),2.67-2.77(m,1H),2.55-2.62(m,1H),2.39-2.46(m,1H),2.12-2.31(m,2H),1.53-1.78(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-55.12,-63.62. 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)

[0242] Starting from (3-(trifluoromethoxy)phenyl)methanol, a procedure analogous to Example 3 was used to obtain (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. MS Calcd: 688.2; MS Found: 689.1 [M+H]+.

[0243] 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.41 (s, 1H), 7.71 (t, J = 8.0Hz, 1H), 7.49-7.55 (m, 2H), 7.43 (s ,1H),7.31(d,J=7.6Hz,1H),6.94(d,J=7.2Hz,1H),6.78(d,J=8.0Hz,1H),5.45(s,2H),5.08-5.14( m,1H),4.85-4.97(m,3H),4.73-4.77(m,1H),4.50-4.56(m,1H),4.37-4.43(m,1H),3.74-3.84(m,2 H),3.26-3.43(m,2H),2.91-3.01(m,1H),2.70-2.81(m,1H),2.33-2.39(m,1H),2.01-2.17(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-56.70,-63.76. Example 12: (S)-2-((4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H- Imidazolo[4,5-c]pyridine (Compound 12) Step A: 2-(Methoxycarbonyl)-5-methylpyridine 1-oxide

[0244] At 0°C in N 2 To a mixture of methyl 5-methylpicolinate (2.0 g, 13.2 mmol) in DCM (50 mL) was added m-CPBA (4.6 g, 26.5 mmol). The mixture was stirred at 30 °C for 2 hours. After the reaction was complete, the reaction was cooled to 0 °C. The mixture was treated with NaHCO 3 (aqueous solution, 50 mL) was quenched and extracted with DCM and MeOH (DCM / MeOH=20 / 1, 3 x 80 mL). The combined organic layers were washed with brine (60 ml). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate 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 value: 167.1; MS found value: 168.1 [M+H] + . Step B: Methyl 6-hydroxy-5-methylpicolinate

[0245] 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 room temperature. The mixture was stirred at 35 ° C for 2 h. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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 value: 167.1; MS found value: 168.1 [M+H] + . Step C: Methyl 6-(difluoromethoxy)-5-methylpicolinate

[0246] At 0°C in N 2 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). 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 room temperature for 3 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. The residue was purified by column chromatography on silica gel (EA / PE=1 / 3) to give methyl 6-(difluoromethoxy)-5-methylpicolinate (770 mg, yield: 98.8%). MS calculated value: 217.1; MS found value: 218.1 [M+H] + . Step D: (6-(difluoromethoxy)-5-methylpyridin-2-yl)methanol

[0247] At room temperature in N 2 To a mixture of methyl 6-(difluoromethoxy)-5-methylpicolinate (740 mg, 3.4 mmol) in THF (8 mL) was added LiBH 4(300 mg, 13.6 mmol). The mixture was stirred at 40 °C for 30 min. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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] + . Step E: tert-Butyl 4-(6-((6-(difluoromethoxy)-5-methylpyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0248] To a solution of (6-(difluoromethoxy)-5-methylpyridin-2-yl)methanol (470 mg, 2.5 mmol) in DMF (10 mL) at room temperature was added tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (836 mg, 3.0 mmol), NaOH (199 mg, 5.0 mmol). The resulting mixture was stirred at 70 ° C for 16 h. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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] + . 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

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

[0250] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),7.45-7.88(m,3H),7.23(d,J=7.6Hz,1H),6.89(d,J=7 .2Hz,1H),6.74(d,J=8.0Hz,1H),5.33(s,2H),5.12-5.22(m,1H),4.85-4.96(m,1H),4.70-4.79(m,1H),4. 51-4.55(m,1H),4.37-4.43(m,1H),3.99(d,J=14.0Hz,1H),3.84(d,J=13.6Hz,1H),2.95-3.04(m,1H),2. 80-2.89(m,1H),2.68-2.78(m,1H),2.53-2.64(m,2H),2.21-2.34(m,2H),2.19(s,3H),1.60-1.84(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.58,-86.96. Example 13: (S)-2-((4-(6-((5-chloro-6-(difluoromethoxy)pyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 13)

[0251] 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 using a similar procedure as described herein. MS Calcd: 705.20; MS Found: 705.9 [M+H]+.

[0252] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),8.10(d,J=8.0Hz,1H),7.51-7.90(m,2H),7.33(d,J=8.0 Hz,1H),6.90(d,J=7.2Hz,1H),6.77(d,J=8.4Hz,1H),5.37(s,2H),5.13-5.22(m,1H),4.87-4.94(m,1H),4.7 1-4.77(m,1H),4.38-4.54(m,2H),3.49(d,J=13.6Hz,1H),3.84(d,J=13.6Hz,1H),2.94-3.03(m,1H),2.80- 2.88(m,1H),2.65-2.77(m,1H),2.53-2.63(m,1H),2.41-2.47(m,1H),2.13-2.30(m,2H),1.55-1.83(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.59,-87.67. Example 14: (S)-2-((4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 14) Step A: Methyl 5-fluoropicolinate

[0253] At 0°C in N 2 To a mixture of 5-fluoropicolinic acid (2.0 g, 14.2 mmol) in MeOH (20 mL) was added SOCl 2(10.1 g, 85.1 mmol). The mixture was stirred at 0 °C for 10 min, warmed to room temperature for 10 min, and then heated to 70 °C for 16 h. After the reaction was complete, the reaction was concentrated to dryness in vacuo to give methyl 5-fluoropicolinate (2.0 g, yield: 93.3%). MS calculated: 155.0; MS found: 156.1 [M+H] + . Step B: 5-Fluoro-2-(methoxycarbonyl)pyridine 1-oxide

[0254] At 0°C in N 2 To a mixture of 5-fluoropicolinic acid methyl ester (2.0 g, 12.9 mmol) in DCM (20 mL) was added m-CPBA (6.7 g, 38.7 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction was cooled to 0 ° C and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel (EA / PE=1 / 1) to obtain 5-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (1.2 g, yield: 54.5%). MS calculated value: 171.0; MS found value: 172.1 [M+H] + . Step C: Methyl 5-fluoro-6-hydroxypicolinate

[0255] 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 room temperature. The mixture was stirred at 35 ° C for 2 h. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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 value: 171.0; MS found value: 172.1 [M+H] + . Step D: Methyl 6-(difluoromethoxy)-5-fluoropicolinate

[0256] At 0°C in N 2To 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). 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 room temperature for 3 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. The residue was purified by column chromatography on silica gel (EA / PE=1 / 3) to give methyl 6-(difluoromethoxy)-5-fluoropicolinate (720 mg, yield: 60.6%). MS calculated value: 221.0; MS found value: 222.1 [M+H] + . Step E: (6-(Difluoromethoxy)-5-fluoropyridin-2-yl)methanol

[0257] At room temperature in N 2 To a mixture of methyl 6-(difluoromethoxy)-5-fluoropicolinate (720 mg, 3.3 mmol) in THF (5 mL) was added LiBH 4 (287 mg, 13.0 mmol). The mixture was stirred at 40 °C for 30 min. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL×3). The organic layers were combined and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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] + . Step F: tert-Butyl 4-(6-((6-(difluoromethoxy)-5-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0258] To a solution of (6-(difluoromethoxy)-5-fluoropyridin-2-yl)methanol (200 mg, 1.0 mmol) in THF (10 mL) at 0 °C was added tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (518 mg, 1.9 mmol), PPh 3(543 mg, 2.1 mmol) and DIAD (418 mg, 2.072 mmol). The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, 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 and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. 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] + . 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

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

[0260] 1H NMR (400MHz, DMSO-d6): δ9.14(s,1H),8.27(s,1H),7.50-7.97(m,3H),7.37(dd,J=8.4Hz,J=3.2Hz,1H),6.90( d,J=7.6Hz,1H),6.75(d,J=8.0Hz,1H),5.34(s,2H),5.12-5.22(m,1H),4.85-4.96(m,1H),4.67-4.78(m,1H), 4.47-4.55(m,1H),4.39-4.46(m,1H),3.99(d,J=14.0Hz,1H),3.84(d,J=13.6Hz,1H),2.95-3.03(m,1H),2.86 -2.95(m,1H),2.69-2.81(m,1H),2.55-2.63(m,1H),2.42-2.47(m,1H),2.14-2.31(m,2H),1.59-1.84(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.40, -86.99, -140.71. Example 15: (S)-2-((4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H- Imidazolo[4,5-c]pyridine (Compound 15) Step A: tert-Butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0261] At room temperature in N 2 The mixture was stirred for 2 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. To 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 K 2 CO 3 (3.2 g, 23.0 mmol) in dioxane / H 2 O (10 mL / 1 mL) was added to the mixture 2· DCM (938 mg, 1.15 mmol). The mixture was stirred at 95°C for 16 h. After the reaction was completed, 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 and purified by Na 2 SO 4 Dry, filter and concentrate to dryness in vacuo. The residue was purified by column chromatography on silica gel (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 value: 276.2; MS found value: 277.2 [M+H] + . Step B: tert-Butyl 4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0262] 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, wetted with approximately 55% water) at room temperature. 2 The mixture was stirred at room temperature for 1 h. After the reaction was complete, 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 product). MS calculated value: 278.2; MS found value: 279.2 [M+H] + . Step C: tert-Butyl 4-(6-((2-(difluoromethoxy)-6-methylpyridin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0263] To 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 PPh 3 DIAD (319 mg, 1.6 mmol) was added dropwise to a solution of 415 mg, 1.6 mmol) in THF (5.0 mL). The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, 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 and purified by Na 2 SO 4Dry, filter and concentrate to dryness in vacuo. 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] + 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

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

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

[0266] 19 F NMR (377MHz, DMSO-d6): δ-63.51,-86.91. Example 16: (S)-2-((4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl)- 4-(4-(4-yl)-3H-imidazo[4,5-c]pyridine (Compound 16) Step A: 3-Bromo-6-chloro-2-hydroxybenzaldehyde

[0267] Paraformaldehyde (11.2 g, 124.4 mmol), MgCl 2 (7.88 g, 82.9 mmol) was stirred in a mixture of THF (150 mL) and TEA (11.5 ml) at 70 °C under Ar for 15 min. 2-Bromo-5-chlorophenol (8.5 g, 41.5 mmol) was then added and the reaction was stirred at 70 °C under Ar overnight. After the reaction was complete, the reaction mixture was filtered and washed with H 2 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then, 3-bromo-6-chloro-2-hydroxybenzaldehyde (6.6 g, yield: 68%) was added to 4-bromo-6-chloro-2-hydroxybenzaldehyde (10.6 g, yield: 68%).Then, 3-bromo-6-chloro-2-hydroxybenzaldehyde (6.6 g, yield: 68%) was added to 4-bromo-6-chloro-2-hydroxybenzaldehyde (10.6 g, yield: 68%). Step B: 3-Bromo-6-chlorobenzene-1,2-diol

[0268] 3-Bromo-6-chloro-2-hydroxybenzaldehyde (2.0 g, 8.55 mmol) was added in H 2 O 2 To a mixture of 4-nitropropene (5 ml, 30% aqueous solution), THF (20 ml) was added NaOH (5 ml, 2 M in water) and stirred at room temperature overnight. After the reaction was complete, the reaction mixture was washed with H 2 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then, 3-bromo-6-chlorobenzene-1,2-diol (1.33 g, yield: 70%) was added to 4-bromo-6-chlorobenzene-1,2-diol (1.33 g, yield: 70%). Step C: 4-Bromo-7-fluorobenzo[d][1,3]dioxole

[0269] 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 K 2 CO 3 The reaction was stirred at 110 ° C for 2 hours. After the reaction was completed, the mixture was quenched with H2O (40mL) and extracted with ethyl acetate (40mL x 3). The organic layers were combined and washed with brine (30mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by column chromatography (PE / EA=1 / 10) to obtain 4-bromo-7-fluorobenzo [d] [1,3] dioxole (470mg, yield: 89%). Step D: Ethyl 7-chlorobenzo[d][1,3]dioxole-4-carboxylate

[0270] 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 2 (dppf) (147 mg, 0.20 mmol) and KOAc (394 mg, 4.02 mmol). The mixture was stirred at 75 °C under CO for 2 h. After the reaction was complete, the mixture was washed with H 2 The mixture was stirred for 2 hours at 4 ℃ for 1 h.O (50 mL) was quenched and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with brine (30 mL x 2), dried over sodium sulfate, filtered and concentrated in a vacuum. The reaction was purified by column chromatography (PE / EA=10 / 1) to obtain 7-chlorobenzo [d] [1,3] dioxole-4-ethyl formate (360 mg, yield: 79%). Step E: (7-Chlorobenzo[d][1,3]dioxol-4-yl)methanol

[0271] 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 4 (144.7 mg, 6.58 mmol). The solution was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was washed with H 2O (30mL) quench and extract with ethyl acetate (30mL x 3). The organic layers are combined and washed with brine (20mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is purified by column chromatography (PE / EA=3 / 1) to give (7-chlorobenzo[d][1,3]dioxol-4-yl)methanol (190mg, yield: 65%). Step F: tert-butyl 4-(6-((7-chlorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0272] 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), NaOH (81.72 mg, 2.04 mmol) in DMF (4.5 mL) was stirred at 70 °C overnight. After the reaction was complete, the mixture was washed with H 2 O (40mL) quench and extract with ethyl acetate (30mL x 3). The organic layers are combined and washed with brine (20mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is 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 (270mg, yield: 59%). MS calculated value: 446.2; MS found value: 447.2[M+H] + . 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

[0273] (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 using a similar procedure as in Example 1. MS calculated value: 682.2; MS found value: 683.3 [M+H] + .

[0274] 1H NMR: δ9.15(s,1H),8.28(s,1H),7.62(t,J=8.0Hz,1H),6.98(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.88(d ,J=7.2Hz,1H),6.67(d,J=8.4Hz,1H),6.18(s,2H),5.28(s,2H),5.14-5.22(m,1H),4.87-4.96(m,1H),4.74 -4.78(m,1H),4.39-4.53(m,2H),4.01(d,J=13.6Hz,1H),3.86(d,J=13.6Hz,1H),3.00-3.08(m,1H),2.84-2 .92(m,1H),2.69-2.78(m,1H),2.58-2.65(m,1H),2.38-2.45(m,1H),2.17-2.31(m,2H),1.65-1.87(m,4H).

[0275] 19 F NMR (377MHz, DMSO-d6): δ-63.56. Example 17: (S)-2-((4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazole-3-yl)- yl)-3H-imidazo[4,5-c]pyridine (Compound 17) Step A: 4-Bromo-7-fluorobenzo[d][1,3]dioxole

[0276] To a solution of 3-bromo-6-fluorobenzene-1,2-diol (1.50 g, 7.28 mmol) in DMF (30 mL) was added dibromomethane (6.33 g, 36.41 mmol) and K 2 CO 3 (3.01 g, 21.84 mmol). The solution was stirred at 110°C for 2 hours. After the reaction was complete, the mixture was treated with H 2 O (50 mL), extracted with EA (60 mL x 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%). Step B: Ethyl 7-fluorobenzo[d][1,3]dioxole-4-carboxylate

[0277] 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 2 The mixture was stirred at 75 ° C for 2 hours under CO. After the reaction was completed, 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%). Step C: (7-Fluorobenzo[d][1,3]dioxol-4-yl)methanol

[0278] 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 4 (102.74 mg, 4.72 mmol). The solution was stirred at 40°C for 16 hours. After the reaction was complete, the mixture was washed with NH 4 The mixture was diluted with aqueous Cl solution (30 mL) and extracted with DCM (30 mL x 2). The organic layers were combined and purified by Na 2 SO 4 Dried, filtered, and concentrated to dryness in vacuo to give (7-fluorobenzo[d][1,3]dioxol-4-yl)methanol (340 mg, yield: 85%). Step D: tert-Butyl 4-(6-((7-fluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0279] (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), PPh 3 A mixture of 4-nitropropene (896 mg, 3.4 mmol), DIAD (691 mg, 3.4 mmol) in THF (6 mL) was stirred at room temperature for 3 h. After the reaction was completed, the mixture was washed with H 2O (20mL), extracted with EA (30mL×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=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 value: 430.2; MS found value: 431.0 [M+H] + . 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

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

[0281] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),7.63(t,J=8.0Hz,1H),6.96-7.02(m,1H),6.80- 6.90(m,2H),6.65(d,J=8.0Hz,1H),6.17(s,2H),5.27(s,2H),5.15-5.21(m,1H),4.88-4.96(m,1H), 4.73-4.80(m,1H),4.39-4.53(m,2H),4.02(d,J=13.2Hz,1H),3.86(d,J=13.6Hz,1H),3.01-3.08(m, 1H),2.86-2.93(m,1H),2.70-2.79(m,2H),2.43-2.48(m,1H),2.18-2.35(m,2H),1.71-1.87(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.37,-139.35. Example 18: (S)-2-((4-(6-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 18)

[0282] 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 using a similar procedure as in Example 3. MS Calcd: 684.2; MS Found: 685.4 [M+H] + .

[0283] 1H NMR: δ9.16(s,1H),8.28(s,1H),7.64(t,J=8.0Hz,1H),7.35(dd,J=1.2Hz,J=8.0Hz,1H),7.29(d,J=7.2Hz,1H),7.19( t,J=8.0Hz,1H),6.88(d,J=7.2Hz,1H),6.70(d,J=8.0Hz,1H),5.44(s,2H),5.14-5.21(m,1H),4.88-4.96(m,1H),4.7 4-4.78(m,1H),4.47-4.54(m,1H),4.38-4.46(m,1H),4.00(d,J=13.6Hz,1H),3.85(d,J=13.6Hz,1H),2.96-3.04(m,1 H),2.83-2.89(m,1H),2.70-2.78(m,1H),2.55-2.66(m,1H),2.38-2.44(m,1H),2.14-2.31(m,2H),1.60-1.84(m,4H). 19 F NMR: (377MHz, DMSO-d6): δ-48.85,-63.63. 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-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 19) Step A: 4-Bromobenzo[d][1,3]dioxole-2,2-d2

[0284] To a solution of 3-bromobenzene-1,2-diol (1.0 g, 5.3 mmol) in DMF (15 mL) was added dibromomethane-d2 (1.8 g, 10.6 mmol) and K 2 CO 3 (2.2 g, 15.9 mmol). The reaction was stirred at 110 °C for 2 h. After the reaction was complete, the mixture was treated with H 2 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then 4-bromobenzo[d][1,3]dioxole-2,2-d2 (829 mg, yield: 77%) was added to 4-bromobenzo[d][1,3]dioxole-2,2-d2 (829 mg, yield: 77%). Step B: Ethyl benzo[d][1,3]dioxole-4-carboxylate-2,2-d2

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

[0286] 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 LiAlH 4 (130 mg, 3.42 mmol). The solution was stirred at room temperature for 1.5 hours. After the reaction was complete, EA (20 mL) and H were added to the mixture. 2 O (0.15 mL), stirred at room temperature for 10 min, and then added NaOH solution (2 M, 0.15 mL) and H 2 The 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 in vacuo. The reaction 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%). Step D: tert-Butyl 4-(6-((Benzo[d][1,3]dioxol-4-yl-2,2-d2)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0287] A mixture of (benzo[d][1,3]dioxol-4-yl-2,2-d2)methanol (366 mg, 2.38 mmol), tert-butyl 4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (560 mg, 2.00 mmol), NaOH (160 mg, 4.00 mmol) in DMF (10.0 mL) was stirred at room temperature at 70° C. for 4 hours. After the reaction was complete, the mixture was washed with H 2 O (60mL) quench and extract with ethyl acetate (40mL x 3). The organic layers are combined and washed with brine (30mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is 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 (550mg, yield: 56%). MS calculated value: 414.2; MS found value: 415.3[M+H] + . 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

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

[0289] 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.29 (s, 1H), 7.62 (t, J = 5.6Hz, 1H), 6.92-6.98 (m, 1H), 6.7 8-6.90(m,3H),6.65(d,J=8.0Hz,1H),5.30(s,2H),5.11-5.23(m,1H),4.86-4.97(m,1H),4.74-4 .78(m,1H),4.36-4.53(m,2H),4.01(d,J=13.2Hz,1H),3.86(d,J=13.2Hz,1H),2.98-3.08(m,1H) ,2.82-2.93(m,1H),2.68-2.78(m,1H),2.57-2.67(m,1H),2.14-2.37(m,3H),1.63-1.91(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.64. 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)

[0290] 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 using a similar procedure as in Example 3. MS Calcd: 661.22; MS Found: 662.2 [M+H] + .

[0291] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.27(s,1H),8.06(d,J=7.6Hz,1H),7.98(d,J=8.0Hz,1H),7.67-7.75(m,1H),7 .45-7.51(m,1H),7.38-7.44(m,1H),6.94(d,J=7.6Hz,1H),6.81(d,J=8.0Hz,1H),5.81(s,2H),5.11-5.21(m,1H),4.8 4-4.96(m,1H),4.68-4.77(m,1H),4.36-4.50(m,2H),3.98(d,J=13.6Hz,1H),3.82(d,J=13.6Hz,1H),2.94-3.01(m,1 H),2.82-2.85(m,1H),2.66-2.75(m,1H),2.56-2.63(m,1H),2.37-2.46(m,1H),2.12-2.29(m,2H),1.59-1.85(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.54. 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) Step A: (6-Methylpyridazin-3-yl)methanol

[0292] To a solution of methyl 6-methylpyridazine-3-carboxylate (500 mg, 3.29 mmol) in MeOH (10 mL) was slowly added LiBH 4(217 mg, 9.87 mmol). The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was quenched with water (1 mL) and filtered. The filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography on silica gel (DCM / MeOH=12 / 1) to give (6-methylpyridazine-3-yl)methanol (350 mg, 86.0% yield). MS calculated value: 124.1; MS found value: 125.2 [M+H] + Step B: tert-Butyl 4-(6-((6-methylpyridazin-3-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0293] 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 the reaction was complete, the mixture was diluted with EA (20 mL) and washed with H 2 The product was stirred for 2 hours at 4 ℃ for 10 minutes. The mixture was stirred for 2 hours at 4 ℃ for 3 ... + . Step C: 3-Methyl-6-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridazine TFA salt

[0294] 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. After 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 value: 284.2; MS found value: 285.2 [M+H] + . 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

[0295] 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 by a similar method to Example 1. MS calculated value: 620.3; MS found value: 621.4 [M+H] + .

[0296] 1H NMR (400MHz, DMSO-d6): δ9.31(s,1H),8.40(s,1H),7.73(t,J=8.0Hz,1H),7.66(d,J=8.4Hz,1H),7. 59(d,J=8.8Hz,1H),6.92-7.00(m,1H),6.82(d,J=8.0Hz,1H),5.63(s,2H),5.08-5.17(m,1H),4.84 -4.99(m.3H),4.73-4.82(m,1H),4.48-4.56(m,1H),4.36-4.46(m,1H),3.65-3.86(m,2H),3.21-3. 41(m,2H),2.82-3.05(m,1H),2.70-2.81(m,1H),2.62(s,3H),2.30-2.43(m,1H),2.00-2.15(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.71. Example 22: (S)-2-((4-(6-((1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 22) Step A: 1-Cyclopropyl-1H-pyrazole-3-carboxylic acid methyl ester

[0297] 1H-pyrazole-3-carboxylic acid methyl ester (2.0 g, 15.9 mmol), cyclopropylboronic acid (2.7 g, 31.7 mmol), Na 2 CO 3 (3.4 g, 31.8 mmol), Cu(OAc) 2 A mixture of 2,2′-bipyridine (2.9 g, 15.9 mmol) and 2,2′-bipyridine (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 and washed with H 2 The mixture was quenched with 1% O (60 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (40 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (3 / 1)) to give 1-cyclopropyl-1H-pyrazole-3-carboxylic acid methyl ester (1.7 g, yield: 64.9%). MS calculated value: 166.1; MS found value: 167.1 [M+H] + . Step B: 1-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylic acid methyl ester

[0298] Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (1.5 g, 9.0 mmol) and (9.6 g, 27.1 mmol) were dissolved in CH 3 CN (20 mL) was heated at 70 °C under N 2 The reaction mixture was cooled to room temperature. The mixture was washed with H 2 The mixture was quenched with 1% O (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (eluted with PE / EA (4 / 1)) to give methyl 1-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylate (1.5 g, yield: 90.3%). Step C: (1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methanol

[0299] 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 4 (0.265 g, 12.06 mmol). The mixture was stirred at 50 °C for 5 h. The reaction mixture was cooled to room temperature and heated with H 2The mixture was quenched with 1% O (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL). The organic layer was purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (eluted with PE / EA (4 / 1)) to give (1-cyclopropyl-4-fluoro-1H-pyrazol-3-yl)methanol (510 mg, yield: 54.2%). 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

[0300] (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 by a similar method to compound 3. MS calculated value: 652.26; MS found value: 653.0 [M+H]+.

[0301] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.28(s,1H),7.91(d,J=4.4Hz,1H),7.61(t,J=7.6Hz,1H),6.87(d,J=7.6Hz,1H),6. 62(d,J=8.0Hz,1H),5.25(s,2H),5.15-5.22(m,1H),4.90-4.96(m,1H),4.73-4.79(m,1H),4.47-4.53(m,1H),4.40-4.45(m ,1H),4.01(d,J=13.6Hz,1H),3.86(d,J=13.6Hz,1H),3.62-3.68(m,1H),2.99-3.09(m,1H),2.84-2.94(m,1H),2.71-2.79 (m,1H),2.59-2.65(m,1H),2.44-2.48(m,1H),2.16-2.35(m,2H),1.71-1.90(m,4H),0.96–1.03(m,2H),0.86-0.94(m,2H). 19 F NMR (377MHz, DMSO-d6): δ-63.53,-176.75. Example 23: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 23) 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

[0302] 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 minutes, (S)-6-bromo-2-(chloromethyl)-3-(oxetane-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 hours. After the reaction was complete, the mixture was diluted with EA (100 mL) and washed with H 2 O (2x 50mL). 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)-oxetanes-2-yl)methyl)-3H-imidazo[4,5-c]pyridine (535mg, yield: 81.6%). MS calculated: 626.1; MS found: 627.1[M+H] + . 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

[0303] 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 2 (125 mg, 0.17 mmol) and KOAc (250 mg, 2.56 mmol). The mixture was stirred at 70 °C for 16 hours under an atmosphere of CO (balloon). The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (DCM / MeOH=20 / 1) to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid ethyl ester (400 mg, yield: 75.6%). MS calculated value: 620.2; MS found value: 620.9 [M+H] + . 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

[0304] 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)-oxetanes-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, 2M solution in water). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (5 mL), and the mixture was then adjusted to pH 5-6 with 1N HCl(aqueous solution). 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)δ9.09(s,1H),8.27(s,1H),7.49-7.59(m,2H),7.29-7.34(m,1H), 6.69-6.80(m,3H),5.13-5.18(m,1H),4.86-4.92(m,1H),4.72-4.75(m,1H),4.46-4.51(m ,1H),4.38-4.44(m,1H),3.99-4.02(m,1H),3.83-3.86(m,1H),2.97-3.01(m,1H),2.85- 2.88(m,1H),2.63-2.74(m,2H),2.21-2.27(m,2H),1.98-2.02(m,4H),1.65-1.77(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-110.78. 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)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-yl Formamide (Compound 24)

[0306] 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), methylamine (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 one hour. After the reaction was completed, 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)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (15.93 mg, yield: 31.2%). MS calculated value: 605.2; MS found value: 606.1 [M+H] + .

[0307] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.71(q,J=4.8Hz,1H),8.21(s,1H),7.53-7.59(m,2H),7.33(dd,J=8.4 Hz,J=1.6Hz,1H),6.73-6.80(m,3H),5.13-5.19(m,1H),4.88-4.92(m,1H),4.73(dd,J=15.2Hz,J=2.8Hz,1H ),4.47-4.52(m,1H),4.38-4.43(m,1H),3.99(d,J=13.6Hz,1H),3.83(d,J=13.6Hz,1H),3.02-3.04(m,1H), 2.84-2.86(m,4H),2.62-2.76(m,2H),2.41-2.48(m,1H),2.19-2.31(m,2H),2.03(s,3H),1.65-1.80(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-110.79. Example 25: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-N-(2,2,2-trifluoroethyl)-3H-imidazo[4-((S)-oxetane-2-yl)methyl)- [4,5-c]pyridine-6-carboxamide (Compound 25)

[0308] 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 one hour. After the reaction was completed, 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)-oxetane-2-yl)methyl)-N-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-c]pyridine-6-carboxamide (24.3 mg, yield: 42.8%). MS calculated value: 673.21; MS found value: 674.1 [M+H] + .

[0309] 1 H NMR (400MHz, DMSO-d6) δ9.33(t,J=6.4Hz,1H),9.22(s,1H),8.39(s,1H),7.56-7.64(m,2H),7.35(d d,J=8.4Hz,J=1.6Hz,1H),6.86(d,J=4.0Hz,2H),6.73-6.81(m,1H),5.05-5.15(m,1H),4.84-4.96( m,3H),4.73-4.76(m,1H),4.47-4.55(m,1H),4.34-4.42(m,1H),4.08-4.19(m,2H),3.69-3.84(m,2 H),3.29-3.41(m,2H),2.94-3.05(m,1H),2.71-2.80(m,1H),2.33-2.40(m,1H),1.98-2.20(m,7H). 19 F NMR (377MHz, DMSO-d6): δ-70.35,-110.50. 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)-oxetane-2-yl)methyl)-3H-imidazo[ ... [4,5-c]pyridine-6-carboxamide (Compound 26)

[0310] 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), T 3 A mixture of P (95 mg, 0.30 mmol) and DIEA (58 mg, 0.45 mmol) in DMF (1.5 mL) was stirred at room temperature for 2 h. After the reaction was complete, the mixture was diluted with EA (30 mL) and washed with H 2 O (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the mixture was purified directly 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)-oxetane-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] 1 H NMR(400MHz,DMSO-d6)δ9.17(d,J=0.8Hz,1H),8.69-8.75(m,1H),8.34(d,J=0.8Hz,1H),7.56-7.64(m ,2H),7.35(dd,J=8.4Hz,2.0Hz,1H),6.86-6.87(m,2H),6.74-6.80(m,1H),5.05-5.14(m,1H),4.84-4 .96(m,3H),4.73-4.77(m,1H),4.48-4.53(m,1H),4.35-4.40(m,1H),3.61-3.77(m,6H),3.49-3.52(m ,3H),3.31-3.42(m,2H),2.95-3.06(m,1H),2.71-2.79(m,1H),2.31-2.39(m,1H),1.96-2.21(m,7H). 19 F NMR (377MHz, DMSO-d6): δ-110.50. 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound 27)

[0312] 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

[0313] A similar method to Example 23 was used to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid. MS calculated value: 609.2; MS found value: 610.0 [M+H] + .

[0314] 1 H NMR(400MHz, DMSO-d6)δ:7.69-7.76(m,1H),7.50-7.59(m,3H),7.33(dd,J=8.4Hz,2.0Hz,1 H),6.72-6.82(m,3H),5.08-5.16(m,1H),4.73-4.79(m,1H),4.59-4.66(m,1H),4.35-4.50( m,2H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.2Hz,1H),2.97-3.05(m,1H),2.82-2.90(m,1H ),2.61-2.74(m,2H),2.39-2.46(m,1H),2.14-2.30(m,2H),2.03(s,1H),1.65-1.83(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-110.79,-124.83. 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)

[0315] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine TFA salt,

[0316] A similar method to Example 23 was used to obtain (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid. MS calculated value: 565.2; MS found value: 566.2 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.39 (d, J = 0.4Hz, 1H), 7.70 (t, J = 7.6Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7. 49(dd,J=10.0Hz,2.0Hz,1H),7.33(dd,J=8.4Hz,2.0Hz,1H),6.92-6.97(m,1H),6.75(d,J=8.4Hz,1H),5.41( s,2H),5.06-5.12(m,1H),4.85-4.96(m,3H),4.71-4.79(m,1H),4.48-4.54(m,1H),4.35-4.41(m,1H),3.75- 3.82(m,2H),3.22-3.36(m,2H),2.89-3.01(m,1H),2.69-2.79(m,1H),2.31-2.39(m,1H),2.02-2.19(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-115.20. Example 29: (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 29)

[0318] Starting from 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridinium HCl salt, a similar procedure as in Example 23 was used to obtain (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridinium]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid. MS Calcd: 563.2; MS Found: 564.0 [M+H] + .

[0319] 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.28(s,1H),7.69(t,J=7.6Hz,1H),7.55(t,J=8.0Hz,1H),7.46(dd,J= 10.0Hz, 2.0Hz, 1H), 7.30 (dd, J=8.4Hz, 1.6Hz, 1H), 7.09 (d, J=7.6Hz, 1H), 6.70-6.78 (m, 2H), 5.40 (s, 2H), 5. 06-5.15(m,1H),4.84-4.94(m,1H),4.69-4.78(m,1H),4.45-4.51(m,1H),4.35-4.41(m,1H),4.11(d,J=13.6 Hz,1H),3.99(d,J=13.6Hz,1H),3.18-3.26(m,4H),2.75-2.82(m,2H),2.64-2.70(m,1H),2.37-2.44(m,1H). 19 F NMR (377MHz, DMSO-d6): δ-115.27. Example 30: (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Compound 30)

[0320] Starting from 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine TFA salt,

[0321] A similar method to Example 23 was used to obtain (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid. MS calculated value: 580.2; MS found value: 581.1 [M+H] +

[0322] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ9.10(s,1H),8.51(s,1H),7.54(t,J=7.4Hz,1H),7.29-7.17(m,3H),7.12-7.02(m,2H),6.09(s,1H),5.28-5.16(m,3H),4.69 -4.59(m,2H),4.52-4.39(m,4H),3.55-3.48(m,2H),3.21-3.01(m,3H),2.84-2.77(m,1H),2.70-2.63(m,1H),2.56-2.48(m,1H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-117.54). Example 31: (S)-2-((4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 31) Step A: tert-Butyl 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0323] 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 3 (183 mg, 0.70 mmol) and DIAD (178 mg, 0.88 mmol), and then the mixture was stirred at 0 °C for 3 hours. After the reaction was completed, the mixture was treated with H 2O (40mL) quench and extract with ethyl acetate (30mL x 3). The organic layers are combined and washed with brine (25mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is 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 (170mg, yield: 65%). MS calculated value: 447.2; MS found value: 391.9 [M-56+H] + . Step B: 4-(3-((4-chloro-2-methoxybenzyl)oxy)-4-fluorophenyl)-1,2,3,6-tetrahydropyridine HCl salt

[0324] 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 (4M, 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] + . 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

[0325] (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 using a similar method as described herein. MS Calcd: 683.2; MS Found: 684.5 [M+H] + .

[0326] 1H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.30 (s, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.25 (dd, J = 2.0Hz, J = 8. 4Hz,1H),7.12-7.20(m,2H),7.03-7.09(m,1H),6.94-7.01(m,1H),6.12-6.16(m,1H),5.13(s,3H) ,4.88-4.97(m,1H),4.71-4.81(m,1H),4.46-4.53(m,1H),4.37-4.44(m,1H),4.11(d,J=13.6Hz,1 H), 3.99 (d, J = 13.6Hz, 1H), 3.84 (s, 3H), 3.14-3.26 (m, 2H), 2.63-2.83 (m, 3H), 2.33-2.45 (m, 3H). 19 F NMR (377MHz, DMSO-d6): δ-63.60,-136.52. Example 32: (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (Compound 32) 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

[0327] (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 K 2 CO 3A mixture of (348 mg, 2.52 mmol) in DMSO (3 mL) was stirred at 60 °C for 3 hours. The mixture was poured into water (50 mL) and extracted with DCM (2 x 50 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and the residue was concentrated to afford (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] + 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-carboximidamide

[0328] 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 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 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-carboximidamide (105 mg, yield: 48.7%). MS calculated value: 593.2; MS found value: 594.2 [M+H] + 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

[0329] 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-carboximide (105 mg, 0.18 mmol), 2-hydrazino-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 h. The mixture was purified by preparative HPLC to obtain (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] +

[0330] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ9.12(s,1H),8.48(s,1H),7.54(t,J=8.0Hz,1H),7.27-7.24(m,2H),7.20(d,J=9.2 Hz,1H),7.09-7.02(m,2H),6.11-6.05(m,1H),5.31-5.25(m,1H),5.20(s,2H),4.99-4. 93(m,1H),4.83-4.78(m,1H),4.69-4.63(m,1H),4.53-4.46(m,1H),4.18(d,J=14.0Hz ,1H),4.05(d,J=14.0Hz,1H),3.29-3.19(m,2H),2.91-2.76(m,3H),2.59-2.53(m,3H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-117.52),(-137.79). Example 33: (S)-5-(2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-yl Formonitrile (Compound 33)

[0331] 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 h. The mixture was poured into water (30 mL) and extracted with DCM (2 x 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 obtain (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] +

[0332] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ9.06(s,1H),8.35(s,1H),7.54(t,J=8.0Hz,1H),7.26(d,J=7.6,2H),7.20(d,J=8.0Hz ,1H),7.09-7.05(m,2H),6.08(s,1H),5.31-5.24(m,1H),5.20(s,2H),4.98-4.92(m,1H),4 .81-4.75(m,1H),4.68-4.62(m,1H),4.52-4.46(m,1H),4.17(d,J=13.6Hz,1H),4.05(d,J =13.6Hz,1H),3.28-3.22(m,2H),2.89-2.83(m,2H),2.82-2.76(m,1H),2.60-2.50(m,3H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-117.52),(-137.88). 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-yl 1,2,4-oxadiazol-5(4H)-one (Compound 34) 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

[0333] 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 the reaction was complete, the mixture was washed with H 2 O (40mL), extracted with EA (30mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (eluted 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole (170 mg, yield: 87.8%). MS calculated value: 643.10; MS found value: 644.3 / 646.3[M+H] + . 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

[0334] 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) 2 (11.87mg, 0.10mmol), Ruphos-Pd-G 3 A solution of (33.44 mg, 0.04 mmol) in NMP (2.0 mL) was stirred at 115 °C for 1.5 h. After the reaction was complete, the mixture was washed with H 2 O (20mL), extracted with EA (20mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography (eluted 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)-oxetanes-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (120mg impure, 59% pure, yield: 100%). MS calculated value: 590.2; MS found value: 591.5[M+H] + . 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-carboximidazole

[0335] 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 2 A solution of 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 hours. After the reaction was complete, the mixture was washed with H 2O (20 mL) and extracted with EA (15 mL x 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboximidamide (86 mg, crude). MS Calcd: 623.21; MS Found: 624.2 [M+H] + . 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

[0336] 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-carboximidazole (86 mg, 0.14 mmol) and CDI (112 mg, 0.69 mmol) in THF (2.0 mL) was stirred at 50° C. for 3 h. After the reaction was complete, the mixture was directly purified by preparative HPLC (0.1% FA / H 2 O / CH 3 CN) 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, yield: 12.8%). MS calculated: 649.2; MS found: 650.1 [M+H] + .

[0337] 1H NMR (400MHz, DMSO-d6): δ6.69(d,J=8.8Hz,1H),7.50-7.62(m,3H),7.34(d,J=8.8Hz,1H), 6.71-6.84(m,3H),5.09-5.17(m,1H),4.75-4.84(m,1H),4.61-4.71(m,1H),4.35-4.53(m, 2H),3.99(d,J=13.2Hz,1H),3.83(d,J=13.6Hz,1H),2.98-3.09(m,1H),2.84-2.93(m,1H) ,2.61-2.76(m,2H),2.38-2.47(m,1H),2.16-2.35(m,2H),2.03(s,2H),1.66-1.84(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-110.78,-126.12. 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)

[0338] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine HCl salt, a similar procedure to Example 34 was used to obtain (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.

[0339] MS calculated value: 622.19; MS found value: 623.2 [M+H] + .

[0340] 1H NMR (400MHz, DMSO-d6): δ12.74(br s,1H),7.69(d,J=8.4Hz,1H),7.63(t,J=7.6Hz,1H),7.53-7.60(m,2H),7.46(dd,J=9.6Hz,2.0Hz,1H),7.30(dd, J=8.4Hz,2.0Hz,1H),6.88(d,J=7.6Hz,1H),6.68(d,J=8.0Hz,1H),5.38(s,2H),5.09-5.17(m,1H),4.76-4.85(m ,1H),4.64-4.71(m,1H),4.44-4.51(m,1H),4.36-4.44(m,1H),3.99(d,J=14.0Hz,1H),3.85(d,J=13.6Hz,1H),2 .98-3.06(m,1H),2.85-2.92(m,1H),2.61-2.75(m,2H),2.39-2.46(m,1H),2.20-2.33(m,2H),1.66-1.84(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.63,-111.38. 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-yl 1,2,4-oxadiazol-5(4H)-one (Compound 36)

[0341] Starting from (S)-5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine, a similar procedure to Example 34 was used to obtain 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.

[0342] MS calculated value: 632.20; MS found value: 633.2 [M+H] + .

[0343] 1H NMR (400MHz, DMSO-d6): δ12.89 (br s,1H),8.73(d,J=2.4Hz,1H),8.02(dd,J=8.4Hz,2.4Hz,1H),7.82(d,J=8.4Hz,1H),7.6 1-7.72(m,2H),6.83-6.89(m,2H),6.72-6.80(m,1H),5.01-5.11(m,1H),4.76-4.87(m,2 H),4.61-4.70(m,1H),4.45-4.53(m,1H),4.30-4.38(m,1H),3.65-3.81(m,2H),3.21-3 .34(m,2H),2.89-3.04(m,1H),2.64-2.77(m,2H),2.25-2.38(m,1H),1.93-2.18(m,7H). 19 F NMR (377MHz, DMSO-d6): δ-73.73,-124.85. 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-yl 1,2,4-oxadiazol-5(4H)-one (Compound 37) Step A: (S)-5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)pyridine HCl salt

[0344] To a solution of (S)-tert-butyl 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 in vacuo 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 calcd: 330.11; MS found: 331.3 [M+H] + . 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

[0345] 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 in vacuo. The reaction 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] + . 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

[0346] 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) 2 (66 mg, 0.38 mmol), dppf (8.0 mg, 0.015 mmol) and Pd 2 (dba) 3 A solution of (11 mg, 0.0096 mmol) in DMF (2 mL) was stirred at 125 °C for 16 h. After the reaction was complete, the reaction mixture was washed with H 2O (10mL) and extracted with ethyl acetate (20mL x 3). The organic layers are combined and washed with brine (10mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is purified by column chromatography (DCM: MeOH = 95: 5) to obtain 2- ((4- ((S) -2- (5-chloropyridin-2-yl) -2-methylbenzo [d] [1,3] dioxol -4-yl) piperidin-1-yl) methyl) -7-fluoro-1- (((S) -oxetanes -2-yl) methyl) -1H- benzo [d] imidazole -5-carbonitrile (100mg, 91.7% yield). MS calculated value: 573.2; MS found value: 574.4 [M + H] + . 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-carboximidazole

[0347] 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), NH 2 A mixture of OH 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 hours. After the reaction was completed, the reaction was washed with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was merged and washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in a vacuum. The reaction was purified by column chromatography (DCM: MeOH = 95: 5) to obtain 2- ((4- ((S) -2- (5- chloropyridine -2- bases) -2- methylbenzo [d] [1,3] dioxole -4- bases) piperidin -1- bases) methyl) -7- fluoro- N- hydroxy -1- (((S) -oxetanes -2- bases) methyl) -1H- benzo [d] imidazole -5- formamidine (80 mg, 76.2% yield). MS calculated value: 606.2; MS found value: 607.3 [M+H] + . 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

[0348] 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)-oxetanes-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 the reaction was complete, the reaction was washed with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. 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%).

[0349] MS calculated value: 632.20; MS found value: 633.4 [M+H] + .

[0350] 1H NMR: δ8.72(d,J=2.4Hz,1H),8.01(dd,J=2.4Hz,J=8.4Hz,1H),7.93(d,J=1.2Hz,1H),7.60(d,J=8.4Hz,1H ),7.50(d,J=12.0Hz,1H),6.71-6.85(m,3H),5.07-5.17(m,1H),4.79-4.90(m,1H),4.67-4.71(m,1H),4. 45-4.50(m,1H),4.34-4.39(m,1H),3.97(d,J=13.6Hz,1H),3.84(d,J=13.6Hz,1H),2.99-3.08(m,1H),2. 88-2.97(m,1H),2.62-2.77(m,2H),2.41-2.50(m,1H),2.17-2.31(m,2H),2.01(s,3H),1.68-1.83(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-130.81. 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)

[0351] Starting from 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine hydrochloride, a similar procedure to Example 37 was used to obtain (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.

[0352] MS calculated value: 622.2; MS found value: 623.3 [M+H] + .

[0353] 1 H NMR (400MHz, CD 3 OD-d 4): δ7.97(s,1H),7.62-7.50(m,3H),7.24-7.19(m,2H),6.86(d,J=7.2Hz,1H),6.66(d,J=8.0Hz,1H ),5.44(s,2H),5.33-5.26(m,1H),5.03(dd,J=7.2Hz / J=15.6Hz,1H),4.86-4.85(m,1H),4.69-4.63 (m,1H),4.51-4.45(m,1H),4.08(dd,J=13.2Hz / J=39.6Hz,2H),3.16-3.14(m,1H),3.08-3.04(m,1 H),2.90-2.81(m,1H),2.75-2.66(m,1H),2.59-2.53(m,1H),2.50-2.36(m,2H),1.99-1.87(m,4H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-117.63),(-133.66). 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 39)

[0354] Starting from 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine HCl salt, a similar procedure to Example 37 was used to obtain 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.

[0355] MS calculated value: 647.17; MS found value: 648.3 [M+H] + .

[0356] 1H NMR: δ7.93(s,1H),7.45-7.62(m,3H),7.32-7.35(m,1H),6.82-6.88(m,3H),6. 35-6.42(m,1H),5.04-5.14(m,1H),4.80-4.90(m,1H),4.65-4.75(m,1H),4.47- 4.52(m,1H),4.32-4.43(m,1H),4.02-4.10(m,1H),3.88-3.99(m,1H),3.20-3.2 7(m,2H),2.69-2.82(m,3H),2.55-2.62(m,1H),2.36-2.46(m,2H),2.03(s,3H). 19 F NMR (377MHz, DMSO-d6): δ-110.90,-131.21. 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole (Compound 40) 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

[0357] (S)-5-bromo-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole (78 mg, 0.15 mmol), K 2 CO 3A mixture of (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 x 50 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and purified by column chromatography on silica gel (DCM:MeOH=30:1) to afford 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 calcd: 643.1; MS found: 644.2 [M+H] + 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

[0358] 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)methyl)-4H-1,2,4-triazole (83 mg, 0.39 mmol), Pd(OAc) and 4-((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)methyl)-4H-1,2,4-triazole (83 mg, 0.39 mmol), and Pd(OAc) were added. 2 (3.0 mg, 0.013 mmol), pivalic acid (2.7 mg, 0.026 mmol), Pcy 3 .HBF 4 (3.0 mg, 0.0079 mmol) and K 2 CO 3A mixture of 4-(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 value: 776.3; MS found value: 777.5 [M+H] + 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

[0359] 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 h. The mixture was concentrated and the residue was purified by preparative HPLC to afford 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] +

[0360] 1 H NMR (400MHz, CD3 OD-d 4 ): δ7.84(s,1H),7.58(t,J=8.4Hz,2H),7.28(dd,J 1 =10.4Hz / J 2 =8.8Hz,1H),7.21(d,J=8.8Hz,1H),6.79-6.68(m,3H),5.31-5.26(m,1H),4.92-4.81(m ,1H),4.72(d,J=15.2Hz,1H),4.66-4.61(m,1H),4.50-4.45(m,1H),4.04(d,J=14.4Hz, 1H),3.91(d,J=13.6Hz,1H),3.13-3.07(m,1H),2.97-2.93(m,1H),2.84-2.79(m,1H),2 .74-2.69(m,1H),2.57-2.44(m,4H),2.37-2.26(m,2H),2.03(s,3H),1.95-1.78(m,4H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-112.35),(-130.41). 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole (Compound 41) 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

[0361] 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) and 2(1.7 mg, 0.0078 mmol), pivalic acid (0.47 mg, 0.0047 mmol), Pcy 3 .HBF 4 (5.7 mg, 0.016 mmol) and K 2 CO 3 A mixture of 4-(65 mg, 0.47 mmol) and toluene (5 ml) was stirred at 120° C. under Ar for 16 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 column chromatography on silica gel (DCM:MeOH=30:1) to afford 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 value: 776.3; MS found value: 777.4 [M+H] + 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

[0362] 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 aqueous TBAF solution in THF (1 M, 1 ml) in THF (4 mL) was stirred at 50 °C for 4 h. The mixture was concentrated and the residue was purified by preparative HPLC to afford 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] +

[0363] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ8.12(s,1H),7.69(d,J=13.2Hz,1H),7.58(t,J=8.4Hz,1H),7.27(dd,J 1 =10.8Hz / J 2 =9.2Hz,2H),7.20(d,J=9.2Hz,1H),6.77-6.68(m,3H),5.28(d,J=5.2Hz,1H),5.05-5.0 0(m,1H),4.80-4.79(m,1H),4.66-4.58(m,2H),4.49-4.45(m,1H),4.05(d,J=12.8Hz,1 H),3.94(d,J=14.4Hz,1H),3.13-3.08(m,1H),3.02-2.98(m,1H),2.86-2.80(m,1H),2. 75-2.70(m,1H),2.57-2.50(m,4H),2.36-2.31(m,2H),2.03(s,3H),1.97-1.79(m,4H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-112.37),(-134.90). 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole (Compound 42)

[0364] 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole was obtained by a similar method to Example 41. MS calculated value: 629.2; MS found value: 630.4 [M+H] +

[0365] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ8.60-8.59(m,1H),8.13(s,1H),7.87(dd,J 1 =8.4Hz / J 2 =6Hz,1H),7.72-7.64(m,2H),6.79-6.65(m,3H),5.28(s,1H),5.03-4.9 2(m,1H),4.81-4.79(m,1H),4.63(d,J=6.8Hz,1H),4.45(d,J=13.2Hz,1 H),4.09-4.04(m,1H),3.98-3.95(m,1H),3.15-3.04(m,2H),2.84-2.76 (m,2H),2.50(s,4H),2.39-2.31(m,2H),2.01(s,3H),1.94-1.77(m,4H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-74.00),(-75.88). 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)-oxetane -2-yl)methyl)-1H-benzo[d]imidazole (Compound 43)

[0366] 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)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole was obtained using a similar method to Example 41. MS calculated value: 644.2; MS found value: 645.3 [M+H] + .

[0367] 1 H NMR (400MHz, CD 3 OD-d 4 ): δ8.13(s,1H),7.69(d,J=13.2Hz,1H),7.56(t,J=9.2Hz,1H),7.27(d,J =9.6Hz,1H),7.20(d,J=8.8Hz,1H),6.87-6.78(m,2H),6.74(d,J=7.2Hz,1 H),6.40(s,1H),4.65-4.58(m,5H),4.14(d,J=14.0Hz,1H),4.03(d,J=13. 2Hz,1H),2.91-2.77(m,3H),2.70-2.53(m,3H),2.50(s,5H),2.03(s,3H). 19 F NMR (377MHz, CD 3 OD-d 4 ):δ(-112.51),(-134.62). 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)-oxetane-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (Compound 44)

[0368] 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)-oxetane-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine was obtained. MS calculated value: 681.19; MS found value: 682.0 [M+H] + .

[0369] 1H NMR (400MHz, DMSO-d6): δ9.13(s,1H),8.28(s,1H),7.51-7.60(m,2H),7.33(d, J=8.0Hz,1H),6.81-6.88(m,3H),6.35-6.42(m,1H),5.09-5.18(m,1H),4.85-4 .95(m,1H),4.70-4.78(m,1H),4.36-4.53(m,1H),4.07-4.15(m,1H),3.94-4.0 2(m,1H),3.17-3.32(m,2H),2.65-2.84(m,3H),2.39-2.46(m,3H),2.03(s,3H). 19 F NMR (377MHz, DMSO-d6): δ-63.15,-110.92. Example 45: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4- 6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine (Compound 45)

[0370] 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)-oxetane-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-b]pyridine was obtained. MS calculated value: 681.19; MS found value: 682.0 [M+H] + .

[0371] 1H NMR (400MHz, DMSO-d6): δ9.00 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 7.52-7. 61(m,2H),7.34(dd,J=8.4Hz,2.0Hz,1H),6.81-6.90(m,3H),6.38-6.45(m,1H) ,5.13-5.22(m,1H),4.66-4.87(m,2H),4.33-4.53(m,2H),4.11(d,J=13.6Hz,1 H), 4.02 (d, J = 13.6Hz, 1H), 2.65-2.83 (m, 5H), 2.39-2.45 (m, 3H), 2.04 (s, 3H). 19 F NMR (377MHz, DMSO-d6): δ-62.97,-110.90. Example 46: 6-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4- 4-(((S)-oxetane-2-yl)methyl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-7H-imidazo[4,5-c]pyridazine (Compound 46)

[0372] 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)-oxetane-2-yl)methyl)-3-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-7H-imidazo[4,5-c]pyridazine was obtained. MS calculated value: 682.18; MS found value: 683.0 [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d6): δ8.53(s,1H),7.50-7.62(m.2H),7.33(dd,J=8.4Hz,1.6Hz,1H),6.80-6.91(m,3H),6.36-6.44(m,1H), 5.20-5.31(m,1H),4.84-5.06(m,2H),4.33-4.55(m,2H),4.09-4.24(m,2H),2.57-2.91(m,6H),2.30-2.46(m,2H),2.03(s,3H). 19FNMR (377 MHz, DMSO-d6): δ-63.65, -110.89. Example 47: 6-[(4-chloro-2-fluorophenyl)methoxy]-3-fluoro-2-{1-[(3-{[(2S)-oxetane-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]piperidine -4-yl}pyridine (Compound 47) Step A: 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine

[0374] 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 under N 2 The reaction mixture was stirred at 0°C for 1 hour. 2 The product was quenched with 4-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (446 mg, 86.2% yield) by silica gel column chromatography (PE / EA=10 / 1) to give 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine as a white solid. Step B: tert-Butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0375] 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (446 mg, 1.34 mmol) was dissolved in dioxane (15 mL) and H 2 Pd(dppf)Cl was added to the solution in O (1.5 mL). 2 .DCM (109 mg, 0.13 mmol), K 2 CO 3 (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 N 2 The reaction mixture was stirred at 95 °C for 16 h. 2O (50mL) quenched, extracted with ethyl acetate (70mL × 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 6- ((4-chloro-2-fluorobenzyl) oxy) -3-fluoro-3 ', 6 '-dihydro- [2,4 '-bipyridine] -1 ' (2 'H) -carboxylic acid tert-butyl ester (575mg, 98.4% yield) as a colorless oil. MS calculated value: 436.1; MS found value: 437.0 [M + H] + . Step C: tert-Butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridin-2-yl)piperidine-1-carboxylate

[0376] 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 2 The mixture was stirred for 2 hours at room temperature. 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 value: 438.2; MS found value: 383.0 [M+H-56] + . Step D: 6-((4-chloro-2-fluorobenzyl)oxy)-3-fluoro-2-(piperidin-4-yl)pyridine

[0377] 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 in vacuo 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] + . 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

[0378] 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 by a similar method to Example 1. MS calculated value: 674.2; MS found value: 675.2 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.27(s,1H),7.52-7.65(m,2H),7.47(dd,J=10.0Hz,2.0Hz,1H ),7.27-7.33(m,1H),6.75(dd,J=8.8,2.8Hz,1H),5.37(s,2H),5.16-5.25(m,1H),4.87-4.97(m,1H) ,4.73-4.81(m,1H),4.39-4.54(m,2H),4.01(d,J=13.6Hz,1H),3.86(d,J=14.0Hz,1H),2.98-3.08(m ,1H),2.84-2.96(m,2H),2.65-2.79(m,1H),2.18-2.36(m,3H),1.73-1.90(m,2H),1.61-1.73(m,2H). 19 F NMR (377 MHz, DMSO-d 6 ):δ-63.37,-115.28,-138.88. 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) Step A: 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine

[0380] 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 the reaction was complete, the mixture was washed with H2 O (100mL), extracted with EA (60mL×2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (PE) on silica gel to give 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine (2.8 g, yield: 85%) as a white solid. MS calculated value: 350.9; MS found value: 351.9 [M+H] + . Step B: tert-Butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine-1-carboxylate

[0381] 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 2 (dba) 3 (104mg, 0.12mmol), Xantphos (139mg, 0.24mmol), Cs 2 CO 3 A mixture of (741 mg, 42.3 mmol) in dioxane (10.0 mL) was stirred at 110 °C for 3 h. After the reaction was complete, the mixture was treated with H 2 O (40mL), extracted with EA (30mL×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 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] + . Step C: 1-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine TFA salt

[0382] 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 reaction was removed in vacuo 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] + . 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)

[0383] A similar method to Example 1 was used to obtain 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).

[0384] MS calculated value: 693.2; MS found value: 693.9 [M+H] + .

[0385] 1 H NMR (400MHz, DMSO-d6): δ9.28(s,1H),8.37(s,1H),7.85-7.95(m,1H),7.56(t,J =8.0Hz,1H),7.49(d,J=10.0Hz,2.0Hz,1H),7.33(d,J=8.4Hz,2.0Hz,1H),5.42( s,2H),5.06-5.18(m,1H),4.87-4.98(m,1H),4.72-4.81(m,1H),4.48-4.56(m,1 H),4.37-4.46(m,1H),3.11-3.40(m,7H),2.64-2.84(m,4H),2.29-2.46(m,1H). 19 F NMR (377MHz, DMSO-d6): δ-63.72, -115.08, -135.46, -148.17. 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) Step A: tert-Butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylate

[0386] At room temperature in N 2 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridine (1.0 g, 2.85 mmol) was dissolved in dioxane (30 mL) and H 2 To the solution in O (3 mL), 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), K 2 CO 3 (1.2 g, 8.55 mmol) and Pd(dppf)Cl 2 DCM (204 mg, 0.28 mmol). The mixture was stirred at 95 °C for 16 h, cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with H 2 O (50mL * 2) extraction. 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 6- ((4-chloro-2-fluorobenzyl) oxy) -3,5-difluoro-3 ', 6 '-dihydro- [2,4 '-bipyridine] -1 ' (2 'H) -carboxylic acid tert-butyl ester (1.15g, yield: 88.0%) as a yellow solid. MS calculated value: 454.1; MS found value: 399.0 [M-56 + H] + .

[0387] Step B: tert-Butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidine-1-carboxylate

[0388] 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). 2 The solution was stirred at room temperature 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 value: 456.1; MS found value: 401.0 [M-56+H] + Step C: 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt

[0389] 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] + . 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

[0390] 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 by a similar method to Example 1. MS calculated value: 692.2; MS found value: 693.0 [M+H] + .

[0391] 1 H NMR (400MHz, DMSO-d6): δ9.15(s,1H),8.27(s,1H),7.89(t,J=9.6Hz,1H),7.60(t,J=8.0Hz,1H),7.48( dd,J=10.0Hz,1.6Hz,1H),7.32(dd,J=8.0Hz,1.6Hz,1H),5.47(s,2H),5.15-5.24(m,1H),4.88-4.97(m ,1H),4.73-4.81(m,1H),4.40-4.53(m,2H),4.00(d,J=14.0Hz,1H),3.86(d,J=13.6Hz,1H),2.98-3.08 (m,1H),2.85-2.97(m,2H),2.65-2.80(m,1H),2.42-2.49(m,1H),2.19-2.34(m,2H),1.60-1.90(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.30, -115.08, -133.85, -138.38. 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) Step A: 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt

[0392] 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 reaction was removed in vacuo to give 2-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoro-6-(piperidin-4-yl)pyridine TFA salt (890 mg, crude). 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

[0393] 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), K 2 CO 3 A mixture of (648 mg, 5.00 mmol) in DMF (6 mL) was stirred at 60 °C for 3 h. After the reaction was complete, the mixture was washed with H 2 O (30mL) and extracted with EA (30mL×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=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-(oxetane-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine (400mg, yield: 53%). MS calculated value: 592.1; MS found value: 593.0[M+H] + . Step C: (S)-ethyl 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

[0394] 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 2 (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 the reaction was completed, 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 (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetane-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid ethyl ester (330 mg, yield: 76%). MS calculated value: 630.2; MS found value: 631.2 [M+H] + . 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

[0395] To a mixture of (S)-6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperidin-1-yl)methyl)-7-(oxetanes-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid ethyl ester (330 mg, 0.52 mmol) in MeOH (4.0 mL) was added NaOH (2 M, 1.0 mL, aqueous solution). The mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was adjusted to pH=7 with 1N HCl (aqueous solution) 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] + . 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

[0396] (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), NH 4 A mixture of Cl (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 room temperature for 1 h. After the reaction was complete, the mixture was washed with H 2 O (30mL) was diluted and extracted with EA (20mL×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 (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-(oxetane-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide (220mg, yield: 73%). MS calculated value: 601.2; MS found value: 602.2[M+H] + . 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

[0397] 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 room temperature for 2 hours. After the reaction was complete, the mixture was washed with H 2 O (20mL) was diluted and extracted with EA (10mL×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 in vacuo. 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-(oxetane-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile (140mg, yield: 66%). MS calculated value: 583.2; MS found value: 584.1[M+H] + . 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

[0398] (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), HONH 2A solution of HCl (100.13 mg, 1.44 mmol), TEA (96.96 mg, 0.96 mmol) in EtOH (4 mL) was stirred at 90 °C for 1 h. After the reaction was complete, the mixture was filtered and the solid was 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] + . 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

[0399] 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-(oxetane-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 room temperature for 1 hour. After the reaction was complete, 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 and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness in vacuo. 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-(oxetane-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] + . 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)

[0400] (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 N 2 H 4 ·H 2 A mixture of O (12.00 mg, 0.24 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was directly purified by preparative HPLC (0.1% FA / H 2 O / CH 3 CN) 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, yield: 39%) as a white solid. MS calculated value: 693.2; MS found value: 694.0 [M+H] + .

[0401] 1 H NMR (400MHz, DMSO-d6): δ8.49(s,1H),7.89(t,J=9.2Hz,1H),7.58(t,J=8.4Hz,1H),7.49(dd ,J=10.0Hz,2.0Hz,1H),7.32(dd,J=8.0Hz,1.6Hz,1H),5.46(s,2H),5.25-5.36(m.1H),4.99- 5.09(m.1H),4.87-4.96(m,1H),4.39-4.55(m,2H),4.01-4.09(m,2H),2.86-3.06(m,3H),2. 70-2.82(m,1H),2.50-2.63(m,1H),2.26-2.38(m,2H),1.77-1.93(m,2H),1.64-1.75(m,2H). 19F NMR (377MHz, DMSO-d6): δ-63.28,-114.99,-133.85,-138.37. 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] Piperazine-2-one (Compound 51) Step A: tert-Butyl 4-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)-3-oxopiperazine-1-carboxylate

[0402] 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), K 2 CO 3 (831 mg, 6.0 mmol) and (1R,2R)-N 1 ,N 2 -A mixture of dimethylcyclohexane-1,2-diamine (43 mg, 0.3 mmol) in dioxane (15 mL) was stirred at 120 ° C for 16 hours. After the reaction was completed, the reaction was filtered and the filtrate was concentrated in vacuo. 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, yield: 81%) as a white solid. MS calculated value: 452.1; MS found value: 397.2 [M-56 + H] + . Step B: 1-(3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)piperazin-2-one TFA salt

[0403] 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 the reaction was complete, the reaction was concentrated in vacuo 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] + . 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

[0404] 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 (41.7 mg) was obtained by a similar method to Example 1. MS calculated value: 688.2; MS found value: 689.3 [M+H] + .

[0405] 1 H NMR (400 MHz, DMSO-d 6 ):1H NMR: δ9.19(s,1H),8.32(s,1H),7.61(t,J=8.4Hz,1H),7.51(dd,J=10.0Hz,J=2.0Hz,1H),7.32-7.38 (m,2H),7.25(dd,J=11.2Hz,J=8.8Hz,1H),6.90-6.98(m,1H),5.10-5.19(m,3H),4.87-4.96(m,1H), 4.73-4.81(m,1H),4.47-4.55(m,1H),4.38-4.44(m,1H),4.14(d,J=14.0Hz,1H),4.05(d,J=14.0Hz, 1H),3.62-3.69(m,2H),3.38-3.47(m,2H),2.93-3.00(m,2H),2.69-2.80(m,1H),2.40-2.51(m,1H). 19 F NMR (377MHz, DMSO-d6): δ-63.70, -115.03, -136.54. 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) Step A: tert-Butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3-oxopiperazine-1-carboxylate

[0406] To a solution of 6-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-3-fluoropyridine (600 mg, 2.08 mmol) in dioxane (25 mL) were added Xantphos (361 mg, 0.62 mmol), Pd 2 (dba) 3 (380 mg, 0.42 mmol), Cs 2 CO 3 (1.35 g, 4.14 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (830 mg, 4.15 mmol). The mixture was stirred under N 2 The reaction mixture was stirred at 90 °C for 16 h. 2 O (50mL) quenched, extracted with ethyl acetate (70mL × 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] + . Step B: 1-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperazin-2-one

[0407] 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 reaction was removed in vacuo to give 1-(6-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl)piperazine-2-one TFA salt (256 mg, crude) as a yellow oil. MS calculated: 353.1; MS found: 354.0 [M+H] + . 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

[0408] 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 by a similar method to Example 1. MS calculated value: 689.2; MS found value: 690.1 [M+H] + .

[0409] 1 H NMR (400MHz, DMSO-d6): δ9.18(s,1H),8.31(s,1H),7.75(t,J=9.2Hz,1H),7.51-7.60(m,2H),7.48(dd ,J=10.4Hz,2.0Hz,1H),7.33(dd,J=8.0Hz,1.6Hz,1H),5.44(s,2H),5.09-5.18(m,1H),4.86-4.96(m, 1H),4.72-4.81(m,1H),4.46-4.54(m,1H),4.37-4.43(m,1H),4.13(d,J=13.6Hz,1H),4.03(d,J=13.6 Hz,1H),3.82-3.90(m,2H),3.383.51(m,2H),2.93-3.00(m,2H),2.65-2.77(m,1H),2.37-2.47(m,1H). 19 F NMR (377 MHz, DMSO-d 6 ):δ-63.58,-115.00,-144.94. 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- Imidazolo[4,5-b]pyridin-2-yl)methyl]piperidine (Compound 53)

[0410] 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 using a similar method as in Example 1. MS calculated: 667.2; MS found: 668.0 [M+H] + .

[0411] 1 H NMR (400MHz, DMSO-d6): δ9.00(d,J=2.0Hz,1H),8.59(d,J=2.0Hz,1H),7.55-7.65(m.1H),7. 30-7.40(m.1H),7.07-7.16(m.1H),6.70-6.83(m.3H),5.15-5.27(m.1H),4.82-4.91(m.1H), 4.69-4.78(m,1H),4.44-4.53(m,1H),4.34-4.43(m,1H),3.90-4.04(m,2H),2.91-3.06(m,2 H),2.61-2.74(m,2H),2.42-2.52(m,1H),2.20-2.36(m,2H),2.02(s,3H),1.69-1.87(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.64,-108.51,-108.53,-109.09,-109.10,-109.11. 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- Imidazolo[4,5-c]pyridin-2-yl)methyl]piperidine (Compound 54)

[0412] 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 using a similar method as in Example 1. MS calculated: 667.2; MS found: 668.4 [M+H] + .

[0413] 1 H NMR (400MHz, DMSO-d6): δ9.17(s,1H),8.29(s,1H),7.57-7.64(m.1H),7.32-7.40(m.1H),7.08 -7.15(m.1H),6.70-6.81(m.3H),5.14-5.23(m.1H),4.88-4.97(m.1H),4.72-4.79(m,1H),4.39 -4.53(m,2H),4.02(d,J=12.8Hz,1H),3.86(d,J=13.6Hz,1H),3.00-3.08(m,1H),2.85-2.93(m ,1H),2.60-2.80(m,2H),2.43-2.52(m,1H),2.17-2.35(m,2H),2.02(s,3H),1.68-1.85(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.72,-108.48,-108.50,-109.07,-109.10,-109.11,-109.14. 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) Step A: 2-Methyl-5-((trimethylsilyl)ethynyl)pyridine

[0414] 5-Bromo-2-methylpyridine (30.0 g, 174 mmol), ethynyltrimethylsilane (18.8 g, 192 mmol), CuI (663 mg, 3.5 mmol), Pd(PPh3 ) 2 Cl 2 A mixture of (4.9 g, 7.0 mmol) in DMSO (300 mL) and TEA (24 ml) was stirred at 50 °C for 16 h. After the reaction was complete, the mixture was washed with H 2 The mixture was washed with 1,2-dihydro-2-((trimethylsilyl)ethynyl)pyridine (29.5 g, 90% yield) and washed with 4-((trimethylsilyl)ethynyl)pyridine (3 L x 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] + . Step B: 5-ethynyl-2-methylpyridine

[0415] 2-Methyl-5-((trimethylsilyl)ethynyl)pyridine (29.5 g, 156 mmol), K 2 CO 3 A mixture of (107.7 g, 780 mmol) in MeOH (300 mL) was stirred at room temperature overnight. After the reaction was complete, the mixture was filtered and 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 light yellow solid. MS calculated value: 117.1; MS found value: 118.2 [M+H] + . Step C: 5-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-2-methylpyridine

[0416] 3-Bromobenzene-1,2-diol (5.4 g, 28.5 mmol), 5-ethynyl-2-methylpyridine (4.0 g, 34.2 mmol) and Ru 3 (CO) 12 A mixture of (910 mg, 1.42 mmol) in toluene (40 mL) was stirred at 110 °C under N 2 The reaction mixture was stirred for 16 hours. After the reaction was completed, 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 value: 305.0; MS found value: 305.9 [M+H] + . 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

[0417] 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), K 2 CO 3 (3.0g, 21.6mmol), Pd(dppf)Cl 2 (294 mg, 0.36 mmol) in dioxane / H 2 The mixture in 4% 4- (2-methyl-2- (6-methylpyridin-3-yl) benzo [d] [1,3] dioxol-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.5 g, yield: 84.9%) was stirred at 90 ° C for 16 hours. After the reaction was completed, the mixture was filtered and the filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (PE / EA = 3 / 1) to give a yellow oily substance 4- (2-methyl-2- (6-methylpyridin-3-yl) benzo [d] [1,3] dioxol-4-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.5 g, yield: 84.9%). MS calculated value: 408.2; MS found value: 409.3 [M + H] + . 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

[0418] 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-(oxetanes-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 the reaction was complete, 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 light yellow solid. MS calcd: 536.2; MS found: 537.4 [M+H] + 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

[0419] 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), NH 2 A solution of OH·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 the reaction was completed, 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)-oxetanes-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (150 mg, crude) as a yellow solid. MS calculated value: 569.3; MS found value: 570.4 [M+H] +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

[0420] 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)-oxetanes-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 hour. After the reaction was completed, the reaction was quenched with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (15 mL×3). The organic layers were combined and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated to dryness in vacuo. The residue was purified by preparative TLC (DCM / MeOH=60 / 1) to give 2-methyl-5-(2-methyl-4-{1-[(3-{[(2S)-oxetanes-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] + . 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

[0421] 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 N 2 H 4 ·H 2A mixture of 2-nitropropene (2 drops) and 4-nitropropene (1 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was directly purified by preparative HPLC to give 2-methyl-5-[2-methyl-4-{1-[(3-{[(2S)-oxetanes-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 value: 646.3; MS found value: 647.3 [M+H] + .

[0422] 1 H NMR (400MHz, DMSO-d6): δ9.15(d,J=0.8Hz,1H),8.64(d,J=2.0Hz,1H),8.28(d,J=0.8Hz,1H),7.83(dd,J=8.0Hz,J=2.4Hz 1H),7.30(d,J=8.0Hz,1H),6.70-6.82(m,3H),5.13-5.22(m,1H),4.86-4. 98(m,1H),4.71-4.79(m.1H),4.38-4.55(m,2H),4.02(d,J=13.6Hz,1H),3. 85(d,J=13.6Hz,1H),3.00-3.10(m,1H),2.84-2.92(m,1H),2.60-2.80(m, 2H),2.45-2.49(m,4H),2.17-2.37(m,2H),2.00(s,3H),1.65-1.86(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.56. 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) 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

[0423] 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 h. After the reaction was complete, the reaction was washed with H 2 O (20mL) quench and extract with ethyl acetate (25mL x 3). The organic layers are combined and washed with brine (20mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is purified by preparative TLC (DCM: MeOH = 30: 1) to obtain 2- ((4- ((S) -2- methyl -2- (6- methylpyridin-3-yl) benzo [d] [1,3] dioxol -4-yl) piperidin-1-yl) methyl) -3- (((S) -oxetanes -2-yl) methyl) -3H- imidazo [4,5-b] pyridine -6- carbonitrile (100mg, 61% yield) as a yellow oil. MS calculated value: 536.2; MS found value: 537.4 [M + H] + . 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

[0424] 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 by a similar method to Example 55. MS calculated value: 646.3; MS found value: 647.5 [M+H] + .

[0425] 1 H NMR (400 MHz, DMSO-d 6):1H NMR: δ8.99(d,J=2.0Hz,1H),8.64(d,J=2.4Hz,1H),8.56(d,J=2.0Hz,1H),7.84(dd,J=8.0Hz,J=2.4Hz 1H),7.31(d,J=8.0Hz,1H),6.70-6.82(m,3H),5.16-5.25(m,1H),4.79-4.88(m,1H),4.68-4.76(m.1H),4.44-4.51(m,1H),4.34-4.42( m,1H),3.89-4.02(m,2H),2.91-3.05(m,2H),2.60-2.75(m,2H),2.45-2.49(m,4H),2.20-2.35(m,2H),2.00(s,3H),1.68-1.84(m,4H). 19 F NMR (377MHz, DMSO-d6): δ-63.05. 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) Step A: trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-ol TFA salt

[0426] To a mixture of trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (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 the reaction was completed, the reaction was concentrated in vacuo to obtain trans-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-ol TFA salt (235 mg, crude product) as a yellow oil. MS calculated value: 336.1; MS found value: 337.3 [M+H] + . 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

[0427] 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 h. After the reaction was complete, the reaction was washed with H 2 O (20mL) quench and extract with ethyl acetate (25mL x 3). The organic layers are combined and washed with brine (20mL x2), dried over sodium sulfate, filtered and concentrated in vacuo. The reaction is 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) -oxetanes -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] + . 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

[0428] 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 the reaction was completed, the reaction was filtered and the solids were 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)-oxetane-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] + . 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

[0429] 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 the reaction was complete, the reaction was washed with saturated NaHCO 3 The solution (20mL) was quenched and extracted with ethyl acetate (20mL x 3). The organic layers were combined and washed with brine (20mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give (3,4-trans)-4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1-((3-(((S)-oxetanes-2-yl)methyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazole-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] + . 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

[0430] 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) at room temperature. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was purified by preparative HPLC to give (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 (39.9 mg, 40% yield) as a white solid. MS calculated: 672.2; MS found: 673.2 [M+H] + .

[0431] 1 H NMR (400 MHz, DMSO-d 6 ):1H NMR: δ9.16(s,1H),8.28(s,1H),7.56-7.62(m,2H),7.48(d,J=10.0Hz,1H),7.31(d,J=8.0Hz,1H), 6.87(d,J=7.2Hz,1H),6.68(d,J=8.0Hz,1H),5.33-5.45(m.2H),5.13-5.23(m.1H),4.88-4.98(m, 1H),4.73-4.81(m,1H),4.52-4.70(m,1H),4.39-4.52(m,2H),3.75-4.12(m,3H),3.07-3.14(m,1H ),2.90-2.99(m,1H),2.68-2.82(m,2H),2.41-2.50(m,1H),1.95-2.24(m,2H),1.63-1.86(m,2H). 19 F NMR (377MHz, DMSO-d6): δ-63.43,-115.38. Examples 58 and 59: 2-[(4-chloro-2-fluorophenyl)methoxy]-6-[(3,4-trans)-3-fluoro-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 (diastereomer 1) (compound Compound 58) and 2-[(4-chloro-2-fluorophenyl)methoxy]-6-[(3,4-trans)-3-fluoro-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 (diastereomer 2) (Compound 59)

[0432] 2-[(4-chloro-2-fluorophenyl)methoxy]-6-[(3,4-trans)-3-fluoro-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 (300 mg) was purified by chiral SFC ( OZ, supercritical CO 2 / MEOH (+0.1% 7.0 mol / l ammonia in MEOH) = 50 / 50) to give diastereomer 1 as a white solid (which was further purified by preparative HPLC (58 mg, yield: 34.7%)) and diastereomer 2 (102 mg, yield: 34.0%). 2-[(4-chloro-2-fluorophenyl)methoxy]-6-[(3,4-trans)-3-fluoro-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 Diastereomer 1:

[0433] MS calculated value: 674.2; MS found value: 675.3 [M+H] + . SFC retention time: 4.46min.

[0434] 1H NMR: δ9.16(s,1H),8.49(s,1H),7.68(t,J=7.6Hz,1H),7.50(t,J=8.0Hz,1H),7.17-7.2 7(m,2H),6.99(d,J=7.2Hz,1H),6.78(d,J=8.4Hz,1H),5.38-5.49(m,2H),5.15-5.35(m, 2H),4.80-4.96(m,2H),4.64-4.80(m,4H),4.43-4.54(m,1H),3.80-4.00(m,1H),3.43-3 .58(m,1H),3.10-3.29(m,2H),2.79-2.90(m,1H),2.50-2.62(m,1H),2.13-2.26(m,2H). 19 F NMR:(377MHz,CD 3 OD): δ-66.72,-117.76,-185.42. 2-[(4-chloro-2-fluorophenyl)methox...

Claims

1. A compound selected from: as well as or a pharmaceutically acceptable salt or solvate thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

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

4. The method of claim 3, wherein the disease, disorder or condition is selected from 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), latent autoimmune diabetes of adults (LADA), obesity, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral 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, lung hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidosis, 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, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

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

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

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

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

9. The method of claim 8, wherein the additional therapy or therapeutic agent is selected from an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an antiemetic, an agent for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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